Disease & Human Behavior Exam 1

How many women die each year in pregnancy and childbirth?

358,000

On average, how many TB cases (out of 10) aren't being correctly detected and treated?

4/10

Ancient history of polio vaccine

4000 BC Egypt 1500 AD Europe 2000 AD World epidemic Worldwide immunization by 2000 AD

T/F Antibiotics are learning to fight bacteria off

False Bacteria don't learn, they evolve (quickly)

T/F Praziquantel, which treats Schistosomiasis, poses a challenge because it is very expensive for everyone who needs it

False It's not very expensive, but it poses a challenge because it is costly for people who need

T/F Almost 80 women die every day due to complications in pregnancy and childbirth

False... almost 800!

T/F Like the U.S., most African countries go without DDT because they've banned it themselves

False... in fact, it's allowed for public health uses in most areas of the world where malaria is endemic Instead, most African countries go without it because wealthy donor nations and organizations are resistant to funding projects that would spray DDT even in responsible ways

T/F Structural violence results in the premature and untimely death of peoplle of deaths which are inevitable

False... in those deaths who are NOT inevitable

T/F Though Japan was able to eradicate schistosomiasis, its government didn't play much of a role in such eradication efforts

False... major role

T/F There are only a few mosquito species that serve as vectors for malaria

False... many

T/F Sickle cell anemia and thallassemias are types of non-genetic diseases

False... they are genetic

T/F Every 9.5 minutes, someone in the US in infected with HIV today

False... today it's improved to around one every 14 minutes

T/F Child mortality remains a key concern in developing regions, but has nonetheless declined in all WHO regions

True

T/F Malaria has been endemic in Africa, Asia, & Southern Europe for millennia

True

Between 2000 and 2015, malaria incidence rates (new cases) fell by __% globally, and by __% in Africa; during this same period, malaria mortality rates fell by __% globally and by __% in Africa

37; 42; 60; 66

T/F Approximately 1 billion people are affected by more than one of NTDs

True

T/F In many places with continued endemic polio or polio outbreaks, water sources are not well protected from human feces

True... should ensure clean water

T/F While incidence of HIV-TB coinfection has slightly increased since 1990, TB prevalence, incidence, and mortality have fallen

True

T/F Women of child-bearing age are particularly vulnerable to malaria

True

How many deaths have resulted from TB in the past 200 years?

1 billion

T/F Anti-TB drugs attack MTB in different ways, so combining different drugs helps combat the bacterium developing ways to overcome a drug

True

T/F As long as a single child remains infected, children in all countries are at risk of contracting polio

True

T/F Bed nets are a key weapon against malaria

True

T/F Better housing that decreases crowding and enhances air ventilation might favor less powerful strains of TB, but improving living conditions for the one billion people who live in the world's slums is a lot harder than handing out pills.

True

T/F Different TB drugs target different points in the bacterium's life

True

T/F Japan and China were both historically endemic for S. japonicum. While Japan declared itself schistosome-free in 1976 for both its citizens and animals, China still has the infection

True

T/F Malaria causes and is made worse by poverty

True

T/F Malaria parasites resistant to chloroquine spead across the world, and researchers are debating if artemisinin will as well

True

T/F Mosquitoes have strengthened their resistance to insecticides

True

T/F Most (if not all) diseases can potentially worsen by poverty

True

T/F Sexual conflict in mosquitoes may have worsened spread of malaria

True

T/F The bacterium that causes TB has evolved to produce new drug-resistant strains that threaten the world's s population, especially the poor, once again

True

T/F The mosquito's mouth is designed to slip through your flesh

True

T/F A global attack on long-neglected tropical diseases is succeeding

True Donors and drug firms are co-operating to defeat ancient plagues More countries are dispensing preventitive drugs for a selection of NTDs Countries are eliminating diseases like guinea-worm and river blindness

T/F DNA & other data show M. tuberculosis was widespread in the ancient world

True Hippocrates identified it around 460 BC as the most common disease of his time, affecting young adults 18-35, and almost always fatal He thought it was hereditary, but advised physicians not to treat it in advanced stages because the fatality rate would hurt their reputation

T/F Traditional beliefs sometimes divert or delay treatment and prevention

True I.e. "Wabu" is a term traditional healers in Mali use when referring to a condition marked by fever, seizures, delusions, or coma, the hallmarks of severe malaria; traditional thought assigned the cause of wabu to a bird taking the spirit of a child at the moment that the bird and the child cry out simultaneously

T/F Evolutionary sexual conflict theory predicts mosquito mating physiology which enables Plasmodium transmission

True Sexual transfer of a hormone through A. gambiae mating dramatically changes female physiological processes intimately tied to vectorial capacity

T/F There are coverage gaps in Sub-Saharan Africa

True Some people at risk aren't protected by either insecticide-treated nets (ITNs) or indoor residual spraying (IRS) Some pregnant women aren't accessing the WHO-recommended 3 or more doses of preventative therapy

T/F With the exception of a short period during WWI, rates of death by TB were falling long before the advent of antibiotic treatments

True Still declined from 1900 to 1950s (when first TB drug was introduced) Policies, sanatoria, housing improvements

T/F When it costs 1 billion a year to eradicate the last amount of polio, you have to ask, "Compared to what?"

True -- what else could you do with that billion? The last child vaccinated may enjoy only a few short polio-free months before dying of malaria, TB, or HIV/AIDS Gates has emerged as one of the biggest donors, but his "obsession with polio" is arguably distorting priorities in other critical areas; Gates has fought back critics

T/F Countries are eliminating river blindness

True due to ivermectin (developed by a company called Merck) In 2016, Guatemala became the fourth country in the world to eliminate it

T/F Ongoing clinical trials are investigating prophylactic (preemptive) malaria treatment

True... researchers are trying to determine whether routinely treating children for malaria before they contract it will save lives without promoting drug resistance

Treatment for polio*

Tylenol etc. for transient phase (flu-like symptoms) Careful management of bedsores, problems with urination and defecation Crutches, braces, wheelchair Mechanical ventilation if needed

TB, a scourge since prehistoric times, affects more than _________________ people and causes the death of ________________ people each year. Effective treatment has been available for _______________________, but such treatment takes at least ____________, and ____________, which is increasing throughout the world, threatens the effectiveness of treatment."

9 million; 1.5 million people each year; 60 years, 6 months; resistance to the drugs

Multidrug Resistant Tuberculosis (MDR TB)

A form of TB in which the bacteria can no longer be killed by at least the 2 best antibiotics, isoniazid (INH) and rifampin (RIF), commonly used to cure TB Harder to treat, requiring up to 2 years of multidrug treatment

Extreme Drug Resistant Tuberculosis (XDR TB)

A less common form of MDR TB in which the bacteria have evolved resistance to standard antibiotics and most alternatives These include any fluoroquinolone, and at least one other injectable anti-TB drug XDR TB needs up to 2 years of drug treatment & is the hardest to treat

Malaria (background info)

A parasitic infection Found on all continents except Antarctica Caused by one of four principal species of the genus Plasmodium Carried from one animal or person to another by mosquitoes of over 60 species, especially in the genus Anopheles

Cause of polio*

A small RNA virus An enterovirus Highly communicable during and after first phase Fecal-oral transmission; water & food Multiplies in the intestines, also found in throat Nervous system invaded in 1-5% of patients

Life cycle of onchocerciasis (river blindness)

An infected black fly starts the cycle (deposits larvae on the skin while biting, enters the wound) -> larvae develop into clustered worms in the skin tissue -> adult worms mate and produce immature ones (microfilariae) -> thousands of immature worms migrate through skin tissue, causing various symptoms (skin rashes/disease, itching, skin depigmentation, thicker skin, eye infection) Another black fly (feeding on the blood of an infected person and ingesting microfilariae) becomes infected, continuing the cycle; inside its midgut, microfilariae develop into L3 infectious larvae, which migrates to the fly's proboscis as the infected fly seeks a blood meal from a host

Tuberculosis

An often severe and contagious airborne disease caused by the bacterium Mtb TB typically affects the lungs but may affect any organ It is usually treated with a drug regimen taken for 6 months to 2 years People can become infected by breathing in even just a few Mtb bacteria released into the air when those with active TB cough, spit, or talk

Primary prevention for schistosomiasis

Avoid contact with infected water sources Concrete irrigation canals Treatment with praziquantel Treat animals Safe water sources Kill the snails (molluscicides) Eradicate poverty

Diagnosing polio*

Clinically very difficult when it doesn't cause paralysis Many undetected cases for every known case But virus can be isolated and cultured

Facts of DOTS

DOTS cures up to 95% even in the poorest countries DOTS prevents new infections by curing infectious patients DOTS prevents MDR-TB by ensuring the full course of treatment A 6-month supply of DOTS drugs costs US $11 per patient in some parts of the world The World Bank calls DOTS one of the "most cost-effective of all health interventions"

Trachoma symptoms

Eye pain, swelling eyelids, eye irritation Antibiotics are effective, but blindness can gradually develop as active trachoma progress from scarred eyelid to trichiasis and corneal opacity

Primary prevention for malaria

Get rid of mosquitoes Don't get bitten Find a vaccine Better nutrition, etc.

Pulmonary hypertension

High blood pressure in the lungs Difficulty breathing, fatigue, cough, heart palpitations, atypical chest pain Found with chronic schistosomiasis

Intestinal schisto

Hundreds to thousands of eggs/day Enter the intestines and excreted in feces Some get washed back into the liver Our immune response attacking these eggs causes many symptoms

Liberia after Ebola - how human nature affects our response to disease (reading notes)

It's hard to believe that Liberia was the scene of a hard fight against one of the most contagious and deadliest viruses ever seen in Western Africa Through an extraordinary national/international effort, the virus was contained in Liberia Now, the international response has begun to wind down, transitioning from response to recovery, but the healing of survivors' invisible wounds has only begun In a way, all Liberians are considered survivors of Ebola: the people who were infected & physically overcame the disease; the people whose loved ones had the virus; the people who worked on the frontline as healthcare workers; & the now orphaned children At the height of the outbreak in Liberia, 10,675 patients were diagnosed with the virus, & 4,809 died, meaning 1/375 people had the virus, & 1/840 citizens died of it The reasons for Ebola's rampant spread are complex; in part, it can be attributed to physical causes (i.e. dismal hospital supplies & weak telecomm systems), but much of the spread can be attributed to human nature The Ebola virus preyed on universal human feelings like denial, fear, & even love At first, many citizens were in denial about the virus & the impact it could have As it spread, people grew fearful of sending family members to overcrowded, under-resourced hospitals Family members compassionately & desperately tried to take care of their loved ones at home, because hospitals came to be viewed as places of contagion & death The most intense spreading of the virus, it's now believed, sprang from deeply rooted cultural beliefs around burial rituals & funeral practices, which include kissing, washing & lying with the deceased for hours Human nature is also to blame for how survivors are now being treated Those who were infected, their relatives & burial/health care workers are being shunned by their communities, due to misconceptions about the virus & fear of the unknown Many believe that once infected, victims can still transmit the disease; despite the fact that Ebola is very difficult to spread & can only be done so when there's direct contact with bodily fluid with a symptomatic patient As a result, instead of receiving support & care at a time they need it the most, Ebola survivors are having difficulty finding jobs, having their drinking water turned off, being evicted from housing, & facing stigmatization from their communities Many are now suffering from an array of psychological problems including depression, PTSD, & social exclusion Post-Ebola patients also suffer from complications such as headaches, extreme fatigue & even loss of vision The term "Post-Ebola Syndrome" is becoming commonplace to describe symptoms of weakness & pain in joints, muscles and chests For many, these ailments are so severe that they're unable to return to work 20% of employed Liberians have stopped working since the Ebola crisis While news about Ebola dies down in global headlines, there's a new health crisis being fought in West Africa Survivors need psychological & physical care, as part of a comprehensive medical follow-up that tackles both the effects of grief and the traditional belief systems that may leave them ostracized Post-Ebola patients also need legal protection to prevent from unlawful eviction We need to re-educate communities about Ebola: spread knowledge, facilitate dialogue, rectify misconceptions, alleviate fear, & most importantly, empower its survivors We've learned many lessons from this catastrophic & historic event — & it's not a question of if the next outbreak will occur, but when While communities slowly start to putting the pieces back together, let's focus on those who remain among the living

An Ill Wind (read over diagram)

Mtb tends to concentrate in the air sacs of the lungs because it prefers environments rich in oxygen In most people, the immune system is able to keep bacterial replication in check, dispatching defensive cells known as macrophages to the site of infection, where they form a shell around the bacteria In 10% of infected individuals, Mtb breaks down the shell, after which it can multiply ... Unconstrained by the immune system, the bacteria destroy the tissue of the lungs; some may also make their way into the bloodstream and infect other parts of the body, including the brain, kidneys, and bone Eventually affected organs may sustain so much damage they cease to function, and the host dies

Symptoms of guinea-worm

Occur approximately one year after the infection A few days to hours before the worm emerges, a person may experience fever, swelling, pain in area, rash, severe itching, nausea, vomiting, diarrhea, dizziness Lesions may lead to secondary bacterial infections, which in turn may lead to: increased pain, may cause some to have locked joints and permanent crippling Each time a worm emerges, a person may be unable to work or resume daily activities for up to 3 months Emergence usually occurs in planning or harvesting season, leading to heavy crop losses and financial problems for the family Worms that don't emerge may form cysts and eventually calcify

Structural

Poverty reduction Gender-based violence

Another description of malaria lifecycle

Sporozoites are injected from the female anophelene mosquito's salivary glands, where they circulate to liver and enter the liver cell Liver schizont develops as binary fission produces 2,000 or more merozoites Rupture of schizont releases merozoites into the bloodstream to infect RBCs Male and female gametocytes are obtained by female anophelene mosquito

At its peak in the early 1990s, about _______________ Australians died from AIDS each year

1,000

How many children under 5 die every year?

8 million

Trachoma

A (chronic) bacterial infection caused by the Chlamydia microorganism 80 million people infected, 8 million visually impaired, eliminated from Morocco Treatment with Zithromax, part of the SAFE strategy including surgery, environmental improvement, and face washing Leading infectious cause of blindness

Chikungunya

A NTD virus

Malaria-infected cell

A malaria parasite within a human red blood cell The large circle in the parasite is for food storage Stacked heme (the iron part of hemoglobin, indigestible to the parasite) is seen inside the vacuole

The Enemy Within (reading notes)

A new pattern of antibiotic resistance that's spreading around the globe may soon leave us defenseless against a wide range of dangerous bacterial infections A new pattern of resistance has emerged among a particularly challenging group of bacteria called the gram-negatives; it threatens to make many common infections untreatable The bacterial genes responsible confer resistance to the carbapenems, a group of so-called last-resort antibiotics 2 of the most important resistance genes are NDM-1 & KPC Carbapenem resistance in gram-negative bacteria is esp worrisome since these germs are ubiquitous & share genes easily Plus, no new drugs for these bugs are being developed This confluence of factors means many people in hospitals & in the wider community could die of newly untreatable infections of the urinary tract, blood & other tissues ... Klebsiella pneumoniae, a bacterium in hospitalized patients that's one of the most frequent causes of pneumonia & bloodstream infection, contained a new gene that rendered it insensitive to the only remaining group that worked reliably and safely: the carbapenems, the so-called drugs of last resort The one medication the investigators found that had any effect on the resistant strain was colistin, a drug that'd been out of general use for years due to its toxic effects on the kidneys Walsh named the enzyme this gene produced New Delhi metallobeta-lactamase, or NDM-1 If there was one such case, there were likely to be others By 2010 they found 180 instances of patients carrying the gene NDM-1 was widely distributed in India & Pakistan & already traveled to the UK via residents who traveled to South Asia for medical care or to visit friends and family Iy had spread in a few cases into a different bacterial genus; from Klebsiella into E. coli, which lives in the gut of every warm-blooded being & is ubiquitous in our enviro That transfer raised the prospect the gene would not stay confined to hospitals and hospital infections but would begin moving silently through the everyday world, carried in bacteria in the intestines of average people, advancing without detection via handshakes, kisses & doorknobs It raised another possibility as well: the delicate, seesawing balance between bugs & drugs, set into motion in 1928 with the discovery of penicillin, was about to come down for good on the side of the bacteria If so, many lethal infections that antibiotics have held at bay for decades might soon return with a vengeance The end of the antibiotic miracle is not a new theme For as long as there've been antibiotics, there's been antibiotic resistance: the first penicillin-resistant bacteria surfaced before penicillin was even released to the marketplace in the 1940s For almost that long, doctors have raised the alarm over running out of drugs, sparked by the global spread of penicillin-resistant organisms in the 1950s, followed by methicillin resistance in the 1980s & vancomycin resistance in the 1990s This time, the prediction of postantibiotic doom comes from a different part of the microbial world The genes that confer carbapenem resistance, not just NDM-1, have appeared over the past decade or so in a particularly challenging grouping of bacteria called gram-negatives Gram-negative bacteria are promiscuous: they easily exchange bits of DNA, so a resistance gene that arises in Klebsiella quickly migrates to E. coli, Acinetobacter & other gram-negative species In contrast, resistance genes in gram-positives are more likely to cluster within species Gram-negative germs are also harder to kill with antibiotics since they have a double-layered membrane that even powerful drugs struggle to penetrate & possess certain internal cellular defenses as well In addition, fewer options exist for treating them Pharmaceutical firms are making few new antibiotics of any type these days Against the protean, stubborn gram-negatives, they have no new compounds in the pipeline at all Resistance to the carbapenem class of antibiotics has already brought hospital-acquired infections, like the Klebsiella that infected that original Swedish patient, to the brink of untreatability Beyond the carbapenems, there remain only a few drugs that doctors are loathe to prescribe, either because they can't reach all the hiding places in the body where bacteria dwell or they make patients so sick as to be unsafe Even if health care-related infections are difficult to cure, they're usually detected because the patients in whom they occur (elderly, debilitated, confined to an intensive care unit) are usually under close watch Carbapenem-resistance genes may propagate, undetected, beyond the hospital inside of organisms that cause everyday maladies, such as E. coli For almost every antibiotic developed to date, bacteria have evolved a resistance factor that protects them from the drug's attack For almost every resistance factor, pharmaceutical companies have produced a tougher drug, until now Over the decades the battle has gradually tilted to the side of the organisms; bacteria, after all, have evolution on their side It takes bacteria 20 mins to produce a new generation, but a decade or more to research/develop a new drug Any use of antibiotics drives the emergence of resistance by exerting selective pressure Typically a few bacteria with random fortunate mutations survive an antibiotic's attack They reproduce, filling in the living space the antibiotic cleared for them by killing their susceptible brethren and passing on the genes that protected them Must take a full course of antibiotics: to kill all the bacteria causing an infection, not just the most susceptible ones But resistance does not spread only via inheritance By exchanging pieces of DNA, bacteria can acquire resistance without ever having been exposed to the drug the genes protect against You can see that pattern of resistance trumping drug trumping resistance in the evolution of Staphylococcus aureus, a gram-positive (single-membrane) organism: indifferent first to penicillin, then the synthetic penicillins then the cephalosporins such as Keflex, & then vancomycin, the last line of defense against MRSA Gram-negatives followed a similar pattern, disabling penicillins, cephalosporins, macrolides (erythromycin and azithromycin, or Zithromax) and lincosamides (clindamycin) Until recently, the carbapenems could safely & reliably dispatch even the most persistent infections, making them the last resort for gram-negative bacteria, the final barrier between treatable & nontreatable infections They were inexpensive, dependable, broad-spectrum (worked against many organisms) & very, very strong We might be able to research our way out of this dilemma with another new class of antibiotics, at least until the bacteria catch up once again But with no new medications in the 10-year pipeline capable of dispatching these latest superbugs, we may have to live with the risk of many kinds of untreatable infections for an uncomfortably long time The last new antibiotic licensed for gram-negative infections was doripenem, a carbapenem approved by the FDA in 2007 The situation would be grave enough if it were limited to the few hundred cases featuring the NDM-1 gene so far But for the past 5 years another gene conferring similar resistance, KPC for Klebsiella pneumoniae carbapenemase, has moved swiftly across the globe It appears to be following the pattern set in the 1950s by penicillin-resistant organisms & in the 1990s by MRSA: first sparking epidemics among vulnerable hospital patients, then spreading into the community Klebsiella is a common hospital infection, an almost unavoidable consequence of its use as a treatment in intensive care: high doses of broad-spectrum antibiotics disrupt the ecology of the intestinal tract & cause diarrhea, which contaminates the enviro around patients & the hands of the health care workers who treat them If becoming infected with Klebsiella in an ICU was not a surprise, the results of its analysis were As expected, the NC isolate was resistant to a laundry list of antibiotics, including penicillin & other related drugs, but the sample was also resistant to 2 carbapenems (imipenem and meropenem) to which Klebsiella had always responded The sample wasn't completely resistant, but test results at the CDC indicated unusually high doses of carbapenems would be needed to treat any infection it caused The enzyme that provided that resistance attacked the carbapenem drugs before they could even cross the inner membrane of the bacterial wall No one had seen a resistance pattern like KPC before For several years the North Carolina Klebsiella sample remained a worrisome fluke; then, in mid-2000, patients in NYC began developing unusually tough Klebsiella infections that were resistant to almost all the drug classes an intensive care physician would want to use It was the first time physicians at N.Y.U. had ever seen infections resistant to carbapenems 14 patients developed highly drug-resistant pneumonia, surgical infections & bloodstream infections, & another 10 were carrying the KPC bug without symptoms The hospital discovered their Klebsiella strain carried the same key KPC gene as the original NC sample The hospital learned how hard containing the resistant microbe could be With so many drugs found to be ineffective, the only option was to enforce the old-fashioned tool of rigorous cleanliness, to make sure the resistant bacterium didn't travel further on the hands of unknowing health care workers. It took a year to bring the outbreak under control 2 years later the same highly resistant bug appeared in hospitals in Brooklyn, further reinforcing how difficult it can be to contain Klebsiella harboring the KPC gene KPC-bearing bacteria showed up in Harlem Hospital, where they caused an outbreak of seven bloodstream infections in spring 2005; only two patients survived 2% of all of the ICU patients were carrying the resistant strain, not showing symptoms but posing a risk of infection to others NYC hospitals had become a breeding ground for the resistant germs From NYC, KPC Klebsiella spread In 2009, however, half of Chicago hospitals had discovered the KPC gene in at least some By the end of 2010 KPC bacteria had gravely sickened hospital patients in 37 US states Soon KPC organisms from New York were found in patients in Colombia, Canada, China and Greece Health authorities now view the global dissemination of carbapenem resistance, from KPC, NDM-1 & other genes, as a public health event of international concern Little can be done to stop carbapenem-resistant organisms: only a few antibiotics still work against them, & the drugs are far from perfect Most of these infections still respond to tigecycline, a newer drug, and colistin, the decades-old one Tigecycline, released in 2005, was the first of a new antibiotics class called glycylcyclines; because bacteria had never experienced its mechanism of action before, they have been slow to develop resistance to it But tigecycline does not diffuse well through the blood or in the bladder, rendering it ineffective for bloodstream & urinary tract infections caused by KPC & NDM-1 Colistin is one of a small class of drugs called polymyxins that dates back to the 1940s It has its own issues: in addition to its long-standing reputation for damaging the kidneys, it doesn't penetrate well into tissues Those problems kept it from being widely used for decades, & that may be what preserved its usefulness this long—as colistin use has increased in recent years, resistance to it has increased as well Beyond tigecycline & colistin, we have almost nothing Without explicitly saying so, most of the pharmaceutical industry has decided that drugs to treat carbapenem-resistant infections are so challenging to develop & can be used for so short a period before resistance arises, that they're not worth research and development time The expanding epidemic has forced hospitals to reassess the efficacy of their infection-control measures Institutions that have been able to curb the bacteria say that the effort requires ferocious focus; washing down patients with antiseptics every day & cleaning the surfaces in patients' rooms, down to the smallest joints & nooks on monitors and computers, as often as every 12 hours Phillips helped to develop a novel "Clean Team" project that pairs infection-control experts with the hospital's building-service workers; the team cut the occurrence of several health care infections in its first 6 months Health care teams are also boosting surveillance, hoping to identify patients who are carriers so they can be isolated before they infect others In 2009 the CDC published extensive guidelines to help hospitals control carbapenem-resistant bacteria The agency didn't recommend the French strategy of testing every patient before admitting them to the hospital, saying the bacteria are still too unevenly distributed across the country to justify the cost & staff time Keeping carbapenem-resistant organisms out of hospitals is important not only for controlling outbreaks among debilitated patients; it is also vital for preventing spread to health care workers It's even more important for keeping KPC-bearing bacteria from sharing their resistance genes with other bacterial species, like E. coli, that are present in the hospital but also flourish outside it Such a KPC-fortifed E. coli could escape the hospital, passing out of reach of any surveillance scheme Looking ahead, researchers envision the emergence of completely resistant strains of gram-negative bacteria, arriving long before the drugs that could treat them Some don't have to imagine that happening; they have seen it come true The constant use of antibiotics, which helps foster drug resistance across bacterial species, has produced a deadly new threat The new strain began with a few Klebsiella bacteria that happened to carry the KPC gene, which rendered thm insensitive to antibiotics known as carbapenems. Multiple rounds of ineffective treatment cleared the way for the KPC-bearing bacteria to proliferate Even more worrisome, Klebsiella and other gram-negative bacteria easily share KPC & other resistance genes across species, which could make them impermeable to all drugs In an enviro awash with antibiotics, such as intensive care units, only those germs with genes that confer resistance survive & then multiply Extensive treatment favors resistant strains Resistance spreads to other bacterial species The KPC-resistance gene is found on loops of DNA called plasmids, which are present outside the bacterial cell's chromosome During conjugation (bacterial sex), 2 cells form a bridge between them, allowing the plasmid to transfer its genes from one cell to the other Gram-negative bacteria are particularly adept at this type of transfer, which in turn allows cells that've never been treated by antibiotics to become drug-resistant The KPC-resistance pattern grows more dangerous as it spreads from Klebsiella to E. coli to other gram-negative germs that cause common infection For 4 years after the KPC gene was first isolated from an unidentified hospital in NC, no one could find any evidence of its spread; but once the KPC-bearing bacteria gave rise to outbreaks in several NYC hospitals, the assault was on The tough-to-kill germs quickly traveled to France, Colombia, Canada, Greece and China An outbreak in Israel spread to England, Norway and several other European countries Health care workers are often unwitting carriers of bacterial resistance Hospitals that have controlled outbreaks of carbapenem-resistant infection were forced to adopt rigorous hygiene & surveillance measures Identify: To avoid missing any potential cases, hospitals in France use rectal swabs to test incoming patients with a history of previous multi-drug-resistant infection Sterilize: Doctors/nurses must routinely wash hands & wear gloves; patients are wiped down with antiseptics every day; all surfaces in their room are sanitized, including any computer keyboards Review: Lab specimens are continually tested & infection-control measures adjusted until multidrug-resistant germs are eliminated

Pinning Down a Deadly Shape Shifter (reading notes)

A parasite's genome is yielding clues to how malaria kills More people have died from malaria than from any other disease in history If we look at the African parasite that causes its most severe form, it's obvious why the pathogen is so deadly Plasmodium falciparum has a multistage life cycle & highly mutable genes It's already widely resistant to one of the most common medications used to treat it, chloroquine, & it's starting to evolve around a newer drug, artemisinin Falciparum is also a shapeshifter, presenting different proteins on its surface as it develops in the body & remaining 1 step ahead of the immune system All this complexity is bad news for victims, but may be good news for scientists, who sequenced the organism's genome in 2002 & are starting to figure out what malaria's intricate biology says about its natural history Until recently, researchers thought falciparum had jumped into humans from chimps; but in September a team (known for its work on the origin of HIV) showed all falciparum parasites are descended from a single lineage that jumped from gorillas millions of years ago Since then, the parasite has been furiously evolving, & drug resistance is part of that, but the human body itself is a much more important factor The malarial genes under the most intense selection pressure (those with the most variation, generated over a millennium-long cat-and-mouse game with the immune system's antibody response) are the ones that encode the identifying proteins on the surface of the parasite Scientists have struggled to explain why some people get very sick from falciparum, whereas others suffer only mild symptoms; early work suggests that some of these "var" genes are behind serious cases in children One of the crucial next steps in understanding malaria's genome will be assessing how it differs from parasite to parasite & region to region Knowing the amount of variation within an individual is crucial, & we can fortunately quantify that with extraordinary precision MapSeq, is a recent interactive database of genotyped samples from several hundred patients around the world; researchers can use it to look for mutations unique to their areas, & to tailor their control strategies around them

Chagas disease

A protozoan infection Caused by a bite of kissing bug There are an increasing number of cases found in Europe New drugs are needed The parasites can produce a severe dilation of the heart & can prove fatal

How much of the world's population is infected with the TB bacterium? How many of them will become sick with active TB in their lifetime?

A third; 1 in 10

Poor Man's Burden: Why Are HIV Rates So High in the Southern U.S.?

AIDS anomaly: data highlights the unusually high rate of AIDS diagnoses in the South, which sometimes rivals the proportions seen in hotspots like NY and California When the AIDS epidemic first surfaced in the US 30 years ago, the illness was primarily an urban problem, centered in cities like NY, San Francisco & Los Angeles Today NY State & California still rank among the highest in the # of cases, with more than 150,000 people living with AIDS (the later stages of HIV infection) between them; but recently HIV has taken a disproportionate toll on the southern US, including in rural areas Despite making up 37% of the population, the 16 states that constitute the American South accounted for ½ of the 45,000 new cases of HIV infection in the US in 2009 Moreover, the South has the highest rate of newly reported infections & the highest # of deaths caused by AIDS This regional anomaly has set off alarm bells at state & federal health departments alike, because it shows current efforts are failing to contain the infection Considering all that's now known about how HIV is transmitted & how it can be prevented, the rate of new infections should be falling rapidly Deaths should be declining as well since combination therapy inhibiting the progress of the disease has been available since 1996 & the states' AIDS Drug Assistance Programs have been covering the cost of care for many people who can least afford it since 1987 Nor is there anything unusual about the way HIV spreads in the South Unprotected sex between men remains the most common method of transmission, followed by sharing contaminated needles or having sex with people who fall into either of those categories Research has identified several interrelated causes (among them poverty, culture & prejudice) that can explain these #s Now a few states in the area are attempting to turn the findings into helpful programs Surprisingly, Mississippi, a state whose many failings in the struggle against AIDS were well documented, could help show the way; although plenty of pitfalls remain HIV is, of course, not the only health problem that looms large in the South The South has long suffered more than its fair share of diabetes, heart disease, certain types of cancer & obesity compared with the Northeast, Midwest & West As with all these other health problems, addressing the HIV epidemic in the South requires much more than just having effective & affordable medicine; it demands an understanding of why individuals in the South turn out to be particularly likely both to delay testing & to seek medical attention only in the later stages of HIV infection, when it's most difficult to treat 1 reason seems to be the strong stigma in the South attached to HIV infection & AIDS, an attitude that's reinforced by many cultural/religious attitudes against homosexuality Those at risk often shun testing, & people who test positive tend to hide their status until their health deteriorates beyond denial; meanwhile the virus continues to spread Poverty is another major cause for delay in testing & treatment; Mississippi is the poorest state in the Union, followed by West Virginia, Arkansas & South Carolina For people who have little money, HIV may seem like the least of their worries as they struggle to find food, buy clothes, & keep a roof over their heads Many can't afford health insurance but make too much money at their low-paying jobs to qualify for Medicaid and other free or low-cost health care benefits These hassles of everyday living lead large #s of infected individuals to put off medical care until they're seriously ill Even when HIV-positive Southerners attempt to find care, they often have difficulty getting the treatment they need Federal government surveys have found that more than ½ of all people living with HIV in many southern states don't get adequate treatment, compared with ⅓ in other regions For one thing, states sometimes impose payment rules that tie doctors' hands I.e. Mississippi's Medicaid program limits beneficiaries (including those with HIV) to just 5 prescription drugs per month, despite the fact that it often takes many more medications to keep viral levels in check A sheer lack of doctors plays a part as well; Mississippi has one of the lowest ratios of primary care physicians to resident population in the country, and practitioners may not be eager to see infected individuals The Human Rights Watch report included anonymous testimony from clinical workers that many Mississippi health care practitioners refuse to treat HIV-positive individuals, resulting in long waiting lists for those willing to see such patients Yet research shows early treatment improves outcomes, lowers the cost of care, and diminishes risky behavior 1 group that's been especially hard-hit by HIV's ties to poverty and prejudice in recent years is African-Americans More than ½ of all households that are poor and black are in the South Public health experts report that black men who have sex with other men are particularly unlikely to think of themselves as homosexual or at risk for HIV & therefore deny the need for condoms, which reduce the transmission of the virus Among black men who have sex with men, more new cases of AIDS were diagnosed in the South in 2006 than in all other regions of the country combined In Mississippi, state health officials report that the # of new cases of HIV among black men aged 13-31 who had sex with other men rose by 48% from 2005 to 2007 Money can't cure all the obstacles to improving the HIV picture in the South, but it could certainly help In 2010 the Obama administration issued a national strategic plan to tackle HIV in the country's hardest-hit regions, including the South; announced funding increases in 2011 But with cuts looming in spending on Medicaid, which is paid for by state & federal governments, the people who most need help may end up not getting much more assistance after all In the meantime, some states are trying to innovate on their own SC has an HIV education program that aims to reduce stigma by reaching out to churches and ministers Arkansas, for the first time, has allotted funds to test the feasibility of offering routine HIV screening to the general population Mississippi has zeroed in on what might seem like a surprising solution for a state in the Bible Belt: in March the state passed a law requiring school districts to offer sex education 75% of Mississippi's high school seniors report being sexually active, and ¼ new HIV cases occurred in young people between the ages of 13-24 Hopes to work with Mississippi's Department of Education to begin testing all students in selected high schools for HIV, whether or not they appear to fall into a high-risk group The move would help anyone who is HIV-positive and does not know it to get treatment Testing everyone also acts to diffuse any stigma that might be attached to HIV screening because no one is singled out Improving access to health care will probably take longer The Prevention and Public Health Fund, a component of the Affordable Care Act, has allotted $198M toward training 500 new primary care physicians & 600 new primary care nurse practitioners across the country by 2015 But Governor Haley Barbour of Mississippi has argued that the state does not need the kind of assistance that the law provides For now the state's health experts hope that their education and testing initiatives can help lessen the alarmingly high rates of HIV infection and death in the US's poorest state

Prognosis of polio

Ability to breathe almost always returns Muscle strength may recover in 3-4 months or more, but paralysis may be permanent Muscle weakness may return many years later (post-polio syndrome)

Aedes (mosquito)

Aggressive day biter Zika, dengue, yellow fever, West Nile virus Aedes aegypti

How does poliovirus cause muscle wasting and paralysis?

By destroying nerve cells in the spinal cord

Genomic Surveillance for Malaria (reading notes)

Can flag pathogens long before patients show up in clinics In 2018 the WHO proposed a "10+1" initiative for malaria control & elimination that targets 10 African countries plus India, which together host 70% of global cases Although promising, it's missing an important component: genomic surveillance Drug resistance threatens all of the progress made so far against malaria, but genomic surveillance can detect resistance years before the 1st warning signs appear in clinics It can also answer critical questions about how resistance emerges/spreads & can help control the balance of interventions, preserve the useful life of already existing drugs, & ensure effective treatment The WHO, global health partners, & the malaria community should incorporate mandatory genomic surveillance by making it a major intervention in countries that have the highest malaria burden This genomic info can help malaria-control programs use quality data sets for regular monitoring of drug resistance, provide evidence-based decision-making around malaria policy, & assist in managing the spread of resistance The countries most affected by malaria all had a 1st-line drug that became resistant In African countries, in the late 1900s, chloroquine was the drug of choice, but malaria parasites grew resistant to it; that was replaced by a combo of pyrimethamine/sulfadoxine in the early 2000s, & resistance again occurred; now the parasites are becoming resistant to the current 1st-line artemisinin-based combination therapies (ACTs) Artemisinin resistance is conferred by the kelch 13 gene, which is located in the propeller region of chromosome 13; although mutation in this gene has occurred in Southeast Asia & is spreading around the region, there are fears that it'll also spread to Africa, as happened with the drugs before ACTs The more drugs we use to treat malaria parasites, the more resistant they become as a result of selective pressure, which creates the preconditions for resistance Because we know this biological response from the parasites is inevitable, we should put in place measures to track down these changes when they arise: doing so would help us prevent the spread of the disease, investigate emergence of resistance & subsequently preserve the efficacy of the current first-line antimalarial treatment With advances in genomic technology, scientists have been able to analyze malaria parasites from the patients carrying them & the mosquitoes transmitting them Analysis has become a source of relevant info for both drug & insecticide resistance Genomic surveillance has helped us understand how different mosquito species arise & transmit malaria to humans, which in turn has led to a better targeting of interventions as vectorial capacity becomes better understood Surveillance has enabled greater knowledge of changing transmission intensity & parasite gene flow, including drug-resistant genes, & has aided in quantifying the risks of importing malaria from a country burdened with the disease Using genomic surveillance as a tool has mostly transpired within the realm of research, with only a few examples of its application in the field where malaria burden remains high Genomic surveillance has been used in countries that have eliminated malaria to prevent its resurgence & in countries that are in a malaria-elimination phase It shouldn't be any different for African countries that have the highest malaria burden Genomic surveillance played a huge role in controlling poliomyelitis Public health officials have used quality data to learn where poliomyelitis emerged from, map the transmission network & determine where to direct their vaccination efforts It's time for genomic surveillance to move from mainly academic research into the field where malaria deaths occur The WHO should incorporate a new "tool kit" that includes malaria genomics in its eradication plans; this would provide valuable info that would make national programs fighting the disease, especially in the 10+1 countries, far more effective As with any public health crisis, the more we know, the better

Main symptoms of pulmonary TB*

Central: appetite loss, fatigue Lungs: chest pain, coughing up blood, productive, prolonged cough Skin: night sweats, pallor

Placebo effect (reading notes)

Colds, asthma, high blood pressure & heart disease are among the many conditions that can respond to a placebo Placebo effect: just seeking & receiving treatment can make you feel better (less disabled, less distressed, more hopeful) & in turn speed your recovery Medicine has become vastly more scientific in the past century, but doctors and their patients continue to ascribe healing powers to pills & procedures that have no intrinsic therapeutic value for the condition being treated (i.e. widespread & medically pointless use of antibiotics to fight colds and flus caused by viruses) Some studies suggest only about 20% of modern medical remedies in common use have been scientifically proved to be effective; the rest haven't been subjected to empirical trials of whether they work &, if so, how It's not that these treatments do not offer benefits: most of them do; but in some cases, the benefit may come from the placebo effect, in which the very act of undergoing treatment (seeing a medical expert or taking a pill) helps the patient to recover The placebo effect is a powerful part of healing & more effort should be made to harness and enhance it Study: contrary to hypothesis, depressed patients responded equally well to an antidepressant, regardless of how much cortisol hormone was present in their system; yet close to half the patients with normal levels of cortisol felt better after taking a placebo; among the nine patients with elevated levels, none improved Depressed patients who respond to placebos differ biochemically from those who don't People suffering from short-term depression, lasting less than 3 months, are more likely to benefit from a placebo; but longer-term depression, lasting more than a year, often doesn't improve after placebo treatment The placebo effect isn't unique to depression or psychiatric illness A study suggests that for a wide range of afflictions, roughly 30-40% of patients experience relief after taking a placebo Among patients who received the actual routine arterial ligation surgery, 76% improved, but, notably, 100% of the placebo group (incision made, no surgery) got better Placebos are often described as inactive, but placebo agents are clearly active: they exert influence & can be quite effective in eliciting beneficial responses Placebos are also described as nonspecific, presumably since they relieve multiple conditions & because exactly how they work is not fully understood; yet by either of these standards, placebos are no less specific than many valid & accepted remedies, like aspirin A placebo is a pharmacologically inert capsule or injection, yet even this definition doesn't capture the full range of procedures that can have a placebo effect Today the most common situation in which people use be placebos is during double-blind clinical trials Patients who take a placebo in the course of such trials receive much more than a pharmacologically inert substance: like the patients receiving a "real" drug, they benefit from a thorough medical evaluation, a chance to discuss their condition, a diagnosis, a plausible treatment plan, & the enthusiasm/commitment of their doctors/nurses These factors, which many people view as incidental to the healing process, provide an important clue as to why placebos work The healing enviro is a powerful antidote for illness: the decision to seek medical assistance restores some sense of control, & the symbols and rituals of healing (the doctor's office, the stethoscope, the physical examination) offer reassurance An explanation for the illness & a prognosis, when favorable, reduce fear; even when the report is unfavorable, it allays the anxiety of uncertainty Merely the act of taking a pill can have a therapeutic effect The drug propranolol is often prescribed after a heart attack to regulate the heartbeat & prevent further damage In a recent study of more than 2,000 patients, the death rate was cut in half among patients who took propranolol regularly compared to those who took the medication less regularly In the same study, patients who took placebos regularly also had half the death rate of those who took them less regularly, even though the two groups of placebo users were similar medically and psychologically Placebos seem to be most reliably effective for afflictions in which stress directly affects the symptoms: in certain forms of depression & anxiety, for example, distress is the illness Conditions like pain, asthma & moderate high blood pressure can become worse when the patient is upset Placebos may work in part by lessening the apprehension associated with disease It isn't inconceivable that by reducing anxiety, placebos could influence countless diseases, including some we don't usually think of as subject to psych influence A patient's expectation of improvement is also crucial Across a wide range of illnesses, patients who think they will feel better are more likely to do so Expectation operates more specifically as well: when participants in a study were told that their inert drink contained alcohol, they often felt & acted intoxicated & even showed some of the physiological signs of intoxication Patients with asthma who were given an inhaler containing only nebulized saltwater but were told they would be inhaling an irritant or allergen displayed more problems with airway obstruction; when the same group was told that the inhaler had a medicine to help asthma, their airways opened up Placebos have a dubious reputation because of the word's negative connotation stuck & definition as a medicine given to please patients rather than to benefit In the modern era, the lack of pharmacological activity became part of the placebo definition as well A modern myth about placebos reflects the stigma: if a condition improves with placebos, the condition is supposedly "all in the head" The very effectiveness of a placebo worries doctors & medical experts since it seems to threaten their livelihood; nevertheless, given the recent advances in med tech, including the development of indisputably efficacious drugs & procedures, the medical community may now be ready to accept & put to good use this component of healing they do not fully understand Decades of research offer guidance as to how physicians can incorporate aspects of the placebo effect, in ways that are both medically & ethically sound, to make accepted medicines more effective; yet many of these ideas have not been tried by doctors Some suggestions aren't surprising: i.e. patients should be made to feel confident and secure that they are in the hands of a recognized healer; diplomas, board certifications and medical instruments in sight generally provide these signals A careful analysis of a patient's complaint is far more comforting than an immediate diagnosis, no matter how accurate Administering a thorough evaluation doesn't mean a patient should be subjected to unnecessary diagnostic procedures; rather the doctor should listen carefully, ask suitable questions & perform a complete exam The fact someone has bronchitis may be obvious to a doctor within seconds; an additional 5 minutes of evaluation that includes a stethoscope on the chest may not add to the accuracy of the diagnosis, but it does add to the patient's confidence Many of today's medical experts still appreciate the healing power of a compassionate consultation, but under pressure to provide "cost-effective" care, they (& particularly insurance companies) may be losing sight of this crucial component of effective care The initial evaluation should include specific questions regarding the patient's previous experiences with a variety of remedies, including treatments (i.e. alternative therapies) most physicians consider to be placebos In particular, the doctor or nurse should elicit the patient's ideas about what might or might not be helpful for the present complaint The physician should provide a diagnosis & a prognosis whenever possible In a recent study of 200 patients with physical complaints but no identifiable disease, doctors told some that no serious disease had been found and that they would soon be well; others heard that the cause of their ailment was unclear; 2 weeks later 64% of the first group had recovered, but only 39% of the second group had recuperated If a specific drug or medical procedure is called for, it should be offered with realistic optimism & info about its specific desirable effects—something along the lines of "This medicine will help you breathe" for an asthma medication The doctor should also provide info about side effects & the most likely course of symptoms If a # of treatment options are equally appropriate, the patient should be given the chance to make a choice, but doctors should offer a limited number of options (no more than 3-4) & should provide sound information to help the patient make the decision Allowing patients to choose whatever course of therapy they would like deprives them of a major benefit of seeking medical advice If people want to treat themselves, & many do, they don't go to experts When managing conditions like the cold that tend to run their course without treatment or when handling diseases that have no effective treatment, doctors often prescribe palliative medication to relieve symptoms such as congestion/pain; for these therapies to be most useful, it's important that doctors offer them with the same thoughtfulness and authority as when they recommend other, more definitive remedies Doctors often tell patients with colds or the flu they'll probably feel better in a few days & that they can take cold medicine if they want to; such patients, feeling miserable & bereft of treatment, often request/receive antibiotics, pharmacologically active but inappropriate drugs that they are unwittingly using as placebos These same patients would feel quite differently if, after a medical exam complete with diagnostic instruments, their doctors wrote the name of a cold medicine on a prescription form (even if the drug didn't require a prescription) & handed it to them with instructions on how and over what interval this medicine will be helpful For many afflictions, 30-40% of patients experience relief after taking a placebo Placebos are effective for various conditions: patients with angina pectoris (insufficient blood flow to the heart) responded to placebo surgery in which doctors made only an incision in the chest but did nothing further In a study of patients with generic symptoms but no organic ailment, researchers found that reassuring words from a doctor helped patients to feel better In a study of the drug propranolol, investigators noticed that patients who took placebo pills regularly had a lower death rate than patients who took placebos sporadically In the case of the common cold, such an approach could go a long way toward reducing the unnecessary use of antibiotics & the attendant expenses/dangers of the practice Should physicians, in order to take advantage of the placebo effect, prescribe drugs or procedures that they know to be of no intrinsic value? For many medical experts, this situation presents what has seemed an insolvable dilemma Doctors have felt that if they tell patients they are prescribing a sugar pill, the placebo response, which depends in part on patients' expectations of receiving a plausible remedy, will be lost On the other hand, if doctors tell patients that the placebo is a pharmacologically active medicine, they are engaging in a type of deception that is neither ethical nor, in the long run, therapeutic If physicians can see placebos—like many conventional drugs—as broadly effective therapies, whose mechanisms of action aren't completely understood & which tend to be more effective for some conditions than others, they can then offer placebos both honestly and as plausible treatment The decision to prescribe a placebo should be based, as with any drug, on the risks/benefits The specific placebo chosen should be free of toxicity and should be in keeping with the patient's beliefs and expectations Although alternative medicine healers &their patients believe fervently in the effectiveness of megavitamins & herbal mixtures, many of these popular remedies probably derive their benefit from the placebo effect Disease is typically defined as an abnormal state of the body—high blood glucose, a fractured forearm, a lung infection; but illness is something else: it is the suffering that accompanies disease In our culture, pills & other symbols of the physician's healing arts have great power to ease suffering As physicians, we should respect the benefits of placebos (their safety, effectiveness & low cost) & bring the full advantage of these benefits into our everyday practices

Urinary schisto

Egg retention in the urinary tract (S. haematobium) can lead to: - Hematuria (bloody urine) - Dysuria (painful urination) - Bladder polyps, ulcers, cancers - Obstructive urinary disease

Malaria symptoms*

Fever and chills Dizziness, seizures, coma Heart and lung failure Other organ failure Death

A Weakness in Bacteria's Fortress (reading notes)

Evolutionary biologists are trying to attack bacteria in a new way: by short-circuiting their social life Researchers from an emerging field called sociomicrobiology believe they have a new approach to fight antibiotic resistance among illness-causing bacteria; they want to disrupt the processes that let bacteria communicate & cooperate with one another Evolutionary theory predicts acquiring resistance to "antisocial" drugs should be difficult Not everyone is convinced this new strategy for developing antibiotics will work ... A new branch of science, sociomicrobiology, is revealing that some of the same principles that govern ants can explain the emergence of bacterial societies Like ants, microbes live in complex communities, where they communicate with one another to cooperate for the greater good This insight of social evolution suggests a new strategy for stopping infections: instead of attacking individual bacteria, as traditional antibiotics do, scientists are exploring the notion of attacking entire bacterial societies New strategies are exactly what's needed now Bacteria have evolved widespread resistance to antibiotics, leaving doctors in a crisis CDC estimates 23,000 people die in the US every year of antibiotic-resistant infections Strains of TB & other pathogens are emerging that are resistant to nearly every drug The standard response to this crisis has been to slow the evolution of resistance & find new drugs to replace old ones as they grow weak, but this is only a treadmill solution Bacteria are relentlessly evolving resistance & will keep doing so unless we find a different way to fight them Every time we develop a new drug, it fails, so the solution is to quickly make another antibiotic (but that only helps for a few months and is no longer good enough) Many infectious species of bacteria depend on their collective behavior to make us sick Sociomicrobiologists are looking for opportunities to disrupt bacteria societies, by interfering with their communication, or blocking their cooperative efforts to gather nutrients Evolutionary theory predicts the collective behavior of bacteria should be a ripe target for medicine Attacking the social life of bacteria may not be a fully evolution-proof strategy, but, at the very least, it might slow down the evolution of resistance dramatically Sociomicrobiologists have a lot of skepticism to overcome While they have presented detailed theoretical arguments & a few promising experimental results, some researchers doubt their evolution-inspired drugs will be able to stop the rise of resistance Pharmaceutical companies, which have shied away from antibiotics in general, aren't yet ready to push such drugs through the approval pipeline & into the market Still, the sociomicrobiologists are getting some attention NIH has been laying plans for research into antibiotic resistance, & investigators have made the social life of bacteria a top priority If the work pans out, they will have succeeded in reversing the relation between medicine & evolution Traditionally an enemy in the fight against bacteria, evolution would become a friend The crisis of antibiotic resistance has been long in the making A few years after the first antibiotics were introduced in the mid-1900s, doctors already discovered some bacteria that could withstand them At the time, it wasn't entirely clear what was happening; today scientists can probe the evolution of resistance in all its molecular details I.e. Penicillin kills bacteria by grabbing onto a protein that helps in building the bacteria's cell membrane; without this protein, a bacterium will spring a leak & die In any population of bacteria, a few mutants will be able to defend themselves against penicillin I.e. Bacteria have pumps to flush toxic chemicals out of their interior A mutant microbe may produce extra pumps, letting it rid itself of penicillin quickly, freeing up its proteins to build its membranes Normally such a mutation doesn't provide any evolutionary advantage to a microbe If a patient takes a dose of penicillin to clear an infection, those extra pumps can make a huge difference Bacteria without the extra pumps die, while many mutants manage to survive The survivors multiply, increasing the proportion of mutants in the population In later generations, the descendants of the original mutants may evolve even better defenses, sometimes by picking up genes from other bacterial species For decades new drugs came out of the development pipeline quickly enough to replace the old ones that failed, but now that pipeline is drying up As the expense of developing new antibiotics has cut into profits, many pharmaceuticals have bailed out of the antibiotics business & invested instead in more profitable drugs for cancer or hepatitis As the crisis deepened, scientists yearned for an antibiotic that wouldn't become obsolete, and sometimes they did find what they believed to be an evolution-proof drug In 1987, for example, it was found African clawed frogs produce a powerful toxin against bacteria in their skin Zasloff soon found that the amphibians were not the only toxin makers Just about every animal they looked at made small, positively charged proteins that could kill bacteria, a class of molecules that came to be known as antimicrobial peptides In reports, Zasloff predicted bacteria would be unlikely to evolve resistance against the drugs Animals, he pointed out, had been using antimicrobial peptides to kill bacteria for hundreds of millions of years, & yet bacteria today remain vulnerable to the peptides In 2003 Graham Bell, predicted Zasloff would be proved wrong Penicillin & many other drugs had also been discovered being made in nature, but modern medicine delivered them in huge concentrations to patients, creating a tremendous evolution pressure that drove the rise of resistant mutants As soon as doctors started giving pills packed with antimicrobial peptides to patients, history would repeat itself Zasloff challenged Bell to see if bacteria could become resistant to pexiganan, one of his best-studied peptides Bell & Gabriel Perron reared a batch of E. coli & exposed it to a low dose of pexiganan; then they took some of the surviving bacteria to start a new colony, which they exposed to a higher dose of the drug Increasing the dose over a few weeks, the scientists watched the bacteria evolve to be completely resistant to pexiganan, as Bell had predicted; Zasloff immediately acknowledged that Bell had been right The experiment made him far more cautious about antimicrobial peptide Today we don't know for sure if anticrobial peptide could evolve resistance, & we will not unless antimicrobial peptides are eventually approved for use for infections Currently pharmaceutical companies are running several clinical trials, but 28 years after their discovery, not a single antimicrobial peptide has been approved for use for infections; they're victims of a slow pipeline Darwin could've had no idea that bacteria would become one of the best illustrations of his theory of natural selection; he and other scientists knew very little about how microbes grow When he presented his theory in On the Origin of Species in 1859, he instead wrote about traits that were familiar to fellow Victorians, like fur on mammals & the colors of feathers Darwin also wrote about familiar features of nature that had initially made him worry his idea might be wrong One of them was that in many species of ants, female workers are sterile In Darwin's theory, natural selection emerged from the competition between individuals to survive & reproduce But worker ants, which don't reproduce themselves, seemed to be dropping out of the competition altogether Darwin suspected a solution to the worker ant paradox lay in kinship An ant colony is not just a random jumble of strangers, it's more like an extended family Together a group of related ants may be able to produce more offspring than if they all try to breed on their own Darwin's ideas on cooperation inspired generations of evolutionary biologists to explore them further "Social" and "bacteria" may not be tightly joined in most people's minds, but it turns out microbes live in intimate communities full of conversation & cooperation Take Pseudomonas aeruginosa, a species that can cause serious lung infections When 1 of the microbes invades a host, it sends out signaling molecules Other members of its species can grab those molecules with special receptors Releasing & grabbing these molecules is a way for bacteria to say, "I'm here—is anyone else here?" If the bacteria sense they have enough members, they'll begin to cooperate to build a shelter They spray out gooey molecules that grow into a mat, inside of which the bacteria embed themselves; this biofilm can stick to the lining of lungs or other organs Nestled deep inside the biofilm, the bacteria are shielded from the attacks of immune cells Pseudomonas bacteria also work together to gather nutrients I.e. Bacteria can't grow without iron, but the human body is a tough place to find it since our cells snap up iron & lock it away in hemoglobin and other molecules To get an iron supply, each microbe releases molecules called siderophores,, which can wrest the atoms away from our own molecules They basically steal the iron The bacteria can then absorb the iron-bearing siderophores & use the iron to grow The effort is deeply cooperative because each siderophore that a microbe takes in was probably made by one of its millions of neighbors 1 cell will pay a cost that'll benefit the whole infection, not that one cell Evolutionary theorists have a name for such molecules: public goods, benefit the community of bacteria They are the opposite of private goods, which only benefit the individual bacteria that made them Public goods represent a Darwinian paradox Natural selection should, in theory, wipe them out Mutants don't make their own public goods can still use the public goods made by others This imbalance should put the freeloader at an evolutionary advantage A mutant that doesn't make siderophores can still get iron without paying the cost of making siderophores It should reproduce faster than cooperative bacteria & become more common Yet cooperators dominate species such as P. aeruginosa, not freeloaders Pseudomonas bacteria don't produce a steady stream of siderophores; instead they churn them out suddenly, in an initial burst Once the bacteria have created a supply of siderophores, they can recycle the molecules They absorb iron-bearing siderophores, pull away the iron atoms & then spit the siderophores back out Thanks to the durability of siderophores, the bacteria do not have to use up much energy making new siderophores to replace old ones Recycling thus lowers the cost of cooperation It also helps cut down the advantage of being a freeloader As sociomicrobiologists discovered, they began to wonder if they could apply their insights in a very practical way: by finding new kinds of drugs to fight infections Today, all antibiotics in use today are basically the same Each attacks bacteria's private goods If a microbe mutates to protect its own private goods, it will outcompete other bacteria that cannot Sociomicrobiology reveals a different target for stopping infections: public goods Evolutionary theory predicts bacteria will be less likely to evolve resistance to drugs that go after public goods Imagine researchers were to develop a drug that attacked siderophores; as a result, bacteria would become starved of iron Now imagine that an individual microbe acquired a mutation that protected its siderophores from the drug That mutant would not gain any advantage Bacteria collectively release all their siderophores into their host, where the molecules get mixed up When a microbe takes up an iron-bearing siderophore, it is almost certainly not one of its own As a result, mutants can't outreproduce their fellow bacteria Previous research revealed siderophores made by Pseudomonas grab a metal called gallium just as easily as they grab iron The researchers wondered if they could use gallium as a drug to starve the bacteria of iron Having shown that gallium could act as an antibacterial drug, the scientists ran another experiment to see if the bacteria could evolve resistance to it Evolutionary theory predicted that they should not A drug that targeted public goods had prevented bacteria from evolving resistance Siderophores are just one of a number of public goods sociomicrobiologists are studying as potential targets for drugs Drugs that can disarm toxins may be able to render bacteria helpless without even killing them Other researchers are investigating the signals bacteria send to one another Molecules can jam this communication in various ways, such as blocking the receptors that usually grab signaling molecules If bacteria cannot communicate with one another, then they cannot cooperate Antisocial drugs could have another advantage over conventional antibiotics: instead of wiping out lots of species of bacteria at once, they may be able to narrow their targets That is because the public goods made by one species are typically only useful to that species alone Thus, antisocial drugs might be less likely to wipe out good germs along with the bad Some scientists are skeptical antisocial drugs will avoid resistance Bacteria might evolve a way to live without a public good Even if antisocial drugs turn out only to slow down resistance, they will be an important advance The collective activities of Pseudomonas aeruginosa bacteria let them trigger hard-to-eradicate infections Researchers hope to develop more effective antibacterial treatments by interfering with the way various germs communicate & cooperate with one another; such an approach should trigger less drug resistance, in theory, since no single cell should be able profit by changing the way it responds One idea targets a molecule Pseudomonas bacteria use to scavenge iron Pseudomonas bacteria produce molecules called siderophores to steal iron from their host, Each siderophore can be reused by many different germ cells & in that way is a public, not private, good Siderophore release & wrestle iron away from host molecules Gallium, which has many chemical similarities to iron, is introduced as a drug; the siderophores pick up gallium instead of iron Bacterial cells reabsorb the siderophores (though usually not the exact ones they produced) & use the iron to fuel cell division Siderophores return to the bacterial colony with gallium, which the cells can't use, stopping their growth Delivery of gallium undermines the ability of siderophores to provide iron to the bacterial population Even if a single cell develops a favorable siderophore mutation, that cell will still probably starve because it is likely to take up siderophores made by other bacteria

HIV: The Ultimate Evolver (reading notes)

Evolutionary biologists can help uncover clues to new ways to treat/vaccinate against HIV; these clues emerge from the evolutionary origins of the virus, how human populations have evolved under pressure, from other deadly pathogens, and how the virus evolves resistance to the drugs we've designed Controlling the disease may be a matter of controlling the evolution of this constantly adapting virus The human immunodeficiency virus (HIV) is one of the fastest evolving entities known HIV reproduces sloppily, accumulating lots of mutations when it copies its genetic material; it also reproduces at a lightning-fast rate (a single virus can spawn billions of copies in just one day) To fight HIV, we must understand its evolution within the human body & then ultimately find a way to control its evolution Taking an evolutionary perspective on HIV has led scientists to look in 3 new directions in their search for treatments/vaccines: What are the evolutionary origins of HIV? Why are some people resistant to it? How can we control its evolution of resistance to our drugs? HIV, like any evolving entity, has been deeply marked by its history Scientists studying the evolutionary history of HIV found it's closely related to other viruses, including SIVs (simian immunodeficiency viruses), which infect primates, & more distantly related FIVs (the feline strains), which infect cats Studies of related viral lineages showed something surprising: primates with SIV & wild cats with FIV don't seem to be harmed by the viruses they carry If scientists can figure out how nonhuman primates & wild cats are able to live with viruses, they may learn how to better treat HIV infections or prevent them altogether An ancestral virus evolved into strains that infected chimpanzees, and, over time, new strains began to infect humans (HIV) HIV is by no means the first plague that human populations have weathered; many pathogens have deeply affected our evolutionary history The human genome is littered with the remnants of our past battles with pathogens, & 1 of these, a mutation to a gene called CCR5, may lead researchers to a new HIV treatment The mutant CCR5 allele probably began to spread in northern Europe during the past 700 years when the population was ravaged by a plague (possibly bubonic) Mutant CCR5 likely made its bearers resistant to the disease, & so its frequency increased In some parts of Europe today, up to 20% of the population carry at least 1 copy of the protective allele; however, the populations of Asia & Africa weren't exposed to the same epidemics; very few Asians and Africans now carry the allele CCR5 is fairly common in northern Europe but its frequency diminishes as one moves south, and the mutation is rare in the rest of the world We now know that the mutant CCR5 allele has an unexpected side effect: it grants resistance to HIV Scientists hope that studying this by-product of past selection will help them develop new treatments for the HIV epidemic ravaging human populations today HIV evolves so quickly that it evolves right out from under our treatments When a patient begins taking an HIV drug, the drug keeps many of the viruses from reproducing, but some survive because they happen to have a certain level of resistance Because of HIV's speedy evolution, it responds to selection pressures quickly: viruses that happen to survive the drug are favored, & resistant virus strains evolve within the patient, sometimes in just a few weeks Basic evolutionary theory points out a way this evolution of resistant viral strains can be delayed Patients are prescribed "drug cocktails;" several different HIV drugs taken together When taking any single drug, it's fairly likely some mutant virus in the patient might happen to be resistant, survive the onslaught, & spawn a resistant lineage But the probability the patient hosts a mutant virus that happens to be resistant to several different drugs at the same time is much lower While multiple-drug-resistant HIV strains eventually evolve, drug cocktails delay their evolution If a patient is already infected with a drug-resistant HIV strain, basic evolutionary theory has also pointed out a way to make the drug useful again Studies of the evolution of resistance often show that you don't get something for nothing; specifically, it "costs" a pest or pathogen to be resistant to a pesticide or drug If you place resistant & non-resistant organisms in head-to-head competition in the absence of the pesticide or drug, the non-resistant organisms generally win Consider a patient who takes a particular drug & winds up with viruses resistant to the drug: if the patient stops taking the drug for a while, evolutionary theory predicts her viral load will evolve back towards a non-resistant strain; if she then takes very strong doses of the drug, it may be able to halt the replication of those non-resistant viruses & reduce her viral load to low levels Such therapy has shown early, promising results; it may not eliminate HIV, but it could keep patients' virus loads low for a long time, slowing progression of the disease Understanding the evolutionary history of HIV & its pattern of evolutionary change may help us control the disease

T/F 10 million people worldwide are infected with one or more of the 13 neglected tropical diseases (NTDs)

False... 1.4 BILLION

T/F Malaria deaths are mainly found in Europe and Asia

False... Africa

T/F Schistosomiasis has a very high mortality rate

False... MORBIDITY (having the disease or a symptom)

T/F TB is responsible for a death every 60 seconds

False... every 20 seconds

Most common new health problems reported by post-polio patients

Fatigue, muscle pain, joint pain

Basics of HIV/AIDS*

HIV: Human Immunodeficiency Virus AIDS: Acquired Immunodeficiency Syndrome Transmitted through blood, semen, vaginal secretions, breast milk CD4: white blood cells that fight infection; snapshot of immune functioning; drops with HIV progression

Emerging Viruses (reading notes)

Hemorrhagic fever viruses are among the most dangerous biological agents known; new ones are discovered every year, & artificial/natural changes are favoring their spread In 1993 a young couple in New Mexico died from acute respiratory distress; both had suddenly developed a high fever, muscular cramps, headaches & a violent cough Soon 24 were identified, occurring between December 1992, & June 1993 Tests for all known viruses were conducted, & researchers detected in the serum of several patients antibodies against a class known as hantaviruses Studies showed the patients had been infected with a previously unknown type of hantavirus, now called Sin Nombre New, more effective analytical techniques are identifying a growing # of infective agents Most are viruses that 10 years ago would've probably passed unnoticed or been mistaken for other, known types The Sin Nombre infections weren't a unique occurrence; last year a researcher was infected with Sabià Sabià & Sin Nombre both cause illnesses classified as hemorrhagic fevers Patients initially develop a fever, then a health deterioration during which bleeding often occurs Superficial bleeding reveals itself through skin signs, like petechiae (tiny releases of blood from vessels under the skin surface), bruises or purpura (purplish discolorations) Other cardiovascular, digestive, renal & neurological complications can follow In serious cases, the patient dies of large hemorrhages or multiple organ failure Hemorrhagic fever viruses are divided into several families Flaviviruses have been known for the longest & include the Amaril virus (causes yellow fever; is transmitted by mosquitoes) & other viruses responsible for mosquito- & tick-borne diseases, like dengue Viruses that've come to light more recently belong to 3 other families: arenaviruses, bunyaviruses (includes hantaviruses) & filoviruses Arenaviruses & bunyaviruses causing hemorrhagic fevers circulate naturally in various animal populations; it's uncommon for them to spread directly from person to person Epidemics are linked to the presence of animals that serve as reservoirs for the virus & sometimes as vectors that help to transfer it to people The filoviruses are still a mystery: we don't know how they are transmitted Hemorrhagic fever viruses are among the most threatening examples of what are called emerging pathogens, but they aren't really new Mutations or genetic recombinations between existing viruses can increase virulence, but novel viruses have generally existed for millions of years & merely come to light when enviro conditions change to let the virus to multiply & spread in host organisms The seeming emergence of new viruses is also helped along by rapid advances in the techniques for virological identification The first person diagnosed with Sabià was thought to be suffering from yellow fever; the agent responsible was identified only because a sample was sent to an equipped lab The rapid identification of Sin Nombre was possible only because of several years of work previously accumulated on hantaviruses Hantaviruses typically cause an illness known as hemorrhagic fever with renal syndrome; it was described in a Chinese medical text 1,000 years ago Despite efforts, it wasn't until 1976 the agent was identified in the lungs of its principal reservoir in Korea, a field mouse It took more than 4 years to isolate the virus, adapt it to a cell culture & prepare a reagent that permitted a diagnostic serological test, essential steps in a virus study Outbreaks occur regularly in northwestern Europe; the # of cases seems to be increasing, but this is likely because doctors are using more biological tests than formerly, & the tests have recently become more sensitive We've only had the reagents necessary to identify hantaviruses for about a decade Due to reagents & a research technique that spots antibodies marking recent infections, the CDC was quickly on the track of the disease in 1993, but the presence of specific antibodies isn't always definite proof of an infection by the corresponding pathogen A more recent technology, based on the polymerase chain reaction, lets fragments of genes be amplified (or duplicated) & sequenced; it confirmed patients were infected with hantaviruses, & the identification of Sin Nombre took no more than 8 days The primary cause of most outbreaks of hemorrhagic fever viruses is ecological disruption from human activities The expansion of the world population disturbs ecosystems that were stable a few decades ago & facilitates contacts with animals carrying viruses pathogenic to humans This was true of the arenavirus Guanarito, where the first cases were found in a rural community that started to clear a forested region in the center of the country The animal reservoir is a species of cotton rat; workers stirred up dust that'd been contaminated with dried rat urine/feces, 1 of the most frequent modes of transmission Today mechanization has put the operators of agricultural machinery on the front line: combine harvesters not only suspend clouds of infective dust, they also create an aerosol of infective blood when they accidentally crush the animals The arenavirus Sabià has claimed only 1 life, but other cases have likely occurred in Brazil without being diagnosed There's a real risk of an epidemic if agricultural practices bring the inhabitants of São Paulo into contact with rodent vectors In Europe, the main reservoirs of the hantavirus Puumala (the bank vole & yellow-necked field mouse) are woodland animals; the most frequent route of contamination is inhalation of contaminated dust while handling wood gathered in the forest or while working in sheds and barns Humans aren't always the cause of dangerous enviro changes (i.e. Sin Nombre emerged in the US from heavy rain/snow during 1993 in mountains & deserts) The principal animal host of Sin Nombre is the deer mouse, which lives on pine kernels Some bunyaviruses are carried by mosquitoes rather than by rodents; ecological disruptions like building dams & expanding irrigation can encourage such agents Such factors likely explain 2 epidemics of Rift Valley fever in Africa; the virus was recognized as long ago as 1931 as the cause of several animal epidemics Some breeders in contact with sick or dead animals became infected, but at the time the infection wasn't serious in humans; the situation became more grim in 1970 After the construction of the Aswan Dam, there were major losses of cattle; of the 200,000 people infected, 600 died In 1987 a minor epidemic followed the damming of the Senegal River in Mauritania Rift Valley fever virus is found in mosquito species, notably those of the genus Aedes The females transmit the virus to their eggs; under dry conditions the mosquitoes' #s are limited, but abundant rain or irrigation lets them multiply rapidly; in the course of feeding on blood, they transmit the virus to humans, with cattle acting as incubators Ecological disturbances aren't the only causes of emerging novel viruses; poor medical hygiene can foster epidemics Biological industries also present risks; many vaccines are prepared from animal cells, & if cells are contaminated, there's a danger an unidentified virus may be transmitted to those vaccinated (i.e. filoviruses) In 1976, 2 fever epidemics occurred 2 months apart in Zaire; 318 cases were counted, & 280 died; 85 had received an injection in Yambuku Hospital, & the epidemic led to the identification of a new virus, Ebola The Marburg & Ebola viruses are classified as filoviruses & are exceedingly dangerous In 1995 we isolated a previously unknown type of Ebola from a patient who'd infected herself handling samples from wild chimps being killed by a strange epidemic That the chimpanzees, from Ivory Coast, succumbed is further evidence primates aren't filoviruses' natural reservoir, which hasn't yet been identified Although Marburg has infected few people, Ebola surfaced again to cause a human epidemic in Zaire The extreme variability & speed of evolution found among hemorrhagic fever viruses are rooted in the nature of their genetic material Hemorrhagic fever viruses, like many other types, generally have genes consisting of RNA, rather than the DNA employed by most living things The RNA of these viruses is negative stranded: before it can be used to make viral proteins in an infected cell, it must be converted into a positive strand by an enzyme (RNA polymerase), which causes fairly frequent errors during this process Because the errors aren't corrected, an infected cell gives rise to a heterogeneous population of viruses resulting from the accumulating mutations The existence of such quasispecies explains the rapid adaptation of these viruses to enviro changes; some adapt to invertebrates & others to vertebrates, & they confound the immune systems of their hosts; pathogenic variants can easily arise A characteristic common to arenaviruses/bunyaviruses is they have segmented genomes When a cell's infected by 2 viruses of the same class, they can recombine so segments from 1 become linked to another's, making way to new viral types: reassortants Far beyond the limited means of investigation in local tropical hospitals, many reassortants are so hazardous they can't be handled except in a few very safe labs We know hemorrhagic fever viruses have characteristic effects on the body; they cause a diminution in the # of platelets, the principal cells of the blood-clotting system, but this diminution isn't sufficient to explain the hemorrhagic symptoms Some hemorrhagic fever viruses destroy infected cells directly; others disturb the immune system & affect cells' functioning Among cytolytic viruses, there are the bunyaviruses that cause Crimean-Congo fever & Rift Valley fever; the filoviruses Marburg & Ebola; & the prototype of hemorrhagic fever viruses, the flavivirus Amaril Their period of incubation is generally short, often less than a week Serious cases are the result of an attack on several organs, notably the liver The viruses modify the inner surfaces of blood vessels in such a way that platelets stick to them; this clotting inside vessels consumes additional coagulation factors The cells lining the vessels are forced apart, which can lead to the escape of plasma or to uncontrolled bleeding, causing edema, an accumulation of fluid in the tissue, or severely lowered blood pressure The arena viruses fall into the non cytolytic group; their incubation period is longer, & while they invade most of the tissues in the body, they don't usually cause gross lesions Rather the viruses inhibit the immune system, which delays the production of antibodies until perhaps a month after the first clinical signs of infection Arenaviruses suppress the # of platelets only slightly, but they do inactivate them Hantaviruses are like arenaviruses in that they don't destroy cells directly & also have a long period of incubation, from 12 to 21 days; they target cells lining capillary walls Hantaan & Puumala viruses invade the cells of the capillary walls in the kidney, which causes edema & an inflammatory reaction caused by the organ's failure to work properly; Sin Nombre invades pulmonary capillaries & causes death by leading to acute edema of the lung Several research groups are trying to establish international surveillance networks that will track all emerging infectious agents; WHO has established a network for tracking hemorrhagic fever viruses & other insect-borne viruses that's particularly vigilant Once a virus is detected, technology holds some promise for combating it Despite the existence of yellow fever vaccine, that disease is now raging in Africa, where few are vaccinated Other approaches are constrained because it's difficult or impossible to control animals that are natural reservoirs and vectors for viruses or to predict ecological modifications that favor outbreaks of disease There was an effective campaign against rodent vectors during the Lassa & Machupo arenavirus outbreaks, but it's not usually possible to sustain such programs in rural regions for long periods Precautions can be taken in labs & hospitals, which have ironically served as amplifiers in several epidemics In the lab, viruses responsible for hemorrhagic fevers must be handled in maximum confinement conditions, & it must be kept at lowered pressure, so no potentially infectious particle can escape; the viruses themselves should be confined in sealed systems at still lower pressure In hospitals, the risk of infection from a patient is high for some viruses, so strict safety measures must be followed: personnel must wear masks, gloves & protective clothing; wastes must be decontaminated; a room with lowered pressure is another precaution Since penicillin has been in widespread use, many people had started to believe epidemics were no longer a threat The global pandemic of HIV, which causes AIDS, has shown that view to be complacent Hemorrhagic fever viruses are a cause for worry; there are few avenues to reduce their toll Hemorrhagic fever viruses vary greatly in appearance under the electron microscope Agricultural workers in some parts of the world are at risk of infection by arenaviruses, which are often carried by rodents; machinery stirs up dried rodent urine containing the viruses & can create an aerosol of infective blood if the animals are accidentally crushed Rift valley fever virus, a bunyavirus, is transmitted by mosquitoes from cattle & sheep to humans; dams allow multiplication of the insects by raising the water table & bring people/animals together in new locations, causing epidemics Last spring in Kikwit, Zaire, Ebola proved once again that despite the agonizing & usually fatal illness it provokes, the microbe cannot in its present incarnation spread far, unless humans help it to do so; the virus is too swiftly lethal to spread by itself In early epidemic waves, it kills more than 92% of those it infects, usually within 2 weeks Such rapidity affords the microbe little opportunity to spread unaided, given the severity of the illness it causes In each of the 4 known Ebola epidemics during the past 19 years, people helped launch the virus from its obscure rain forest/savanna host into human populations In 1976 in Yambuku, the virus's appearance was multiplied dozens of times over by nuns at a missionary clinic who repeatedly used unsterilized syringes in 300 patients every day One day someone arrived suffering from the then unknown Ebola fever & was treated with injections for malaria; the syringes efficiently amplified the viral threat In 1976 & 1979, humans helped the virus spread wildly in Sudan; improper hospital hygiene played a key role, & local burial practices, which required manual removal of viscera from cadavers, compounded the disaster Medical & funeral settings were crucial in Kikwit earlier this year; infections spread via bodily fluids among those who tended the dying & washed & dressed the cadavers The major amplification event that seems to have started the epidemic, early in the new year, was an open casket funeral for Gaspard Menga; the virus spread rapidly to 13 Menga family members who cared for the ailing man or touched his body in farewell A second amplification event occurred inside Kikwit General Hospital; overrun by incurable bloody diarrhea, hospital officials thought they were facing a new strain of bacteria, so doctors ordered a technician to draw blood samples from patients When he took ill, hospital staff thought his enormously distended stomach & high fever were the results of typhus infection & performed surgery to stave off damage The first procedure was an appendectomy, but the second was a horror; when nurses & physicians opened the technician's abdomen again for what they expected to be repair work, they were immediately drenched in blood; the contaminated surgical team became the second wave of the epidemic The virus's reliance on unintended help from humans forces attention to the common thread that runs through the known Ebola epidemics: poverty All outbreaks have been associated with abysmal medical facilities in which poorly paid (or unpaid) medical personnel had to make do with a handful of syringes, minimal surgical equipment & intermittent or nonexistent running water/electricity It's possible Ebola (&other hemorrhagic fever viruses) might successfully exploit similar conditions occurring anywhere in the world As air transportation becomes more available & affordable, viruses can more easily move The rapid deterioration in public health & medical facilities should be cause for concern The exact risk nature risk depends on Ebola's biology, which remains mysterious Researchers have combed Kikwit for answers to questions that have puzzled scientists since the first Yambuku epidemic Currently, the virus's reservoir remains unknown, as well as if shared drinking water, food & washing facilities can transmit infection Since all outbreaks have involved transmission by fluids, control has consisted of fairly straightforward, low-cost efforts Patients were isolated, & citizens turned over their unwashed dead to authorities Once residents appreciated the links between tending the sick, washing a cadaver & dying of Ebola, epidemics quickly ground to a halt 1 way Ebola could escape controls would be through a major mutational event that made it more easily transmissible Were Ebola, or any hemorrhagic fever virus, to acquire genetic characteristics suitable for airborne transmission, a disease outbreak would pose a threat to all humanity As far as is known, nobody has ever acquired the microbe from inhaled droplets coughed into the air (although it can be passed in saliva during a kiss) There are usually many genetic differences between fluid-borne microbes and airborne ones, so it seems unlikely that the jump could be made easily, but the question has never been specifically studied in the case of Ebola due to poor funding for research on microbes found primarily in developing countries Portable isolator units equipped with air filters have been maintained by the US Army since 1980 for evacuating personnel carrying suspected dangerous pathogens; the equipment would be used to bring patients needing specialized care to an isolation facility, but has never been called on for this mission

Polio (compared to small pox)*

Hard to diagnose Infectious weeks after symptoms pass Needs multiple vaccinations

Types of schistosomiasis

Hepatic/intestinal and urinary Hepatic/Intestinal: Asia and South America Urinary: Middle East and North Africa Both types: Africa

Portal hypertension

High blood pressure in the liver) With ascites (fluid in abdomen); dyspnea (difficulty breathing) with exertion Found with chronic schistosomiasis

Davey Intro (reading notes)

History of presenting complaint is the most important part of the history & exam; it provides the info necessary to create the differential diagnosis & vital insight into the features of the complaints most important to the patient Remember it's the patient's problems that you're trying to understand & record to establish diagnosis If a clear history can't be obtained from the patient then it should be sought from other witnesses (family/friends) May need to seek confirmation of features of the history, like alcohol consumption or details of a collapse The presenting complaint should be obtained by letting the patient talk without interruption, if possible May enable patients to elaborate on areas of medical interest, without directing the history, by indicating these are areas you're interested in; can do this by repeating the last phrase that a patient has voiced in a questioning way After this, open questions should be addressed to reveal more detail about particular aspects of the history (i.e. "Tell me more about the pain") More direct questions can then be addressed to gain info about the chronology & other details of the complaints (i.e. "When did you first notice the breathlessness?" Sometimes patients find it difficult to accurately remember chronology; establish when the patient was last fully well to indicate how long they've been ill Directed questions can then be addressed to establish diagnostically important features about complaints (i.e. "What was the pain like?") In some settings, very focused/abbreviated questioning may be appropriate (ie drug resuscitation of very ill patient) Premorbid functional status is crucial to ascertain because: usually you aim to restore a patient's health to that immediately prior to an illness; need premorbid state to know what to aim for; gunctional status is a most important predictor for life expectancy You should ask the patient what they think is wrong with them & how the problems have affected them/family You must focus on the main problems & may need to divert Perhaps the most important aspect to establishing the presenting complaint is to summarize your understanding of the history to the patient & ask if you've got it right Let the patient talk -> record, use, & present the patient's actual words -> great detail about each historical aspect -> chronology of complaints -> irrelevant info & history of presenting complaints The past medical history is a vital part of the history; it's important to record in detail all previous medical problems & their treatment in chronological order If major diagnoses have been previously made, always ask for info that confirms this Ask if there were any problems with operations If not already discussed, you may need to inquire about specific aspects of past medical history (ie ask if a patient with severe chest pain has ever had chest pain in the past) Record the occurrence of specific common illnesses & ask about vaccines, medicals, screening tests, pregnancies Drug history includes meds, injections, oral contraception, recreationally drugs, compliance with prescribed meds, supervision, & intolerances Must obtain an accurate and detailed description of allergic responses and allergens; inquire about side effects to medications (intolerances) Ask if the patient has ever smoked, what type, for how long, if any relatives have, etc. Ask if the patient drinks alcohol, how much, any problems, etc. Medical history includes previous illness, operations, anaesthetics, treatments; vaccinations, medicals, screening tests; When? What?; any myocardial infarction, stroke, diabetes, asthma, jaundice, TB, rheumatic fever, epilepsy; alcohol/smoking; what drugs (OTC, illicit, alternative, prescribe) & their dose, frequency, and route, as well as compliance & intolerances (allergies, drugs, food, venom, rash, shock) Establish the diseases that have affected relatives given the strong genetic contribution to many diseases Understand the patient's social history (background and the effect of their illnesses on their life/family); particular jobs are at risk of certain illnesses so a full occupational history is important; ask about jobs, living conditions, hobbies, pets, etc. Ask about travel history Family tree & social history (work, hobbies, mobility, home, family, money, travel) Functional enquiry is designed to address any symptoms that haven't been elicited from the patient in the history of the presenting complaint The most important aspects of functional enquiry are: to establish the exercise capacity of the patient (how far they can walk unaided in one go) & the symptom that stops them; to ascertain whether the patient has a systemic illness, the usual manifestations of which are feeling unwell (malaise), loss of appetite and weight loss You should ask about breathlessness, wheeze, chest pain; if the patient has brought up blood or passed it in their urine/stool; ask about gynaecological history (menstrual) & any other symptoms/concerned not discussed (anything else bothering you?) Functional enquiry: nervous system, cardiovascular, skin, musculoskeletal, genitourinary, gastrointestinal, respiratory, general; your checklist to make sure no important symptoms have been overlooked or forgotten by the patient Principles of exam: explain to the patient what you plan to do & ensure patient's comfort, privacy, confidentiality; presence of chaperone if appropriate; use all your senses Inspect: stand back & look at whole patient, ensuring adequate lighting; look for clues (oxygen mask, walking stick), ensure patient is correctly positioned, look carefully (subtle or obvious abnormalities), look with specific manoeuvres (coughing, breathing, movement) Optimize exam conditions (exposure of relevant area, lighting/sound, positioning); then, inspect -> palpate -> percuss -> auscultate -> re-examine Palpate: seek patient's permission and explain what you're going to do; ask if there's any pain or tenderness; begin the exam lightly & then use firmer pressure; define any abnormalities carefully, perhaps with measurement Percuss (gently tap) comparing sides; listen/feel for any differences while ensuring no discomfort/pain Auscultate (listen): ensure the stethoscope is functioning & take time to listen Record findings accurately, measure any abnormality & consider photographic documentation of, ie, a leg ulcer Functional enquiry checklist: ask for/about general (diabetes, appetite, fevers), cardiovascular (chest pain, blackouts, breathless), respiratory (coughing, breathing), gastrointestinal (swallowing, indigestion, constipation), neurological (weaknesses sensory loss, seizures), musculoskeletal (joint pains, mobility) Doctor takes structured history of symptoms, understands how these symptoms affect your life, forms a differential diagnosis, plans investigations & treatment, & communicates effectively with you Structured history: presenting complaint, drug/allergy history, tobacco/alcohol/drug use, functional enquiry checklist, past medical history, family/social/lifestyle history, travel Technique -> establish rapport by general convo & appropriate physical contact (handshake, hand on shoulder) -> open-ended question: what problems have brought you here? -> specific questions around problem & other aspects of a structured history Establishing rapport can be verbal (allow patient time to explain problems, open-ended questions, summarize your understanding, explain what you think is going on & what you'll do, confirm the patient understands what you said) or non-verbal (confident doctor, eye/physical contact, act if you have all the time in world, prevent distractions) Open-ended questions: duration of symptoms, mode of onset (seconds/hrs), time course, improving or worsening, treatment response, patient's understanding Clinical assessment of the patient: competence in the fundamental clinical skills of history taking & physical examination is key to being a good doctor; developing this competence can only be attained by many hours of deliberate practice, & the experience of presenting your findings and thoughts about diagnosis to other doctors Clinical assessment is the foundation of diagnosis & management Your exam should begin while you're taking the history, & you'll often need to expand the history in the light of the examination findings After history/exam, you need to be clear about: patient's clinical problems of the patient; differential diagnosis of these problems (shortlist of possible diagnoses to account for each clinical problem); as well as the most likely diagnosis (working diagnosis), you must also consider other diagnoses that're most serious if missed & most treatable if found; impact of these problems on the patient as a person (work, family); plan of action (to include investigation, treatment, & what you'll say to the patient about the diagnosis/prognosis) Taking the history: open the interview with an intro & establish rapport Begin with an open-ended question (i.e. Perhaps you'd start by telling me the problems that led to you coming into the hospital?) & listen to the story After a few minutes listening, you'll need to clarify points in the history with the intelligent use of questions Cover all the important areas so you have a full picture (age, sex, race, job, main symptoms, history of symptoms, current/previous meds, allergies, tobacco, alcohol, functional enquiry or systems review, past/family/social/personal history) Having taken the history, you should summarize the major problems identified & form a provisional diagnosis, helping focus your exam and ensuring you don't miss key physical signs; don't perform the physical exam on autopilot but rather adjust it in light of the history and ongoing exam findings Before examining the patient, you must obtain their consent, & ensure privacy/dignity will be maintained For intimate exams (breasts, genitalia), chaperone must be a nurse or doctor, you should have the permission of a doctor with responsibility for the care of the patient to carry out this element of the exam, & the patient should confirm consent Record the name/designation of the chaperone when writing the medical record You must also adapt your exam method to the circumstances (ie in detail, general exam by region) Should metaphorically step back & make a general survey of the patient before touching General appearance, conscious level & mental state, nutritional state; presence or absence of signs such as pallor, cyanosis, jaundice, clubbing, breast lump, lymphadenopathy, thyroid enlargement & nodules, skin or nail abnormalities, metabolic flap of the hands; examination of systems (below) Cardiovascular system: pulse rate/rhythm, blood pressure; ECG recording Respiratory: voice, cough, wheeze, upper tract (nose, tonsils), palpitation, chest Alimentary & genitourinary: lips, tongue, teeth, gums, abdomen, genitalia, Nervous: mental state, speech, skull, spine, motor, sensory Musculoskeletal: limb joints, deformity, bones, tenderness If neurological or musculoskeletal disease isn't suspected, the minimum exam is to: inspect the hands, test the fingers, stroke the skin, outstretch hands & turn palms, pull wrist/elbow/shoulder/hip/knee/ankle joints, check spine movements, check visual acuity & eye moments, inspect feet & heel, observe standing/turning/walking Presenting the case: virtues are brevity, clarity, & enthusiasm Your presentation should last under 5 mins, & the listener will ask for more detail if they want it; include the age & job (not sex or race); begin with a short summary of the patient's problems, then deal with info from the history & findings Diagnosis is the central intellectual activity of medicine & the process we turn patient data into the names of diseases A diagnosis serves as a guide to action & helps us foretell the future (prognosis) Providing patients with a diagnosis helps them make sense of what's happening to their bodies & to feel they aren't alone The data we bring to the diagnostic process are of many types: historical elements, & exam finding, or a test result Diagnosis can be difficult since: most disease manifestations aren't specific to 1 diagnosis ; there are ~5,000 manifestations of disease which can occur alone or in combo; over 10,000 diseases; distinguishing between normal/abnormal may be hard (breathlessness can be due to aging); data are often unreliable or partial; physical signs may be overlooked or misinterpreted; test results may be misleading; patients may have more than 1 disease; may encounter disease you're unaware of; some symptoms are inexplicable; humans make mistakes Examination: end-of-bed assessment (general appearance, mental/nutritional state, rash, temperature) -> hands/wrist (clubbing, splinters, palmar erythema, metabolic flap) -> pulse/blood pressure -> head & neck (jaundice, cyanosis, conjunctival pallor, JVP, arterial pulse) -> anterior chest exam -> posterior chest exam -> abdomen exam (lie patient flat) -> legs -> gait The presenting complaint is often key to diagnosis because the problem that took the patient to the doctor generally reflects an important manifestation of the illness The best place to start the diagnostic process is usually with the presenting complaint, which can be analyzed by body region, system, or organ The road to diagnosis has several stages: review the key findings on history & exam, & put them together in coherent groups; form a differential diagnosis, a short list of possible diseases that could account for these clinical problems As well as the most likely diagnosis (the working diagnosis), your differential diagnoses should also include those other possible diseases that are most serious if missed & most treatable if found Final diagnosis is the one made when all the info is in Reasoning about diagnosis is very similar to detective work Having generated a differential diagnosis, you must work through the diagnoses on the list & ask which has the least loose ends & most explanatory power At the end of your reasoning process, you'll have worked through the differential diagnoses, weeded out the diagnoses which don't pass muster, & ranked the other in order of probability; you'll be clear as to what further info will help in discriminating Sometimes one can make the right diagnosis immediately & confidently, but then tests are required; you must treat what's probable/dangerous while data collection continues Misdiagnosis is common & results from lack of knowledge, inexperience, jumping to conclusion, not reconsidering as more data become available The best way to improve your skill at diagnosis is repeated practice with new patients, attending case presentations, & reading literature One of the most important skills a doctor can gain is the recognition a patient is ill The definition of being ill/sick is different in hospital medicine compared to primary care, or from what patients mean by this phrase; patients mean they feel unwell; in primary care the phrase implies a need for immediate hospital admission; mortality risk exists but is low (2-5%); in hospital the phrase means the patient has a high chance of early death or disability; being ill leads to the activation of many resources including specialist wards/clinicians & often expensive out-of-hours investigations & treatment It's important to diagnose the severity of a patient's illness accurately so they can benefit from resources, avoid the inappropriate use of expensive resources, & prepare Clues from history that a patient is ill: lab clues, observational clues (see abnormalities), & clues from the charts (most important; observe blood pressure, consciousness, respiratory rate, pulse) Once you think a patient is ill, go through the ABC checklist to further assess the patient: A (Airway), B (Breathing), C (Circulation) General findings: the patient's comfort level, color, temperature, pain, movement, etc. Assess if the patient is ill: consciousness (speaking, moving, eyes open/closed; Glasgow Coma Score); Airway patent, Breathing, Circulation; vital observations (temperature, blood pressure, respiratory rate, pulse)

Robert Koch

In 1882, he identified tubercle bacillus Mycobacterium tuberculosis as the cause of the disease TB was the first application of Koch's postulates, which became the standard for all research on the causes of disease

How does trachoma blind?

Infections inflame and thicken the upper eyelid -> scarred eyelids turn inward -> the lashes scratch the cornea, leading to blindness

Plasmodium sporozoites

Injected into the skin by the mosquito Within an hour, more than 50% have left the skin, most entering the bloodstream

HIV is not transmitted by*

Insect bites Toilet seats Kissing Sharing cutlery Touching

Dracunculiasis

Like schistosomiasis, it's a helminth infection There are just a few countries with isolated cases There aren't any drugs to control it yet, only prevention

Q&A: Josef Järhult -- Resistance in the wild

Like all microorganisms, viruses can develop resistance to the drugs meant to treat them, & not only in clinical situations The rise of environmental resistance to antiviral drugs is a potential disaster we can avert, argues Josef Järhult, especially when it comes to influenza A, the virus that can lead to a human flu pandemic How could influenza A develop resistance to antiviral medicines? Influenza A has high genetic variability & mutates rapidly; it needs only 1 point mutation to develop resistance to certain antiviral drugs, & such mutations happen all the time For H1N1, the virus subtype that caused the most recent influenza A pandemic in humans, the point mutation H274Y affected the shape of the pocket where the antiviral drug oseltamivir (Tamiflu) binds to the protein neuraminidase Neuraminidase inhibitors such as oseltamivir stop this protein cutting the virus loose from a cell and so stop the virus spreading to other cells, but the drug can't do that if a mutation stops it binding Such mutations rob us of a cornerstone of our defence against pandemics Where in the environment is it most likely that influenza A will pick up resistance to antiviral drugs? You have to consider where the virus is going to meet the antiviral in the environment; 1 place that happens is in rivers; mallard ducks are natural reservoirs for influenza, & drug residues can enter the rivers in which they live Low levels of the drug in water can lead to oseltamivir-resistant influenza A viruses, which can then be passed on through several generations of mallards, even if the drug is removed from the water Mallards act as reservoirs in which the influenza virus can develop drug resistance For some antivirals, rivers downstream of sewage treatment plants are likely breeding grounds of resistance Humans pass the active ingredient of these drugs out of their bodies in their urine Sewage treatment plants don't have the tech to remove antivirals, or pharmaceuticals in general, so these drugs end up in rivers and other natural waters Are antivirals reaching rivers in sufficient quantities to bring about resistance? The highest recorded levels of oseltamivir in river water, 865 ng l−1, were found in Japan during the 2004-05 influenza season The lowest levels at which viruses developed resistance was 950 ng l−1, which is a little higher than the levels measured in the environment but the same order of magnitude Japan is one of the top consumers of oseltamivir, which is why it has such high levels of the drug in its river water, but several other countries, including the US, have a liberal policy for oseltamivir Have viruses that are resistant to antiviral medicines been found in the wild? There have been a few reports of viruses in wild birds that have an antiviral-resistance mutation; it's uncommon but it's there Whether this is due to drug pressure or just natural variation is hard to say Human examples have demonstrated that oseltamivir-resistant flu virus can outcompete all other flu strains in some circumstances, even in the absence of drug pressure If a resistant virus is circulating in wild birds, there's a risk that it will form the basis of a new pandemic or highly pathogenic flu Are some drugs more likely than others to give rise to resistant viruses? Experiments have shown that zanamivir (Relenza) is less likely than oseltamivir to give rise to genetic resistance in influenza A viruses in wild ducks, but it's still possible For any new class of drugs, such as the polymerase inhibitors recently approved in the US & Japan, we need to study the mechanisms of environmental resistance asap, before they're used at high levels; if they aren;t chemically stable, or don't pass through sewage treatment plants intact, resistance may not be a problem The sooner we know the better, so we have the opportunity to use them prudently or propose sewage treatment techniques to destroy the drugs before they get to the enviro What can we do to prevent antiviral resistance arising? There's no simple solution; good to keep broad mindset & take multidisciplinary approach The network One Health Sweden brings together doctors, virologists, epidemiologists, veterinarians & others; everyone working on some aspect of problems that include humans, animals & the enviro In the same way we think about cutting antibiotics use to reduce antimicrobial resistance, we also need to use antiviral drugs more carefully I.e. we shouldn't use oseltamivir for uncomplicated seasonal influenza in otherwise healthy people; we need effective treatment at sewage treatment plants to reduce the levels of antivirals in rivers Ozonation treatment works but is expensive and has practical problems We need drug manufacturers to not release antivirals/precursors into natural waters Researchers in Germany have found oseltamivir's parent compound in the Rhine, probably from a pharmaceutical manufacturer We also need more monitoring of both the levels of drug residues in the enviro and the flu viruses themselves, particularly in wild ducks It's possible for resistance to develop in the enviro; now it's time to go find it in nature

WHO Overview of Malaria (notes)

Malaria is a life-threatening disease caused by parasites transmitted to people through the bites of infected female Anopheles mosquitoes; it's preventable/curable In 2018, there were an estimated 228 million cases of malaria worldwide & 405,000 malaria deaths Children aged under 5 years are the most vulnerable group affected by malaria; in 2018, they accounted for 67% (272,000) of all malaria deaths worldwide The WHO African Region carries a disproportionately high share of the global malaria burden; in 2018, the region was home to 93% of malaria cases & 94% of malaria deaths Total funding for malaria control & elimination reached $2.7B in 2018; contributions from governments of endemic countries amounted to $900 million, representing 30% of total funding Malaria is caused by Plasmodium parasites, which spread to people through the bites of infected female Anopheles mosquitoes, called "malaria vectors" There are 5 parasite species that cause malaria in humans, and 2 of these species - P. falciparum and P. vivax - pose the greatest threat In 2018, P. falciparum accounted for 99.7% of estimated malaria cases in the WHO African Region, 50% of cases in the WHO South-East Asia Region, 71% of cases in the Eastern Mediterranean, & 65% in the Western Pacific P. vivax is the predominant parasite in the WHO Region of the Americas, representing 75% of malaria cases Malaria is an acute febrile illness; in a non-immune individual, symptoms usually appear 10-15 days after the infective mosquito bite The first symptoms (fever, headache, chills) may be mild & difficult to recognize as malaria; if not treated within 24 hours, P. falciparum malaria can progress to severe illness, often leading to death Children with severe malaria frequently develop 1 or more of the following symptoms: severe anemia, respiratory distress related to metabolic acidosis, or cerebral malaria; multi-organ failure also frequent in adults In malaria endemic areas, people may develop partial immunity, allowing asymptomatic infections to occur In 2018, nearly 1/2 of the world's population was at risk of malaria Most malaria cases/deaths occur in sub-Saharan Africa, but the WHO regions of South-East Asia, Western Pacific, Eastern Mediterranean, & Americas are also at risk Some population groups are at much higher risk of contracting malaria, & developing severe disease, than others including infants, children under 5 years of age, pregnant women & patients with HIV/AIDS, as well as non-immune migrants, mobile populations and travellers National malaria control programs need to take special measures to protect at risk population groups from malaria infection, considering their specific circumstances In 2018, 6 countries accounted for more than ½ of all malaria cases worldwide: Nigeria (25%), Democratic Republic of the Congo (12%), Uganda (5%), and Côte d'Ivoire, Mozambique (5%) & Niger (4% each) In most cases, malaria is transmitted through the bites of female Anopheles mosquitoes There are 400+ different species of Anopheles mosquito; around 30 are malaria vectors of major importance All important vector species bite between dusk & dawn The intensity of transmission depends on factors related to the parasite, the vector, the human host, & the enviro Anopheles mosquitoes lay their eggs in water, which hatch into larvae, eventually emerging as adult mosquitoes The female mosquitoes seek a blood meal to nurture their eggs Each species of Anopheles mosquito has its own preferred aquatic habitat; some prefer small, shallow collections of fresh water, like puddles & hoof prints, which are abundant during the rainy season in tropical countries Transmission is more intense in places where the mosquito lifespan is longer (so the parasite has time to complete its development inside the mosquito) & where it prefers to bite humans rather than other animals The long lifespan & strong human-biting habit of the African vector species is the main reason why 90% of the world's malaria cases are in Africa Transmission also depends on climatic conditions that may affect the # and survival of mosquitoes, such as rainfall patterns, temperature & humidity In many places, transmission is seasonal, with the peak during & just after the rainy season Malaria epidemics can occur when climate & other conditions suddenly favor transmission in areas where people have little or no immunity to malaria; they can also occur when people with low immunity move into areas with intense malaria transmission, ie to find work, or as refugees Human immunity is another important factor, especially among adults in areas of moderate or intense transmission conditions Partial immunity is developed over years of exposure, & while it never provides complete protection, it reduces the risk that malaria infection will cause severe disease Most malaria deaths in Africa occur in young children, whereas in areas with less transmission & low immunity, all age groups are at risk Vector control is the main way to prevent/reduce malaria transmission If coverage of vector control interventions within a specific area is high enough, then a measure of protection will be conferred across the community WHO recommends protection for all people at risk of malaria with effective malaria vector control 2 forms of vector control (insecticide-treated mosquito nets & indoor residual spraying) are effective in a wide range of circumstances Sleeping under an insecticide-treated net (ITN) can reduce contact between mosquitoes & humans by providing both a physical barrier & an insecticidal effect Population-wide protection can result from the killing of mosquitoes on a large scale where there's high access & usage of such nets within a community In 2018, about ½ of all people at risk of malaria in Africa were protected by an ITN, compared to 29% in 2010; but ITN coverage has been at a standstill since 2016 Indoor residual spraying (IRS) with insecticides is another powerful way to rapidly reduce malaria transmission; involves spraying the inside of housing structures with an insecticide, typically 1-2x per year To ensure significant community protection, IRS should be implemented at a high level of coverage Globally, IRS protection declined from a peak of 5% in 2010 to 2% in 2018, with decreases seen across all WHO regions, apart from the WHO Eastern Mediterranean Region The declines in IRS coverage are occurring as countries switch from pyrethroid insecticides to more expensive alternatives to mitigate mosquito resistance to pyrethroids Antimalarial medicines can also be used to prevent malaria For travellers, malaria can be prevented through chemoprophylaxis, which suppresses the blood stage of malaria infections, thereby preventing malaria disease For pregnant women living in moderate-to-high transmission areas, WHO recommends intermittent preventive treatment with sulfadoxine-pyrimethamine, at each scheduled antenatal visit after the first trimester Similarly, for infants living in high-transmission areas of Africa, 3 doses of intermittent preventive treatment with sulfadoxine-pyrimethamine are recommended, delivered alongside routine vaccinations Since 2012, WHO has recommended seasonal malaria chemoprevention as an additional malaria prevention strategy for areas of the Sahel sub-region of Africa; the strategy involves administering monthly courses of amodiaquine plus sulfadoxine-pyrimethamine to all children under 5 years of age during the high transmission season Since 2000, progress in malaria control has resulted primarily from expanded access to vector control interventions, esp in sub-Saharan Africa; however, these gains are threatened by emerging resistance to insecticides among Anopheles mosquitoes According to the latest World malaria report, 73 countries reported mosquito resistance to at least 1 of the 4 commonly-used insecticide classes in the period 2010-2018 In 27 countries, mosquito resistance was reported to all of the main insecticide classes Despite the emergence & spread of mosquito resistance to pyrethroids, ITNs continue to provide a substantial level of protection in most settings WHO continues to highlight the urgent need for new & improved tools in the global response to malaria To prevent an erosion of the impact of core vector control tools, WHO also underscores the critical need for all countries with ongoing malaria transmission to develop & apply effective insecticide resistance management strategies Early diagnosis & treatment of malaria reduces disease, prevents deaths, & contributes to reducing transmission The best available treatment, particularly for P. falciparum malaria, is artemisinin-based combination therapy (ACT) WHO recommends that all cases of suspected malaria be confirmed using parasite-based diagnostic testing (either microscopy or rapid diagnostic test) before treatment; results can be available in 30 minutes or less Treatment solely on the basis of symptoms should only be considered when a parasitological diagnosis isn't possible Resistance to antimalarial medicines is a recurring problem Resistance of P. falciparum malaria parasites to previous generations of medicines, like chloroquine & sulfadoxine-pyrimethamine (SP), became widespread in the 1950s & 1960s, undermining malaria control efforts & reversing gains in child survival Protecting the efficacy of antimalarial medicines is key to malaria control & elimination Need regular monitoring of drug efficacy to inform treatment policies in malaria-endemic countries, & to ensure early detection of, & response to, drug resistance In 2013, WHO launched the Emergency response to artemisinin resistance (ERAR) in the Greater Mekong subregion (GMS), a high-level plan of attack to contain the spread of drug-resistant parasites & to provide life-saving tools for all populations at risk of malaria Even as GMS was under way, additional pockets of resistance emerged independently in new geographic areas of the subregion; in parallel, there were reports of increased resistance to ACT partner drugs in some settings -> needed a new approach At the WH Assembly in May 2015, WHO launched the Strategy for malaria elimination in the Greater Mekong subregion, which was endorsed by all countries in the subregion; urging immediate action, it calls to eliminate all species of human malaria across the region by 2030, with priority action targeted to areas where multidrug resistant malaria has taken root With technical guidance from WHO, all countries in the region have developed national malaria elimination plans With partners, WHO is providing ongoing support for country elimination efforts through the Mekong Malaria Elimination program, an initiative evolved from the ERAR Surveillance entails tracking the disease & programmatic responses, & taking action based on the data received Currently, many countries with a high burden of malaria have weak surveillance systems & aren't in a position to assess disease distribution & trends, making it difficult to optimize responses & respond to outbreaks Effective surveillance is required at all points on the path to malaria elimination Stronger malaria surveillance systems are urgently needed to enable a timely & effective malaria response in endemic regions, to prevent outbreaks & resurgences, to track progress, & to hold governments & the global malaria community accountable In 2018, WHO released a reference manual on malaria surveillance, monitoring & evaluation, which provides info on global surveillance standards & guides countries in their efforts to strengthen surveillance systems Malaria elimination: the interruption of local transmission of a specified malaria parasite species in a defined geographical area as a result of deliberate activities Continued measures are required to prevent re-establishment of transmission Malaria eradication: the permanent reduction to 0 of the worldwide incidence of malaria infection caused by human malaria parasites as a result of deliberate activities Interventions are no longer required once eradication has been achieved Globally, the elimination net is widening, with more countries moving towards the goal of 0 malaria; in 2018, 27 countries reported fewer than 100 indigenous cases of the disease, up from 17 countries in 2010 Countries that have achieved at least 3 consecutive years of 0 indigenous cases of malaria are eligible to apply for the WHO certification of malaria elimination Over the last decade, 10 countries have been certified by WHO as malaria-free The WHO Framework for Malaria Elimination (2017) provides a detailed set of tools & strategies for achieving and maintaining elimination RTS,S/AS01 is the first and, to date, only vaccine to show that it can significantly reduce malaria, & life-threatening severe malaria, in young African children; it acts against P. falciparum, the most deadly malaria parasite globally and the most prevalent in Africa Among children who received 4 doses in large-scale clinical trials, the vaccine prevented approximately 4 in 10 cases of malaria over a 4-year period WHO's top advisory bodies for malaria & immunization have jointly recommended phased introduction of RTS,S in selected areas of sub-Saharan Africa 3 countries (Ghana, Kenya, Malawi) began introducing the vaccine in selected areas of moderate & high malaria transmission in 2019 Vaccinations are being provided through each country's routine immunization program The pilot program will address several outstanding questions related to the public health use of the vaccine & will be critical for understanding how best to deliver the recommended 4 doses of RTS,S; the vaccine's potential role in reducing childhood deaths; & its safety in the context of routine use The WHO-coordinated program is a collaborative effort with Ministries of Health in Ghana, Kenya & Malawi & a range of in-country & international partners, including PATH, a non-profit organization, & GSK, the vaccine developer/manufacturer Financing for the vaccine programme has been mobilized through a collaboration between 3 major global health funding bodies The WHO Global technical strategy for malaria 2016-2030, adopted by the WH Assembly in May 2015, provides a technical framework for all malaria-endemic countries; it's intended to guide and support regional & country programs as they work towards malaria control & elimination The Strategy sets ambitious but achievable global targets, including: reducing malaria case incidence by at least 90% by 2030; reducing malaria mortality rates by at least 90% by 2030; eliminating malaria in at least 35 countries by 2030; preventing a resurgence of malaria in all countries that are malaria-free This Strategy was the result of an extensive consultative process that spanned 2 years & involved the participation of more than 400 technical experts from 70 Member States The WHO Global Malaria Program coordinates WHO's global efforts to control & eliminate malaria by: setting, communicating & promoting the adoption of evidence-based norms, standards, policies, technical strategies, & guidelines; keeping independent score of global progress; developing approaches for capacity building, systems strengthening, & surveillance; & identifying threats to malaria control and elimination as well as new areas for action The Programme is supported by the Malaria Policy Advisory Committee (MPAC), a group of global malaria experts appointed following an open nomination process The mandate of MPAC is to provide strategic advice & technical input, & extends to all aspects of malaria control & elimination, as part of a transparent, responsive & credible policy-setting process At the WH Assembly in May 2018, the WHO Director-General, called for an aggressive new approach to jump-start progress against malaria; a new country-driven response, "High burden to high impact," was launched in Mozambique in November 2018 The approach is currently being driven by the 11 countries that carry a high burden of the disease Key elements of "High burden to high impact" include: political will to reduce the toll of malaria; strategic information to drive impact; better guidance, policies and strategies; and a coordinated national malaria response. Catalysed by WHO and the RBM Partnership to End Malaria, "High burden to high impact" builds on the principle that no one should die from a disease that can be prevented and diagnosed, and that is entirely curable with available treatments

Declining Malaria Transmission and Pregnancy Outcomes in Southern Mozambique (reading notes)

Malaria is declining in many parts of the tropical world due to increased provision of effective control interventions (mainly insecticide-treated bed nets & artemisinin-based combination therapies) The effects on the clinical epidemiology of malaria differ depending on the level of transmission intensity Where the transmission intensity was previously low, mortality & case numbers have declined even more, making elimination of malaria at the local & regional levels increasingly possible Where the transmission intensity was high, the consequences are more complex, reflecting the interplay between malaria transmission & an imperfect acquired immunity There are places in Africa where a person could be infected with malaria parasites up to 3x daily; in these conditions of intense malaria transmission, the rates of disease & death are highest among young children Profound anemia is the main clinical manifestation of severe Plasmodium falciparum infection If children who are infected at a young age survive, then malaria later in childhood or adulthood is largely asymptomatic Lowering transmission intensity reduces childhood mortality but also results in a slower acquisition of immunity, extending the age range for symptomatic malaria Cerebral malaria Y metabolic acidosis become the predominant lethal manifestations of severe P. falciparum malaria As transmission declines further, & the population becomes less immune, older children & adults become susceptible to severe malaria, with acute renal failure as an important cause of death Among pregnant women with severe P. falciparum malaria, mortality approaches 50% The incidence of malaria may become increasingly unstable, with greater fluctuations from year to year & occasional epidemics Malaria is particularly hazardous to the developing fetus In areas where rates of P. falciparum transmission are high, an increased risk of anemia may be the only maternal manifestation of repeated malaria infections during pregnancy, but enormous #s of parasitized erythrocytes are sequestered in the placenta (which at delivery may appear black from the accumulated malaria pigment) This results in structural damage & interference with placental transfer, causing intrauterine growth retardation, particularly in the 1st pregnancy, & a low-birth-weight baby is at increased risk for death in the first few months after delivery Where transmission of malaria is low, malaria is dangerous for both the mother & the fetus, causing abortion, stillbirth, & reduced birth weight Low birth weight from malaria during pregnancy is estimated to result in 100,000 infant deaths each year in Africa Improvements in malaria control in the south of Mozambique, & the consequent declines in malaria transmission & immunity, have reduced the incidence of malaria but have adversely affected the outcome of pregnancy in women who were infected In recent years, the main strategy used to protect women in Africa from the adverse effects of malaria during pregnancy has been to provide insecticide-treated mosquito nets & to give 2 spaced treatment doses of sulfadoxine-pyrimethamine Each dose provides protection from malaria for approximately 4-6 weeks, depending on the prevailing levels of resistance This is called intermittent preventive treatment in pregnancy The overall risk of P. falciparum malaria during pregnancy decreased substantially from the earlier to the later period, but for the offspring of infected women, as compared with the offspring of uninfected women, the reduction in birth weight was greater in 2010-2012 10 years ago, the mean reduction in birth weight associated with maternal malaria infection was 45g, whereas more recently, it was 165g; this change was attributed mainly to loss of protective immunity, worsening the clinical consequences of malaria & extending the adverse effects to the fetuses of multigravid women, as well as to those of primigravid women The prevention of malaria during pregnancy is increasingly compromised by drug resistance In southern Mozambique, resistance to antifolates & sulfonamides resulting from mutations in the genes encoding dihydrofolate reductase (Pfdhfr) & dihydropteroate synthase (Pfdhps), has increased steadily over the past 10 years Parasites with "quintuple" mutations now predominate Studies from areas of higher transmission (where maternal immunity is correspondingly greater) suggest the efficacy of intermittent preventive treatment with sulfadoxine-pyrimethamine during pregnancy starts to decline with Pfdhps 437G (i.e., quintuple mutations), is further reduced with Pfdhps 581G (sextuple mutations), and is presumed to be lost completely with Pfdhfr 164L (mutations that are prevalent in parts of East and Central Africa, South and East Asia, and South America) The recent recommendation to increase the # of preventive doses of sulfadoxine-pyrimethamine to 3 or more in later pregnancy will provide only temporary respite if resistance increases further Although reducing the transmission of malaria is clearly good, the concomitant reduction in immunity to malaria increases the risk of adverse consequences for women who become infected during pregnancy From a public health perspective, there can be no letup in malaria-control activities; otherwise, malaria will return with a vengeance (i.e. from the 1970s to the 1990s, when malaria-control activities declined in the aftermath of the failed global eradication effort and resistance spread to antimalarial agents (chloroquine) and insecticides (DDT)) An increase in resistance to pyrethroid insecticides in Africa & uncontained artemisinin resistance in Asia do not bode well for the future Preventing malaria during pregnancy in areas where drug resistance is increasing & where transmission rates are low and unstable remains a serious challenge

Malaria (reading notes)

Malaria is primarily a disease of the tropics & subtropics, but is also the most common imported infection in the UK It's still estimated to cause over a million deaths per year worldwide, esp in children in sub-Saharan Africa In highly epidemic areas, malaria mainly causes morbidity & mortality in children, but where transmission is less intense it is a disease of both adults & children The severity of clinical illness is highly modified by the degree of immunity of an individual Malaria in an emigrant traveller is far more likely to be life-threatening than in someone who has grown up in an endemic malarial area Malaria is a protozoal infection transmitted by the bite of the mosquito Anopheles app Injected sporozoites initially multiply in the liver & then invade red blood cells Classicially, 4 species of Plasmodium infect humans: P. falciparum, P. vivax, P. ovale, & P. malariae; recently a primate parasite, P. knowlesi, has been shown to cause a significant # of cases in parts of Asia P. ovale & P. vivax have forms that remain dormant in the liver for a # of years (hypnozoites) & cause subsequent relapsing infection P. falciparum is the main cause of severe disease as a result of its ability to infect red blood cells of all ages, & to adhere to vascular endothelium & sequester in vital organs like the brain, liver, kidneys & muscles The incubation period is usually 10-14 days, rarely longer than 6 weeks, but may be several years (unusual in P. falciparum); Prophylaxis may delay onset of symptoms The predominant symptoms are: malaise (uneasiness), headache, fever, rigors; occasionally gastrointestinal or respiratory symptoms dominate, making the clinical diagnosis difficult Irregular fever occurs in the acute stages of malaria; classic periodic fever occurs only if untreated; examination is often unremarkable apart from mild hepatosplenomegaly Malaria doesn't cause rashes; other diagnoses should be considered in this situation (although patients with rashes from other causes, i.e. drugs, may have malaria) Malaria doesn't cause rashes; other diagnoses should be considered in this situation (although patients with rashes from other causes, like drugs, may have malaria) Only P. falciparum causes severe malaria, which is a medical emergency; case fatality rates may be 20% or higher Cerebral malaria: coma, often with seizures; low (<5%) risk of long-term damage in adults, with a greater risk in children (hemiplegia, cortical blindness, mental handicap) Severe anemia: due to haemolysis & a depressed marrow response Respiratory distress: particularly prominent in children, associated with acidosis & sometimes with severe anaemia Hypoglycemia: as a result of increased glucose consumption, impaired gluconeogenesis & quinine-induced hyperinsulinemia Acute renal failure: multifactorial in origin; rare in children; rare in children; rarely blackwater fever occurs; dialysis is needed in 10% of cases of severe malaria Jaundice: caused by haemolysis & hepatic dysfunction, particularly in adults Disseminated intravascular coagulation Non-cardiogenic pulmonary oedema/ARDS Shock may be caused by concomitant bacteria The standard diagnosis is the demonstration of malaria trophozoites on blood film using strains like Giemsa or Field's'; thick blood films are used to screen for the presence of parasites; thin films demonstrate detail of parasites, allowing species determination Patients may have a low parasite burden, esp. if malaria prophylaxis has been used Repeated thick blood films may be needed to make the diagnosis Commercial rapid diagnostic stick tests detect parasite antigens or enzymes & require less expertise, but are less sensitive for detecting some species Differential diagnosis: uncomplicated malaria needs to be distinguished from the long list of tropical & non-tropical diseases that can cause a fever; the differential diagnosis of cerebral malaria includes bacterial, viral & fungal meningitis, arbovirus & other viral causes of encephalitis, & non-infectious causes of coma Treatment of malaria depends on the malaria species; antimalarial drug resistance is a significant problem in the treatment of falciparum malaria, particularly in the Southeast Asia P. ovale, P. vivax, P. malaria, & P. knowlesi: treat with chloroquine on 3 successive days to eliminate red blood cell infection; primaquine is required in P. vivax, P. ovale, & P. knowlesi malaria to eliminate hepatic forms; glucose-6-phosphate dehydrogenase (G6PD) status should be checked to avoid primaquine-induced haemolysis Uncomplicated P. falciparum: chloroquine resistance is present in most areas of the world; first-line treatment should be with artemisinin combination therapy for 3 days or oral quinine & doxycycline for 7 days Severe P. falciparum infection: parental therapy should be given to those with severe malaria or in high-risk subgroups; Parenteral artesunate is now the first-line drug of choice but may be hard to obtain Most patients become afebrile & aparasitameic within 2-3 days There's a significant case fatality rate from severe malaria, esp in non-immune patients Antimalarials must be continued for the full course; if inadequate treatment courses are given, or if parasites are particularly resistant to the drug, then recrudescence of infection can occur Avoid mosquito bites by physical measures (i.e. long-sleeves, nets); choice of a chemoprophylactic regimen depends on local resistance patterns; chloroquine & proguanil are used in limited areas; mefloquine, doxycycline & atovaquone-proguanil can be used for most areas; parts of Southeast Asia has extensive resistance to antimalarial drugs & specialist advice Resistance to malaria: immunity acquired through growing up in malaria endemic areas; blood group Duffy negative lack red blood cell receptor for P. vivax; haemoglobinopathies may protect against severe disease Severe malaria more common in: non-immunes (i.e. travellers & children), pregnant women, splenectomized patients, infections with a high parasite count Symptoms: fever, rigors (shivering then drenching sweats), malaise, headache, anorexia, may have cough and/or mild GI symptoms

What part of the malaria lifecycle causes the peaks of fever?

Merozoites entering the circulation

Medical prophylaxis (reduce risks)

Microbicides: vaginal creams, cheaper to produce than vaccines Post-exposure antiretroviral prophylaxis vertical (mother to fetus) Several vaccines are in development; effective for limited subtypes

The Diabolical Genius Ancient Scourge (reading notes)

More than 1 million men, women & children around the globe die of TB every year, & about a third of the world's population harbors a latent infection Studies suggest TB may be evolving into a new bug that's far more deadly, spreads more quickly & is more likely to become resistant to treatment with antibiotics Designers of new treatments should take findings into account if they don't want to make matters worse Changing the host environment with improved housing may also prove key ... TB seems to be evolving in unexpected ways that outsmart humans Scientists have long assumed TB emerged ~10,000 years ago, when humans began domesticating cattle; but recent genetic analysis suggests the TB germ may predate the first major human migration 60,000-70,000 years ago; as TB-infected people spread across the world, the pathogen eventually evolved into at least 7 families Different families of TB germs spread at different rates, & Africa is the only continent where all the TB lineages that have so far been identified can still be found A particularly dangerous member of the East Asian family of TB germs, known as the Beijing group, is now threatening the globe Today most people in richer parts of the world think of TB, if at all, as a ghost of history Throughout ancient times the tenacious bacterial infection consumed the bodies of untold millions, rich & poor, filling their lungs with bloody sputum As TB spread in the centuries that followed, it continued to attack across economic & class lines, affecting both the famous & the obscure By the early 20th century humanity had begun fighting with public health campaigns, improved living standards, & eventually antibiotics & a modestly effective vaccine In 2011 TB sickened nearly 9 million people, killing 1.4 million of them, mostly in the poorer regions of the globe, but the death rate's fallen by more than ⅓ since 1990 New genetic research suggests the bacterium responsible for TB could be poised to emerge stronger & more deadly than ever before, & not just because some strains have become resistant to treatment with the standard set of antibiotics A group of investigators believes the microbe, Mtb, may have evolved along an unexpected & particularly dangerous path TB can be divided into 7 families of genetically related strains, at least 1 of which is surprisingly virulent, prone to drug resistance & esp well suited to spreading disease in our increasingly interconnected, densely populated world Researchers worry current approaches to treatment & the sole, partially effective vaccine may actually be helping the bacterium to become more intractable Clinicians have long known incomplete treatment can produce antibiotic-resistant TB strains; yet they're now realizing even successful interventions can be problematic if they're better at weeding out the milder, slower-growing groups of TB microbes This divergent effect would allow the more aggressive, faster-spreading bacterial families to establish a stronger foothold Efforts to develop new therapies & diagnostic tests may be doomed to fail if the strains being targeted aren't the ones that are spreading around the planet TB rates could one day begin rising again globally, &the disease could become harder to treat &spread more widely among populations that have so far been relatively free of the scourge Still, there is room for hope; the genetic work provides some insight into how to fight back against the more worrisome groups of TB germs Instead of trying to eliminate all disease-causing TB microbes, some propose the aim should be to favor milder bacteria more likely to stay in a dormant state In 1986, NYC officials were caught off guard by an aggressive outbreak of multidrug resistant TB that took about a decade & hundreds of millions of dollars to bring under control, mostly by rigorously tracking patients with active illness & making sure they finished 6-9 months of treatment with a combo of antibiotics At the time, experts had become so confident in their ability to control TB that most TB programs had shut down & funding for research had slowed to a trickle NIH reduced its spending on TB to a meager $300,000 in 1985, & the academics who studied TB were few In NYC, which for more than a century had been the site of both the illness's worst ravages & the greatest public health strides against TB, only 8 treatment clinics were still open by the late 1980s; within a few years the steady decline in cases stopped, & without apparent warning, the trend line reversed itself Standard anti-TB medicines could no longer predictably tame the infection, even with a diligent patient who stuck to the arduous regimen Many of the new cases occurred in recent immigrants & some HIV patients About ⅓ of the global population harbors a latent TB infection until something (i.e. stress or another illness) reactivates the bugs, leading the bacteria & the body's own immune response to attack lung tissue, setting transmission to other individuals into motion Immigrants were arriving from Southeast Asia, East Asia & Mexico, where TB rates were 10-30x higher than the US The high incidence in HIV patients in the mid-1980s also seemed logical because those individuals often had compromised immune systems, which might allow a latent infection to become active This time around, TB was spreading faster through NYC's vulnerable populations than anyone had seen for at least a couple of generations, & people were dying at a much higher rate than normal Something else had to be driving TB's reemergence, which quickly began claiming lives in Florida, Hawaii, Texas and California as well The answer, at least in part, turned out to be activity by a formerly unrecognized group of TB bacteria that spread more readily & are more deadly than the classic bug, which tends to proliferate slowly & enters a long quiescent phase after the initial infection, including in untreated cases The body, mounting an immune response, walls off the bacteria into a cavity, & the 2 begin an uneasy truce that can last for decades Today researchers call the newly identified collection of TB microbes the Beijing group (because the greatest concentration of cases was later found in the Chinese capital) Eventually they learned that it is a subset of 1/6 large families of TB germs (A seventh family, found so far only in the Horn of Africa, has been reported in the past 6 months) Until the early 1990s, no one realized that Mtb even had multiple families The first clues that TB strains fall into distinct groups came in 1991 in San Fran, during an outbreak in a homeless shelter for people with HIV Peter Small was then a resident at San Fran General Hospital, where he worked with Philip Hopewell, a prominent TB expert Small had just learned how to track the spread of individual TB strains using certain patterns that appeared in their DNA, a powerful new molecular biology technique that was then being developed While public health servants took up the time-honored task of contacting everyone who'd come into contact with an infected person, Small was identifying & tracing the TB germs involved The results were frightening: of the 14 people from the shelter who had fallen ill over four months, Small found 11 shared the same strain of TB, which was identified by its unique DNA fingerprint, a pattern of code letters found only in that strain Having the same strain meant that the illness in those 11 individuals stemmed from recent transmission of the infection, as opposed to reactivation of latent infections (which would have yielded dissimilar genetic profiles) The progression from initial infection to full-blown disease & transmission to another person was lightning-fast Investigators expected to find reactivated disease in individuals with compromised immune systems, not new infections, &they were stunned by how quickly the bacterium spread from one person to the next & by how rapidly the illness progressed HIV and TB seemed to be acting synergistically in their attacks on people's immune systems A germ that raced through its latent stages faster &that was more infectious would be especially tough to bring under control & to keep contained When the team broadened its study to include immigrants, they found exactly the pattern that they had expected, which provided no comfort This time genetic tests showed the illness stemmed mostly from latent infections that had been reactivated Not all the TB strains found spread at the same rate, which was odd because they believed at the time that all strains behaved more or less alike Small would find the TB fingerprint of 1 patient all over the city, while that of another, very similar patient would not show up in anyone else Their findings had important implications for public health; clinicians needed to step up their efforts to reduce transmission & ensure patients completed their treatments They also challenged researchers to rethink their understanding of the organism itself, including when TB might've first affected humans If all TB strains belonged to one big family that caused illness in the same manner, chances were that Mtb had originated fairly recently, perhaps 10,000 years ago If separate families of TB microbes had evolved & were spreading at different rates, then the organism had probably been around much longer than anyone had suspected, giving it plenty of time to diversify Indeed, in 2005 researchers performed a genetic analysis that suggested Mtb could have evolved from an ancestor species as early as 3 million years ago The San Francisco Bay Area turned out to be an ideal location to test the hypothesis that Mtb could be divided into distinct families of microbes associated with specific geographical regions With immigrants from Africa, Latin America, Eastern Europe & Asian regions, it's a microcosm of the world In the early 2000s investigators began studying samples from various TB patients & comparing the molecular markers in their bacterial genomes Using 875 strains collected between 1991 & 2001 from individuals representing 80 countries, the group identified fragments of DNA present in some strains but not in others Based on these differences, they found that the strains sorted into 6 main families that apparently originated in different regions of the world &, it seemed, were still infecting people who had recently lived in those places There were 3 ancient ones, including 2 found only in West Africa & another that arose in Africa, then migrated with humans along the Indian Ocean more than 60,000 years ago 3 more modern lineages developed in western Europe (traveling to the Americas at the end of the 19th century), northern India & East Asia (the Beijing group turned out to be a prominent member of this family) Africa was the only location that seemed to play host to all 6 lineages, but the Euro-American family was widespread, & the Beijing strains were rapidly gaining a foothold around the globe Gagneux traced each lineage's ancestral life story By comparing the DNA sequences of 89 critical genes (most of which were vital to the bacterium's continued survival), he could estimate different lineages' ages and geographical movements So-called housekeeping genes are under tremendous evolutionary pressure to stay the same; any changes are more likely to harm rather than help the bug So the more closely matched the strains, the more closely related they would be, & the most genetically diverse groups would belong to the oldest families The oldest TB lineages from Africa, the researchers theorized, may have taken root in small, scattered hunter-gatherer groups. At that time, limited opportunities for transmission may have produced TB's characteristic latency. It could, for instance, infect a child, wait a generation and reactivate in time to infect new family members. As ancient humans began to migrate over land, the group proposed, the organism tagged along, and the Indo-Oceanic lineage developed, taking advantage of an increasing population. Later migrations and population expansions provided fertile ground for the three more modern lineages to emerge and adapt to their hosts. As humans traveled, traded, crammed into crowded cities, went to war, and died, tuberculosis went along for the ride, causing increasingly frequent and more severe illness. The genetic clustering among the lineages provided the evidence that the mycobacterium had evolved along with its hosts. Gagneux, emphasizing that it was all a careful guess, proposed an Out of and Back to Africa hypothesis. Modern lineages had emerged along early human migration routes out of Africa, he suggested, then had more recently gone back to the continent and out again. The Euro-American family of strains, for instance, followed colonization to Africa, Asia and the Middle East. The East Asian lineage moved to South Africa via Southeast Asian slaves in the 17th and 18th centuries, with another wave following via Chinese gold miners. The diversification of the bacterial families & their dissemination around the globe pointed to a complex coevolution between host & pathogen that's probably still under way Whenever people jammed into overcrowded living spaces, the more aggressive TB strains with shorter latency periods spread rapidly Meanwhile the older, West African & Indo-Oceanic lineages, which tended to thrive in less populated areas, caused an illness that progressed more slowly If there are very few hosts, it doesn't pay to be very virulent, because you kill all your hosts, then you die out together with all your hosts One 2 year study in the Gambia seems to support this idea: patients exposed to modern TB strains were nearly 3x as likely to progress to active disease In fact, the more aggressive strains of TB have begun overtaking the oldest pair of lineages even in Africa All the data generated since the 1990s have consistently marked the Beijing group of strains as particularly worrisome It seems to spread more easily & to cause more severe disease, & it may even be adept at becoming resistant to antibiotic drugs In 1998 investigators determined the aggressive strains that had spurred the outbreaks in NYC in the 1980s & 1990s fell within this group as well Just as important in fueling TB's continuing ravages around the globe are the enviro conditions under which people live. TB germs don't spread in a vacuum People with tuberculosis might also be malnourished or alcoholic or might avoid taking medication Not just HIV but also diabetes seems to interact synergistically with the organism to manipulate the immune response in ways that facilitate transmission & activation Social conditions such as crowded housing, poor air quality, hunger & stigma tend to make matters worse The interplay of bacteria & human enviros is worth noting Investigators suspect some strains of TB tend to provoke a brisk immune response, leading to the quick development of cavities in the lung & rapid progression from latency to illness Other strains tend to suppress the immune system, making their home in different organ In the complex dialogue between host & pathogen, some of these strains seem to be really good at dialing down the immune system and others at dialing it up The bug didn't follow the evolutionary pathway of most human pathogens; instead of changing over time, the DNA that gave rise to the germ's outer proteins (the part that's recognized & targeted by the body's immune system) stayed the same More typically, disease-causing bacteria are forced to change their protein coverings or risk being eliminated from the human population within a few generations This bizarre finding has serious implications for some of the new vaccines now being developed against TB Vaccines are designed to boost the body's immune response to quash an infection Yet for TB, this enhancement could perversely enhance transmission A family of bacteria that's evolved to boost the immune response might be helped, not hurt, by a vaccine that has further activated the immune system of people who were inoculated Once inside the body, the TB germ actually doesn't do very much It is the body's own attempts to rid itself of the infection that causes the most damage I.e. the white blood cells of the immune system create the cavities in the lungs where TB gets walled off Augmenting the host response could be helping the bug, not the host," he says The vaccine in use today, which primarily protects children in high-risk areas from developing such severe complications as TB meningitis, is about 90 years old & has been given to about one billion people The inoculation, based on a weakened strain of a closely related bacterium that infects cattle, may have inadvertently encouraged more deadly strains of Mtb to flourish It's dawning on people that this is a sophisticated organism that's evolving with humans Learning how to direct evolution of TB through the use of standard public health measures & more sophisticated therapies might help defeat it Better housing that decreases crowding & enhances air ventilation might favor less powerful strains of TB Improving living conditions for the 1 billion people who live in the world's slums is a lot harder than handing out pills On the other hand, the passage and enforcement of a law in 1901 that mandated greater access to air and light in tenement buildings helped to decrease TB infection rates in New York City in the years before antibiotics. Gagneux foresees the need to bring together immunologists, ecologists, evolutionary biologists, population geneticists & social scientists to tackle all aspects of TB's ability to transmit itself, cause disease & adapt to different environments Cross-disciplinary partnerships often sound better on paper than they work in practice, but could help Gagneux would like researchers who are developing new diagnostic tools, treatments and vaccines to at least consider testing them against various strains from different parts of the world Right now most are checked solely against strains that were first grown in laboratories more than 60 years ago and may no longer be relevant With some lineages potentially being naturally resistant to new drugs or predisposed to evade diagnostic tests, ignoring TB's family tree could prove to be a death sentence for millions more people around the world Scientists have long assumed that TB emerged around 10,000 years ago, when humans began domesticating cattle, but recent genetic analysis suggests the TB germ may in fact predate the first major human migration 60,000 to 70,000 years ago As TB-infected people spread across the world, the pathogen eventually evolved into at least 7 families, or lineages The 2 oldest families of TB germs began in West Africa, where they're still found 4 more lineages took hold around the Indian Ocean & in India, East Asia & Europe Further migration & colonization led to a greater spread Still unclear: why the slave trade did't establish the West African lineages in the Americas Different families of TB germs spread at different rates Africa is the only continent where all the TB lineages that have so far been identified can still be found A particularly dangerous member of the East Asian family of TB germs, known as the Beijing group, is now threatening the globe An outbreak in NYC, from 1986 until well into the 1990s, was eventually traced to the Beijing group of TB germs A seventh lineage, limited to the Horn of Africa, has recently been identified

Malaria life cycle

Mosquito bites human, injecting saliva that contains Plasmodium sporozoites Sporozoites infect liver cells Infected liver cells burst, releasing Plasmodium cells that infect red blood cells Infected red blood cells burst, releasing Plasmodium cells; some can infect other red blood cells, and others can infect mosquitoes Anopheles mosquito bites infected human and picks up Plasmodium cells Plasmodium undergoes several stages of development in mosquito's body

Buzz Kill (reading notes)

Mosquitoes are responsible for over 725,000 deaths annually, making them the deadliest creatures on the planet Climate change & globalization are exacerbating the threat the insects pose, & mosquitoes are developing resistance to common insecticides Vector-control experts are fighting back with new tools ranging from low-tech traps to genetic-modification schemes ... As mosquito-borne diseases spread, scientists are fighting back with new poisons, traps & genetic engineering techniques Humans have been locked in a struggle with disease-carrying mosquitoes for most of recorded history With just 2 bites, one to pick up a pathogen & another to transmit it, the bugs have fueled countless outbreak Malaria exploded across Africa as humans first gathered for agricultural development; Yellow fever nearly wiped out Memphis in the 1870s as urbanization & river transport brought infected people & mosquitoes together In parts of the world where people are exposed to the bugs during much of the year, including sub-Saharan Africa & swathes of South America & Asia, mosquitoes cripple economic growth The bugs are responsible for killing more people than all the wars in history combined It once seemed like we would defeat mosquitoes through DDT, but the insecticide came with unknown consequences for human health & a steep enviro cost The chemical accumulated in fish, plants & the fatty tissue of mammals, wreaking havoc throughout the food chain By the early 1970s DDT use was severely restricted, & mosquitoes & malaria soon flourished once again In recent decades climate change & globalization have combined to exacerbate the mosquito threat, making mosquito-borne disease an increasingly common problem in myriad settings, including the US Last year about 2,000 people contracted West Nile virus in the U.S.; in the past 5 years chikungunya virus, including multiple large outbreaks in the U.S. territories; & Zika virus is still a problem in many parts of the world 47,000+ cases of human illness caused by mosquito bites were reported throughout the US and its territories in 2016; a decade earlier there were less than 7,000 The best mosquito-control strategies home in on specific mosquito species that carry diseases & kill enough of them to disrupt transmission Yet increasingly it's become clear our existing weapons are failing: mosquitoes have developed resistance to many of the insecticides that we place on bed nets to ward off malaria, & it's incredibly difficult to effectively kill off certain species of mosquitoes that live in our homes & can breed in tiny pools of stagnant water Scientists have been working to develop new tools for mosquito control: improved insecticides, better traps, & even schemes to use radiation or gene manipulation to render mosquitoes sterile Of the diseases spread by mosquitoes, malaria has proved particularly deadly Malaria's wide reach & alarming death toll have netted it the biggest & best-funded mosquito-control efforts In 2016, $2.7B was spent on malaria research/elimination Yet the greatest obstacle is often pinning down where the control should be applied—finding ways to wipe out the bugs in their enviro while minimizing harm to nearby humans and wildlife Enter eave tubes: the small gap between the roof & the top of the exterior wall in most tropical houses is an eave Mosquitoes find human prey in many ways, like following a person's carbon dioxide output through the eaves in their house In the past few years researchers have started to roll out eave tubes that simultaneously close off those openings & help to reduce malarial transmission An eave tube is a simple, safe device consisting of a plastic tube & an electrostatic screen dusted with insecticide powder; the tubes transform entire homes into mosquito traps with humans as the bait; when mosquitoes try to enter the home through the tube, they land on the insecticide-coated screen & die Researchers have been testing eave tubes in the field for close to a decade The hope is eave tubes will eventually replace indoor residual spraying, a technique that works well but is more difficult to apply & requires more insecticide Eave tubes are also safer for kids; the poison is located too high up for them to reach; the approach can also help minimize the growth of insecticide resistance As the bugs try to wriggle through these small openings, the powder coats the whole body with a much larger dose than when the bugs briefly land on a surface treated with insecticides, making it more likely the tubes will kill their target Not all mosquitoes feed indoors & not every house is suitable for eave tubes To fight those bugs, scientists have been developing insecticide-laced sugar baits that attract male/female mosquitoes; the baits deliver massive doses of poison compared with other traps designed to kill adult mosquitoes because they think the poison is sugar they need to survive; a mosquito will imbibe about 20% of its body weight in the sweet bait; the bugs consistently fly up to the trial product and bite through a sheath that contains small chambers of poison-laden bait Field experiments in Mali have shown that the sheath membrane's tiny openings allow mosquitoes & other insects adapted for blood feeding to access the poison while keeping it out of reach for pollinators like bees Researchers reported at a recent tropical medicine conference that when they hung two traps on the outside of each home in a Malian village, almost half of the malaria-carrying mosquitoes in that immediate area consumed the poison Rather than killing mosquitoes, what if we could prevent them from ever being born? One plan, spearheaded by the UN's International Atomic Energy Agency, is to release male mosquitoes sterilized by exposure to ionizing radiation, which harms cellular growth & development in the testes The idea is that lab-grown sterile insects will mate with wild females, producing eggs that'll never hatch; since most females mate only once in their life, this method could substantially decrease mosquito populations Sterilization offers the possibility of a nearly permanent area-wide solution to the mosquito problem with minimal ongoing maintenance work; yet it requires a lot of organization & infrastructure without much possibility of financial profit, so it's mostly been explored by governments rather than by private enterprise Private companies, energized by new interest in mosquito control following the Zika crisis, are hoping a different type of sterilization effort will prove to be a faster, easier, more thorough way to take out mosquitoes In these schemes, scientists manipulate the genetics of the bugs themselves I.e. to help Brazil get rid of the mosquitoes that transmit dengue & Zika, private company Oxitec has been releasing genetically engineered mosquitoes into the wild, mosquitoes that have been bred in the lab to pass on a gene that kills female offspring The genetically altered mosquitoes go on to mate with wild mosquitoes, rapidly spreading the trait in a population; but this work remains controversial, & critics say there are lingering questions about unintended enviro consequences Genetically driven sterilization efforts could take years to work on any significant scale, but there's another option Some researchers contend we should employ "gene drive" tools to quickly push specific genetic changes through the mosquito population The best way to control malaria is to use gene-editing tools like CRISPR to introduce a specific gene into individual bugs & then "drive" that change throughout an entire population The CRISPR-editing system is encoded into an embryonic insect's DNA, ensuring the trait is preferentially passed on to its offspring Theoretically, after many generations, the entire population will have that gene, overriding the natural rules of inheritance in which sexually producing organisms have a 50-50 chance of inheriting a gene from each of their parents because scientists make the desired change on both chromosomes For malaria control, that altered genetic information could either change the mosquitoes so they couldn't transmit malaria, disrupt the sex ratio in the next generation or simply kill the next generation of bugs There are clear similarities to the radiation- & gene-based sterile insect techniques, but gene drive would potentially work with far fewer mosquito releases because the modified genes would spread throughout the population within several generations of its introduction Gene drive is also controversial because of concerns about unforeseen consequences -> no trials yet & some say wild mosquito populations will develop resistance to gene drives over time Such resistance could arise in several ways In one, natural genetic variation could alter the short genetic sequences that gene-drive systems would otherwise target; alternatively, cellular repair processes may alter target DNA sequences so that a gene-drive system can no longer recognize them Eliminating all mosquitoes is a fantasy In the US, the most effective abatement districts spend from about $1-10 per person per year to spray insecticides, remove standing water & clear mosquito-friendly vegetation, yet even that doesn't completely get rid of them Killing all mosquitoes could also disrupt food chains & plant pollination in ways we don't even suspect Besides, only a couple of hundred of the 3,500 mosquito species scientists have identified bite humans and carry diseases, so it'd also be overzealous to obliterate them all The best we could hope for, & probably the only option that would be environmentally safe, would be to eliminate some of the key species from specific areas In Haiti perhaps we could kill off the main malaria-transmitting species with the sterile male technique while protecting people against other disease-carrying mosquito species with effective eave tubes & sugar-bait traps We'd also need to preemptively monitor human patients and the local mosquito population for signs of emerging threats and tamp down any small outbreaks that may arise With such comprehensive strategies, it's not unimaginable that within 5 years the parasites that cause malaria would be gone from the entire island Even then, however, there would still be a danger of reintroduction History demonstrates that if a ship of infected people arrives in a previously disease-free area (or worse, a mosquito species capable of carrying the disease from Africa or Southeast Asia) maladies like malaria can resurface While the worldwide trend has been to free countries from malaria, there are at least 68 documented examples of resurgence of the disease in communities following a reduction in mosquito control Ie the A. aegypti mosquito made a comeback in Brazil in the 1980s after DDT spraying ceased there As a result, dengue and yellow fever reappeared in the nation, & chikungunya and Zika viruses cropped up, too When DDT spraying stopped in India, because of shortages of the chemical & other factors, malaria returned there as well We've never had so much innovation or funding in the area of mosquito control Private foundations such as ours, government agencies & the WHO are collectively spending about $570 million annually on dedicated malaria research, whereas in 2002 the annual spending levels were closer to $100 million But even with the aid of new tools, mosquito control requires constant vigilance Mosquito problems are seldom solved permanently and must be attended to constantly, just like any other public health hazard Malaria symptoms: fever, chills, sweats, headaches, nausea, vomiting Malaria deaths reached 445,000 in 2016, with most cases & deaths occurring in Africa; that year 91 countries reported a total of 216 million cases Certain species of mosquito are capable of carrying a raft of diseases at the same time I.e. the Aedes aegypti mosquito lives in the same areas as half the world's population, & it can transmit Zika, dengue, chikungunya & yellow fever

Modes of HIV transmission

Needle stick, sharing needles, motherhood (breastfeeding, delivery to child), sex, blood transfusion

T/F While we can't cure post-polio, we can make better use of the neurons remaining

True (remodeling)

Polio lifecycle (video)

Poliovirus usually enters through the mouth Once inside the body, poliovirus reaches the intestine If the virus finds a cell with the correct receptor, infection begins The poliovirus genome (RNA) enters the cell The viral RNA takes over the cell The RNA makes many copies of itself New RNA + new capsids (shells) = new poliovirus Thousands of new polioviruses burst out of the cell and into the bloodstream

Evolution and the Origin of Disease (reading notes)

Principles of evolution by natural selection are finally beginning to inform medicine Thoughtful contemplation of the human body elicits awe & perplexity For each exquisite heart valve, we have a wisdom tooth Seeming incongruities make sense but only when we investigate the origins of the body's vulnerabilities while keeping in mind that "Nothing in biology makes sense except in the light of evolution" Evolutionary biology is the scientific foundation for all biology, & biology is the foundation for all medicine Much suffering is unnecessary but inevitable because of the smoke-detector nature of our defenses The cost of a false alarm (a strong reaction like vomiting in the absence of a true threat to life) is temporary unpleasantness; the cost of no alarm in the presence of a true threat, like a food toxin, could mean death A lack of defensive response during pregnancy, for example, could kill the fetus To a surprising degree,, evolutionary biology is just now being recognized as a basic medical science The enterprise of studying medical problems in an evolutionary context has been termed Darwinian medicine Most medical research tries to explain the causes of an individual's disease & seeks therapies to cure or relieve deleterious conditions; these efforts are traditionally based on consideration of proximate issues, the straightforward study of the body's anatomic & physiological mechanisms as they currently exist In contrast, Darwinian medicine asks why the body is designed in a way that makes us all vulnerable to problems like cancer, depression & choking, offering a broader context in which to conduct research The evolutionary explanations for the body's flaws fall into few categories First, some discomforting conditions (pain, fever, cough, vomiting, anxiety) are neither diseases nor design defects but rather are evolved defenses Example of a defense: symptoms like cough or fever aren't defects but are the body's defenses in action Second, conflicts with other organisms (i.e. E. coli) are a fact of life Example of a conflict: human beings battle with other organisms that've been fine-tuned by evolution Third, some circumstances, like the ready availability of dietary fats, are so recent that natural selection hasn't yet had a chance to deal with them Example of a novel environment: the human body has only recently adopted its current enviro, filled with former rarities like high-fat foods Fourth, the body may fall victim to trade-offs between a trait's benefits & its costs; an example is the sickle cell gene, which also protects against malaria Example of a trade-off: overdesign of any one system, like a pair of unbreakable arms, would upset the entire organism's functioning Finally, the process of natural selection is constrained in ways that leave us with suboptimal design features, as in the case of the mammalian eye Example of a constraint: design of the human eye leads to a blind spot & permits detached retinas, but a squid eye is free of such problems Useful defense mechanism is coughing; people who can't clear foreign matter from their lungs are likely to die from pneumonia The capacity for pain is certainly beneficial; the rare individuals who can't feel pain fail to even experience discomfort from staying in the same position for long periods; unnatural stillness impairs their joints' blood supply, which then deteriorate Pain-free people usually die by early adulthood from tissue damage & infections Cough or pain is usually interpreted as disease or trauma but is actually part of the solution rather than the problem; these defensive capabilities, shaped by natural selection, are kept in reserve until needed Less widely recognized as defenses are fever, nausea, vomiting, diarrhea, anxiety, fatigue, sneezing & inflammation Fever: higher body temperature facilitates destruction of pathogens People suffering from chronic infection often have decreased levels of blood iron Although low iron is sometimes blamed for the illness, it's really a protective response: during infection, iron is sequestered in the liver, which prevents invading bacteria from getting adequate supplies of this vital element Morning sickness has long been considered an unfortunate side effect of pregnancy, but the nausea coincides with the period of rapid tissue differentiation of the fetus, when development is most vulnerable to interference by toxins Nauseated women tend to restrict their intake of strong-tasting, potentially harmful substances. Hypothesis that nausea of pregnancy is an adaptation where the mother protects the fetus from exposure to toxins: women with more nausea less likely to suffer miscarriages; increase in birth defects among offspring of women who have little/no morning sickness & thus eat a wider food variety when pregnant Anxiety, originated as a defense in dangerous situations by promoting escape & avoidance Fear in guppies in the presence of small-mouth bass; timid hid and many survived compared to bold who aided bass genes not own Selection for genes promoting anxious behaviors implies there should be people who experience too much anxiety, & indeed there are There should also be hypophobic individuals who have insufficient anxiety, either because of genetic tendencies or anti-anxiety drugs If natural selection shapes the mechanisms that regulate defensive responses, how can people get away with using drugs to block these defenses without doing their bodies obvious harm? Part of the answer is that we sometimes do ourselves a disservice by disrupting defenses I.e. an anti nausea drug was recently blamed for birth defects Another obstacle to perceiving the benefits of defenses arises from the observation that many individuals regularly experience seemingly worthless reactions of anxiety, pain, fever, diarrhea or nausea The explanation requires an analysis of the regulation of defensive responses in terms of signal-detection theory A circulating toxin may come from something in the stomach; an organism can expel it by vomiting, but only at a price The cost of a false alarm (vomiting when no toxin is truly present) is only a few calories, but the penalty for a single missed authentic alarm (failure to vomit when confronted with a toxin) may be death Natural selection tends to shape regulation mechanisms with hair triggers, following the smoke-detector principle The price of the human body's numerous "smoke alarms" is much suffering that is completely normal but in most instances unnecessary This principle also explains why blocking defenses is so often free of tragic consequences Natural selection is unable to provide us with perfect protection against all pathogens, since they tend to evolve much faster than humans do Our defenses, whether natural or artificial, make for potent selection forces Pathogens either quickly evolve a counter-defense or become extinct Proposal: classifying phenomena associated with infection according to whether they benefit the host, the pathogen, both or neither Humanity won huge battles in the war against pathogens with the development of antibiotics & vaccines; our victories were so rapid & seemingly complete, but the enemy, & the power of natural selection, had been underestimated Pathogens apparently can adapt to every chemical researchers develop Antibiotic resistance is a classic demonstration of natural selection Bacteria that have genes that let them prosper despite the presence of an antibiotic reproduce faster than others, so genes that confer resistance spread quickly Many people, including some physicians and scientists, still believe the outdated theory that pathogens become benign after long association with hosts; an organism that kills rapidly may never get to a new host, so natural selection would seem to favor lower virulence The virulence of a pathogen is, however, a life history trait that can increase as well as decrease, depending on which option is more advantageous to its genes For agents of disease spread directly from person to person, low virulence tends to be beneficial, as it allows the host to remain active & in contact with other potential hosts Some diseases, like malaria, are transmitted just as well, or better, by the incapacitated; for such pathogens, which usually rely on intermediate vectors like mosquitoes, high virulence can give a selective advantage A less ill & more mobile host, able to infect many others over a much longer time, is an effective vehicle for a pathogen of lower virulence Evolutionary theory predicts that clean needles & the encouragement of safe sex will do more than save numerous individuals from HIV infection If humanity's behavior itself slows HIV transmission rates, strains that don't soon kill their hosts have the long-term survival advantage over the more virulent viruses that then die with their hosts, denied the opportunity to spread Conflicts with other organisms aren't limited to pathogens In times past, humans were at great risk from predators looking for a meal; except in a few places, large carnivores now pose no threat to humans People are in more danger today from smaller organisms' defenses, like the venoms of spiders & snakes Ironically, our fears of small creatures, in the form of phobias, probably cause more harm than any interactions with those organisms do Far more dangerous than predators or poisoners are other members of our own species We attack each other not to get meat but to get mates, territory & other resources Violent conflicts between individuals are overwhelmingly between young men in competition & give rise to organizations to advance these aims Armies, again usually composed of young men, serve similar objectives, at huge cost Even the most intimate human relationships give rise to conflicts & medical implications The reproductive interests of a mother & her infant may seem congruent at first but soon diverge; when her child is a few years old, the mother's genetic interests may be best served by becoming pregnant again, whereas her offspring benefits from continuing to nurse (even in the womb there is contention) From the mother's vantage point, the optimal size of a fetus is a bit smaller than that which would best serve the fetus & the father This discord gives rise to an arms race between fetus & mother over her levels of blood pressure/sugar, sometimes resulting in hypertension & diabetes during pregnancy Making rounds in any modern hospital provides sad testimony to the prevalence of diseases humanity has brought on itself Heart attacks result mainly from atherosclerosis, a problem that became widespread only in this century and that remains rare among hunter-gatherers Info should help us prevent heart attacks (limit fat intake, eat lots of vegetables, and exercise hard each day), but hamburger chains proliferate, diet foods languish on the shelves, and exercise machines serve as expensive clothing hangers throughout the land Our poor decisions about diet and exercise are made by brains shaped to cope with an environment substantially different from the one our species now inhabits On the African savanna, where the modern human design was fine-tuned, fat, salt & sugar were scarce & precious Individuals who had a tendency to consume large amounts of fat when given the rare opportunity had a selective advantage; they were more likely to survive famines that killed their thinner companions, and we, their descendants, still carry those urges for foodstuffs that today are anything but scarce Such evolved desires, inflamed by ads from competing food corps that themselves survive by selling us more of what we want to buy, easily defeat our intellect/willpower Increasingly, people also have easy access to many kinds of drugs, esp. alcohol/tobacco, that're responsible for a huge proportion of disease, health care costs & premature death While individuals have always used psychoactive substances, widespread problems materialized only following another enviro novelty: the ready availability of concentrated drugs & new, direct routes of administration, especially injection Most of these substances (nicotine, cocaine & opium) are products of natural selection that evolved to protect plants from insects; since humans share a common evolutionary heritage with insects, many of these substances also affect our nervous system It's not just defective individuals or disordered societies that are vulnerable to the dangers of psychoactive drugs; all of us are susceptible because drugs and our biochemistry have a long history of interaction The relatively recent & rapid increase in breast cancer must be the result in large part of changing enviros & ways of life, with only a few cases resulting solely from genetic abnormalities Boyd Eaton and his colleagues at Emory reported that the rate of breast cancer in today's "non-modern" societies is only a tiny fraction of that in the US They hypothesize that the amount of time between menarche and first pregnancy is a crucial risk factor, as is the related issue of total lifetime # of menstrual cycles In hunter-gatherers, menarche occurs at about age 15 or later, followed within a few years by pregnancy and 2-3 years of nursing, then by another pregnancy soon after Only between the end of nursing & the next pregnancy will the woman menstruate & thus experience the high levels of hormones that may adversely affect breast cells In modern societies, in contrast, menarche occurs at age 12 or 13—probably at least in part because of a fat intake sufficient to allow an extremely young woman to nourish a fetus—& the first pregnancy may be decades later or never A female hunter-gatherer may have a total of 150 menstrual cycles, whereas the average woman in modern societies has 400 or more Although few would suggest women should become pregnant in their teens to prevent breast cancer later, early administration of a burst of hormones to simulate pregnancy may reduce the risk Compromise is inherent in every adaptation, & trade-offs exist at the genetic level Arm bones 3x their current thickness would almost never break, but Homo sapiens would be lumbering creatures on a never-ending quest for calcium More sensitive ears might sometimes be useful, but we'd be distracted by the noise of air molecules banging into our eardrums If a mutation offers a net reproductive advantage, it'll tend to increase in frequency in a population even if it causes vulnerability to disease I.e. people with 2 copies of the sickle cell gene suffer terrible pain & die young; people with two copies of the "normal" gene are at high risk of death from malaria; individuals with 1 of each are protected from both malaria & sickle cell disease Where malaria is prevalent, such people are fitter, in the Darwinian sense, than members of either other group Even though the sickle cell gene causes disease, it's selected for where malaria persists Many other genes that cause disease must also have offered benefits, at least in some enviros, or they wouldn't be so common Because cystic fibrosis (CF) kills 1/2,500 Caucasians, the responsible genes would appear to be at great risk of being eliminated from the gene pool; & yet they endure For years, researchers mused the CF gene, like the sickle cell gene, probably conferred some advantage Having 1 copy of the CF gene appears to decrease the chances of the bearer acquiring a typhoid fever infection, which once had a 15% mortality Aging may be the ultimate example of a genetic trade-off The influence of pleiotropic genes (having multiple effects) has been seen in fruit flies and flour beetles, but no specific example has yet been found in humans Antioxidants have anti-aging effects, & plasma levels of uric acid in different species of primates are closely correlated with average adult life span Perhaps high levels of uric acid benefit most humans by slowing tissue aging, while a few pay the price with gout Strong immune defenses protect us from infection but also inflict continuous, low-level tissue damage It's possible that genes that cause aging have no benefit at any age, they simply never decreased reproductive fitness enough in the natural environment to be selected against; before we tinker we should determine whether these actions have benefits early in life The human eye's flaw results from simple bad luck; millions of years ago, the layer of cells that happened to become sensitive to light in our ancestors was positioned differently from the corresponding layer in ancestors of squids The two designs evolved along separate tracks, & there's no going back Path dependence also explains why the simple act of swallowing can be life-threatening Our respiratory & food passages intersect because in an early lungfish ancestor the air opening for breathing at the surface was understandably located at the top of the snout & led into a common space shared by the food passageway Since natural selection can't start from scratch, humans are stuck with the possibility that food will clog the opening to our lungs The path of natural selection can even lead to a potentially fatal cul-de-sac, as in the case of the appendix, that vestige of a cavity our ancestors employed in digestion Since it no longer performs that function, & as it can kill when infected, the expectation might be that natural selection would've eliminated it; the reality is more complex Appendicitis results when inflammation causes swelling, which compresses the artery supplying blood to the appendix; if the blood supply is cut off completely, bacteria have free rein until the appendix bursts A slender appendix is esp susceptible to this chain of events, so appendicitis may, paradoxically, apply the selective pressure that maintains a large appendix An evolutionary analysis reveals we live with some very unfortunate legacies & some vulnerabilities may even be actively maintained by the force of natural selection Despite the power of the Darwinian paradigm, evolutionary biology is just now being recognized as a basic science essential for medicine Most diseases decrease fitness, so it'd seem that natural selection could explain only health, not disease A Darwinian approach makes sense only when the object of explanation is changed from diseases to the traits that make us vulnerable to diseases The assumption natural selection maximizes health is INCORRECT, selection maximizes the reproductive success of genes Those genes that make bodies having superior reproductive success will become more common, even if they compromise the individual's health in the end Finally, history & misunderstanding have presented obstacles to the acceptance of Darwinian medicine An evolutionary approach to functional analysis can appear akin to naive teleology or vitalism, errors banished only recently, & with great effort, from medical thinking Whenever evolution/medicine are mentioned together, the specter of eugenics arises Discoveries made through a Darwinian view of how all human bodies are alike in their vulnerability to disease will offer great benefits for individuals, but such insights don't imply that we can or should make any attempt to improve the species If anything, this approach cautions that apparent genetic defects may have unrecognized adaptive significance, that a single "normal" genome is nonexistent & that notions of "normality" tend to be simplistic The systematic application of evolutionary biology to medicine is a new enterprise Darwinian medicine very likely will need to develop before it can prove its power & utility If it must progress only from the work of scholars without funding to gather data to test their ideas, it'll take decades for the field to mature Departments of evolutionary biology in medical schools would accelerate the process, but for the most part they don't yet exist If funding agencies had review panels with evolutionary expertise, research would develop faster, but such panels remain to be created The evolutionary viewpoint provides a deep connection between the states of disease & normal functioning & can integrate disparate avenues of medical research as well as suggest fresh and important areas of inquiry Its utility & power will ultimately lead to recognition of evolutionary biology as a basic medical science Changes in virulence relate to the life history of the infectious agent & its mode of transmission Infection requiring direct contact will ordinarily drive a pathogen toward a state of lowered virulence, because the host must remain mobile enough to interact with others; but intermediaries that spread disease-causing agents, even from totally incapacitated hosts, can cause a change toward more virulence Behavioral choices, such as safer sex, can also alter the makeup of the pathogen Selection factors favoring higher virulence: intermediary disease vectors (mosquitoes, health care workers' hands, unsanitary water supplies); unprotected and/or promiscuous sex Selection factors favoring lower viruelnce: casual human-to-human transmission (sneezing, coughing, touch; protected and/or monogamous sex) New enviros bring new health threats The appendix is most likely here to stay; evolutionary pressure selects against the smaller appendix, because inflammation & swelling can cut off its cleansing blood supply, making infections more life-threatening; larger appendices are thus actually selected for A Darwinian approach to medical practice leads to a shift in perspective; the following principles provide a foundation for considering health/disease in an evolutionary context: Defenses & defects are 2 fundamentally different manifestations of disease Blocking defenses has costs as well as benefits Because natural selection shapes defense regulation according to the smoke-detector principle, much defensive expression & associated suffering are unnecessary in the individual instance Modern epidemics are most likely to arise from the mismatch between physiological design of our bodies and novel aspects of our environment Our desires, shaped in the ancestral enviro to lead us to actions that tended to max. reproductive success, now often lead us to disease & early death The body is a bundle of compromises There's no such thing as "the normal body" or "the normal human genome" Some genes that cause disease may also have benefits, & others are quirks that cause disease only when they interact with novel environmental factors Genetic self-interest will drive an individual's actions, even at the expense of the health and longevity of the individual created by those genes Virulence is a trait of the pathogen that can increase as well as decrease Symptoms of infection can benefit the pathogen, the host, both or neither Disease is inevitable because of the way that organisms are shaped by evolution Each disease needs a proximate explanation of why some people get it and others don't, as well as an evolutionary explanation of why members of the species are vulnerable to it Diseases aren't products of natural selection, but most of the vulnerabilities that lead to disease are shaped by the process of natural selection Aging is better viewed as a trade-off than a disease Specific clinical recommendations must be based on clinical studies; clinical interventions based only on theory aren't scientifically grounded & may harm

Tackling Malaria (reading notes)

Researchers are working to create vaccines that would prevent malaria or lessen its severity, but existing interventions (insecticide-treated bed nets, indoor spraying, & new combination drugs based on an ancient Chinese herb) could fight the disease now The question comes down to one of will & resources: In view of all the competing scourges (particularly HIV/AIDS), is the world ready to take on malaria in its principal remaining stronghold, sub-Saharan Africa? ... Interventions available today could lead to decisive gains in prevention and treatment, if only the world would apply them Dr. Ebrahim Samba survived malaria and eventually became one of the most well-known leaders in Africa: Regional Director of the WHO After centuries of fighting malaria (& conquering it in much of the world) it's amazing what we still don't know about the ancient scourge, including what determines life & death in severely ill children in its clutches Despite lingering questions, today we stand on the threshold of hope Investigators are studying malaria survivors & tracking other leads to develop vaccines Most important, proven weapons (insecticide-treated bed nets, other antimosquito strategies, & new combination drugs) are moving to the front lines In the coming years the world will need all the malaria weapons it can muster; after all, malaria not only kills, it holds back human & economic development 4 principal species of the genus Plasmodium, the parasite that causes malaria, can infect humans, & at least 1 still plagues every continent save Antarctica to a degree Today sub-Saharan Africa isn't only the largest remaining sanctuary of P. falciparum (the most lethal species infecting humans) but the home of Anopheles gambiae, the most aggressive of the more than 60 mosquito species that transmit malaria to people Every year 500 million falciparum infections befall Africans, leaving 1-2 million dead, mainly children Within heavily hit areas, malaria & its complications may account for 30-50% of inpatient admissions & up to 50% of outpatient visits The clinical picture of falciparum malaria, whether in children or adults, isn't pretty In the worst-case scenario, the disease's trademark fever & chills are followed by dizzying anemia, seizures & coma, heart & lung failure, & death Those who survive can suffer mental or physical handicaps or chronic debilitation, or no residual effects at all (like Ebrahim Samba) We've learned things regarding inborn & acquired defenses against malaria We now know inherited hemoglobin disorders like sickle cell anemia can limit bloodstream infection; & antibodies & immune cells that build up over time eventually protect many Africans from malaria's overt wrath Ebrahim Samba is a real-life example of a transformed state following repeated infection; after his early brush with death, he had no further malaria crises & to this day uses no preventive measures to stave off new attacks Samba's story also affirms the hope certain vaccines might one day mimic the protection that arises naturally in people like him, thereby lessening malaria-related deaths & complications in endemic regions A different malaria vaccine might work by blocking infection altogether (for a short time, at least) in visitors like travelers, aid workers or military peacekeepers, whose need for protection is less prolonged The promise of vaccines shouldn't be overstated Since malaria parasites are far more complex than disease-causing viruses & bacteria for which vaccines now exist, malaria vaccines may never carry the same clout as measles or polio shots, which protect over 90% of recipients who complete all recommended doses In the absence of a vaccine, Africa's malaria woes could continue to grow Leading the list of current problems are drug-resistant strains of P. falciparum (which first developed in South America & Asia, then spread to Africa), followed by insecticide resistance among mosquitoes, crumbling public health infrastructures, & profound poverty that hobbles efforts to prevent infections in the first place Finally, the exploding HIV/AIDS pandemic in Africa competes for precious health dollars & discourages the use of blood transfusions for severe malarial anemia There are challenges, but they shouldn't lead to despair that Africa will always be shackled to malaria; economic history teaches us it simply isn't so Malaria wasn't always confined to the tropics; until the 20th century, it also plagued unlikely locales like Scandinavia & the American Midwest The events surrounding malaria's exit from temperate zones &, more recently, from large swaths of Asia & South America reveal as much about its perennial ties to poverty as about its biology Malaria's flight from its last US stronghold: the poor, rural South): The showdown began in the wake of the Great Depression when people started draining & oiling thousands of mosquito breeding sites & distributing quinine (a plant-based antimalarial first discovered in South America) to purge humans of parasites that might otherwise sustain transmission TVA also regulated dam fl-w to maroon mosquito larvae & installed acres of screen in windows & doors As malaria receded, local economies grew After military forces used DDT to aerially bomb mosquitoes in the malaria-ridden Pacific theater during WWII, public health authorities took the lead Selective spraying within houses later became the centerpiece of global malaria eradication By 1970 DDT spraying, elimination of mosquito breeding sites & the expanded use of antimalarial drugs freed more than 500 million people, or roughly ⅓ of those previously living under malaria's cloud Sub-Saharan Africa was always a special case: with the exception of some pilot programs, no sustained eradication efforts were ever mounted there; instead the availability of chloroquine (a cheap, man-made relative of quinine) let countries with scant resources replace large, technical spraying operations with solitary health workers Dispensing tablets to almost anyone with a fever, village foot soldiers saved millions of lives in the 60s/70s; then chloroquine slowly began to fail against falciparum malaria With little remaining infrastructure & expertise to counter Africa's daunting mosquito vectors, a rebound in deaths was ordained Today in many African households, malaria not only limits income & robs funds for basic necessities like food &youngsters' school fees, it fuels fertility because victims' families assume they'll always lose children to the disease On the regional level, it bleeds countries of foreign investment, tourism & trade Continentwide, it costs up to $12 billion a year, 4% of Africa's GDP In many places malaria remains entrenched because of poverty &, at the same time, creates & perpetuates poverty Nighttime bites of parasite-laden Anopheles mosquitoes infect humans with malaria Some residents of malaria-plagued communities still believe an evil spirit or certain foods cause malaria, a fact underscoring a pressing need: better malaria education Long before we learned in the late 19th century that mosquitoes transmit malaria, savvy humans were devising ways to elude mosquito bites Writing almost 5 centuries before the common era, Herodotus described how Egyptians living in marshy lowlands protected themselves with fishing nets Some view nets steeped in fish oil as the world's earliest repellent-impregnated cloth It wasn't until WWII, when American forces in the South Pacific dipped nets & hammocks in 5% DDT, that insecticides & textiles were formally partnered After public opinion swung against DDT, treating bed nets with a biodegradable class of insecticides (pyrethroids) was the logical next step; it proved a breakthrough The first major use of pyrethroid-treated nets paired with antimalarial drugs, in 1991, halved mortality in children younger than 5 in the Gambia, & later trials, without the drugs, in Ghana, Kenya and Burkina Faso confirmed a similar lifesaving trend, plus substantial health gains in pregnant women With wide enough use, whole families & communities benefited from the nets; even people who didn't sleep under them Insecticide-treated bed nets also have drawbacks: they only work if malaria mosquitoes bite indoors during sleeping hours, which isn't a universal behavior; nets make sleepers hot, discouraging use; until recently, nets had to be redipped every 6-12 months to stay effective; at $2-6 each, nets with/without insecticide are unaffordable for many people A recent study in Kenya found only 21% of households had even 1 bed net, of which 6% were insecticide-treated A summary of surveys concluded only 3% of African youngsters were protected by insecticidal nets, but reports on the ground now suggest use is quickly rising Insecticide resistance could also undermine nets as a long-term solution: mosquitoes genetically capable of inactivating pyrethroids have now surfaced in several locales, including Kenya & southern Africa, & some anophelines are taking longer to succumb to pyrethroids, a worrisome adaptive behavior known as knockdown resistance Because precious few new insecticides intended for public health use are in sight (largely because of paltry economic incentives to develop them), 1 solution is rotating other agricultural insecticides on nets Decoding olfactory clues that attract mosquitoes to humans in the first place is another avenue of research that could yield dividends in new repellents How about harnessing the winged creatures themselves to kill malaria parasites? In theory, genetic engineering could quell parasite multiplication before the protozoa ever left the insects' salivary glands If such insects succeeded in displacing their natural kin in the wild, they could halt the spread of malaria parasites to people Recently native genes hindering malaria multiplication within Anopheles mosquitoes have been identified, & genetically reengineered strains of several important species are now on the drawing board Once reared in the lab, releasing these Trojan insects into the real world poses a whole new set of challenges, including ethical ones Bottom line: for the time being, old-fashioned, indoor residual spraying with DDT remains a valuable public health tool in many settings in Africa & elsewhere Applied to surfaces, DDT is retained for 6 months or more & reduces human-mosquito contact by 2 key mechanisms: repelling some mosquitoes before they ever enter a dwelling & killing others that perch on treated walls after feeding A stunning example of its effectiveness surfaced in KwaZulu-Natal in 1999 & 2000; reintroduction of residual spraying of DDT along with new, effective drugs yielded a 91% drop in cases within 2 years Antimosquito measures alone can't win the war against malaria; better drugs & health services are also needed for the millions of youngsters and adults who, every year, still walk the malaria tightrope far from medical care In Africa, 70% of antimalarials come from the informal private sector (small, roadside vendors as opposed to licensed clinics or pharmacies) Despite plummeting efficacy, chloroquine, at pennies per course, remains the top-selling antimalarial pharmaceutical downed by Africans The next most affordable drug in Africa is sulfadoxine-pyrimethamine, an antibiotic that interferes with folic acid synthesis by the parasite Unfortunately, P. falciparum strains in Africa & elsewhere are sidestepping this compound as they acquire sequential mutations that'll ultimately render the drug useless Now most experts believe multidrug treatments can also combat drug resistance in falciparum malaria, especially if they include a form of Artemisia annua, a medicinal herb once used as a generic fever remedy in ancient China Artemisia-derived drugs (artemisinins) beat back malaria parasites more quickly than any other treatment does & block transmission from humans to mosquitoes Because of these unequaled advantages, combining them with other effective antimalarial drugs in an effort to prevent or delay artemisinin resistance makes sense, not just for Africa's but for the entire world's sake After all, there's no guarantee malaria will not return someday to its former haunts; we know it can victimize global travelers Infected mosquitoes have even stowed away on international flights, infecting innocent bystanders within a few miles of airports, far from malaria's natural milieu Yet there's a hitch to the new combination remedies: their costs, currently 10-20x higher than Africa's more familiar but increasingly impotent malaria drugs, are daunting to most malaria victims & heavily affected countries Even if they were more modest in price, the global supply of artemisinins is well below needed levels & requires donor $ to jumpstart the 18-month production cycle to grow, harvest & process the plants Novartis, the 1st producer sanctioned by the WHO to manufacture a co-formulated artemisinin combination treatment, may not have enough funding & raw material to ship even a portion of the 120 million treatments it once hoped to deliver in 2006 Cheaper, synthetic drugs that retain the distinctive chemistry of plant-based artemisinins are on the horizon, possibly within 5-10 years Another promising tactic that could bypass botanical extraction or chemical synthesis altogether is splicing A. annua's genes & yeast genes into E. coli, then coaxing pharmaceuticals out of the bacterial brew Preventing, as opposed to treating, malaria in highly vulnerable hosts (primarily African children and pregnant women) is also gaining adherents In an ideal world, prevention equals vaccine No doubt that creating malaria vaccines that deliver long-lasting protection has proved more difficult than scientists first imagined, but progress has occurred At the root of the dilemma is malaria's intricate life cycle, which encompasses several stages in mosquitoes & humans; a vaccine effective in killing one stage may not inhibit the growth of another A second challenge is malaria's complex genetic makeup: of the 5,300 proteins encoded by P. falciparum's genome, fewer than 10% trigger protective responses in naturally exposed individuals; the question is, Which ones? Several arms of the human immune system (i.e. antibodies, lymphocytes, spleen) must work together to achieve an ideal response to malaria vaccination Even in healthy people, such responses don't always develop So far most experimental P. falciparum vaccines have targeted only 1 of malaria's three biological stages (sporozoite, merozoite or gametocyte), but multistage vaccines, which could well prove more effective in the end, are also planned Some of the earliest insights on attacking sporozoites (the parasite stage usually vaccinated into humans through the mosquito's proboscis) came in the 1970s, when investigators found x-ray-weakened falciparum sporozoites protected human volunteers, albeit only briefly The demonstration that antibodies artificially elicited against sporozoites could help fend off malaria prompted further work 3 decades later (2004) efforts bore fruit when a sporozoite vaccine more than halved serious episodes of malaria in 2,000 rural Mozambican children when African children are most susceptible to dying from the disease Realistically, the earliest that an improved version of the vaccine known as RTS,S (or any of its 3 dozen vaccine brethren currently in clinical development) might come to market is in 10 years, at a big final price tag Because of anticipated costs, public-private partnerships are now helping fund ongoing trials Even when malaria vaccines become available, effective treatments & anti-mosquito strategies will still be needed because: rates of protection will never reach 100% in those who actually receive the vaccines; other malaria-prone individuals (esp the rural African poor) may not have access to the shots at all Once again the world is coming to terms with the truth about malaria: the ancient enemy still claims at least 1 million lives every year while, at the same time, imposing tremendous physical, mental & economic hardships Given our current tools & promising weapons on the horizon, it's time to fight back The past decade has already witnessed significant milestones In 1998 the WHO and World Bank established the Roll Back Malaria partnership In 2000 the G8 named malaria as ⅓ of pandemics they hope to curb/vanquish The UN created the Global Fund to Fight AIDS, TB & Malaria and pledged to halt & reverse the rising tide of malaria within 15 years In 2005 the World Bank declared a renewed assault on malaria, & George W. Bush announced a $1.2-billion package to fight malaria in Africa over 5 years, using insecticide-treated nets, indoor spraying of insecticides &combination drug treatments More recently, the World Bank's begun looking for ways to subsidize artemisinin combination treatments The Gates Foundation announced 3 grants totaling $258.3 million to support advanced development of a malaria vaccine, new drugs & improved mosquito-control methods Despite positive steps, the $ at hand are not equal to the task Simultaneously with the announcement from the Gates Foundation, a major new analysis of global malaria r R&D funding noted only $323 million was spent in 2004, falling short of the projected $3.2 billion a year needed to cut malaria deaths in half by 2010 Perhaps it's time to mobilize not only experts and field-workers but ordinary folk A bite from an infected mosquito begins the deadly cycle of malaria: a disease that kills 1-2 million people annually, mainly young children in sub-Saharan Africa How malaria spreads: While feeding, an infected female Anopheles mosquito passes sporozoites of the malaria parasite Plasmodium into the victim's bloodstream Within 30-60 minutes, the sporozoites enter the victim's liver cells, where they reproduce asexually, forming thousands of merozoites, most of which are later released into the bloodstream The merozoites invade red blood cells and multiply, causing the cells to rupture, releasing yet more merozoites; the cycle repeats Eventually some of the merozoites develop into male & female gametocytes, which can be ingested by a previously uninfected mosquito taking a blood meal In the mosquito's gut, the gametocytes develop into gametes & fuse to eventually produce an oocyst that releases sporozoites; these travel to the mosquito's salivary glands, ready to be transferred into another victim The rupture of infected blood cells causes malaria's fever, chills & progressive anemia Death may occur from severe anemia, clogging of blood vessels in the brain, lungs & other organs by parasitized red blood cells In pregnancy, malaria-laden placentas rob babies of growth before they are even born Vaccine targets: Sporozoite: the goal of sporozoite vaccines is to block parasites from entering/growing within human liver cells Merozoite: Vaccines based on merozoite antigens lessen malaria's severity by hobbling the invasion of new generations of red blood cells or by reducing complications Gametocyte: So-called altruistic gametocyte-based vaccines don't affect human disease but are designed to evoke human antibodies that derail parasite development within the mosquito Malaria & poverty cover common ground: costs levied by the disease go beyond expenditures on prevention & treatment to include lost income, investment & tourism revenue; annual economic growth in countries with endemic malaria averaged 0.4% of per capita GDP between 1965 and 1990, compared with 2.3% in the rest of the world In the 1950s a worldwide campaign to eradicate malaria had as its centerpiece the spraying of houses with DDT In less than 2 decades, the pesticide enabled many countries to control the disease (in India, malaria deaths plummeted from 800,000 annually to almost 0 for a time) Then, in 1972, the US govt banned DDT for spraying crops; although public health & a few other minor uses were excepted The book Silent Spring is often said to have sparked the ban since it meticulously charted the way DDT travels up the food chain in increasing concentrations, killing insects & some animals & causing genetic damage in others DDT became a symbol of the dangers of playing God with nature, & the developed countries, having got rid of malaria within their borders, abandoned the chemical Most of Europe followed the US in banning the pesticide for agricultural applications in the 1970s; for sub-Saharan Africa, where malaria still rages, these decisions have meant the loss of a valuable weapon Most African countries go without DDT not because they've banned it themselves (in fact, it's allowed for public health uses in most areas of the world where malaria is endemic) but because wealthy donor nations & organizations are resistant to funding projects that would spray DDT even in responsible ways Many malaria researchers think DDT should be given another look In addition to being toxic to mosquitoes, DDT drives the insects off sprayed walls &out of doors before they bite, &it deters their entry in the first place It's a toxin, irritant & repellent all rolled into one that lasts 2x as long as alternatives & costs a quarter as much as the next cheapest insecticide DDT's deadly trajectory through the food chain had its roots in massive agricultural spraying (mainly of cotton fields); not in its much more moderate use inside dwellings to repel mosquitoes Dusting a 100-hectare cotton field required some 1,100 kilograms of DDT over 4 weeks, but spraying the interior surfaces of a house would require roughly ½ a kilogram, applied once or twice a year DDT alone will not save the world from malaria; for instance, spraying houses works only against mosquitoes that bite indoors Effective drugs for patients already infected are essential, as are other measures to control mosquitoes But most malaria health professionals support the targeted use of DDT as an important part of the tool kit Malaria cases declined dramatically in KwaZulu-Natal when the South African government sprayed dwellings with DDT and later also treated patients with an artemisinin-based combination treatment One of the few African countries wealthy enough to fund its own program, it didn't have to rely on aid from donors reluctant to use the chemical Ebrahim Samba, who recently retired as the WHO's Regional Director for Africa, still bears delicate hatch marks incised on his cheeks at the age of 2, when he was close to death from severe malaria

Toward the Elimination of Schistosomiasis (reading notes)

Schistosomiasis remains one of the world's most prevalent diseases Despite more than a century of control efforts & the introduction of highly effective anti-schistosomal drug therapy in the 1980s, the disease won't go away More than 207 million of the world's poorest people are currently infected with schistosomiasis, which is often a decades-long, chronic inflammatory disorder that's associated with disabling anemia, under-nutrition, & poor school/work performance Schistosomiasis (aka bilharziasis) results from long lived infection by multicellular intravascular parasites of ⅕ trematode species — S. japonicum, S. mansoni, S. haematobium, S. intercalatum, or S. mekongi Parasite transmission & the consequent risk of human infection are strongly linked to specific geographic locations, because the parasite goes through several developmental stages that must occur in fresh water, including a period of growth within particular species of intermediate host snails Even after infection ends, disease persists In some patients, esp those with intestinal schistosomiasis, the late fibrotic complications of schistosomiasis-associated inflammation lead to portal hypertension, which conveys a substantial risk of death due to variceal gastrointestinal bleeding In patients with urinary schistosomiasis, late complications include irreversible urinary tract obstruction with an associated risk of renal failure & inflammation-induced bladder cancer Arguably, the Asian form of intestinal schistosomiasis caused by the species S. japonicum carries the highest risks of infection-related inflammation & other complications In the 1980s, after the introduction of the highly effective antischistosomal drug praziquantel, it was believed that large-scale drug delivery through school-based or community-based programs could solve the problem of schistosomiasis transmission & eliminate the risk of parasite-associated disease Although mass-treatment campaigns reduced the infectious burden & the parasite-associated morbidity, they often failed to curb parasite transmission in high-risk communities Since these efforts failed to prevent immediate reinfection itself, they also didn't do a very good job of reducing the substantial rates of illness associated with reinfection Why didn't mass treatment stop transmission? As it turns out, the very complexity of the parasite's life cycle helps ensure its transmission continues within local ecosystems Whereas public health planners assumed a treatment-related reduction in the excretion of parasite eggs by humans would stem the transmission of the parasite, the process of infection is, in fact, more complicated, being assisted by "super-spreaders" (esp untreated children who don't attend school) & by social & hydrologic linkages among focal "hot spots" of transmission where the requisite human-snail interactions are most likely to occur The problem of persistent transmission is compounded in the case of S. japonicum, because domesticated & wild animals can also be infected by this species, providing a persistent zoonotic reservoir that perpetuates local parasite transmission In implementing any new schistosomiasis-control campaign, the first priority will always be to reduce the burden of illness & prevent deaths, & these objectives are usually achieved through the currently accepted mass-treatment strategies However, the next, more comprehensive & effective phase of disease control, the elimination of reinfection, will require efforts substantially more intensive & expensive The incremental expense of these additional control efforts would ultimately be offset by the greater health benefits achieved with complete elimination of parasite transmission In high-risk ecologic settings, drug treatment alone may suppress transmission only partially In such enviros, any program based solely on drug delivery will need to be continued for decades (or perhaps indefinitely) to prevent a reemergence of infection & disease It's only through the incorporation of additional strategies for interruption of parasite transmission that all forms of schistosomiasis-associated disease can be prevented Because much schistosomiasis-associated illness remains subclinical in resource-poor settings, it's effectively gone unmeasured & has often been overlooked in assessments of global burdens of disease The burden of illness due to schistosomiasis is quite substantial, whether measured in terms of quality adjusted life-years or recalibrated disability-adjusted life-years or simply assessed through careful consideration of the process of schistosome infection & its known complications Schistosomiasis is a disease of chronic inflammation that substantially affects the daily performance of the millions of people who are or have been infected In particular, S. japonicum has important effects on nutritional status, anemia, growth, development, & pregnancy outcomes The problem is due not only to fibrotic damage to specific organs but also to the constant process of granulomatous inflammation caused by the deposition of parasite eggs in host tissues Chronically elevated levels of interleukin-6 & tumor-necrosis factor cytokines lead to the chronic elevation of acute-phase reactants, such as hepcidin, that impair iron uptake and mobilization, resulting in anemia of chronic inflammation Even with low-intensity infection or reinfection, the process of new inflammation (manifesting as hepatosplenomegaly & anemia) in response to schistosomiasis can be substantial Lapses in parasite-control efforts can result in a worsening of immunopathologic features when reinfection occurs It is becoming clear that the interruption of schistosome transmission in high-risk areas will require more complicated, integrated control strategies; a combo of drug treatment, water management, snail control (through habitat modification, irrigation changes, and the use of molluscicidal sprays), & the control or treatment of sewage In the case of S. japonicum, it'll also require a reduction in the size of animal reservoirs Such a combination strategy can work to significantly reduce or eliminate schistosome transmission in rural China Moreover, their strategy has external environmental benefits, biofuel generation & improved water sanitation, that are likely to yield additional gains for the targeted community A good analogy for integrated vector-control approaches to disease elimination can be found in the malaria-eradication efforts of the early 20th century in the US & Europe, during which public health authorities came to realize that quinine wouldn't eradicate malaria, since human treatment alone cannot prevent the environmental transmission of a parasitic disease Nonetheless, long before the advent of synthetic insecticides and modern antimalarial-drug prophylaxis, malaria was effectively eradicated in many locales through combination interventions that interrupted vectorborne transmission In the southern US, these involved a combination of water management, reduction of habitats favorable to mosquitoes, introduction of mosquito-proof housing, & barrier screening Similarly, until now, preventive chemo has been seen as the most appropriate means of controlling schistosome-related disease in resource-poor areas Now we are coming to realize that drug delivery may be only a stopgap measure If the process of schistosoma infection continues unchecked, its disabling effects in the context of rural poverty will always limit the potential benefits of drug-treatment programs while also necessitating that treatment continue indefinitely Obviously, the elimination of schistosomiasis will be a long term process requiring a long-term investment, but we must shoulder the necessary extra effort, including long-term planning, intersectoral government coordination, & decades-long commitment Informed & locally adaptive prevention strategies for long-term control will be necessary The integrated schistosomiasis-control strategies are clearly an important step in this direction Life Cycle of the Schistosome: Infection of humans with schistosoma species causes chronic hepatic & intestinal fibrosis or fibrosis, stricturing, and calcification of the urinary tract Infection follows contact with fresh water harboring larval parasites called cercariae, which penetrate humans' skin, become schistosomula, and enter capillaries and lymphatic vessels The worms migrate to the portal venous system, where they mature and unite, & then to the superior mesenteric veins, the inferior mesenteric and superior hemorrhoidal veins, or the vesical plexus and veins draining the ureters ... Eggs are produced and pass into adjacent tissues; many are shed in feces or urine The eggs hatch, releasing miracidia that infect freshwater snails, which ultimately release cercariae Eggs excreted in stool or urine; eggs hatch in freshwater, releasing miracidia, which penetrate intermediate host (snail) Miracidia develop into sporocysts within the snail in 2 successive generations & produce cercariae, which are released into water & penetrate human skin Cercariae lose tails during penetration and become schistosomula Larvae first migrate to the lungs through the venous circulation, then migrate to the left heart and into circulation, & mature into adults in the liver -> chronic schistosomiasis Worms mature & mate for life (life span, 3-30 yr) Eggs retained in tissue leading to portal hypertension -> chronic schistosomiasis Meanwhile, S. haematobium migrate to venous plexus of bladder, where females lay eggs that are shed in urine; S. japonicum and S. mansoni migrate to mesenteric vessels of bowel or rectum, where females lay eggs that are shed in stool

Sickle Cell (reading notes)

Sickle cell haemoglobin results from a point mutation (BS) & is common in Africa, the Arabian peninsula & southern Europe Heterozygous carriers have one normal B & one BS globin gene - sickle cell trait (AS) Sickle cell trait is usually asymptomatic, but haematuria & sudden death may occur The blood count & film are normal The diagnosis is made on finding a positive sickle solubility test & one band of HbA (normal adult haemoglobin) & one of HbS on electrophoresis General anaesthesia requires no special precautions Sickle cell disease occurs in those homozygous for HbS (SS) Sickle cells are more rigid than normal red cells & obstruct blood flow, particularly in small blood vessels Deoxygenation of sickle haemoglobin causes the characteristic shape change Blood examination shows sickle-shaped cells, even when not in crisis, features of splenic atrophy Electrophoresis shows the HbS band The sickle solubility test is positive The natural history of this condition is variable but typically patients are well with occasional crises which can be severe Painful bone crisis is the most common & may be precipitated by cold, infection or hypoxia - often no cause is found Treatment is with simple or opiate-based analgesia (morphine, because pethidine may cause seizures & is more addictive) Intravenous or oral fluids, oxygen & antibiotics may be given Most episodes settle within a few days Acute chest syndrome may be fatal & is characterized by the rapid onset & progression of chest pain associated with hypoxia, cough & bilateral lung infiltrates Exchange blood transfusion is the treatment of choice Splenic sequestration is more common in children than in adults, because splenic atrophy from auto infraction occurs by the age of 5-6 years Typical features are worsening anemia & progressive splenomegaly Blood transfusion is used as necessary The condition is usually short-lived If patients have recurrent attacks splenectomy is undertaken Aplastic crises are caused by parvovirus infection, which switches off red cell production for 2-3 days; this doesn't matter in normal individuals In haemolytic anemias, where red cell lifespan is short, temporary cessation of red cell production causes an abrupt, life-threatening fall in haemoglobin Red cell transfusion is life saving Aplastic crisis is characterized by severe anaemia with a near absence of reticulocytes Strokes are common in children & adults with sickle cell disease, & pulmonary hypertension is a contributory factor for early death Sickle cell disease: anaemia (pale, tired, short of breath), jaundice (due to ongoing haemolysis), pigment gallstones, splenic atrophy, chronic leg ulcers, short stature Most patients are treated conservatively with specific treatment for crises Hyposplenism from splenic infarction is common, so appropriate immunization & prophylaxis against encapsulated bacteria with penicillin are essential Folic acid is often prescribed Disease severity is very variable: those with the highest concentration of HbF have the mildest clinical course Bone marrow transplantation may be used in young people with severe disease

Acute schistosomiasis

Skin rash (not all cases) Fever, headache, pain associated with initial immune response (may occur weeks after exposure)

In the developing world, how can we diagnose schistosomiasis?

Stool samples for intestinal schistosomiasis (look for eggs) Urine sample for urinary schistosomiasis Ultrasound for portal (liver) hypertension

Capsule vs. RNA Core

The RNA Core is the "business part" of the virus, but the capsule is what is recognized by our immune systems

Tuberculosis, The Unromantic Killer (reading notes)

TB has never stopped being one of the world's most lethal infections Most Americans have the luxury of knowing almost nothing about TB Because it's not typically a fact of life for us or those we know (99% of victims are the poor residing in developing countries), TB can sit comfortingly outside our awareness, perhaps colored by wisps of romanticized claptrap; yet TB is anything but romantic TB is a grindingly awful, painful, wretched affliction that preys on the weak & those already worst served by society Roughly 5,000 more of them will die of it on the day you read this column This miserable state of affairs is at least an improvement over that of 1882, when TB more routinely killed 1/7 of people even in Europe & the Americas, esp in the unhygienic, crowded cities packed by the rise of industrialism On March 24 of 1882, a microbiologist presented his isolation of the TB bacillus to his colleagues; that date, which is commemorated annually as World TB Day, marked a turning point (but not a decisive victory) in humanity's struggle against the disease Because TB strikes those with weakened immune systems, it's joined forces in recent decades with HIV, further complicating the management/treatment of both conditions TB is also adept at evolving resistance to antibiotics Health authorities have helplessly watched the emergence of both a multidrug-resistant strain that survives the 2 most powerful treatments & an extensively drug-resistant strain that shrugs off the second-line antibiotics as well The depleted state of medicine's arsenal against TB is all the more irritating because it could & should've been avoided TB became aggressively antibiotic-resistant because so many patients stopped taking their pills when they started to feel better; a failure of both human nature & the health care system Economics, too, has aided TB's survival: small financial incentives for serving the huge but poor market of its patients have historically dulled pharmaceutical industry interest Fortunately, philanthropic & governmental grants are reinvigorating that research The most promising news is that scientists are beginning to understand interactions between the TB bacillus & its human hosts at the molecular level Not only do such studies directly suggest new drug targets for future antibiotics, but they can also help investigators develop a virtual model of TB in the body that may point to entirely new strategies for thwarting it Simulation might reveal the so-called emergent properties (& potential vulnerabilities) of the microorganism that aren't deducible from its biochemical components Koch's work with TB helped to establish the germ theory as a potent tool for protecting public health Perhaps current efforts to combat TB will prove equally useful in pioneering better ways to contain the broader health threat of antibiotic resistance, too

New Tactics Against Tuberculosis (reading notes)

TB is second only to HIV as the worldwide cause of death from infection, & the pandemic is growing in many places TB is caused by a bacterium; most cases are treatable, but strains resistant to first- & second-line drugs are on the rise Conventional approaches to developing new antibiotics & vaccines against the disease have mostly failed New tools are enabling scientists to study the TB-causing bacterium in greater detail, offering unprecedented insight into the interactions between pathogen & host; the results are exposing promising new targets for drug therapy ... The pandemic is growing in many places, & strains resistant to all existing drugs are emerging To fight back, biologists are applying a host of cutting-edge drug development strategies History is punctuated with diseases that have shaped the social atmospheres of the eras, defined the scope of science & medicine, & stolen many great minds before their time There's one disease that seems to have stalked humanity far longer than any other: TB Fossil evidence indicates that TB has haunted humans for more than half a million years No one is exempt; it affects rich, poor, young, old, risk takers, abstinent By coughing, spitting or even talking, an infected individual can spread the bacterium that causes the disease Today TB ranks second only to HIV among infectious killers worldwide, claiming nearly 2 million lives annually, even though existing drugs can actually cure most cases The problem is that many people lack access to the medicines, & those who can obtain the drugs often fail to complete the lengthy treatment regimen TB is also evolving faster than our therapies are In recent years, investigators have observed a worrying rise in the # of cases resistant to more than 1 of the first-line drugs used to treat the illness We've begun to see the emergence of strains that are resistant to every last one of the antibiotic defenses The disease is particularly devastating for developing nations, where 90% of cases & 98% of TB deaths occur Beyond bringing untold suffering & sorrow, TB harms entire economies With 75% of cases arising in people between the ages of 15 and 54, TB will rob the world's poorest countries of an estimated $1-3 trillion over the next 10 years The disease forces struggling nations to divert precious resources from other important areas into health care The developed world would be mistaken to consider itself safe: while incidence there is comparatively low, that could change if a highly resistant strain were to gain traction As bleak as this state of affairs is, we have reason to be hopeful Cutting-edge biomolecular technologies are enabling researchers to study the complex interactions between the TB bacterium & the body in detail, generating insights that are informing the development of novel diagnostic tests & drug therapies Every year TB kills nearly 2 million people & infects some 8 million more First identified in 1882, Mtb, the rod-shaped bacterium that causes tuberculosis, exists in both latent & active forms In a latent infection, the immune system prevents the bacteria from multiplying, thus keeping them from disrupting tissues; individuals with this form show no symptoms & aren't contagious Latent Mtb may persist for months, years or even decades without multiplying or making its host ill 90% of people infected with Mtb never develop active TB disease; but 10% of them do develop the active form, esp those with weakened immune systems, such as young children and individuals who have HIV or are undergoing chemo In people with active TB, the bacteria outpace the immune system, rapidly multiplying & spreading out to attack the organs Primarily an aerobic bacterium, meaning it prefers enviros rich in oxygen, Mtb has a special affinity for the lungs; ~75% of patients with active TB exhibit the pulmonary variety of the disease As bacteria multiply, they destroy lung tissue, commonly causing the host to develop a severe cough, chest pain & coughing up of blood; other organs are vulnerable too Active TB can affect nearly every organ in the body In children, TB can invade the cerebrospinal column, where it provokes a high fever with systemic shock, a condition known as meningitis Left untreated, half of people with active TB die of it, most from lung destruction A century ago society had no way to combat TB, except by sequestering affected individuals in sanatoriums Back then TB, often called "consumption," was widespread even in places that today have a relatively low incidence of the scourge, like North America & western Europe Scientists began to gain on the disease in 1921, when a vaccine first entered into public use (initially believed to protect against both adult & childhood forms of the disease, the BCG vaccine, as it is known, was later shown through an extensive series of tests to confer consistent protection against only severe childhood forms) Years later, treptomycin was developed, which despite causing some side effects was the first effective therapy for TB; this opened the door for the creation in the 1950s of a rapid succession of antibiotics that compensated for streptomycin's weaknesses Developments brought the era of sanatoriums to a close & significantly lowered the incidence of TB in countries that had the money and infrastructure to tackle the problem By the 1970s many experts believed TB had been almost completely eradicated; in reality, with international travel rising the largest epidemics were just beginning Those hit hardest were those who could least afford it: residents of the poorest nations, who'd soon also be facing a new and costly killer, HIV Today more than 50 years after the debut of the first anti-TB drugs, the WHO estimates that fully ⅓ of the world's population (more than 2 billion people) is infected with Mtb On average, 8 million carriers a year will develop active TB, & each will infect between 10-15 more individuals annually, maintaining the pandemic The picture becomes more frightening when one considers the rising incidence of HIV People with latent TB & are HIV-positive are 30-50x more likely than their HIV-negative counterparts to develop active TB, because HIV leaves their immune systems unable to keep TB in check TB is the leading cause of death among HIV-positive individuals, claiming the lives of ⅓ worldwide & ½ in sub-Saharan Africa, where healthcare is especially hard to come by Even if HIV-positive individuals have access to anti-TB drugs, their health will likely worsen because dangerous interactions between antiretroviral therapy & first line TB drugs often force patients to suspend their antiretroviral therapy until TB is controlled Perhaps the most disquieting aspect of the present pandemic is the growing problem of the TB bacterium's resistance to antibiotics Current treatment course, developed in the '60s, is a demanding regimen consisting of 4 first-line drugs created in the 50s/60s: isoniazid, ethambutol, pyrazinamide & rifampin Patients who follow the regimen as directed take an average of 130 doses of the drugs, ideally under direct observation by a health care worker This combo is extremely effective against active, drug-susceptible TB as long as patients are compliant and complete the entire 6-9 month course Drug-resistant strains develop when patients don't complete the full protocol, whether because they start feeling better or because their drug supply is interrupted Inconsistent antibiotic use gives the bacteria time to evolve into a drug-resistant form Once a drug-resistant strain has developed in one person, that individual can spread the resistant version to others Nearly 5% of the roughly 8 million new TB cases that occur every year involve strains of Mtb that are resistant to the 2 most commonly used drugs in the current first line regimen: isoniazid & rifampin Most cases of this so-called multidrug resistant TB (MDR-TB) are treatable, but they require therapy for up to 2 years with second-line anti-TB drugs that produce severe side effects MDR-TB treatment can cost up to 1,400 times more than regular treatment Most MDR-TB occurs in impoverished countries, so this expensive treatment isn't often an option Failure to properly diagnose MDR-TB, along with the high cost of treatment, means only an estimated 2% of MDR-TB cases worldwide are being treated properly Over the past few years health surveys have revealed a more ominous threat, extensively drug-resistant TB (XDR-TB) which is resistant to virtually all the highly effective drugs used in second-line therapy While XDR-TB is less common than MDR-TB, the possibility that XDR-TB will evolve & spread looms wherever second-line TB drugs are in use Very few countries have labs equipped to diagnose XDR-TB To say that scientists erred in assuming the first-line drugs from the 1950s would be sufficient to combat TB is a profound understatement With the majority of TB patients concentrated in some of the world's poorest countries, large pharmaceutical companies have had little incentive since then to invest heavily in R&D for new drugs The prevailing wisdom among the greater pharmaceutical conglomerates is still that the cost of drug development far outweighs the potential global market for such products Thanks to government programs & private philanthropic organizations, many efforts are underway to create TB antibiotics to both treat drug-resistant cases & reduce the time that it takes to treat normal TB cases; as a result, a few promising agents are currently in early clinical trials An agent, SQ109, inhibits cell wall synthesis & recently completed phase I (safety) trials Another drug candidate is PA-824, a compound whose ability to attack Mtb in both its actively dividing stage & its slow-growing one has generated hopes that the drug could significantly reduce the time needed to treat the disease; it's in phase II efficacy trials The odds are against these candidates: historically, fewer than 105 of antibiotics that enter early clinical trials garner approval, a success rate that derives in large part from the outmoded logic used to discover these drugs 15 years ago developing new antibiotics was mostly following a simple formula; yet even the large pharmaceutical companies, masters of developing medicines to treat nearly any disease, have been unsuccessful in producing new antibiotics using this approach The TB battleground is littered with the corpses of drug candidates that failed Many of these compounds were highly specific & potent inhibitors of key TB enzymes In some cases, although they effectively foiled isolated enzymes, they flopped when tested on whole bacterial cells In others, the compounds thwarted whole bacteria in test tubes (in vitro) but missed their mark when tested in infected animals TB offers perhaps the most extreme example of the troubling disconnect between the in vitro & in vivo effects of antibiotics Most of the time investigators have no idea why drug candidates fail The crux of the problem is that bacteria are autonomous life-forms, selected throughout evolution for their ability to adapt and respond to external threats Until we truly appreciate the complexities of how TB interacts with humans, new drugs against it will remain elusive; though we are making progress on that front A key turning point in our TB education came in 1998 with the sequencing of the DNA code "letters" in the Mtb genome; the sequence, & those of related organisms, has yielded a trove of insights Results showed that of all the enzymes & chemical reactions that are required for TB to survive in a human, we were considering only a third of them in our in vitro (test tube) tests We learned that Mtb devotes a huge amount of its genome to coding for proteins that synthesize and degrade lipids, suggesting that some of those proteins might be worth considering as drug targets Analysis of the TB genome also hinted that the bacterium is perfectly capable of living in the absence of air, a suggestion now verified Under anaerobic conditions, Mtb's metabolism slows down, making it intrinsically less sensitive to existing antibiotics Targeting the metabolic elements that remain active under these circumstances is one of the most promising strategies for shortening treatment time Translating the info we've gleaned from the genome into discoveries that can help save lives has neither been simple nor straightforward, but recently researchers have used those data to make significant advances in diagnostic tests for the disease Diagnosis can be complicated by the effects of the childhood vaccine given to more than ½ of all infants worldwide; the vaccine contains a strain of Mtb that has lost its virulence yet is still able to induce a child's immune system to react against the TB bacterium Vexingly, the predominant test for TB can't distinguish between immune responses elicited by virulent Mtb & the vaccine form The test results for someone who's infected look exactly like the results for someone who has been vaccinated While the Mtb genome was undergoing sequencing, scientists discovered that a large stretch of DNA was missing from the bacterial strain used in the vaccine; later showed the missing genes were essential to virulence The deleted region in the vaccine strain offered investigators a strategy for improving the specificity of the test A test that searched only for an immune response directed against the virulence factors absent from the vaccine strain, the researchers reasoned, should be able to distinguish infected individuals from those who had been vaccinated Such a test was developed & approved by the FDA in 2005, & many recent studies have confirmed its accuracy; so far the cost of the test is high, which restricts its use to the First World The Mtb genome is not the only new source of data able to provide insight into the TB bacterium's potential vulnerabilities Scientists can now study all kinds of cell components & processes, from all the proteins in a cell (proteomics) to the amount of messenger RNA (the templates from which proteins are made) made from every gene (transcriptomics) to the intermediate & final products of cell metabolism (metabolomics) Now synthesizing compounds that stimulate the release of larger amounts of nitric oxide than are elicited by PA-824 & so should be even more potent against Mtb Structural genomics seeks to uncover the 3D structure of every protein in Mtb; work that can help identify the still-mysterious functions of many Mtb proteins & aid the design & synthesis of drugs targeting particular sites on critical proteins A global consortium with members from 17 countries is focusing its efforts entirely on the structural genomics of Mtb; so far they've helped determine the structure of about 10% of the organism's proteins Another "omics" branch worth noting is chemical genomics, a recently established field of research that effectively reverses the standard process of drug discovery Instead of starting with a protein of known function & looking for a compound that inhibits its activity, investigators begin with a compound known to have a desirable trait (such as an ability to inhibit Mtb reproduction in cell cultures) & work backward to identify the microbial enzyme impaired by the substance What makes this approach so appealing is that it lets us harness the power of natural selection in our quest to thwart Mtb Before Mtb & other mycobacteria found humans to be such appealing hosts, they occupied enviro niches where they had to compete with countless other bacteria for food in a constant arms race Bacterial ecosystems have undergone multiple rounds of natural selection, & in most cases other bacteria have evolved ways of keeping the mycobacteria in check, as is evident from the diversity of bacteria types in these ecosystems If researchers could tap into the amazing reservoir of weapons that competitor bacteria have evolved (applying modern omics tools to identify the defensive molecules, screen them for their anti-TB potential & pinpoint their molecular targets in Mtb) we could well uncover entirely new classes of drugs We could then select those agents that knock out the pathogen's whole system, as opposed to just a single process for which Mtb likely has a workaround To reap the full benefits of the omics revolution, we need IT tools capable of making sense of the vast data sets generated by omics experiments In fact, the development of such tools has become a discipline unto itself: bioinformatics Only with such tools can researchers help clear another obstacle to drug development: that posed by so-called emergent properties—behaviors of biological systems that can't be predicted from the basic biochemical properties of their components With the aid of bioinformatics, we hope to ascertain how all 4,000 of Mtb's genes, their corresponding proteins & the bacterium's metabolic by-products react when Mtb is treated with a new drug in vitro In the past 10 years we've begun piecing together exactly how the bacterium operates inside of TB patients, as opposed to in vitro The ultimate goal is to replicate Mtb in silico, that is, produce a computer simulation of the bacterium that behaves just like the real thing does in the body The significance of such an achievement can't be overstated, because it'll enable investigators to accurately predict which bacterial components make the best drug targets & which drug candidates will likely hit those targets most effectively Scientists will need to trace in exquisite detail all of the organism's biochemical pathways and identify more of the emergent properties that arise from the operation of the We still don't know what ⅓ of Mtb's proteins do in the first place, never mind what their associated pathways are or what emergent properties they spawn Confident that within the next 20 years we'll see a complete in silico bacterium that acts exactly like its counterpart growing in a test tube in the lab; and maybe even in a human Preventing TB infection in the first place is, of course, better than treating people after they have become sick Efforts to create a vaccine that confers better protection against the disease than does the BCG vaccine are underway Some developers are trying to improve the existing vaccine; others are trying to make entirely new ones But for the moment, the work is mostly doomed to trial & error because we don't understand why the current vaccine doesn't work nor how to predict what will work without testing candidates in humans In other diseases for which vaccines are available, surviving an initial infection provides immunity to future infection, but, in TB, initial infection doesn't offer any such protection A vaccine based simply on an attenuated version of TB therefore will not work Never has the need for better diagnostic tests, drug therapies & vaccines against TB been greater Much work remains to be done, but with the genomes of both Homo sapiens & Mycobacterium tuberculosis decoded & with an unprecedented amount of brainpower now trained on the problem, the momentum for change truly is unstoppable ⅓ of the world's population is infected with TB bacterium; 1/10 of them will become sick with active TB in their lifetime On average, nearly 4/10 TB cases aren't being correctly detected and treated TB is responsible for a death every 20 seconds An estimated 490,000 new cases of TB resistant to first-line drugs * 40,000 cases of TB resistant to second-line drugs occur every year TB, caused by the bacterium Mtb, occurs in both latent and active forms People can become infected by breathing in even just a few Mtb bacteria released into the air when those with active TB cough, spit or talk Mtb causes coughing, the most familiar symptom, because it accumulates abundantly in the lungs, but it can harm other organs as well Mtb tends to concentrate in the air sacs of the lungs because it prefers environments rich in oxygen In most people, the immune system is able to keep bacterial replication in check, dispatching defensive cells known as macrophages to the site of infection, where they form a shell around the bacteria In 10% of infected individuals, Mtb breaks down the shell, after which it can multiply Unfettered by the immune system, the bacteria destroy the tissue of the lungs; some may also make their way into the bloodstream & infect other parts of the body, including the brain, kidneys & bone Eventually affected organs may sustain so much damage they cease to function, & the host dies TB occurs in almost every country, but it's most widespread in developing nations The incidence of TB caused by strains of Mtb resistant to 2 or more of the first-line drugs for the disease, so-called multidrug-resistant TB (MDR-TB). has been rising as a result of improper use of antibiotics Worse still is extensively drug-resistant TB (XDR-TB), a largely untreatable form identified in 2006; as of June 2008, 49 countries had confirmed cases The first-line drugs currently used to treat TB were developed in the 50s/60s The 6-9 month regimen is demanding, & failure to comply with it completely has led to the emergence of resistant forms of TB Developing agents that are easier to administer & cheaper & that hit the Mtb bacterium in new ways is critical Today: traditional trial-and-error approaches to identifying drugs against TB have produced some new candidates now in clinical trials Future: more recently, scientists have begun trying to understand Mtb in far greater detail by studying its genome and other cell components; researchers should be able to inhibit synthesis of ATP much more effectively than drugs now in development can Far future: Ultimately, investigators want to create an in silico model of Mtb, a computer model that behaves exactly like its real counterpart does in a human; such a model would enable researchers to predict the organism's responses to various compounds with far greater precision than is currently feasible

The New Threat From Tuberculosis (video notes)

TB: a new menace from an old disease Archaeological evidence shows TB has affected humans for thousands of years Formerly known as consumption, the disease manifests itself when latent TB bacteria are activated by some factor such as exposure to active bacteria or a weakened immune symptoms Symptoms typically include cough with a thick mucus, swollen lymph nodes, fever, chills, and unexplained weight loss In the 1940s, US scientists discovered a combination of drugs that reverse the effects of TB Thanks to these advances, TB deaths and infections plummeted in developed countries, causing TB to fall off the radar over time But in developing nations, where people have historically lacked access to proper medical care, the carefully designed treatment regimen is often followed incorrectly This has allowed some TB bacteria to develop a resistance to first-line drugs and become MDR, or multi-drug resistant TB While second-line treatments have been engineered to counter this threat, the same process that led to the MDR bacteria has resulted in a newer, deadlier type: XDR, or extensively drug resistant TB Only 50-60% of patients with XDR-TB respond to available treatment A string of cases in South Africa, in early 2007, has produced 180 deaths so far In one hospital, 52/53 XDR-TB patients have died, an unprecedented death rate XDR spreads at a rate much faster than ordinary or even MDR types The countries most affected by the AIDS pandemic are also the ones hit hardest by TB, as institutional deficiencies are largely responsible for poor health standards People living with HIV are much more likely to contract TB than others While 1/10 HIV negative people are likely to contract TB in their lifetime, 1/10 HIV positive people are likely to contract TB for the course of a single year TB is among the most common diseases affecting people living with HIV Drug-resistant TB is not yet prevelant in places with with relatively high rates of HIV infection The South African outbreak brings the total # of countries reporting XDR-TB cases to 27, including every country in the 8 highly-industrialized states plus Russia There's a risk of TB esp. in urban settings and in urban settings that often see a great play or span of immigration, refugee, and adoptees (children who have a lot of health issues, esp since many haven't had primary immunizaitons that US children normally have) in cities like NYC Because public health systems in countries such as the US are so strong, most cases are treated quickly and followed aggressively But as new strains become more aggressive, it's imperative to block their spread in poor societies in order to ensure immigration and tourism will not overwhelm the public health sector and lead to a global pandemic WHO has proposed a 6-point strategy, Stop TB, requiring 650 million dollars annually to reverse current trends; but this year contributions have fallen 400 million short, placing plan in jeopardy While there's still time before drug-resistant TB obtains the high profile of HIV/AIDs and avian flu, substantial effort is needed to prevent this from ever being the case We must not overlook this threat

Polio's Last Act (reading notes)

The global campaign to eradicate polio began in 1988; since then, naturally occurring cases worldwide have dropped to, at last count, around 650 in 2011 Completely eliminating polio requires a change in the current vaccination program because 1 component in the most widely used vaccine now causes more cases of polio than it prevents The WH Assembly is expected to approve a plan this May that should decrease the # of vaccine-linked cases of polio & may speed up overall eradication efforts Yet questions have arisen over the safety of making the change rapidly; if health officials don't manage the transition correctly, polio can keep crippling children for years to come ... As the # of cases of the paralytic disease fall, world health officials have to grapple with a vexing problem: a component of the most widely used polio vaccine now causes more disease than the virus it's supposed to fight While polio has disappeared from the Western Hemisphere & Europe, the virus still permanently cripples children in Africa & Asia every year T. Jacob John, one of India's polio experts who's a longtime critic of the continued reliance on the oral polio vaccine (OPV) used by the nearly 25-year-old international campaign to rid the planet of the paralyzing and sometimes fatal disease The vaccine is at once an excellent & imperfect tool Inexpensive & easy to administer (each dose is of a few drops of serum on the tongue), it's brought the world to the point where polio eradication is visible on the horizon The WHO announced this past January there've been no cases of naturally occurring polio in India for a year But if the distribution of OPV isn't choreographed with exquisite care, its continued use, at least as currently formulated, could keep the world from eliminating polio A specific component of OPV, which uses weakened viruses to elicit immunity against the 3 strains of polio (1, 2, 3), has a problem The issue: type 2 poliovirus no longer exists in nature; the last case stemming from naturally circulating virus was reported 13 years ago IPV is an expensive, alternative vaccine, popular in wealthy nations, that consists of an injected formulation made up of completely inactivated, or "killed" viruses Ongoing vaccination against type 2 wouldn't be worrisome if the viruses in the oral vaccine were perfectly friendly; but in rare cases, the weakened viruses from the vaccine can revert to disease-causing pathogens & provoke the very illness they're meant to prevent In places where wild polioviruses are still a threat, the risk from natural infection is greater than the small hazard the vaccine poses But if the only risk of paralysis from type 2 polio comes from the strain in the vaccine itself, then that strain's continued usage could well be considered unproductive & possibly unethical As long as the oral vaccine contains the type 2 virus, children in more than 100 countries around the globe must paradoxically be vaccinated against type 2 polio to protect them from the type 2 virus in the vaccine In 2004 John wrote a letter to a medical journal, urging the international community to remove the type 2 component from the oral vaccine, making it a "bivalent" vaccine that'd protect against types 1 & 3 polioviruses The suggestion went nowhere—until now The Global Polio Eradication Initiative is marshalling support for an initiative to drop the type 2 component from the OPV The proposal is part of a substantial overhaul of the plan to eventually phase out OPV altogether once all types of wild polioviruses are demonstrated to be extinguished The WHO's governing council, the WH Assembly, will be asked to approve the early withdrawal of the oral vaccine's type 2 component at its annual meeting If the policy change passes (& the assembly is expected to vote in its favor), it'd eliminate an ethical problem that's been bedeviling the eradication effort for years It could also speed the job of wiping out the remaining 2 strains of polio in the 3 countries where they remain endemic (Afghanistan, Pakistan & Nigeria); a 2010 Lancet study showed the 2-target vaccine is at least 30% more effective than the one that has to protect against 3 strains; yet the polio virus has a nasty habit of avoiding efforts to contain it Last year China reported its first cases in over a decade Adjusting the OPV, some fear, could have unintended consequences & thus disrupt an eradication campaign that's already 12 years past its original deadline Countries have used the injected/oral vaccines to protect against polio for 50 years The greatest advantage of the oral vaccine, besides its low cost (about 15¢ a dose vs. $3 a dose for the injectable), is its ability to trigger a low-level & generally safe infection that prompts the immune system to respond, thereby immunizing the recipient An added bonus is that vaccinated children excrete vaccine viruses in their stool; in households, playgrounds & communities, those vaccine viruses spread from vaccinated to unvaccinated youngsters, eliciting a protective immune response in children who haven't been inoculated Health authorities had known from the early 1960s that Sabin's live-virus vaccine would occasionally paralyze a child who received the drops (or even more rarely their immediate contacts), but they felt the millions protected justified that unfortunate cost The idea that vaccine viruses can also circulate on their own, causing problems in large groups of unvaccinated children, wasn't recognized until much later Eventually most countries adopted Sabin's OPV to protect their children, but some, such as the US, later switched back to Salk's injected formulation For years the global eradication strategy was pretty straightforward: use the oral vaccine in the countries that preferred it or couldn't afford the more expensive inactivated polio vaccine until wild polioviruses were declared gone Then, at a prearranged time, all countries would simultaneously stop using the oral Wealthy countries would undoubtedly continue to vaccinate with the killed-virus vaccine for a time as further protection against an unexpected reemergence, but if developing countries couldn't afford that option, their children would go without vaccination, & the world would hold its breath waiting to see if polio was gone Over the past decade many polio experts have argued against that plan, calling it a high-stakes experiment that'd put millions of children at risk Promising research on the effectiveness of ultrasmall doses of inactivated polio vaccine is creating the hope that eventually a tiny, or fractional, dose of injectable polio vaccine could be bundled into a 6-in-1 childhood vaccine that'd offer the world's children protection against diphtheria, tetanus, pertussis, hepatitis B, Haemophilus influenzae B & polio; but that objective would be considered sometime down the road For now the focus is on safely eliminating the type 2 virus from the OPV In addition to ethical issues raised by retaining the type 2 component, the WHO & other health agencies are grappling with another concern: the component is standing in the way of completely eliminating polio Must find way to phase out the 3-part (trivalent) oral vaccine using a formula targeting types 1/3 instead; the 2-strain version would be more effective than the trivalent vaccine India & Nigeria have been using a 2-strain vaccine in some immunization rounds for the past couple of years Global officials are increasingly feeling the need to alter the trivalent vaccine because the cases of paralysis attributed to the type 2 vaccine component become harder to justify as the # of naturally occurring cases continues to decrease Years of experience with the oral vaccine have shown that 2-4 out of every 1 million children born in the same year will develop polio from the OPV, with roughly 40% of these cases caused by the type 2 viral component A child's risk of contracting polio from the vaccine falls with each extra dose he/she gets The WHO estimates that ~120 children get polio every year as a result of the inoculation There are the rare indirect deleterious effects of polio vaccination From 2000-2010 the secondary spread of vaccine viruses from vaccinated to unvaccinated children led to at least 538 cases of polio; the type 2 vaccine virus was responsible for 84% of those secondary cases When the vaccine itself causes polio, the resulting malady is called vaccine-associated paralytic poliomyelitis, or VAPP; when a non-vaccinated person contracts polio from vaccine viruses that are spreading from person to person, the virus is termed vaccine-derived poliovirus, or VDPV The biggest outbreak of VDPV began in 2005 & is still under way in Nigeria, where the spread of the type 2 vaccine virus among unvaccinated children has crippled at least 376 Vaccine-derived viruses from that epidemic have also spread to nearby Niger & Guinea The Nigerian outbreak will have to be halted before the world can safely drop the type 2 component from the oral polio vaccine In a sad twist of fate, vaccination with a formulation that includes the type 2 strain has to continue despite its risks because for now it's the most feasible way to confer immunity to that strain Once the type 2 component can be safely removed, officials foresee a transition period when first the injected & then the 2-strain oral vaccines are used in successive waves The killed-virus vaccine is needed to drive up immunity levels to the type 2 virus in case any residual viruses of this strain are still circulating Health authorities hope to keep the price down below what a full-fledged injected vaccine campaign would cost by giving all children 1 or 2 fractional doses of the inactivated formula Under certain circumstances, & when done sequentially with the application of the oral vaccine in the same person, splitting doses of inactivated vaccine should be as effective as providing full-potency injections The cost of the injectable vaccine needed to prepare for the across-the-board move to the bivalent vaccine could be brought down to 35 or 40 cents a dose with bulk buying, local manufacture (in places such as India & China) and fractional dosing Economic analyses suggest that if the price per injection can be reduced to 50 cents a dose, using the inactivated vaccine becomes feasible even in very poor countries The bottom line is that a supercheap version of the injected vaccine, at least supercheap relative to the usual formulation, changes the game Transitioning between polio vaccines is a complex undertaking even in countries, such as the US, with substantial resources Many officials were opposed when the US first started considering a switch back to Salk's inactivated vaccine in the early to mid-1990s; they feared the move would backfire badly Relying strictly on the inactivated vaccine would mean that some nonvaccinated individuals who previously would have gained protection from the spread of the vaccine virus would no longer be afforded that passive protection It took a good bit of time to convince people that in a nation like this, where we were so successful in our immunization program, that we could switch to IPV Walter Orenstein, a polio specialist now at Emory University was an ardent supporter of the OPV & was convinced the US had only managed to rid itself of the scourge of polio because of the secondary spread of Sabin's vaccine The U.S. began a gradual phasing out of the OPV in 1997 (it inoculated children with both vaccines in tandem through 1999 to guarantee an adequate level of public protection was maintained) Experience soon proved the US made the right decision Within months of switching to inactivated polio vaccine, the # of vaccine-associated cases of polio dropped to 0 Currently 56 countries use the inactivated vaccine exclusively 16 countries immunize with both vaccines, & 121 countries use the oral vaccine alone The switch from trivalent to bivalent oral vaccine could come sometime between 2013-2014; many things have to fall into place before the move can be made, including ensuring that countries that make their own OPV quickly move to license a two-strain oral vaccine Unlike the oral vaccine, the injected formulation must be given by a healthcare professional, & many of the countries on the polio front line also have shortages of trained personnel; hence, the need to marshal resources wisely Will development of a 2-strain oral vaccine satisfy John, who pushed for this change 8 years ago? Ironically, he is now one of the people concerned about the plan Having seen how readily vaccine-derived polio viruses spread from person to person, he now believes leaving children without protection to the type 2 virus in the next few years would be unsafe since some of the vaccine-derived virus may yet linger undetected in the enviro John says he'd feel comfortable making the switch only after there's solid evidence the preparatory campaign with inactivated vaccines has resulted in very high, widespread levels of immunity against type 2 poliovirus; otherwise, he fears, even the painfully slow progress of the past few years will vanish, & polio will continue crippling children for years to come Polio once crippled hundreds of thousands of youngsters Widespread use of OPV has brought the # of cases down dramatically, & by early 2012 eradication efforts had limited the # of countries where polio outbreaks are endemic, or self-sustaining, to 3 As the # of naturally occurring infections drops, the rare instances of vaccine-related polio cases become less tolerable, necessitating a change in vaccine strategy Public health officials have used 2 major types of vaccines to protect children against polio: 1 made from live but weakened virus & the other made from killed virus Eliminating the disease will require making a tricky transition from the widely used live vaccine with 3 components to new versions with 2 components & ultimately to withdrawing the live-virus vaccine altogether Trivalent live vaccine (tOPV) contains weakened versions of all 3 strains of poliovirus - Pros: delivered by mouth, so only minimal training is needed to administer the vaccine; inexpensive; nonvaccinated children can benefit - Cons: in rare cases, weakened virus from the vaccine can cause paralytic polio; natural type 2 virus no longer circulates, so now all cases of type 2 polio come from the vaccine itself Bivalent live vaccine (bOPV): contains only types 1 & 3 polioviruses - Pros: all the benefits of trivalent vaccine but will not cause type 2 polio - Cons: unsafe to use if type 2 vaccine poliovirus is still circulating undetected Killed-virus vaccine (IPV): contains chemically inactivated versions of all 3 polio strains - - Pros: doesn't cause polio Cons: expensive; injected, so must be administered by health care personnel (who are scarce in poor countries)

Koch's Postulates*

The organism must be found in all animals (cases) with the disease, but not in healthy ones The organism must (can) be isolated from a diseased animal and grown in pure culture The (pure) cultured organism causes disease when given to a healthy animal The organism must be re-isolated from the experimentally infected animal (and shown to be the same as the originally injected pathogen)

Sanitoriums

The standard treatment for a century (before antibiotics were discovered) Bed rest, fresh air, and good nutrition TB

What is the world's leading infectious cause of avoidable blindness?

Trachoma: someone loses their sight every 15 minutes, but they don't have to

T/F Polio traces back to Ancient Egypt

True

T/F Pthisis and consumption (or wasting away) are both synonymous for TB

True

T/F Resistance to malaria can be acquired by growing up in malaria endemic areas

True

T/F Schistosomiasis is a helminth infection

True

Secondary prevention for malaria*

Treat with appropriate drugs any child with a fever in a malaria-endemic region Institute anti-mosquito measures in the home and village of the child or adult with malaria

T/F Schistosomiasis may stunt growth

True

T/F The BCG freezer-dried vaccine is only for select individuals

True

T/F 1 in 6 people worldwide suffer from diseases you have never heard of

True

T/F Africa is very high at risk for schistosomiasis

True

T/F An antibiotic's desired effect on bacterial density is a decrease to zero after a few hours, but the actual effect is an initial sharp decrease followed by a moderate decline

True

T/F An estimated 490,000 new cases of TB resistant to first-line drugs and 40,000 cases of TB resistant to second-line drugs occur every year

True

T/F Anopheline eggs are laid upon water surface

True

T/F Maternal deaths in the US are on the rise

True, as other developed regions are decreasing theirs

T/F Up until recently, some polio patients would spend parts of their day in an iron lung

True (A mechanical respirator which lets a person breathe on their own in a normal manner when muscle control is lost, or the work of breathing exceeds the person's ability)

Urine LAM test vs. Xpert DNA test

Urine test (announced January 2018) is cheaper, faster, correlates with severity DNA amplification (approved since 2010) requires sputum sample, identifies rifampicin resistance

Structural violence

Whether or not post-exposure prophylaxis is available Whether or not the steady decline in immune function is hastened by concurrent illness or malnutrition

Categorize the

White MSM (men having sex with men) Black MSM

How is schistosomiasis a result of inequity and poverty?

People get infected because they do not have access to safe water They maintain transmission because of the absence of excreta disposal systems Infection is also acquired in routine domestic, agricultural or occupational duties

How many people are infected with schistosomiasis in Africa?

200 million

Xpert MTB/RIF

A cartridge-based, automated diagnostic test that can identify MTB DNA and resistance to rifampicin (RIF) by nucleic acid amplification technique (NAAT) A new test than can reveal in less than two hours, with very high accuracy, whether someone has TB and if it's resistant to the main drug for treating it Take sputum sample from patient, mix with chemicals in sample cup and let sit for 15 minutes, transfer sample into a test cartridge, load cartridge into machine that amplifies and analyzes bacterial DNA In December 2010, the WHO endorsed it for use in TB endemic countries and declared it a major milestone for global TB diagnosis Studies are underway to test if it works in resource poor countries; South Africa is the biggest buyer of the machines As sales continue to rise, concerns raised about if manufacturer Cerpheid can meet demand

5 ways you can get HIV*

Blood transfusions and organ/tissue transplants Injective drugs (and needle sharing) Unprotected sex Pregnancy, childbirth, and breastfeeding Working in healthcare

How might a person contract pulmonary TB?

By inhaling infected droplets from a cough or sneeze by an infected person

Polio symptoms may include*

Cold or flu-like illness Nausea and vomiting Fever Meningitis-like illness (stiff neck, severe headache) Second phase: paralysis, can be sudden onset

Post-polio syndrome (reading notes)

Decades after recovering much of their muscular strength, survivors of paralytic polio are reporting unexpected fatigue, pain & weakness; the cause appears to be degeneration of motor neurons Motor neurons that control voluntary muscle movement have their cell bodies in the spinal cord and long axons that extend to groups of muscles (i.e. in the arm) Sprouts near the end of each axon innervate individual muscle cells Some motor neurons infected by polio survive, but others die, leaving paralyzed muscle cells; recovered motor neurons develop new terminal axon sprouts that reinnervate orphaned muscle cells A single motor neuron may grow sprouts to innervate 5-10x more muscle cells than it did originally, creating a giant motor unit The adaptation isn't static: in a process called remodeling, the motor unit is constantly losing old sprouts & growing new ones After many years of functional stability, enlarged motor units begin to break down, causing new muscle weakness 2 types of degeneration have been proposed A progressive lesion is produced when normal regeneration of the axon sprouts no longer keeps pace with dying or malfunctioning sprouts A fluctuating lesion occurs when there's a faulty synthesis or release of the neurotransmitter acetylcholine In the 1st 1/2 of the 20th century, paralytic poliomyelitis seemed unstoppable A major polio epidemic hit the NY area in 1916, & in the following decades the epidemics grew in size & became more deadly (i.e. the epidemic of 1952 affected over 50,000 Americans & had a 12% mortality rate) It's difficult to realize today the extent of the fear that gripped the public Polio haunted everyone: families stayed at home; pools were closed; public events were canceled; children in particular were at risk With the introduction of Jonas Salk's injected killed-virus polio vaccine in 1955 & Albert Sabin's oral live-virus vaccine 6 years later, the epidemics were brought to an end By the mid-1960s the # of new polio cases dropped to an average of 20 a year Polio had been vanquished, or so it seemed For the average American, polio no longer meant a disease but a vaccine Medically, polio came to be regarded as a static, nonprogressive neurological disorder It was believed that after rehabilitation & reeducation most survivors could reach a plateau of neurological & functional stability that would last more or less indefinitely, & that's where our understanding of polio as a chronic disease remained until recently Then, in the late 1970s, reports began to surface that people who recovered from paralytic polio decades earlier were developing unexpected health problems like excessive fatigue, joint/muscle pain, &, most alarming of all, new muscle weakness Since there was little in modern medical literature about delayed neurological changes in polio survivors, the initial response by many physicians was the problems weren't real For a time they were dealing with a cluster of symptoms that had no name, & without a name there was essentially no disease By sheer weight of #s, persons experiencing the late effects of polio finally started attracting the attention of the medical community, & in the early 1980s the term post-polio syndrome was coined Today the syndrome is defined as a neurological disorder that produces a cluster of symptoms in individuals who had recovered from paralytic polio many years earlier These symptoms typically appear from 30-40 years after the acute illness The major problems are progressive muscle weakness, debilitating fatigue, loss of function & pain, esp in muscles/joints; less common are muscle atrophy, breathing problems, swallowing difficulties & cold intolerance The critical symptom of post-polio syndrome is new progressive weakness Patients most at risk for post-polio syndrome are those who suffered a severe attack of paralytic polio, but some patients who had a mild attack can also develop it The onset of these new problems often is insidious, but in many cases they appear to be caused by specific events like a minor accident, a fall, a period of bed rest or surgery Patients say a similar event several years earlier wouldn't have caused such a large decline in health & function Post-polio syndrome, it turns out, isn't a new disorder after all It was described in French medical literature in 1875, & then, as often happens in medicine, it was forgotten; over the next century, 35 reports on post-polio weakness were published in med literature By 1984 a growing awareness of the delayed effects of polio prompted researchers to organize an international conference at the Warm Springs Institute for Rehabilitation A 2nd international meeting on post-polio syndrome was held in 1986, & in the following years there was a large increase in basic/clinical research into polio's long-term effects In 1994 the NY Academy of Sciences &the NIH cosponsored another meeting that culminated in the publication of a special issue of the Annals of the New York Academy of Sciences; the conference signaled the acceptance of post-polio syndrome as a legitimate clinical entity Surprisingly, accurate figures about the # of Americans who've had paralytic polio aren't available & probably never will be There's no national registry of persons who were diagnosed with the disease, & there is no way, after all these years, to compile accurate figures from health departments The best estimate is based on info from the federal government's National Center for Health Statistics; based on data from the 1987 survey, there were more than 640,000 survivors of paralytic polio, which would mean there are more survivors of it than there are people with multiple sclerosis, amyotrophic lateral sclerosis or spinal cord injury Since 1987 an unknown # of polio survivors have died, but immigrants, refugees & illegal aliens have added an unknown # to the US population of polio survivors No one knows how many survivors of paralytic polio have post-polio syndrome; some studies indicate the figure could be as high as 40% -> total # of persons in this country currently suffering from post-polio syndrome could reach 250,000 Knowledge of how the poliovirus infects the body can be helpful in understanding the possible causes of post-polio syndrome It's a small RNA virus that can enter the body when contaminated water or food are ingested, & even when contaminated hands touch the mouth Most people who become infected either have no symptoms or experience a self-limited illness characterized by fever & gastrointestinal upset for several days The poliovirus, which replicates in the lymphoid tissue of the throat & small intestine, either passes harmlessly from the gut or travels in the blood to all parts of the body In a small minority of infected persons, usually 1-2%, the virus invades the CNS & produces an unpredictable amount of paralysis A distinctive characteristic of acute polio infection is the liking of the poliovirus for the nerve cells that control muscles; such motor neurons consist of a cell body located in the anterior horn of the spinal cord & a long tentacle (axon) that extends to the muscles Near the end of each axon, tiny sprouts branch out to individual muscle cells At the nerve muscle interface, or synapse, the axon's sprouts release acetylcholine, a neurotransmitter that causes the muscle fibers to contract A motor neuron & the group of muscle cells that it activates are called a motor unit With uncanny precision, the poliovirus invades the motor neurons, leaving intact adjacent nerve cells that control the functions of sensation, bowel, bladder & sex How this exquisitely targeted behavior occurs was a mystery until recently, when researchers identified poliovirus receptors at the nerve-muscle interface; such receptors let the poliovirus enter an axon & then to migrate to the nerve cell body in the anterior horn of the spinal cord The poliovirus typically infects more than 95% of the motor neurons in the spinal cord & many other cells in the brain; the infected cells either overcome the virus or die The extent of paralysis is unpredictable Motor neurons that survive develop new terminal axon sprouts in response to an unknown stimulus; these new sprouts reinnervate/reconnect, with the muscle fibers left orphaned by the death of their original motor neurons In a sense, the growth of additional axon sprouts is the body's effort to keep as many orphaned muscle cells as possible alive & working A single motor neuron that initially stimulated 1,000 muscle cells might eventually innervate 5,000-10,000 cells, creating a giant motor unit These vastly enlarged motor units make it possible for fewer motor neurons to do the work of many Another adaptation that leads to increased strength is the enlargement of muscle cells when regularly exercised These 2 compensatory adaptations—increase in muscle size & axon sprouting—are so effective that up to 50% of the original # of motor neurons can be lost without the muscle losing clinically normal strength; these adaptations aren't static nor permanent To the contrary, after acute polio recovery there's an ongoing process of remodeling motor units consisting of denervation (losing old sprouts) & reinnervation (gaining new) It's this process of remodeling or constant repair that lets motor units achieve a steady state of muscle strength; when this steadiness is disrupted, new muscle weakness occurs Post-polio syndrome likely involves a slow degeneration of the terminal axon sprouts that innervate the muscle cells Possibly 2 types of disintegration of motor neurons: a progressive & a fluctuating lesion The progressive lesion occurs when the normal regeneration of the sprouts from the axon to the muscles is interrupted & malfunctioning sprouts aren't replaced; this interruption of the repair process produces irreversible, progressive muscle weakness The fluctuating lesion is thought to be caused by defective synthesis or release of the neurotransmitter acetylcholine Muscle weakness & fatigue can be reversed in some patients with post-polio syndrome by the drug pyridostigmine, which enhances the effectiveness of acetylcholine in triggering muscle contractions Degeneration of the axon sprouts can explain the new muscle weakness & fatigue, but what causes the degeneration in the first place remains a mystery The most plausible hypothesis proposes the muscle weakness is simply the result of overuse of individual motor neurons over time This explanation assumes that after recovery from polio the surviving giant motor neurons must labor more than normal neurons just to maintain daily activities After many years of continued overuse, enlarged motor neurons eventually suffer from a kind of metabolic exhaustion that leads to an inability to regenerate new axon sprouts to replace degenerating ones There's no direct way to measure metabolic fatigue in motor neurons, but evidence to support this hypothesis can be inferred from abnormalities on muscle biopsies, electrodiagnostic tests & clinical response to exercise Some researchers also report that some motor neurons in the anterior horn of the spinal cord of polio survivors appear to be smaller than normal; it's believed that these smaller motor nerve cells were somehow damaged at the time of the acute polio infection & that they're vulnerable to premature failure Normally, significant attrition of motor neurons doesn't occur until a person reaches 60 Since polio survivors have a greatly reduced # of motor neurons, the loss of even a few functioning motor units could lead to a disproportionate loss of muscle function Attrition of motor neurons because of aging alone, may not be a significant factor in post-polio syndrome Several studies have failed to find a positive relation between the onset of new weakness & chronological age; to the contrary, these studies suggest it's the length of the interval between onset of polio & the appearance of new symptoms that's a determining variable Persistence of the poliovirus in the body (viral particles that have lain dormant for many years & then are reactivated by some unknown mechanism) may also play a role Researchers have reported poliovirus-like RNA fragments in the spinal fluid & spinal cord tissue of some patients with post polio syndrome but not in polio survivors who don't have the syndrome; these small RNA fragments don't appear to have any infectious potential Other causes of post polio syndrome, like an immune-mediated response, hormone deficiencies & enviro toxins, have also been proposed Although some of these hypotheses seem plausible, there's not enough evidence to justify strong support for them; no definitive tests exist for post-polio syndrome Diagnostic tests of blood, muscle biopsies & EMG recordings of muscle activity often show the same abnormalities in polio survivors with post-polio syndrome as in those without it; so diagnosis relies primarily on systematically ruling out other causes of a patient's symptoms A set of criteria for diagnosing post-polio syndrome has been developed by the Post-Polio Task Force, a group of researchers, clinicians & polio survivors The onset of new muscular weakness after many years of stable functioning is perhaps the most characteristic symptom; yet many of the symptoms of post-polio syndrome are so general that ruling out all possible causes is often impractical (new weakness may result simply from the lack of use of the muscles) Regardless of the underlying cause, once the weakness begins it may initiate a cascade of other complaints that makes the original symptom impossible to identify As with many other chronic conditions, the essence of good medical care is to relieve symptoms, improve muscular function & enhance the patient's sense of well-being; this management strategy is frequently referred to as bracing & pacing Effective intervention can be as simple as prescribing a cane or as complicated as putting someone in an iron lung or providing some other form of assisted ventilation For both physical & psychological reasons, patients are encouraged to remain as active as possible; but the new lifestyle should incorporate regular rest breaks An exercise program is desirable for virtually all patients, ranging from stretching to more vigorous aerobic workouts depending on the person With certain types of exercise in carefully monitored settings, some patients have been able to regain & maintain muscle strength Although there are no magic bullets, meds can occasionally be helpful (i.e. low doses of tricyclic antidepressant may relieve muscle pain in some patients, & pyridostigmine may reduce fatigue & improve muscle strength) As a general rule, the progression of symptoms is fairly slow & the overall prognosis is good, unless there are severe breathing or swallowing difficulties Yet when reserves of strength & stamina are low, a minor change in the stability of the motor neurons can result in a disproportionately large loss of muscular function, which often is psychologically devastating Most polio survivors tell a story of struggle and triumph: the sudden, random onset of paralysis, the gradual restoration of strength seemingly due to individual willpower & , finally, for many, resumption of an active, productive life, which leads them to believe they have put polio behind them The story, for most, is made possible by denying their disability & the reality of what was lost and the life that might've been Perhaps the most famous example of disability denial is provided by FDR: while he regained normal use of his arms quickly after his polio illness, he spent many years in a heroic, but largely unsuccessful, effort to relearn to walk; even after becoming president, FDR went to extraordinary lengths to disguise the extent of his disability; in the waning months of his life, he experienced increasing muscular weakness that appears to be compatible with post-polio syndrome Virtually every polio survivor displays self-deception or denial Until recently, most tended to avoid other polio survivors & polio help groups They knew we weren't physically normal, but if they thought about it at all, they considered themselves as inconvenienced, not disabled By retraining the muscles that remained, they felt they could do just about anything, even become president, like Roosevelt Later in life, when polio survivors begin to experience the new weakness of post-polio syndrome, the denial usually is still intact, which makes understanding & accepting the new changes all the more difficult As they begin to accept the fact that they're disabled, they may be overcome by feelings of anger, bitterness and despair Fortunately, a post-polio support movement has sprung up, & there are now more than 300 support groups throughout the country Many post-polio survivors exhibit an extraordinary commitment to exercise, a legacy from their recovery from polio For many, exercise became a daily obsession, for others, almost a religious devotion Polio survivors developed a special relation to their bodies & experienced a new mastery over their muscles and movements, an element of control that had not existed before polio It was a visceral lesson that carried over into other aspects of their lives and probably accounts for why so many polio survivors have excelled at school and at work Over the past few decades much of the leadership for the disability movement has come from polio survivors; their efforts have led to the founding of the Independent Living movement and to the passage of legislation What's not widely known is that many of these leaders were among the most disabled: walking with braces, riding motorized wheelchairs & attached to portable ventilators Polio has had a far-reaching effect on medicine The successful development of a safe vaccine after years of effort was a triumph of enormous proportions; it involved the eager participation of millions of ordinary Americans, initially through door-to-door fund-raising and later in volunteering their children to participate in the 1954 field test of the Salk vaccine The massive research effort to develop a polio vaccine led to many discoveries that have since revolutionized the fields of virology & immunology The polio epidemics accelerated the development of rehabilitation medicine In contrast to traditional medicine with its focus on the curing and repairing of diseased organs, rehabilitation medicine emphasizes the rebuilding of body functions & the teaching of the skills necessary for independent living The principles developed to treat polio decades ago are essentially the ones used today to rehabilitate persons with head/spinal injuries, strokes & degenerative disorders The intensive care unit that's now an integral part of every modern hospital is another legacy from the era of polio epidemics When large numbers of polio patients requiring iron-lung vents started to overwhelm the staff in rehabilitation centers, the iron lungs were clustered together so they could be readily monitored by only a handful of nurses Regional respiratory centers were also created to treat the most severely affected polio patients; some of these centers have survived & continue to provide care for persons with spinal-cord injuries Americans asked to mail dimes to support the fight against polio For a while, the fight against polio brought out many of the best qualities of American society: neighbors carried food to families quarantined at home, teen clubs raised $ to help hospitalized classmates, & women's groups adopted local polio wards for the year Then the vaccines were developed, and not only did polio disappear in America but the war against polio seemed to be forgotten, along with the survivors Once held up as examples of heroic human fortitude, thousands of polio survivors who continued to need medical & financial help were largely ignored by the public As veterans of other wars would continue to discover, the public doesn't like to be reminded of the wounded and the dead after the war is over As with other conflicts, the polio war left more wounded and uncounted survivors than are generally recognized Even the miracle vaccines have their problems Most scientists agree that the Sabin oral vaccine is superior to Salk's injected one, but the oral polio vaccine isn't free of risk; in fact, it causes the very disease it's designed to prevent in 10-15 people every year because of a virus mutation or an immune deficiency in the recipient that allows the weakened virus to take hold & produce paralysis The federal government has changed its vaccination policy & is now recommending 2 initial immunizations with the injected killed-virus vaccine followed some time later by two doses of oral live-virus vaccine; in theory, this combo provides the advantages of both vaccines and, we hope, will end forever this nation's rendezvous with polio Chronic disruption of the acetylcholine cycle may result in progressive muscle weakness Iron lungs & rocking beds were clustered together to make it possible for nurses and doctors to monitor many polio patients in rehabilitation centers The concept of clustering patients who require special care is one of polio's legacies, & it can be found today in the intensive care unit that's essential to every modern hospital FDR, after being stricken by paralytic polio in 1921, believed swimming in naturally heated water at Warm Springs, Ga., strengthened his muscles; he went to great lengths to hide his disability from the public Most common new health problems reported by post-polio patients in several clinical studies are fatigue, muscle pain, joint pain and weakness; functional problems include walking and stair climbing

US malaria eradication efforts in the 1930s

Drain and oil mosquito-breeding areas Treat large populations with quinines Install screens in windows and doors Build dams to isolate mosquitoes Gradually improve cycle of poverty

The Neglected Tropical Diseases (reading notes)

For the equivalent of a few days' worth of military spending, devastating illnesses of the global poor could be controlled worldwide Our planet is filled with marvelous science-based opportunities for improving human welfare at a tiny cost, but these opportunities are often unrecognized by policymakers & the public There is no better example than treatment of a group of tropical diseases that maim and kill millions, but which are largely unknown to Americans & Europeans Experts formally refer to them as the "neglected tropical diseases," or NTDs, NTDs are hellish infections whose combined impact on disease, disability & death rivals the impacts of AIDS, TB & malaria, yet they're far less known, partly because they are diseases that afflict only the poor in the tropics 7 of the diseases are caused by helminths (worm infections): hookworm, trichuriasis, ascariasis, schistosomiasis and dracunculiasis (guinea worm), onchocerciasis and lymphatic filariasis Another 3 are protozoan infections: leishmaniasis, trypanosomiasis and Chagas' disease 3 more are bacterial: leprosy, trachoma and Buruli ulcer Of the 13 diseases, 9 (the 7 helminth infections, plus leprosy & trachoma) have powerful, low-cost preventive or curative interventions that're easy to administer As President Jimmy Carter has shown through his steadfast personal leadership over 20 years, filtering water through cheesecloth can dramatically reduce the burden of dracunculiasis Insecticide-treated bed nets, which cost just $5 & last for 5 years, can break the transmission of lymphatic filariasis & greatly reduce the transmission of malaria Medicines can handle all the helminths other than guinea worm by keeping the # of worms infecting an individual at a tolerably low level through routine treatments I.e. where the helminth infections & schistosomiasis are prevalent, all schoolchildren should be treated with deworming medicine up to 3x annually The pharmaceutical companies have stepped up to do their par Merck & Co., Glaxo SmithKline, Johnson & Johnson, Pfizer, Novartis and Sanofi-Pasteur have donated medicines & made other contributions to the fight against various illnesses All these companies eagerly support the expansion of control programs It's for governments to join in, too The US has recently committed $15 million to the fight against NTDs, a start but still less than one tenth of the $250 million or so a year needed for a comprehensive campaign for Africa The best strategy would be to link the control of the NTDs with malaria control The same bed nets & community health workers can attend to both malaria & the NTDs, which have a very high geographic overlap throughout the tropical countries Millions of children in Africa are polyparasitized, infected with both malaria & NTD combinations These multiple infections seem to be especially injurious Our policymakers should ponder that effective disease control does more to promote global stability & goodwill, via economic development, than do vastly larger outlays for military approaches after instability has broken out Targeted disease-control measures have been highly effective in the past, even in the poorest countries Smallpox was eradicated, & polio has been brought down 1,000-fold worldwide by vaccine efforts Comprehensive, Africa-wide control of malaria & NTDs together would probably cost no more than $3 billion a year, or just 2 days of Pentagon spending If each of the billion people in the rich world devoted the equivalent of one $3 coffee a year to the cause, several million children every year would be spared death & debility, & the world would be spared the grave risks when disease and despair run unchecked A new Global Network for NTD Control is helping to make this opportunity a reality The best strategy would be to link control of NTDs and malaria

Sickle cell's balanced polymorphism

HbA HbA (normal) and HbS HbS (disease) both have the same low fitness; HbA HbS (heterozygotes) have the highest fitness Heterozygotes (sickle cell trait) are protected from malaria because the parasite that causes malaria cannot live well in the blood stream of heterozygotes Sickle cells are more difficult to penetrate by P. falciparum; HbS heterozygotes are less prone to infection HbA HbA (normal), HbA HbS (trait), HbS HbS (disease)

What three things are involving in malaria?*

Parasites Mosquitoes Humans

Fighting Killer Worms (reading notes)

Parasitic worms known as schistosomes are a major cause of disability and death in many parts of the world, especially sub-Saharan Africa Although a treatment exists, reinfection is the rule A vaccine would make a world of difference, but none has yet proved effective; genetic & other tools hold promise for generating new candidates ... Schistosome adults, about a cm long, travel through the blood in pairs, with the smaller female held in a slit in the male's body; the worm's name derives from this slit: schisto means "split," and some means "body" Bloodsucking worms called schistosomes are among the world's most worrisome human parasites; a new genome sequence & powerful genetic tools promise to help crack their secrets Schistosomes are infectious worms that dwell in human veins and eat our blood Among parasitic illnesses, the WHO ranks schistosomiasis, the disease caused by the worms, second only to malaria in terms of the # of people it kills and chronically disables and the drag it imposes on the social & economic development of nations Schistosomes have achieved invisibility; cameras can capture these creatures, but our immune system doesn't Investigators have struggled for years against the schistosome's evasiveness; they've been trying to create vaccines able to rally a defense that would pounce on the parasite quickly, thereby preventing disease, or that'd help the body clear existing infections Vaccines are a necessary, missing component of a global effort to eradicate this illness, & so far results have disappointed; however, schistosome researchers feel they may be at the start of a great leap forward Genome projects are laying bare the DNA sequence of the parasite, & scientists are beginning to develop powerful new tools to probe its molecular secrets Such weapons may help make it possible to enhance immunity & accelerate vaccine efforts A vaccine would help avoid an enormous amount of suffering 200 million people, mostly in tropical & subtropical countries, have schistosomiasis, meaning they harbor schistosomes in their blood In children, persistent infection can retard growth & cause cognitive deficits In anyone, it can lead to anemia as well as damage to the intestines, bladder, spleen & liver, resulting in symptoms ranging from bloody diarrhea & cramping to life-threatening internal bleeding & kidney failure Schistosomiasis can drastically reduce someone's ability to work, crippling individuals & the economy People become infected when they encounter water infested by immature schistosome forms, which, though toothless, easily degrade & penetrate human skin & then enter blood vessels There the immature parasites develop into adult bloodsucking worms & mate, after which the females begin laying eggs Then the eggs make matters worse As many as half of the hundreds laid daily by each female will lodge in a variety of organs Unrestrained, they'd secrete toxins at a lethal level The immune system, though usually unable to eliminate the worms, blocks the acute lethality, although at the cost of doing damage of its own: it provokes the formation of scar tissue, a major cause of the organ impairment seen in the disease The immune response to the eggs also helps them puncture blood vessels, which in the intestinal tract lets them make their way into feces & thus out of the body to continue development Eggs that invade the bladder may, alternatively, escape in urine In water the eggs hatch; then larvae emerge & infect snails Inside snails the schistosomes replicate asexually before pouring into the water to infect, or reinfect, new human victims Good sanitation & snail control have limited the disease in many countries, but in poverty-stricken regions, where clean water is still not available, it thrives A safe anti-schistosomal drug, praziquantel, was developed in the 1970s; it has few side effects, is now relatively cheap, & a single treatment can clear the infection Reinfection, however, occurs frequently, & the worry looms that schistosomes will gain resistance to this drug Already cases of schistosomiasis have surfaced that require higher than normal levels of the drug to clear, a possible sign of incipient resistance It's because of concern over drug resistance & because prevention is always the best medicine that health officials are eager to add a vaccine to the fight against the parasite, if a practical, effective one can be created Typical vaccines deliver dead or inactive pathogens or distinctive segments of molecules (often proteins) made by those organisms in a way that induces the immune system to behave as if a true infection has occurred The system produces cells that specifically recognize molecules present in the vaccine; thereafter some of these cells remain on the alert for the pathogen, ambushing it with antibody molecules directed to the recognized targets with other weapons before the menace can cause illness Investigators didn't expect development of a vaccine against schistosomiasis to be as difficult as it has been The worms' life cycle suggested the parasites would be a soft target for our mighty immune system, yet they turn out to be anything but simple to handle One reason schistosomes initially seemed like they should be an easy target is that they're relatively large and make no effort to find hiding places in the body Unlike microscopic bacteria & viruses, schistosomes are big enough to be viewed by the naked eye; an adult is a cm long The worms that start an infection on day 1 are the same ones present days, years or even decades later; inside the human body their #s don't grow, except by new infections Evolution has chosen a hostile home for schistosomes Lying exposed in the bloodstream wouldn't appear to be an ideal habitat for a parasite Blood, though nutritious, is a major conduit for all the forces of immunity, which, somehow, the worms avoid Beyond being big & brazen, schistosomes possess other features that suggest the immune system could be induced to recognize them if conditions were right Globally, an estimated 200 million people are infected (20 million severely) & 200,000 die annually The schistosome species that cause human disease don't multiply in people but can survive in their blood for 30-40 years The worms (flukes) spread in water, and in 1948 they incapacitated large #s of soldiers from the People's Republic of China who were preparing for an amphibious assault on Taiwan (formerly Formosa: "the fluke that saved Formosa") The body's strong reaction to their eggs is one sign of this possibility There is nothing intrinsically immunologically invisible about the molecules that make up the worms Lethally wounded schistosomes serve as effective vaccines, protecting the animal against later challenge by hundreds of healthy schistosomes, but using similarly prepared worms to vaccinate people is impractical Hope that vaccines can be created inexpensively & in abundance using a single schistosome molecule or a mixture of selected ones as their basis 3 separate species of schistosomes account for the vast majority of human disease: Schistosoma mansoni, S. haematobium & S. japonicum, so the ideal vaccine would work against all 3 For now, researchers are focusing on finding a vaccine that can ward off infection by one species before trying to knock all of them down in one fell swoop To date, several schistosome molecules have been explored as vaccines but none has proved strongly effective; one, though, has performed well enough to enter large, phase III (final) clinical trials Knowing how schistosomes typically escape immune detection is important if we're to develop vaccines that can overcome that propensity The parasites have several tricks at their disposal that may explain their seeming invisibility to our defenses One is that they come armed with various molecules that may let them disable or "blind" the immune system Some schistosome molecules can, at least in a test tube, inhibit proliferation of immune cells or induce the cells' death Some newly identified schistosome genes look like human ones that're switched on in immune cells 3 schistosome species cause most human infections (schistosomiasis); because the parasite spreads in water contaminated by urine or feces, it is most common in places that lack sanitation systems (some 85% of cases occur in sub-Saharan Africa) Schistosomes likely originated in Asia & then dispersed to India & Africa; they jumped to the Americas in the blood of African slaves The worms lack an anus, so they vomit wastes out the mouth, for the host's bloodstream to whisk away Females don't mature unless they have contact with males; removed from a male's slit, a female will physically regress Schistosomes that sicken humans replicate in aquatic snails Governments could help limit the worms' spread by eradicating snails from freshwater & by preventing them from colonizing new bodies of water, like lakes formed when dams are built Many fear construction of the Three Gorges Dam in China will foster new schistosome infections In snails, schistosome larvae often compete with other parasites, some of which like to munch on the larvae Researchers are considering trying to reduce schistosome populations by seeding ponds with these competitors Schistosome species that mainly infect water birds can cause a rash (swimmer's itch) in the US & elsewhere Other genes encode receptors, or docking sites, that are closely related to human receptors that bind small molecules called cytokines (which control the activity of immune cells) or hormones (which convey messages between cells over longer distances) The parasites would benefit from intercepting signaling molecules that help our bodies to react to infection The worms presumably use their receptors to essentially spy on intercellular chatter, to gain info about the state of their enviro & to prepare counteractive measures before immune cells have a chance to strike Schistosomes also possess what seems to be a cloak of invisibility: an unusual covering known as the tegument The outer part of the tegument sports a second, external membrane that contributes to the parasite's ability to hide The tegument provides ample protection to the worm as it migrates through our blood, but in the hands of scientists, it's extraordinarily fragile (so, hard to study) We do know this outer coat can actually acquire human molecules from the blood It is possible to detect our own blood-group molecules (which establish the familiar blood types A, B, etc) attached to the worm's surface A controversial idea is these stolen human molecules could act as a disguise, covering the parasite's own molecules & making them invisible to immune surveillance Reinfection by schistosomes is common even after successful treatment because few individuals develop protective immunity & because in many areas, such as Morogoro, Tanzania, people have little choice but to wash clothes, bathe or cool off in infested water; the high rate of reinfection underscores the urgent need for a preventive vaccine For decades, researchers have tried to pierce this impressive armor of disappearing tricks using the classic tools of molecular biology: isolating schistosome proteins & their genes one by one, then trying to discern the proteins' functions & turn those molecules into effective vaccines Now this slow and meticulous process may be thrown into higher gear by new technologies & the approaches they make possible Overcoming the known, yet undiscovered, schistosome evasions would be vastly accelerated by having a cataloge of all the worm's proteins Schistosome researchers are eager to decipher the organism's genome, the complete sequence of DNA codes it uses as a blueprint for constructing every protein it contains But like so much else about these creatures, this goal initially proved elusive For one thing, the schistosome genome, with more than 300 million nucleotide base pairs, is the largest parasitic genome biologists have yet attempted to sequence In an international effort, the genome of S. mansoni has recently been sequenced, & the sequence is available online for all to analyze; the Chinese National Human Genome Center in Shanghai is further closing in on a listing of all of S. japonicum's active genes One great advantage of revealing the full schistosome genome is every gene can now be seen in context of this organism's entire genetic background We have learned the parasite has more than 1 version of some proteins that vaccines could potentially target; this variety might allow schistosomes to function in spite of vaccine-induced immune activity by using the nontargeted version Genomic analysis can now identify common structural features shared by such proteins so that those features might be incorporated in a vaccine & thus prevent the worms from escaping immune attack Recognition of TSP-2 is a component of rare, natural immunity to schistosomes & that the protein might be useful for eliciting protective immunity in a vaccine as well If molecules that fail to evoke an immune response in the human body during an infection are presented to the immune system in the right way, they can, at times, elicit a strong protective response Along with examining the schistosome genome, researchers are working to understand the functions of the proteins made by the parasites; such info can help pinpoint which proteins might be the most reasonable to pursue as vaccine candidates Molecules that the worm always requires to survive or to make eggs in the human body could be useful, because an immune response targeted to them should in principle be deadly to the parasite or limit the destructive egg production Certain molecules are potentially very attractive as vaccine targets because prompting immunity against them could both direct a damaging attack against the parasite (since these proteins are on its surface) & impede its ability to absorb food from the blood A focus on function has also raised the possibility of making a vaccine from proteins that the parasites secrete Until recently, standard tools for shutting off genes didn't work in schistosomes, but it's now possible to silence the genes of secreted proteins & other schistosome proteins to probe their function Going forward, vaccine researchers will have other new tools for uncovering schistosome proteins' function, where they reside & when in the parasite's life cycle they're made Researchers are developing methods for genetically engineering worms, making it possible to add distinctive tags to a selected parasite protein; such tags will allow scientists to easily track the protein's production and location; this technique could put to rest the question of which proteins normally reside in the tegument and protrude from its surface Various groups have created devices called DNA microarrays (gene chips) that can reveal which mixtures of schistosome genes are switched on at each stage of development The many fresh approaches to studying the parasite may yield benefits beyond ideas for vaccines Knowing this organism's complete genetic makeup should help pinpoint proteins that are unique to schistosomes & crucial for their survival; novel drugs might then be found that act on those proteins to defeat the worm The path from all this new knowledge & know-how to an effective vaccine or treatment isn't straightforward or certain; success will depend on researchers' intellect, intuition, dumb luck, & the level of funding governments & foundations provide Schistosome eggs do harm by working their way into tissues & eliciting destructive immune reactions Responses to S. mansoni & S. japonicum eggs often compromise the liver/intestines & can also lead to bloody diarrhea, lethal internal bleeding &, possibly, colon cancer Responses to S. haematobium eggs can damage the urinary tract & kidneys & may induce bladder cancer The intricate life cycle of the schistosome includes multiplying in snails & laying eggs in a person's blood; those eggs account, by & large, for the long-term effects of infection Schistosome eggs produced in infected individuals enter freshwater in urine or feces -> snail-invading larvae called miricadia hatch from the eggs -> larvae in snails reproduce & morph repeatedly, ultimately into a human-infecting form -> released larvae (cercariae) swim to a new victim, usually emerging in midday to maximize the chance of finding a host -> cercariae bore through the skin (despite being toothless), transform into schistosomula & enter veins -> schistosomula float to the liver circulation, where they pair up & mature into adults -> worm pairs migrate (against the flow of blood) to distant sites to lay eggs -> eggs lodge in the intestines or bladder & enter feces or urine, restarting the cycle In experimental animals, schistosomes can prevent or ameliorate a range of debilitating autoimmune disorders, such as Crohn's disease, which causes chronic intestinal inflammation (colitis) in humans After mice with colitis were injected with schistosome eggs, they suffered less intestinal swelling and were better protected from lethal inflammation than other mice were The eggs and Crohn's disease invoke diametrically opposite immune responses In this immunological tug-of-war, the response elicited by the eggs has the upper hand Investigators are now hunting for the molecules that elicit these responses, because some might be valuable as therapies for autoimmune diseases Schistosomes have many ways of evading the immune system; to make successful vaccines, investigators will need to find worm molecules that when delivered to humans will elicit immune responses not defeated by such subterfuges How worms hide in plain sight: - Larvae release molecules that cripple (disarm) immune cells needed to clear the larvae - Adult worms in the blood are covered by an unusual skin, the tegument, that displays few parasite proteins on its outer membrane; as a result, the immune system usually takes little notice of the adults - Human molecules, such as those that determine blood type, can stick to the surface of the worms, possibly helping to further shield the parasites from notice by the immune system The vaccine candidate in the most advanced stage of human testing relies on the schistosome protein glutathione S-transferase (Sm28GST) to awaken an immune attack targeted to schistosomes In some trials of this vaccine in animals, fewer worms than usual survived, and those that did produced fewer eggs Recent work has identified other schistosome proteins having promise as vaccines Those called tetraspanins peek through the outer surface of adult worms & so can provide clear targets for immune defenses Tetraspanin vaccines have provided some protection from infection in animal trials Other leads include nutrient transporters (which have to contact the host's blood directly to access nutrients and thus should be accessible to the immune system), as well as molecules secreted by the parasites to maintain infection—such as proteins that degrade host molecules or dampen antiparasite immunity

What 3 factors explain why HIV is more common in the South?

Poverty, culture, and prejudice

Treatment for schistosomiasis

Praziquantel: kills adult worms Treating symptoms for complicated cases may require hospitalization and/or supportive care

Prophylaxis

Pre-exposure A new HIV prevention method in which people who do not have any

Polio (basics)*

Real name: Poliomyelitis Majority: passing non-specific illness (i.e. fever) Minority: neurological symptoms Small minority: lasting neurological damage

TB (book notes)

Remains the cause of over 1.5 million deaths per year despite a reduction over the past 2 decades Most infection occurs in tropical regions but there are also a significant number of patients in of patients in Europe & the USA, often in poorer, homeless populations and in HIV-infected patients The HIV pandemic has caused a huge global increase in cases, particularly in sub-Saharan Africa The emergence of multidrug resistant (MDR) TB and extensively drug resistant TB is a new barrier to improving global control MTB is spread by respiratory droplets; transmission occurs from close proximity to an infected individual Household contacts of patients with M. TB in their sputum have a ¼ chance of becoming infected; clinical disease develops in 5-15% of those infected, & this risk is higher in HIV Following inhalation of organisms, multiplication occurs in subpleural and mid-zone terminal airspaces Bacteria ingested by alveolar macrophages survive and spread to local lymph nodes Bloodstream spread occurs to the lung apices and other orgams, where latent infection may infection spread may persist for many years The slow development of a cellular immune response leads to TB granulomas in tissues and cutaneous hypersensitivity to mycobacterial antigens Exposure occurs in childhood endemic areas, but in later life in most western regions The immune response limits damage to a localized area of the lung hilar node involvement, termed the primary on Ghon focus: calcification may subsequently be of primary infection in adolescent and adults, although primary pulmonary TB does occur 80% of TB used to be pulmonary, but the proposition of extrapulmonary disease is increasing and is over 50% in HIV patients The majority of cases are the results of reactivation; reinfection also occurs The major symptoms are cough, weight, loss, malaise, fever and night sweats Haemoptysis occurs in a third; examination findings are often unremarkable The CXR is usually abnormal, classically, apical disease with infiltration and cavitation that heals with fibrotic changes Complications include severe hemoptysis, bronchopleural fistula and aspergilloma within cavities Pleural TB: commonly occurs after primary infection; there are systemic symptoms, cough and pleuritic pain Unilateral effusions are common Often self-limiting, sometimes with resolution of symptoms Most develop active disease within 3 years Lymph node TB: occurs after primary infection, reactivation and contagious spread Cervical in 70%; systemic symptoms occur in 30-60% Painless discrete nodes enlarge in size and become matted Nodes eventually break down with discharging sinuses and chronic skin lesions Bone/joint TB: affects any bone or joint Most common form is spinal (Pott's disease) Vertebral destruction leads to collapse and, sometimes, severe angulation of the spine (gibbus) Paravertebral absences may occur Watch for cord compression; most can be treated medically TB meningitis: important; there's a risk of permanent neurological damage or death if not treated promptly Initial bloodborne spread, followed by rupture of focus into the cerebrospinal fluid (CSF) There are non-specific symptoms for 2-8 weeks, with onset that's often insidious Fever and headache are prominent Mild neck stiffness, cranial nerve palsies, papilloedema and long tract signs also occur; seizures are common in children Differential diagnosis: fungal or partially treated bacterial meningitis, cerebral abscess Pericardial TB: usually caused by spread from the lungs or mediastinal lymph nodes; there are 3 clinical syndromes: acute pericarditis effusion, chronic pericardial effusion, and chronic constrictive pericarditis Systemic symptoms, shortness of breath and signs of effusion/constriction may occur; pericardial calcification (late) on CXR may be seen in constrictive pericarditis; echocardiography is helpful Miliary TB: disseminated disease from blood spread in those with underlying chronic disease or immunosuppression Insidious nervous symptoms: weight loss, fever, malaise Pulmonary, central nervous system and liver involvement are most frequent Choroidal tubercles (15%) are pathognomonic Classic CXR; multiple 1-2 mm nodules in lung fields Miliary TB: Definitive diagnosis depends upon demonstrating or culturing the organism Pulmonary TB is normally diagnosed by Ziehl-Neelsen staining of acid-fast bacilli (AFB) in the sputum; culture of samples on selective media (takes up to 8 weeks) Open TB describes the presence of AFB in sputum Extrapulmonary TB Mantoux test Treatment: short-course chemotherapy (6 months) is given for most forms of TB; longer courses may be needed for TB meningitis and bone/joint TB Combinations of 4 drugs are used to prevent the development of resistance The clinical response to therapy may be important in confirming the diagnosis; reductions in fever and weight gain are helpful Steroids are of proven benefit in pericardial disease and are commonly used in TB meningitis and genitourinary Resistance to individual TB drugs is a major clinical problem in some countries, particularly in eastern Europe, the former Soviet states, and some African countries Some isolates are resistant to multiple drugs The risk of MDR TB is increased in patients who've had previous treatment, contact with resistant disease, or who are from the prison population Prolonged treatment with second- and third-line agents is necessary, with a poor response in many patients Surgery is useful for chronic constrictive pericarditis, Pott's disease if there is severe cord compression or spinal instability and intractable haemoptysis or bronchopleural fistula Infection control issues need to be considered; those with smear-positive TB should be isolated for the first 2 weeks of treatment and if factors suggest the possibility of MDR TB, special precautions must be taken Diagnosis: high index of suspicion, organisms seen/grown, response to empirical treatment Complications: cavitation (late developments of aspergilloma), pleural effusion, TB empyema with bronchopleural fistula, massive haemoptysis High-risk groups: developing world residents, ethnic minorities in the UK, contact of sputum-positive cases, poverty, overcrowding, malnutrition, alcoholic, HIV positive, diabetes, haematological malignancy, steroids Symptoms: persistent cough, haemoptysis, pleurisy, tiredness, chronic ill health, weight loss, fever of unkwn origin (FUO)

Putting the Patient Back Together — Social Medicine, Network Medicine, and the Limits of Reductionism (reading notes)

Research & clinical practice has begun to shift away from universal models of disease that generalize from close examination of diseased parts (organs, tissues, cells, or molecules) to an approach that celebrates "personalized medicine" & focuses on the whole person as a unit of analysis Superficially, this transition appears to mark a return to the early modern conception of the patient as "sick person," whose disease was considered inseparable from his/her complex constitutional inheritance & lived experience Yet in practice, personalized medicine still tends to reduce the patient to a collection of precise molecular sequences with detailed clinical phenotyping (precision medicine) As biomedical research & clinical practice try to assemble atomized pieces into meaningful wholes, the process of putting the patient back together again has proven to be highly complex One disappointment of the postgenomic age is how little the Human Genome Project has taught us to date about human disease Only a small minority of diseases are caused by monogenic (or oligogenic) disorders Instead, complex interactions among numerous genetic and enviro factors determine disease phenotype These observations, coupled with the increasing availability of bioinformatic data & high throughput interaction screening, have led to calls for a new science of "network medicine" focused on the interrelational structures emerging from complex interactions among genes, proteins, internal milieu, & external enviro Network biologists echo a lineage of critical medical history, sociology, & anthropology that's long argued that biomedical reductionism misses crucial aspects of the etiology, pathobiology, prognosis, & treatment of human disease Critiques of reductionism by clinicians & social scientists & those from biology & complexity science seem to ignore each other almost completely A potentially productive intersection between the 2 intellectual streams has important implications for our post-omic future Although reductionism in scientific thought can be traced back far, it was perhaps most clearly articulated in Nagel's 1949 essay which described reduction as the clarification of one field using the tools of another, more fundamental, field (i.e. the explication of biologic phenomena using the principles of physics) Subsequent debates over reductionism in the physical sciences addressed the question of if one science can be "reduced" to another or if independent fields of knowledge display irreducible or emergent properties Reductionism in medical science & practice is often equated with older conceptions of disease as something that can be separated from the sick person & scrutinized with successively finer analytic tools This ontological approach to disease, studying diseases as knowable categories that exist in the world, was at the heart of the empirical observation championed in the 17th century by Thomas Sydenham, who maintained that to discover specific remedies for specific diseases, "it is necessary that all diseases be reduced to definite/certain species with the same care which we see exhibited by botanists in their phytologies" Historians of medicine have mapped the history of disease specificity as successive reductions in the scope of lesions: as analysis becomes more refined & narrower, the power of biomedical explanations & interventions increases The long arc of reductionism in medicine: 18th century (sick person, phthisis), early 19th century (lesions of organs & tissues), late 19th century (lesions of cells & microbes, M. TH), late 20th century (lesions detected at a molecular level; interferon testing), 21st century (the challenge of reassembly) By the 19th century, a science of cellular pathology reduced the scope of the lesion still further, & the 20th century saw exploration of molecular bases of disease A similar logic of reductionism within diagnostics & therapeutics followed an early 20th-century vision of "magic bullets" that might single out disease while sparing healthy host tissue, simultaneously giving rise to the "receptor" theory in pharmacology & immunology & the hope every disease might contain a single specific target for powerful, selective, tailored chemotherapeutics The importance of visualizing disease through lenses of increasing magnification was reflected in the new genre of the clinicopathological conference (CPC), which begins with a patient's relation of a subjective history of problems, followed by an objective exam of pathological signs visible to physicians either directly (physical) or indirectly (through lab & imaging tests) The conclusion is traditionally a pathology specimen, analyzed first grossly, then microscopically at the level of tissue, cell, molecule, & today genome/proteome As a weekly ritual in hospitals & medical journals, the CPC recapitulates the diagnostic & therapeutic power & the objectification/alienation inherent in biomedical reductionism The history of TB demonstrates the transformative power of such reductionism In the 19th century, pathological characterization of TB lesions defined the disease & unify its local manifestations (scrofula, Pott's disease, etc.) into a single category Lesions were subjected to increasingly specific analysis, but this approach has limitations Reductionism attracted strong critics both inside and outside medicine In the late 19th & early 20th centuries, many other scientists warned that no diagnostic or therapeutic advance would make up for losing sight of the patient as a whole person By the mid-20th century, the history of TB attracted revision In his 1952 book, Dubos reassessed the relevance of reductionist knowledge to the epidemiology of TB; given that nearly 100% of urban populations in 1882 had been exposed to TB, how could mere exposure to the bacterium be the most important determinant of who survived & who died from the disease? Dubos suggested reduction ignored social determinants of TB morbidity & mortality, like nutrition, occupation, & social geography McKeown argued that the clinical & public health claims of biomedical reductionism were grossly overstated & that most of these mortality decreases reflected the roles of nutrition and economic development critiques of reductionism questioned both the prominence of materialism in biomedical approaches to disease & the loss of the person as an individual in a knowledge system that privileges the atomization of the body In recent years, biomedical researchers have increasingly encountered limits of biomedical reductionism as a means of understanding biology & disease A reductionist focus on 1 or a few genetic variants is misleading even for classic mendelian disorders, since a single genetic variant rarely predicts a true complex path phenotype precisely Even the prototypical monogenic disorder of sickle cell disease presents as multiple phenotypes: patients may appear well or present with mild anemia, aplastic anemia, or stroke syndromes, among others Other genetic and environmental factors contribute to the pathophenotype of even simple, monogenic diseases, modulating the presentation, disease course, & response to therapy Whereas some "disease-modifying" genes contribute to phenotypic variations, many more environmental, epigenetic, & proteomic factors affect disease expression The biomedical community is hindered by reductionist approaches whose application to disease is repeatedly foiled by biologic complexity The pharmaceutical industry's dwindling product pipeline further illustrates the limits of reductionism Drug targets operate within a network of interacting biologic structures; a narrow focus on the target fails to consider other potential downstream effects of treatment Without knowledge of the broader network context of disease & drug, one can't develop meaningful approaches to addressing complex disease pathways, like cancer's development of resistance to precision therapy It's important to reconceive biologic & pathobiologic phenomena in terms of complex networks of interacting genes or gene products and layers of environmental modulators Any set of complex interacting elements, including genes, proteins, or metabolites, can be topologically depicted as a set of nodes (elements) & their links (processes that govern their interactions) Most biologic systems are clustered, or scale-free: a few nodes are highly connected to others, while most are weakly connected to the network Mutations or polymorphisms in weakly connected nodes (genes) account for normal biologic variability and complex illness, whereas those in highly connected genes (hubs) lead to early death of an organism These structures help explain the organism's ability to accommodate metabolic perturbations and many biologic errors in DNA replication or transcription with minimal functional consequences Another property of biologic networks is emergence: their behavior can't be predicted on the basis of a reductionist understanding of their component parts For decades, investigators have focused on 1 gene, transcription factor, or enzyme, gleaning a thorough understanding of its function but rarely in the context in which it normally operates Before the omic revolution, this approach reflected our limited knowledge of biologic networks' elements & the limitations of quantitative & computing methods In the past decade, these limitations have diminished, & a holistic study of network medicine has become more achievable The arc we've traced from holism to reductionism & back again isn't a full circle; it's been affected by other, more linear developments of disciplinary fragmentation & increasing technological dependence in the biomedical sciences Any strict distinction between holism & reductionism in medicine is now doubly complicated by critiques from network science & from clinical/social sciences To speak of any whole is to define the parts as well: a holistic vision of network medicine is itself dependent on a field of atomized parts, including genes, proteins, digital data sources, and computational infrastructures Yet with an appreciation of these limitations and a sustained commitment to asking what is being rendered invisible, as well as visible, by any given network model, a biosocial approach to medicine promises increased understanding and predictability of the complexity governing human biology and disease Network science can help us understand human disease at both micro and macro levels, yet it's limited by decisions about what's included in, & excluded from, the data it uses Network analyses of disease & treatment have provided insights into novel approaches to disease classification, the identification of inflammatory network determinants of many chronic diseases and infection outcomes, and polypharmaceutical treatment strategies and otherwise-unpredictable drug side effects Complex disease cannot be viewed as caused by a single gene or gene product that can be targeted in drug development Network analysis can also potentiate an understanding of the social & political contexts within which behaviors or environmental exposures contribute to disease development Unlike earlier "biopsychosocial" approaches, which quickly replicated a dualism of "bio" as "hard science" and "psychosocial" as "soft science," network medicine offers a potentially synthetic arena for interactions of genomic, environmental, & social determinants of disease We might consider this analysis a biosocial approach, in which biologic & social dimensions of causation are seen as equally important in producing a 3D understanding of disease The 2 separate critiques of reductionism may be converging toward work that could illuminate both the network biology & social science understandings of health & disease Social science critiques that fail to recognize the anti reductionist developments within biomedical science increasingly attack a straw man Network medicine can benefit from and include these perspectives only if social factors are viewed as important determinants of disease In the arc of Western understandings of disease that began with the holism of the sick person & then atomized it into units of pathology, we're attempting a reassembly or reconstruction The task of putting the patient back together again will be complex, arduous, & time consuming, but it promises a new articulation of the biologic and social sciences that are inextricably linked and essential to the advancement of medicine

Totally Drug Resistant Tuberculosis (TDR TB)

Responds to no available treatment It's been noted in individual cases for some time, but in 2012 at least 12 new cases were found in India The cases are a story of mismanagement Resistance is man-made, caused by exposure to the wrong treatment, the wrong regimen, the wrong treatment duration

Sick of Poverty (reading notes)

Researchers have long known that people with low socioeconomic status (SES) have dramatically higher disease risks & shorter life spans than people in the wealthier strata of society The conventional explanations (that the poor have less access to health care & a greater incidence of harmful lifestyles like smoking & obesity) cannot account for the huge discrepancy in health outcomes New studies indicate that the psycho-social stresses associated with poverty may increase the risks of many illnesses The chronic stress induced by living in a poor, violent neighborhood, for example, could increase one's susceptibility to cardiovascular disease, depression & diabetes Other studies show a correlation between income inequality & poor health in the US Some researchers believe the poor feel poorer, & hence suffer greater stress, in communities with wide gaps between the highest and lowest incomes ... New studies suggest the stress of being poor has a staggeringly harmful influence on health The spread of disease has much to do with appalling living conditions, & those in power have enormous means to conquer the powerless As Virchow summarized in his famous epigram, "Physicians are the natural attorneys of the poor" Physicians (and biomedical scientists) are advocates of the underprivileged because poverty and poor health tend to go hand in hand Poverty means bad or insufficient food, unhealthy living conditions & endless other factors that lead to illness Yet it's not merely that poor people tend to be unhealthy while everyone else is well When you examine socioeconomic status (SES), a composite measure that includes income, occupation, education & housing conditions, it becomes clear that, starting with the wealthiest stratum of society, every step downward in SES correlates with poorer health An SES gradient has been documented throughout Westernized societies for problems including respiratory & cardiovascular diseases, ulcers, rheumatoid disorders, psychiatric diseases & many of cancers; it isn't a subtle statistical phenomenon If you compare the highest vs. the lowest rungs of the SES ladder, the risk of some diseases varies 10-fold Some countries exhibit a 5-10 year difference in life expectancy across the SES spectrum Of the Western nations, the US has the steepest gradient (the poorest white males in America die about a decade earlier than the richest) Lower SES may give rise to poorer health, but poorer health could also give rise to lower SES After all, chronic illness can compromise one's education and work productivity, in addition to generating enormous expenses The bulk of the facts suggests that the arrow goes from economic status to health, that SES at some point in life predicts health measures later on Nun study: all took their vows as young adults & spent many years thereafter sharing diet, health care & housing; yet in their old age, patterns of disease, incidence of dementia and longevity were still significantly predicted by their SES status from when they became nuns, at least half a century before SES's effect on health may be due to the poor having less easily accessible & lower quality health care; but that explanation soon falls by the wayside Whitehall studies show that low-ranked British civil servants (office messengers & other support staff) are almost 2x as likely to die from heart disease as administrators of the same age; differences in risk (i.e. higher smoking rates among the support staff) account for less than ½ the gap in mortality rates Lack of access to medical attention cannot explain the phenomenon, because the UK, unlike the U.S., has universal health care SES gradients exist for diseases for which health care access is irrelevant No amount of medical checkups, blood tests & scans will change the likelihood of someone getting type 1 (juvenile-onset) diabetes or rheumatoid arthritis, yet both are more common among the poor The next "obvious" explanation centers on unhealthy lifestyles As you descend the SES ladder in Westernized societies, people are more likely to smoke, drink excessively, be obese, & to live in a violent or polluted or densely populated neighborhood Poor people are also less likely to have access to clean water, healthy food & health clubs, not to mention adequate heat in the winter and AC in the summer It seems self-evident that lower SES gets under the skin by increasing risks & decreasing protective factors It's surprising how little of the SES gradient these risk/protective factors explain In the Whitehall studies, controlling for factors like smoking & level of exercise accounted for only a third of the gradient Among the wealthiest quarter of countries on earth, there's no relation between a country's wealth and the health of its people; thus, health care access, health care utilization, & exposure to risk/protective factors explain the SES/health gradient far less well than one might've guessed One must therefore consider whether most of the gradient arises from a different set of considerations: the psychosocial consequences of SES Chronic stress may explain how poverty gets under the skin & exerts a harmful influence on health The risk of stress-sensitive diseases increases if individuals lack social support, have no outlets for their frustration & feel their circumstances are worsening, exactly the conditions in many US poor communities Ideally, the body is in homeostatic balance, a state in which the vital measures of human function (heart rate, blood pressure, blood sugar levels) are in their optimal ranges A stressor is anything that threatens to disrupt homeostasis For most organisms, a stressor is an acute physical challenge (ie the need for an injured gazelle to sprint for its life or for a hungry predator to chase down a meal) The body is very adapted to dealing with short-term physical challenges to homeostasis But cognitively & socially sophisticated species, such as us primates, routinely inhabit a different realm of stress For us, most stressors concern interactions with our own species, & few physically disrupt homeostasis Instead these psychosocial stressors involve the anticipation (accurate or otherwise) of an impending challenge & the striking characteristic of such psychological and social stress is its chronicity For most mammals, a stressor lasts only a few minutes; but humans can worry chronically over a 30-year mortgage Our body's response, though adaptive for an acute physical stressor, is pathogenic for prolonged psychosocial stress Chronic increase in cardiovascular tone brings stress-induced hypertension The constant mobilization of energy increases the risk or severity of diseases like type 2 (adult-onset) diabetes The prolonged inhibition of digestion, growth, tissue repair & reproduction increases the risks of various gastrointestinal disorders, impaired growth in children, failure to ovulate in females & male erectile dysfunction A too-extended immune stress response ultimately suppresses immunity & impairs disease defenses Chronic activation of the stress response impairs cognition, & health, functioning, survival of some neuron types Individuals are more likely to activate a stress response and are more at risk for a stress-sensitive disease if they (a) feel as if they have minimal control over stressors, (b) feel they have no predictive info about the duration/intensity of the stressor, (c) have few outlets for the frustration caused by the stressor, (d) interpret the stressor as evidence of circumstances worsening, & (e) lack social support for the duress caused by the stressors Psychosocial stressors aren't evenly distributed across society Just as the poor have a disproportionate share of physical stressors (hunger, manual labor, chronic sleep deprivation with a second job, the bad mattress that can't be replaced), they have a disproportionate share of psychosocial ones An occupational lifetime spent taking orders erode workers' sense of control; unreliable cars that may not start in the morning and paychecks that may not last the month inflict unpredictability Poverty rarely allows stress-relieving options like health club memberships, costly but relaxing hobbies, or sabbaticals for rethinking one's priorities Despite the heartwarming stereotype of the "poor but loving community," the working poor typically have less social support thanks to the extra jobs, long commutes on public transit, & other burdens Regardless of SES, the less autonomy one has at work, the worse one's cardiovascular health Low control in the workplace accounts for about half the SES gradient in cardiovascular disease 3 lines of research provide more support for the influence of psychological stress on SES-related health gradients Subjects were shown a diagram of a ladder with 10 rungs and then asked, "In society, where on this ladder would you rank yourself in terms of how well you're doing?" The very openness of the question allowed the person to define the group that felt most emotionally salient A person's subjective assessment of his/her SES takes into account the usual objective measures (education, income, job & residence) as well as measures of life satisfaction and of anxiety about the future Subjective SES is at least as good as objective SES at predicting patterns of cardiovascular function, measures of metabolism, incidences of obesity & levels of stress hormones, suggesting that the subjective feelings may help explain the objective results A relatively poor person in the U.S. may objectively have more financial resources to purchase health care & protective factors than a relatively wealthy person in a less developed country yet, on average, will still have a shorter life People in Greece on average earn ½ the income of Americans yet have a longer life expectancy Once the minimal resources are available to sustain a basic level of health through adequate food and housing, absolute levels of income are of remarkably little importance to health Although the study suggests the objective state of being poor adversely affects health, at the core of that result is the subjective state of feeling poor The human body is superb at responding to the acute stress of a physical challenge, like chasing down prey or escaping a predator; the circulatory, nervous/immune systems are mobilized while the digestive and reproductive processes are suppressed If the stress becomes chronic, though, the continual repetition of these responses can cause major damage Effects of acute stress Brain: Increased alertness & less perception of pain Thymus Gland & Other Immune Tissues: Immune system readied for possible injury Circulatory System: Heart beats faster, blood vessels constrict to bring more oxygen to muscles Adrenal Glands: Secrete hormones that mobilize energy supplies Reproductive Organs: Reproductive functions are temporarily suppressed Effects of chronic stress: Brain: Impaired memory & increased risk of depression Thymus Gland & Other Immune Tissues: Deteriorated immune response Circulatory System: Elevated blood pressure & higher risk of cardiovascular disease Adrenal Glands: High hormone levels slow recovery from acute stress Reproductive Organs: Higher risks of infertility & miscarriage Income inequality appears to exacerbate the stress of poverty; as the divide between the rich and poor grows wider, social support typically becomes less available and the frustrations of the poor intensify A community's income inequality is even more predictive than SES for an array of health measures Absolute levels of income aside, greater disparities in income between the poorest and the wealthiest in a community predict worse average health Originally suggested income inequality was relevant to health in many European & North American countries & communities; it's become clear, however, this holds only in the developed country with the greatest of income inequalities (US) Whether considered at the level of cities or states, income inequality predicts mortality rates across nearly all ages in the US; why, though, isn't this relation observed elsewhere? 1 possibility is these countries have too little income variability to tease out correlation Some critics have questioned if the linkage between income inequality & worse health is merely a math quirk The relation between SES & health follows an asymptotic curve: dropping from the uppermost rung of society's ladder to the next-to-top step reduces life expectancy & other measures much less drastically than plunging from the next-to-bottom rung to the lowest level Because a community with high levels of income inequality will have a relatively high # of individuals at the very bottom, where health prospects are so dismal, the community's average life expectancy will inevitably be lower than that of an egalitarian community, for reasons that have nothing to do with psychosocial factors Wilkinson has shown that decreased income inequality predicts better health for both the poor & the wealthy, indicating the association between illness & inequality is more than just a mathematical artifact Wilkinson & others have long argued that the more unequal income in a community is, the more psychosocial stress there'll be for the poor Higher income inequality intensifies a community's hierarchy & makes social support less available: truly symmetrical, reciprocal, affiliative support exists only among equals Having your nose rubbed in your poverty is likely to lessen your sense of control in life, to aggravate the frustrations of poverty & to intensify the sense of life worsening If Adler's work demonstrates the adverse health effects of feeling poor, Wilkinson's income inequality work suggests that the surest way to feel poor is to be made to feel poor: to be endlessly made aware of the haves when you are a have-not In our global village, we're constantly made aware of those whose resources dwarf ours Spending money on public goods (better public transit, universal health care) is a way to improve the quality of life for the average person, but, the bigger the income inequality in a society, the greater the financial distance between the average & wealthy The bigger this distance, the less the wealthy have to gain from expenditures on the public good (instead they'd benefit more from keeping their tax money to spend on their private good: a better chauffeur, a gated community, bottled water, private schools, private health insurance) So the more unequal the income is in a community, the more incentive the wealthy will have to oppose public expenditures benefiting the health of the community; in the US, the more income inequality there is, the more power will be disproportionately in the hands of the wealthy to oppose such public expenditures This scenario ultimately leads to "private affluence & public squalor" This "secession of the wealthy" can worsen the SES/health gradient in 2 ways: by aggravating the conditions in low-income communities (which account for at least part of the increased health risks for the poor) & by adding to the psychosocial stressors If social and psychological stressors are entwined with feeling poor, & even more so with feeling poor while being confronted with the wealthy, they'll be even more stressful when the wealthy are striving to decrease the goods and services available to the poor A third branch of support for psychosocial explanations for the relation between income inequality & health comes from Ichiro Kawachi, based on the concept of social capital (broad levels of trust & efficacy in a community) Do people generally trust one another and help each other? Do people feel an incentive to take care of commonly held resources (i.e. to clean up graffiti in public parks)? And do people feel that their organizations (i.e. unions) actually have an impact? Most studies of social capital employ 2 simple measures: how many organizations people belong to & how people answer a question such as, "Do you think most people would try to take advantage of you if they got the chance?" At the levels of states, provinces, cities & neighborhoods, low social capital predicts bad health, bad self-reported health & high mortality rates Using a complex statistical technique called path analysis, Kawachi has demonstrated that the strongest route from income inequality to poor health is through the social capital measures; to wit, high degrees of income inequality come with low levels of trust and support, which increases stress and harms health As a culture, America has neglected its social safety nets while making it easier for the most successful to sit atop the pyramids of inequality We've chosen to forgo the social capital that comes from small, stable communities in exchange for unprecedented opportunities for mobility and anonymity As a result, all measures of social epidemiology are worsening in the U.S. Of Westernized nations, America has the greatest income inequality (40% of the wealth is controlled by 1% of the population) & the greatest discrepancy between health care expenditures (#1 in the world) & life expectancy (as of 2003, number 29) When it comes to health, there's far more to poverty than simply not having enough money The psychosocial school has occasionally been accused of publicizing an antiprogressive message: don't bother with universal health care, affordable medicines & other salutary measures because there'll still be a robust SES/health gradient after all the reforms; but the lesson of this research is not to abandon such societal change... it's that so much more is needed The robin hood index is a measure of income inequality; it's the % of total community income that must be taken from the rich (those with above-average incomes) and given to the poor (those below the average) to achieve an equal distribution U.S. states with a high Robin Hood index also tend to have high mortality rates

IPV

Salk's inactivated polio vaccine, introduced in 1956 Injected kill virus

Schistosomiasis life cycle

Schistosome "cloaks" itself in host antigens during chistosomula (baby) stage Male & female flukes (worms) pair and mate in blood vessels; female can produce upwards of 3,000 eggs/day Mature flukes in intestine's blood vessels -> blood flukes reproduce sexually in human host, fertilized eggs exit host in feces -> eggs develop in water into ciliated larvae, larvae infects snails -> snail host -> asexual reporduction within snail results in another type of mortile larva -> larvae penetrates skin and blood vessels of humans Human (with adult worm) -> schistosome egg -> miracidia (free-swimming larva) -> snail (intermediate host) -> cercaria -> human

Global Trachoma Mapping Project

The largest infectious disease survey in history Uses modern techniques like smartphone technology to examine millions of people

Polio's target

The poliovirus targets spinal nerves controlling muscles Virus enters at nerve endings Virus travels to the nerve body and damages or destroys it When the virus attacks neurons in the brain stem, breathing is breathing is affected

Muscles commonly weakened by polio

Those that strengthen or bend hip, spread or close legs, straighten knee, lift foot, shoulder, behind arm (weakness raising arm), back muscles (either side or backbone), thumb

Explain the trend in malaria-related annual deaths

Use of quinine, early stages of vector control (moderate decrease in deaths from 1900s to 1930s) Significant DDT spraying (giant decrease in deaths to 1970s) Drug resistance increasing, limited vector control (moderate increasing to 2000s) Scaling up of vector control (decreasing again)

Importance of schistosomiasis's high morbidity rate

Usually non-fatal but debilitating disease Growth stunting, anemia in kids Liver or urinary tract problems: - Hepatomegaly (enlarged liver): 8.5 million in Africa - Bladder pathology: 18/10 million in Africa - #1 cause of (bladder) cancer in Egypt, Iraq, Kuwait

The Challenge of Antibiotic Resistance (reading notes)

Last year an event doctors feared finally occurred In 3 geographically separate patients, an often deadly bacterium, Staphylococcus aureus, responded poorly to a once reliable antidote, the antibiotic vancomycin Fortunately, in those patients, the staph microbe remained susceptible to other drugs & was eradicated But the appearance of S. aureus not readily cleared by vancomycin foreshadows trouble Worldwide, many strains of S. aureus are already resistant to all antibiotics except vancomycin Emergence of forms lacking sensitivity to vancomycin signifies variants untreatable by every known antibiotic are on their way S. aureus, a major cause of hospital-acquired infections, has moved 1 step closer to becoming an unstoppable killer The looming threat of incurable S. aureus is just the latest twist in an international public health nightmare: increasing bacterial resistance to many antibiotics that once cured bacterial diseases readily Ever since antibiotics became widely available in the 1940s, they've been hailed as miracle drugs Yet with each passing decade, bacteria that defy not only single but multiple antibiotics have become increasingly common Strains of at least 3 bacterial species capable of causing life-threatening illnesses (Enterococcus faecalis, Mtb & Pseudomonas aeruginosa) already evade every antibiotic in the clinician's armamentarium, a stockpile of more than 100 drugs In part because of the rise in resistance to antibiotics, the death rates for some communicable diseases (like TB) have started to rise again, after having declined in the industrial nations Several interacting processes are at fault Analyses of them point to a # of actions that could help reverse the trend, if individuals, businesses & governments around the world can find the will to implement them One component of the solution is recognizing bacteria are a natural, needed, part of life Bacteria: microscopic, single-cell entities, abound on inanimate surfaces & on parts of the body that make contact with the outer world, including the skin, mucous membranes & lining of the intestinal tract Most live blamelessly; they often protect us from disease, because they compete with, & limit the proliferation of, pathogenic bacteria; the minority of species that can multiply aggressively (into the millions) & damage tissues or otherwise cause illness. The benign competitors can be important allies in the fight against antibiotic-resistant pathogens People should also realize that while antibiotics are needed to control bacterial infections, they can have broad, undesirable effects on microbial ecology They can produce long-lasting change in the kinds & proportions of bacteria, & the mix of antibiotic-resistant & antibiotic-susceptible types, not only in the treated individual but also in the enviro & society at large The compounds should thus be used only when truly needed, & they should not be administered for viral infections, over which they have no power While many factors can influence if bacteria in a person or in a community will become insensitive to an antibiotic, the 2 main forces are the prevalence of resistance genes (which give rise to proteins that shield bacteria from an antibiotic's effects) & the extent of antibiotic use If the collective bacterial flora in a community have no genes conferring resistance to a given antibiotic, the antibiotic will successfully eliminate infection caused by any of the bacterial species in the collection On the other hand, if the flora possess resistance genes & the community uses the drug persistently, bacteria able to defy eradication by the compound will emerge & multiply Antibiotic-resistant pathogens aren't more virulent than susceptible ones: the same #s of resistant & susceptible bacterial cells are required to produce disease The resistant forms are harder to destroy Those that are slightly insensitive to an antibiotic can often be eliminated by using more of the drug; those highly resistant require other therapies To understand how resistance genes let bacteria survive an attack by an antibiotic, it helps to know exactly what antibiotics are & how they harm bacteria The compounds are defined as natural substances (made by living organisms) that inhibit the growth of bacteria or kill them directly In practice, most commercial antibiotics have been chemically altered in the lab to improve their potency or to increase the range of species they affect Aantibiotics, by inhibiting bacterial growth, give a host's immune defenses a chance to outflank the bugs that remain The drugs typically retard bacterial proliferation by entering the microbes & interfering with the production of components needed to form new bacterial cells The antibiotic tetracycline binds to ribosomes (internal structures that make new proteins) & impairs protein manufacture; penicillin & vancomycin impede proper synthesis of the bacterial cell wall Certain resistance genes ward off destruction by giving rise to enzymes that degrade antibiotics or that chemically modify & inactivate the drugs Some resistance genes cause bacteria to alter or replace molecules normally bound by an antibiotic; changes that eliminate the drug's targets in bacterial cells Bacteria might also eliminate entry ports for the drugs or, more effectively, may manufacture pumps that export antibiotics before the medicines have a chance to find their intracellular targets Bacteria can acquire resistance genes through a few routes Many inherit the genes from their forerunners Other times, genetic mutations, which occur readily in bacteria, will spontaneously produce a new resistance trait or will strengthen an existing one Frequently, bacteria will gain a defense against an antibiotic by taking up resistance genes from other bacterial cells in the vicinity The exchange of genes is so pervasive that the entire bacterial world can be thought of as a huge multicellular organism in which the cells interchange their genes with ease Bacteria have evolved several ways to share their resistance traits with one another Resistance genes commonly are carried on plasmids, tiny DNA loops that can help bacteria survive various hazards in the enviro But the genes may also occur on the bacterial chromosome, the larger DNA molecule that stores the genes needed for the reproduction and routine maintenance of a bacterial cell Often one bacterium will pass resistance traits to others by giving them a useful plasmid Resistance genes can also be transferred by viruses that occasionally extract a gene from one bacterial cell and inject it into a different one After a bacterium dies and releases its contents into the enviro, another will occasionally take up a liberated gene for itself In the last two situations, the gene will survive & provide protection from an antibiotic only if integrated stably into a plasmid or chromosome Such integration occurs frequently because resistance genes are often embedded in small units of DNA, transposons, that readily hop into other DNA molecules Many bacteria play host to specialized transposons, integrons, that are like flypaper in their propensity for capturing new genes These integrons can consist of several different resistance genes, which are passed to other bacteria as whole regiments of antibiotic-defying guerrillas Many bacteria possessed resistance genes even before commercial antibiotics came into use Scientists don't know exactly why these genes evolved & were maintained A logical argument holds natural antibiotics were initially elaborated as the result of chance genetic mutations Then the compounds, which turned out to eliminate competitors, enabled the manufacturers to survive & proliferate Later, these protective genes found their way into other species, some of which were pathogenic Regardless of how bacteria acquire resistance genes today, commercial antibiotics can select for (promote the survival & propagation of) antibiotic-resistant strains. By encouraging the growth of resistant pathogens, an antibiotic can actually contribute to its own undoing. When an antibiotic attacks a group of bacteria, cells that are highly susceptible to the medicine will die But cells that have some resistance from the start, or that acquire it later (through mutation or gene exchange), may survive, esp if too little drug is given to overwhelm the cells that are present Those cells, facing reduced competition from susceptible bacteria, will then go on to proliferate When confronted with an antibiotic, the most resistant cells in a group will outcompete all others Promoting resistance in known pathogens isn't the only self-defeating activity of antibiotics When the meds attack disease-causing bacteria, they also affect benign bacteria, bystanders—in their path They eliminate drug-susceptible bystanders that could otherwise limit the expansion of pathogens, & simultaneously encourage the growth of resistant bystanders Propagation of these resistant, nonpathogenic bacteria increases the reservoir of resistance traits in the bacterial population as a whole & raises the odds that such traits will spread to pathogens Sometimes the growing populations of bystanders themselves become agents of disease Widespread use of cephalosporin antibiotic has promoted the proliferation of the once benign intestinal bacterium E. faecalis, which is naturally resistant to those drugs In most people, the immune system is able to check the growth of even multi-drug resistant E. faecalis, so it does not produce illness But in hospitalized patients with compromised immunity, the enterococcus can spread to the heart valves & other organs & establish deadly systemic disease Administration of vancomycin over the years has turned E. faecalis into a dangerous reservoir of vancomycin-resistance traits Some strains of the pathogen S. aureus are multidrug-resistant & are responsive only to vancomycin Because vancomycin-resistant E. faecalis has become quite common, public health experts fear it'll soon deliver strong vancomycin resistance to those S. aureus strains, making them incurable The bystander effect has also enabled multidrug-resistant strains of Acinetobacter and Xanthomonas to emerge & become agents of potentially fatal bloodborne infections in hospitalized patients These formerly innocuous microbes were virtually unheard of just 5 years ago Antibiotics affect the mix of resistant and nonresistant bacteria both in the individual being treated & enviro When resistant bacteria arise in treated individuals, these microbes, like other bacteria, spread readily to the surrounds & to new hosts Given that antibiotics & other antimicrobials, like fungicides, affect the kinds of bacteria in the enviro & people around the individual being treated, these substances are societal drugs Anticancer drugs, in contrast, affect only the person taking the medicines On a larger scale, antibiotic resistance that emerges in one place can often spread far and wide The ever increasing volume of international travel has hastened transfer to the U.S. of multi drug-resistant TB from other countrie For those who understand that antibiotic delivery selects for resistance, it's not surprising the international community currently faces a major public health crisis Antibiotic use (and misuse) has soared since the first commercial versions were introduced & now includes many non-medicinal applications In 1954 2 million pounds were produced in the US; today the figure exceeds 50 million pounds Human treatment accounts for roughly half the antibiotics consumed every year in the U.S. Perhaps only half that use is appropriate, meant to cure bacterial infections & administered correctly, in ways that do not strongly encourage resistance Many physicians acquiesce to misguided patients who demand antibiotics to treat colds & other viral infections that cannot be cured by the drugs 50 million of the 150 million outpatient prescriptions for antibiotics every year are unneeded Most antibiotics are available only by prescription, but this restriction does not ensure proper use Patients stockpile leftover doses & medicate themselves, or their family and friends, in less than therapeutic amounts Improper dosing will fail to eliminate the disease agent completely & will encourage growth of the most resistant strains, which may later produce hard-to-treat disorders In the developing world, antibiotic use is even less controlled Many of the same drugs marketed in the industrial nations are available over the counter Unfortunately, when resistance becomes a clinical problem, those countries, which often don't have access to expensive drugs, may have no substitutes available The same drugs prescribed for human therapy are widely exploited in animal husbandry & agriculture More than 40% of the antibiotics manufactured in the U.S. are given to animals Some of that amount goes to treating or preventing infection, but the lion's share is mixed into feed to promote growth In this last application, amounts too small to combat infection are delivered for weeks or months at a time No one is entirely sure how the drugs support growth Clearly this long-term exposure to low doses is the perfect formula for selecting increasing #s of resistant bacteria in the treated animals, which may then pass the microbes to caretakers &, more broadly, to people who prepare and consume undercooked meat In agriculture, antibiotics are applied as aerosols to acres of fruit trees, for controlling or preventing bacterial infections High concentrations may kill all the bacteria on the trees at the time of spraying, but lingering antibiotic residues can encourage the growth of resistant bacteria that later colonize the fruit during processing & shipping The aerosols can be carried considerable distances to other trees & food plants, where they're too dilute to eliminate full-blown infections but can still kill off sensitive bacteria & thus giving edge to resistant versions Resistant bacteria can make their way into people through the food chain, finding a home in the intestinal tract after the produce is eaten The amount of resistant bacteria people acquire from food apparently isn't trivial When human volunteers went on a diet consisting only of bacteria-free foods, the # of resistant bacteria in their feces decreased 1,000-fold We deliver a supply of resistant strains to our intestinal tract whenever we eat raw or undercooked items These bacteria usually aren't harmful, but they could be if by chance a disease-causing type contaminated the food The extensive worldwide exploitation of antibiotics in medicine, animal care and agriculture constantly selects for strains of bacteria that are resistant to the drugs If the drugs are to retain their power over pathogens, they have to be used more responsibly Society can accept some increase in the fraction of resistant bacteria when a disease needs to be treated; the rise is unacceptable when antibiotic use isn't essential Many corrective measures can be taken right now Farmers should be helped to find inexpensive alternatives for encouraging animal growth & protecting fruit trees Improved hygiene could go a long way to enhancing livestock development The public can wash raw fruit & vegetables thoroughly to clear off resistant bacteria & possible antibiotic residues When they receive prescriptions for antibiotics, they should complete the full course of therapy (to ensure all pathogenic bacteria die) & shouldn't "save" any pills for later use Consumers should refrain from demanding antibiotics for colds & other viral infections & may consider seeking nonantibiotic therapies for minor conditions, like certain cases of acne They can continue to put antibiotic ointments on small cuts, but think twice about routinely using hand lotions & a proliferation of other products now imbued with antibacterial agents Bacteria-fighting chemicals being incorporated into consumer products can select for bacteria resistant both to the antibacterial preparations & to antibiotic drugs Physicians, for their part, can take some immediate steps to minimize any resistance ensuing from required uses of antibiotics When possible, they should try to identify the causative pathogen before beginning therapy, so they can prescribe an antibiotic targeted specifically to that microbe instead of having to choose a broad-spectrum product Washing hands after seeing each patient is a major & obvious, but too often overlooked, precaution To avoid spreading multidrug-resistant infections between hospitalized patients, hospitals place the affected patients in separate rooms, where they're seen by gloved and gowned health workers and visitors This practice should continue Having new antibiotics could provide more treatment options In the 1980s pharmaceutical manufacturers, thinking infectious diseases were essentially conquered, cut back severely on searching for additional antibiotics At the time, if one drug failed, another would usually work (at least in the industrial nations, where supplies are plentiful) Researchers are searching for novel antibiotics again Regrettably, few drugs are likely to pass soon all technical & regulatory hurdles needed to reach the mkt That close to being ready are structurally similar to existing antibiotics; they could easily encounter bacteria that already have defenses against them With such concerns in mind, scientists are also working on strategies that'll give new life to existing antibiotics Many bacteria evade penicillin & its relatives by switching on an enzyme, penicillinase, that degrades those compounds An antidote already on pharmacy shelves contains an inhibitor of penicillinase; it prevents the breakdown of penicillin & so frees the antibiotic to work normally As exciting as the pharmaceutical research is, overall reversal of the bacterial resistance problem will require public health officials, physicians, farmers & others to think about the effects of antibiotics in new ways Each time an antibiotic is delivered, the fraction of resistant bacteria in the treated individual &, potentially, in others, increases These resistant strains endure for some time, often for weeks, after the drug is removed The main way resistant strains disappear is by squaring off with susceptible versions that persist in (or enter) a treated person after antibiotic use has stopped In the absence of antibiotics, susceptible strains have a slight survival advantage, since the resistant bacteria have to divert some of their valuable energy from reproduction to maintaining antibiotic-fighting traits Ultimately, the susceptible microbes will win out, if they are available in the first place & are not hit by more of the drug before they can prevail Correcting a resistance problem requires both improved management of antibiotic use & restoration of the environmental bacteria susceptible to these drugs If all reservoirs of susceptible bacteria were eliminated, resistant forms would face no competition for survival & would persist indefinitely. n the ideal world, public health officials would know the extent of antibiotic resistance in both the infectious and benign bacteria in a community To treat a specific pathogen, physicians would favor an antibiotic most likely to encounter little resistance from any bacteria in the community & would deliver enough antibiotic to clear the infection completely but would not prolong therapy so much as to destroy all susceptible bystanders in the body Prescribers would also take into account the # of other individuals in the setting who are being treated with the same antibiotic. f many patients in a hospital ward were being given a particular antibiotic, this high density of use would strongly select for bacterial strains unsubmissive to that drug and would eliminate susceptible strains The ecological effect on the ward would be broader than if the total amount of the antibiotic were divided among just a few people If physicians considered the effects beyond their individual patients, they might decide to prescribe different antibiotics for different patients, or in different wards, thereby minimizing the selective force for resistance to a single medication Prescribers and public health officials might envision an "antibiotic threshold": a level of antibiotic usage able to correct the infections within a hospital or community but still falling below a threshold level that would strongly encourage propagation of resistant strains or would eliminate large #s of competing, susceptible microbes Keeping treatment levels below the threshold would ensure the original microbial flora in a person or a community could be restored rapidly by susceptible bacteria in the vicinity after treatment ceased The problem is no one yet knows how to determine where that threshold lies, & most hospitals/communities lack detailed data on the nature of their microbial populations Yet with some dedicated work, researchers should be able to obtain both kinds of info Control of antibiotic resistance on a wider, international scale will require cooperation among countries around the globe & concerted efforts to educate the world's populations about drug resistance and the impact of improper antibiotic use Various groups are now attempting to track the emergence of resistant bacterial strains The Alliance for the Prudent Use of Antibiotics has been monitoring the worldwide emergence of such strains since 1981 The group shares information with members in more than 90 countries & produces educational brochures for the public and for health professionals The time has come for global society to accept bacteria as normal, generally beneficial components of the world & not try to eliminate them, except when they give rise to disease Reversal of resistance requires a new awareness of the broad consequences of antibiotic use, a perspective that concerns itself not only with curing bacterial disease at the moment but also with preserving microbial communities in the long run, so bacteria susceptible to antibiotics will always be there to outcompete resistant strains Similar enlightenment should influence the use of drugs to combat parasites, fungi and viruses Now that consumption of those medicines has begun to rise dramatically, troubling resistance to these other microorganisms has begun to climb as well Some bacteria types have variants resistant to multiple antibiotics; multidrug-resistant bacteria are difficult & expensive to treat Certain strains red no longer respond to any antibiotics & produce incurable infections Some of the bacteria cause infections mainly in hospitals or mainly in the community; others in both setting Antibiotics aren't the only antimicrobial substances being overexploited today Use of antibacterial agents (compounds that kill or inhibit bacteria but are too toxic to be taken internally) has been skyrocketing as well These compounds, aka disinfectants & antiseptics, are applied to inanimate objects or to the skin Historically, most antibacterials were used in hospitals, where they were incorporated into soaps & surgical clothes to limit the spread of infections More recently, however, those substances have been mixed into soaps, lotions and dishwashing detergents meant for general consumers They've also been impregnated into such items as toys, high chairs, mattress pads & cutting boards There is no evidence that the addition of antibacterials to such household products wards off infection What is clear is the proliferation of products containing them raises public health concerns Like antibiotics, antibacterials can alter the mix of bacteria: they simultaneously kill susceptible bacteria & promote the growth of resistant strains These resistant microbes may include bacteria that were present from the start, but they can also include ones unable to gain a foothold previously & are now able to thrive thanks to the destruction of competing microbes Once interlopers have a chance to proliferate, some may become new agents of disease Bacterial genes that confer resistance to antibacterials are sometimes carried on plasmids (circles of DNA) that also bear antibiotic-resistance genes By promoting the growth of bacteria bearing such plasmids, antibacterials may foster double resistance—to antibiotics as well as antibacterials Routine housecleaning is surely necessary, but standard soaps & detergents (without added antibacterials) decrease the #s of potentially troublesome bacteria Quickly evaporating chemicals—such as the old standbys of chlorine bleach, alcohol, ammonia & hydrogen peroxide— can be applied beneficially They remove potentially disease-causing bacteria from, say, thermometers or utensils used to prepare raw meat for cooking, but they don't leave long-lasting residues that will continue to kill benign bacteria & increase the growth of resistant strains long after target pathogens have been remove If we go overboard and try to establish a sterile environment, we'll find ourselves cohabiting with bacteria that are highly resistant to antibacterials &, possibly, to antibiotics Then, when we really need to disinfect our homes and hands—as when a family member comes home from a hospital and is still vulnerable to infection—we will encounter mainly resistant bacteria With or excessive use of antibacterials & antibiotics, we can make our homes, like our hospitals, havens of ineradicable disease-producing bacteria Bacteria pick up resistance genes from other bacterial cells in 3 main ways Often they receive whole plasmids bearing 1 or more such genes from a donor cell Other times, a virus will pick up a resistance gene from 1 bacterium and inject it into a different bacterial cell Alternatively, bacteria sometimes scavenge gene-bearing snippets of DNA from dead cells in their vicinity Genes obtained through viruses or from dead cells persist in their new owner if they become incorporated stably into the recipient's chromosome or into a plasmid Antibiotic use selects (promotes the evolution & growth of) bacteria insensitive to that drug When bacteria are exposed to an antibiotic, bacterial cells susceptible to the drug will die, but those with some insensitivity may survive & grow if the amount of drug delivered is too low to eliminate every last cell As treatment continues, some survivors are likely to acquire even stronger resistance, either through a genetic mutation that generates a new resistance trait or through gene exchange with newly arriving bacteria These resistant cells will then evade the drug most successfully and will come to predominate Resistant population of bacteria will disappear naturally only if susceptible bacteria live in the vicinity After antibiotic therapy stops, resistant bacteria can persist for a while If susceptible bacteria are nearby they may recolonize the individual In the absence of the drug, the susceptible bugs will have a slight survival advantage since they don't have to expend energy maintaining resistance genes After a time, then, they may outcompete the resistant microbes For this reason, protecting susceptible bacteria needs to be a public health priority 1 pharmaceutical strategy for overcoming resistance capitalizes on the discovery that some bacteria defeat certain antibiotics, like tetracycline, by pumping out the drugs To combat that ploy, investigators are devising compounds that'd jam the pumps, freeing the antibiotics to function effectively In the case of tetracycline, the antibiotic works by interfering with the ribosomes that manufacture bacterial proteins Physicians should wash hands thoroughly between patient visits; not accede to patients' demands for unneeded antibiotics; prescribe antibiotics that target only a narrow range of bacteria; isolate patients with multidrug-resistant infections; familiarize with local data on antibiotic resistance Consumers should: not demand antibiotics; when given, take them exactly as prescribed & complete the full course of treatment; not hoard pills for later use; wash fruits and vegetables thoroughly; avoid raw eggs & undercooked meat, esp in ground form; use soaps and other products with antibacterial chemicals only when protecting a sick person whose defenses are weakened

About HIV/AIDS (reading notes)

zHIV is a virus spread through certain body fluids that attacks the body's immune system, specifically the CD4 cells, often called T cells Over time, HIV can destroy so many of these cells that the body can't fight off infections & disease These special cells help the immune system fight off infections Untreated, HIV reduces the # of CD4 cells (T cells) in the body; this damage to the immune system makes it harder & harder for the body to fight off infections & some other diseases Opportunistic infections or cancers take advantage of a very weak immune system & signal the person has AIDS HIV stands for human immunodeficiency virus Can lead to acquired immunodeficiency syndrome or AIDS if not treated Unlike some other viruses, the human body can't get rid of HIV completely, even with treatment, so once you get HIV, you have it for life HIV attacks the body's immune system, specifically the CD4 (T) cells, which help the immune system fight off infections Untreated, HIV reduces the # of CD4 cells (T cells) in the body, making the person more likely to get other infections or infection-related cancers Over time, HIV can destroy so many of these cells the body can't fight off infections & disease These opportunistic infections or cancers take advantage of a very weak immune system & signal the person has AIDS, the last stage of HIV infection No effective cure currently exists, but with proper medical care, HIV can be controlled The medicine used to treat HIV is called antiretroviral therapy or ART If people with HIV take ART as prescribed, their viral load (amount of HIV in their blood) can become undetectable If it stays undetectable, they can live long, healthy lives & have effectively no risk of transmitting HIV to an HIV-negative partner through sex Before the introduction of ART in the mid-1990s, people with HIV could progress to AIDS in just a few years Today, someone diagnosed with HIV & treated before the disease is far advanced can live nearly as long as someone who doesn't have HIV Scientists identified a type of chimpanzee in Central Africa as the source of HIV infection in humans They believe the chimpanzee version of the immunodeficiency virus (simian immunodeficiency virus, or SIV) most likely was transmitted to humans & mutated into HIV when humans hunted these chimps for meat & came into contact with their infected blood Studies show HIV may have jumped from apes to humans as far back as the late 1800s Over decades, the virus slowly spread across Africa & later into other parts of the world We know the virus has existed in the US since at least the mid to late 1970s When people get HIV & don't receive treatment, they'll typically progress through 3 stages of disease Medicine to treat HIV, known as antiretroviral therapy (ART), helps people at all stages of the disease if taken as prescribed Treatment can slow or prevent progression from one stage to the next People with HIV who take HIV medicine as prescribed & get & keep an undetectable viral load have effectively no risk of transmitting HIV to an HIV-negative partner through sex Stage 1: Acute HIV infection Within 2=4 weeks after infection with HIV, people may experience a flu-like illness, which may last for a few weeks; this is the body's natural response to infection When people have acute HIV infection, they have a large amount of virus in their blood & are very contagious, but people with acute infection are often unaware they're infected because they may not feel sick right away or at all To know if someone has acute infection, either an antigen/antibody test or a nucleic acid (NAT) test is needed Stage 2: Clinical latency (HIV inactivity or dormancy) This period is sometimes called asymptomatic HIV infection or chronic HIV infection During this phase, HIV is still active but reproduces at very low levels People may not have any symptoms or get sick during this time For people who aren't taking medicine to treat HIV, this period can last a decade or longer, but some may progress through this phase faster People who are taking medicine to treat HIV (ART) as prescribed may be in this stage for several decades It's important to remember that people can still transmit HIV to others during this phase, but people who take HIV medicine as prescribed & get/keep an undetectable viral load (or stay virally suppressed) have effectively no risk of transmitting HIV to their HIV-negative sexual partners At the end of this phase, a person's viral load starts to go up & the CD4 cell count begins to go down As this happens, the person may begin to have symptoms as the virus levels increase in the body, & the person moves into Stage 3 Stage 3: Acquired immunodeficiency syndrome (AIDS) AIDS is the most severe phase of HIV infection People with AIDS have such badly damaged immune systems that they get an increasing # of severe illnesses, called opportunistic illnesses Without treatment, people with AIDS typically survive about 3 years Common symptoms of AIDS include chills, fever, sweats, swollen lymph glands, weakness, & weight loss People are diagnosed with AIDS when their CD4 cell count drops below 200 cells/mm or if they develop certain opportunistic illnesses People with AIDS can have a high viral load and be very infectious The only way to know for sure if you have HIV is to get tested; knowing your status is important since it helps you make healthy decisions to prevent getting or transmitting HIV Some people may experience a flu-like illness within 2-4 weeks after infection (Stage 1 HIV infection), but some people may not feel sick during this stage Flu-like symptoms include fever, chills, rash, night sweats, muscle aches, sore throat, fatigue, swollen lymph nodes, or mouth ulcers These symptoms can last anywhere from a few days to several weeks During this time, HIV infection may not show up on an HIV test, but people who have it are highly infectious & can spread the infection to others No effective cure currently exists for HIV, but, with proper medical care, HIV can be controlled Treatment for HIV is called antiretroviral therapy or ART If people with HIV take ART as prescribed, their viral load (amount of HIV in their blood) can become undetectable If it stays undetectable, they can live long, healthy lives and have effectively no risk of transmitting HIV to an HIV-negative partner through sex Today, someone diagnosed with HIV & treated before the disease is far advanced can live nearly as long as someone who does not have HIV HIV is NOT transmitted by air or water, saliva, sweat, tears, closed mouth kissing, insects, pets, sharing toilets/foods/drinks You can get/transmit HIV only through specific activities Most commonly, people get or transmit HIV through sexual behaviors and needle or syringe use Only certain body fluids blood, semen/cum, pre-seminal fluid (pre-cum), rectal fluids, vaginal fluids, & breast milk from a person who has HIV can transmit HIV These fluids must come in contact with a mucous membrane or damaged tissue or be directly injected into the bloodstream (from a needle or syringe) for transmission to occur Mucous membranes are found inside the rectum, vagina, penis, and mouth

3 major aspects of malaria parasite lifecycle

1) Sporozoites: - During a blood meal, a malaria-infected female Anopheles mosquito injects sporozoites into a human's bloodstream, which rapidly invade/infect liver cells - Within a liver cell, a sporozoite matures into schizonts and reproduces asexually, forming thousands of merozoites that rupture out and pour back into the bloodstream to invade red blood cells (RBCs) 2) Asexual red blood cell cycle: - As merozoites invade RBCs, they multiply, causing the cells to rupture and releasing yet more merozoites - Asexual parasites mature within RBCs from rings to schizonts - Disease and death in malaria is caused by this stage of the life cycle 3) Cycle in mosquito: - Eventually some of the merozoites or RBC parasites develop into male and female gametocytes, which can be ingested by a previously uninfected mosquito taking a blood meal (and infect them) - In the mosquito's gut, the gametocytes develop into gametes and fuse to eventually produce an oocyst that releases sporozoites; these travel to the mosquito's salivary glands, ready to be transferred into another victim (male/female gamete -> fertilization -> oocyst -> sporozoites) - Sexual reproduction (in mosquito's gut)

Describe the malaria lifecycle in basic steps (5)

1. Infection takes place when the mosquito bites the human host, injecting sporozoites 2. Sporozoites infect liver cells, where they multiply and become merozoites, which in turn infect red blood cells 3. In the red blood cells, the merozoites multiply, bursting the cell and allowing infection of new cells (asexual cycle) 4. Gametocytes are produced from the merozoites, and can be transmitted to mosquitoes that bite the human host 5. The gametocytes in the mosquito will produce sporozoites, which can cause a new infection once they localize to the mosquito's salivary glands

TB lifecycle

1. Mycrobacteria typically spread through the air Once inhaled, Mtb invade the pulmonary alveoli and are engulfed by the body's front-line defense, the macrophage Once inside (the macrophage) it takes over the cells internal machinery to fend off further internal phagocytic destruction and begins to replicate 2. Infected macrophages signal other immune cells to attack T cells can activate macrophages to kill Mtb as well as targeting the bacteria directly 3. In most people, their immune system is able to control the infection in granulomas 4. When infection overcomes the immune system, it spreads throughout the body Uncontained Mtb in the lungs prompts infectious diseases

Example of how Schistosoma mansoni presents itself as an infection in two boys

11-year old with giant liver and spleen Engorgement of abdominal collateral circulation 9-year old in transition to chronic infection with acute phase (headaches, nausea, anorexia, fever, abdominal cramps, and diarrhea)

TB (history)

150 million years ago: Genus Mycobacterium 3 mya: M. tuberculosis in early hominids in early hominid TB found in Homo erectus: 0.5 mya 15-35,000 years ago: Modern form emerges TB cases are known from: - Egypt 5,000 years ago - India 3,300 years ago - China 2,300 years ago

"The Great White Plague"

1600s to 1800s, epidemic, the most important disease in Europe Brought to Africa, Asia, and the Americas in large numbers for the first time "Consumption" given great cultural importance in European literature and art

History of malaria

1600s: Incas in highland Peru use the bark of the cinchona tree for chills, and Jesuit priests try it for malarial fever; Jesuit powder becomes widely used 1809: Napoleon defeats British in the Netherlands by breaching the dikes; mosquitoes breed, killing hundreds of British a week 1820: French pharmacists Pelletier and Caventou isolate quinine (important malaria medication) from cinchona bark 1880: French doc Laveran discovers the malaria parasite, but most people keep thinking swamp gases cause it 1897: British doc Ronald Ross in India discovers the parasite inside the mosquito's gut and shows the malaria cycle Alexander the Great, Genghis Khan, and George Washington all had malaria People fled Washington, D.C. in summer to avoid it Back then, "swamp" meant swamp

Schistosomiasis's control strategy

20% get treated annually with praziquantel

Schistosomiasis (book notes)

200 million people are infected worldwide and it's common in returned travellers, although patients are rarely unwell Schistosomal cercariae penetrate the skin after freshwater exposure and migrate via the lungs to the vessels of the bladder or gut (depending on the species), where eggs are produced Eggs migrate backs into the gut lumen or urinary tract, but may cause local inflammation Worm burdens are low in expatriates; severe disease is rare Clinical features of the disease: Swimmer's itch: transient rash 1-2 days after exposure, often unrecognized Katayama fever: 3-8 weeks after exposure in a small proportion of patients; acute fever, sweats, malaise (sometimes lymphadenopathy, hepatosplenomegaly or bronchospasm); it is self-limiting Urinary schistosomiasis (Schistosoma haematobium): often asymptomatic and diagnosed because of eosinophilia; may have haematuria, urinary symptoms or altered ejaculate; long-term complications are unusual in travellers intestinal/hepatic schistosomiasis: vague abdominal symptoms/bloody diarrhoea or asymptomatic; the long-term complications of non-cirrhotic portal hypertension is rare in travellers, but is very common worldwide Diagnosis and treatment: Eosinophilia is common Demonstration of eggs in urine, ejaculate, stool or rectal biopsies Schistosomal serology is useful, but may not be positive until several months after exposure Praziquantel is effective for all species Migration to lung -> spread elsewhere: liver, urinary tract, gut

How many people does schistosomiasis infect worldwide? How many are at risk? How many deaths per year?

200 million; 650 million in many countries; more than 280,000 (Sub-Saharan Africa)

A Plan to Defeat Neglected Tropical Diseases (reading notes)

A group of 7 tropical diseases, mostly caused by parasitic worms, afflict a billion impoverished people worldwide They seldom kill directly but cause lifelong misery that stunts children's growth, leaves adults unable to function to their fullest, & heightens the risk of other diseases Fortunately, they can be easily treated, often with a single pill Various agencies & foundations are collaborating to deliver these drugs, although they've reached only about 10% of the population so far The US has its own neglected parasitic diseases that affect millions of rural & urban poor ... The poorest people aren't only poor; they're also chronically sick, making it harder for them to escape poverty A new global initiative may break the vicious cycle In the north of Burkina Faso lies the town of Koumbri, one of the places where the Burkina Ministry of Health began a mass campaign 5 years ago to treat parasitic worms One of the beneficiaries, Aboubacar, then an 8-year-old boy, told health workers he felt perpetually tired & ill and had noticed blood in his urine After taking a few pills, he felt better, started to play soccer again, & began focusing on his schoolwork The Burkina Faso program, which treated more than 2 million children, was both a success story & an emblem of the tragedy of disease in the developing world For want of very simple treatments, a billion people in the world wake up every day of their lives feeling sick -> cannot learn in school or work Most people in richer countries equate tropical disease with the big 3 (HIV/AIDS, TB & malaria) & funding agencies allocate aid accordingly Yet a group of conditions known collectively as neglected tropical diseases has an even more widespread impact They may not often kill, but they debilitate by causing severe anemia, malnutrition, delays in intellectual & cognitive development, & blindness They can lead to horrific limb, genital disfigurement, skin deformities & increase the risk of acquiring HIV/AIDS & suffering complications during pregnancy They not only result from poverty but also help to perpetuate it Children cannot develop to their full potential, &adult workers are not as productive as they could be Such diseases aren't confined to developing nations Millions of Americans living in poverty also suffer from NTD-like infections Parasitic diseases like cysticercosis, Chagas disease, trichomoniasis & toxocariasis occur with high frequency in our inner cities, post-Katrina Louisiana, other parts of the Mississippi Delta, the border region with Mexico, & Appalachia NTDs have plagued humankind for thousands of years Historians have found accurate descriptions of many of them in ancient texts as diverse as the Bible, the Talmud, the Vedas, Hippocrates writings, & Egyptian papyri What is new, however, is that donors, drugmakers, health ministries in low- and middle-income countries, the WHO, and public-private partnerships are linking their efforts to combat the NTDs in a more coordinated and systematic way Over the past half a decade the Bill & Melinda Gates Foundation, the Dubai-based sustainable development fund Legatum, and the U.S. and British governments have committed serious money, while major pharmaceutical companies have donated urgently needed NTD drugs; but the battle has only begun The scale and extent of the global NTD problem are hard to take in Almost every destitute person living in sub-Saharan Africa, Southeast Asia & Latin America is infected with 1 or more of these diseases The illnesses last years, decades & often even a lifetime The 7 most common NTDs have the most devastating impact; 3 of them are caused by parasitic worms, also known as helminths, that live in the intestines The large common roundworm, which results in ascariasis, afflicts 800 million people & the whipworm, which results in trichuriasis, 600 million people These helminths rob children of nutrients, stunting growth Even worse are hookworms, which are found in 600 million people; they're half-inch-long worms that attach to the inside of the small intestine & suck blood Over a period of months or years they produce severe iron-deficiency anemia & protein malnutrition Children with chronic hookworm anemia take on a sickly & sallow complexion & have trouble learning in school More than 40 million pregnant women are also infected with hookworm, rendering them vulnerable to malaria or additional blood losses in childbirth; their babies are born with low birth weights Schistosomiasis is the next most common NTD; it's caused by parasitic worms known as schistosomes that live in the veins draining the intestines or bladder More than 90% of the 200 million cases occur in sub-Saharan Africa, with another few million cases in Brazil & several other countries Female schistosomes release eggs equipped with tiny spears that invade & damage organs, including the intestine & liver or the bladder & kidneys, depending on the species ~100 million school-aged children & young adults pass blood in their urine or feces every day as a result The inflammation produces pain, malnutrition, growth stunting & anemia In women, schistosomes deposit eggs in the cervix & vagina, causing disabling pain during sexual intercourse & tripling the risk of acquiring HIV/ IDS 2 other important helminth infections are lymphatic filariasis (LF) and onchocerciasis The worms that cause LF live in the limbs, breasts and genitals of 120 million people in Asia, Africa & Haiti They lead to elephantiasis, a disfiguring condition that prevents adults from working & leaves women unable to marry or abandoned by their husbands Onchocerciasis, or river blindness, causes a horribly itchy & disfiguring skin disease as well as blindness in middle-aged adulthood Almost all of its 30 million to 40 million cases occur in Africa, except for a few locations in the Americas/Yemen The seventh important NTD, trachoma, isn't caused by a parasitic worm but is a chronic bacterial infection caused by the Chlamydia microorganism Occurring in 60-80 million people, it is the leading infectious cause of blindness Together the 7 NTD's global health damage, as measured by the # of healthy life years lost because of disability, is roughly equal to that of HIV/AIDS or malaria Because of their devastating toll on child education and development, pregnancy, & agricultural worker productivity, these NTDs are a major cause of poverty I.e. chronic hookworm infection in childhood reduced a person's lifetime earning power by more than 40%; more than $800 million lost annually from reduced worker productivity as a result of LF Other studies have found similar effects for onchocerciasis & trachoma The good news is that these NTDs can be treated, or even prevented, simply & cheaply In many cases, a single pill is enough The available drugs have an excellent safety record, & each is either provided free of charge by multinational companies or available as cheap generics costing less than 10 cents per tablet In the early 20th century Rockefeller sponsored mass drug administration to control helminth infection in the American South, & similar efforts began in the Caribbean During the 1950s & 1960s several tropical medicine specialists started programs for other infections & locations In 1988 Merck & Co. began one of the first public-private partnerships for the mass treatment of river blindness Various such partnerships have since been established, & today reach tens of millions of people annually Through the delivery of extremely low cost treatments, these partnerships, in collaboration with WHO, health ministries in low-income countries, & several multinational pharmaceutical companies, have managed to control or eliminate river blindness in 11 African countries, letting farmers return to arable lands they'd abandoned because of high rates of blindness in their community Treatment programs have eliminated LF in more than a dozen previously endemic countries & reduced the prevalence of schistosomiasis by up to 80% in 8 African countries The internal rates of return for these programs have ranged as high as 30% Despite these enormous successes, we still have a long way to go to provide complete drug coverage for the billion or more people with NTDs WHO estimates that treatment programs reach fewer than 10% of people suffering from intestinal infections & schistosomiasis Better organization & technology are part of the answer WHO & other organizations have studied the simultaneous administration of many NTD drugs, & they are moving quickly to provide these drugs as a single package (aka a rapid impact package), which can cost as little as 50 cents annually A # of African countries have already begun to integrate programs that target individual NTDs into a single program Bundling reduces costs & the strain on otherwise overburdened health systems, as well as providing an opportunity to fold in other interventions, among them the delivery of anti malaria bed nets, childhood immunizations & nutritional supplements like vitamin A Although the integration of NTD-control programs has been largely successful so far, it's also encountered some operational challenges, including an increased workload for community drug distributors & the lack of availability of some of the NTD drugs in certain places Health workers have had to be vigilant in looking for signs of drug resistance Ultimately, NTD-control programs will need more money The US & British governments have committed more than $400 million over the next few years to support integrated NTD control, but estimates suggest controlling NTDs in the 56 endemic countries will require $2 billion to $3 billion for the next 5-7 years To make the case for better funding, some major public-private partnerships came together in 2006 to form the Global Network for NTDs, which works closely with WHO & its regional offices Hosted by the Sabin Vaccine Institute, the network receives support from the Gates foundation & other private donors & works to support treatment programs for NTDs around the world through advocacy, policy & logistical effort The Sabin Vaccine Institute has also established an international product development partnership to produce new vaccines for hookworm infection & schistosomiasis A hookworm vaccine is now entering clinical trials, which is welcome news because of concerns that one of the drugs now in use for mass treatment is showing high failure rates, a sign the parasite has become resistant Sabin works with a spectrum of Brazilian research & development institutes & the Brazilian government Brazil has the largest # of cases of these helminth infections in the Americas; these NTDs were originally introduced from the endemic areas of West Africa by the slave trade, making them living vestiges of slavery If fighting NTDs is so obvious/cheap, why's it taken so long to act in a systematic way? That's not an easy question to answer In the Millennium Development Goals for sustainable reduction of poverty, launched in 2000, the NTDs were lumped in an "other diseases" category, & it's hard to get people excited about "other diseases" Moreover, the NTDs debilitate more than they kill, so that the big donor countries have chosen to focus primarily on HIV/AIDS, TB and malaria, which are fatal unless treated Other development programs, viewing NTDs as a symptom rather than the disease, have preferred to concentrate on what they see as the underlying problems, such as poor sanitation, lack of access to clean water, and poverty in general; those are laudable aims, but the empirical reality is that NTD drugs are the single most cost-effective way to improve the health, education and well-being of the world's poor right now NTDs represent an enormous challenge, but since treatment is so inexpensive, individuals can make a difference The US also suffers high rates of parasitic diseases These so-called neglected infections of poverty closely resemble the neglected tropical diseases (NTDs) & are found predominantly in areas of intense poverty They disproportionately affect African-Americans & Hispanic-Americans, because a higher % of these populations live in poverty & under stressful conditions In the Mississippi Delta, post-Katrina Louisiana and other areas of the American South, as well as in inner cities, an estimated 3 million African-Americans are either currently infected or have been infected in the past with a helminth infection known as toxocariasis The worm eggs are found in soil or sand laced with dog feces & can contaminate food Once the worm eggs hatch in the digestive tract, the released larvae migrate through the lungs, liver & brain, leading to wheezing, seizures & developmental delays Another infection is trichomoniasis, a sexually transmitted protozoan parasite that causes inflammation & hemorrhages in the cervix It increases the risk of acquiring additional sexually transmitted diseases, possibly including HIV/AIDS Among Hispanic-Americans, 2 important infections of poverty are Chagas disease & cysticercosis Chagas results from a trypanosome protozoan acquired when people are bitten by a kissing bug, a type of assassin bug; a cockroach-like insect often found in dilapidated housing where rats nest The parasites can produce a severe dilation of the heart & can prove fatal Estimated 300,000 people in the US have Chagas disease Cysticercosis is a parasitic helminth infection that occurs in as many as 170,000 people & is the leading cause of seizures in cities near the Mexican border Most of these infections weren't introduced into the US as a result of immigration Instead they most likely persist through transmission within US borders Despite their prevalence, research on these conditions has been fairly limited Health officials don't know the precise #s of people infected or why poverty is a risk factor; diagnostic methods and treatments are also fairly rudimentary

Guinea-worm

A helminth infection Caused by drinking dirty water The worm can grow up to 3 feet long In 1986, there were 3.5 million cases in 20 countries; in 2014, there were only 126, largely thanks to President Carter (who wants to see guinea worm completely eradicated before he dies)

Onchocerciasis (river blindness)

A helminth infection (like schistosomiasis) Elimination by 2020 is possible 80 million people are treated annually to prevent itching and blindness (and skin disfiguration)

Hookworm

A helminth infection (like schistosomiasis) Over 500 million people infected Treatment with albendazole and mebendazole ... Half-inch-long worms that attach to the inside of the small intestine & suck blood Over a period of months or years they produce severe iron-deficiency anemia & protein malnutrition Children with chronic hookworm anemia take on a sickly & sallow complexion & have trouble learning in school More than 40 million pregnant women are also infected with hookworm, rendering them vulnerable to malaria or additional blood losses in childbirth; their babies are born with low birth weights

Schistosomiasis (video notes)

A parasitic disease that can cause bleeding and severe organ damage Caused by worms hosted by a snail Children urinate in water, their urine contains eggs, the eggs hatch and infect a snail, the snail develops into a form that can infect humans by penetrating the skin Female worms produce thousands of eggs, which work their way out through the bladder into the urine, causing bleeding -> disease manifests itself as blood and urine Can stunt a child's growth and impair learning Young victims are also more vulnerable to other infections like malaria & TB Rampant in Africa's rural areas with little or no access to safe water, but often neglected Hundreds of millions of people in 74 countries are victims, despite the availability of an inexpensive cure (praziquantel) that costs only 20 cents per treatment taking orally once a year Praziquantel is particularly aimed at school children and dramatically reduces the blood in the urine that the children has a result of the infection; children having bloody urine has decreased from 50% to 5% While it can be controlled, treatment and health education must continue as reinfection easily occurs Since 1999, the Carter Center has worked with the Nigerian government to reduce the prevalence of schistosomiasis by providing health education and single annual doses of praziquantel to communities with the highest rates of infection

Polio lifecycle

A poliovirus approaches a nerve cell via the bloodstream Nerve cell receptors attach to the virus The capsid (protein shell) of the virus breaks to release its RNA (genetic material) into the cell Polio RNA moves towards a ribosome, the cell's protein assembly station Polio RNA takes over the ribosome and forces it to make more polio RNA and more caspids The new polio caspids and new polio RNA unite to form more polioviruses The host cell swells and bursts, releasing thousands of new viruses back into the bloodstream

Cause of sickle cell anemia

A single codon change within the beta-globin gene is responsible GAG mutates to GTG, and this base pair difference results in a difference in the amino acid sequence, which in turn causes functional differences The resulting hemoglobin protein (HbS) has the amino acid valine (Val) instead of glutamine (Glu) A double dose of HbS

How polio affects the nerves

Acute polio: nerves are killed by the polio virus Recovery: nerves grow extra roots to renervate muscle fibers Post-polio syndorme: one explanation is that these nerves are dying off; less nerves supply, less functional ability ... Another example: Normal: 3 normal motor units are presented Acute Polio: Invasion of 1 motor neuron by poliovirus produces degeneration of the affected motor neuorn and denervation of associated muscle fibers Recovery: occurs through axonal sprouting from surviving motor neurons with reinnervation of muscle fibers Post-Polio Muscular Atrophy (PPMA) or Post-Polio Syndrome: Distal degeneration of enlarged motor units with denervation of muscle fibers is believed to be the most likely cause of PPS

Prognosis for schistosomiasis

Almost all patients improve with treatment Most patients with early disease or without severe end-organ complications recover Patients with liver and urinary disease, even with fibrosis, may improve significantly over months or years after treatment Co-infection (with malaria, HIV, or hepatitis) worsens the prognosis

IPV vs. OPV

An increasing number of industrialized, polio-free countries are using IPV as vaccine of choice because the risk of paralytic polio associated with continued routine use of OPV is deemed greater than risk of imported wild virus As the number of natural cases drops, the number of vaccine related illnesses from OPV becomes less tolerable, insinuating a change in vaccine strategy from oral to injected A growing number of polio-free countries are using IPV as the vaccine of choice is because the risk of paralytic polio associated with continued routine use of oral polio vaccine (OPV) is deemed greater than the risk of imported wild virus Year of eradication keeps getting postponed

Urine test (reading notes)

An international team of researchers has developed a urine test that can be used to detect TB in human patients Scientists have been trying for some time to develop an easy way to test people for a MTB infection The 2 main types of tests currently in use, the skin test and the culture test, require a high degree of expertise This urine test that can be conducted by untrained health care workers Earlier detection and treatment, it is believed, would reduce suffering and fatalities, which is is why scientists have been working so hard to find a method to detect it in people in a way that doesn't involve a lot of skil Such a test could be administered in third-world outposts, where health care is often lacking The new test works by employing tiny molecular cages that trap a type of sugar that coats the TB bacteria using a type of a dye The test detects TB at both low and high sugar levels, which means it can be used to test people at virtually any stage of the disease Greater than 95% sensitivity The test works on people who aren't HIV positive; all earlier urine tests for TB only worked for people who also had HIV infections, likely because their compromised immune systems allowed very high concentrations of the bacteria to grow Early indications have shown that the test can also offer an approximate degree of severity of infection, higher sugar levels mean more bacteria are active Non-invasive, same day results, low false positives, highly sensitive, measures severity The team plans to continue improving their test, including devising a means for allowing field testing of people given treatments to see how well they respond; they also plan to keep looking to see if there are other markers they can trap that will give away the presence of the bacteria

What is the primary vector of malaria?

Anopheles gambiae

Ebola in Graphics (reading notes)

As of January 14th 2016, the WHO has declared the west African country of Liberia free of Ebola; along with it, Africa as a whole is now clear of the killer virus The outbreak that ravaged the region over the course of the 2 two years was the worst the world's ever seen The first reported case dates back to December 2013, in Guéckédou, a forested area of Guinea near the border with Liberia and Sierra Leone Travelers took it across borders: by late March 2014, Liberia reported 8 suspected cases and Sierra Leone 6 By the end of June 2014, 759 people had been infected and 467 people had died from it To date, 28,637 cases and 11,315 deaths have been reported worldwide, the vast majority of them in these same 3 countries The extremely high mortality rate of the disease, around 60% in this outbreak, means Ebola can quickly claim more lives than other, more established killers The rate at which cases give rise to subsequent cases, R0, is the key variable in the spread of Ebola For easily transmitted diseases, R0 can be high; for measles it is 18 Ebola is much harder to catch: estimates of R0 in different parts of the outbreak range from 1.5-2.2; any R0 above 1 is bad news. But now the outbreak has finally been halted, though it's been a very slow process to stop the last transmissions Guinea was declared Ebola-free in December 2015 & Sierra Leone has been free since November 7th Liberia was the first of the 3 countries to be declared Ebola-free in May 2015, but the virus subsequently re-emerged in late June & again around November 22, on that occasion resulting in 3 confirmed cases and 1 death January's declaration of eradication is the WHO's third for the country, demonstrating how vigilant everyone still needs to be to avoid future flare-ups

Which phase of the malaria lifecycle is responsible for the signs, symptoms, and complications?

Asexual blood cycle (RBC) The rupture of infected blood cells causes malaria's fever, chills, and progressive anemia; in pregnancy, malaria-laden placentas rob babies of growth before they are even born

First vaccination campaign

Based on a simple observation: milk-maids didn't get smallpox Anyone could have noticed this, no medical technology It led to lifesaving inoculations a century before anyone knew what a virus was

Until recently, homozygotes for sickle cell anemia and thallassemias died before having children, yet they are born at rates much higher than the mutation rate. Why?

Because heterozygotes are resistant to malaria

Malaria in KwaZulu-Natal

Cases declined dramatically when the South African government sprayed dwellings with DDT and later also treated patients with an artemisinin-based combination treatment One of the few African countries wealthy enough to fund its own program, it didn't have to rely on aid from donors reluctant to use the chemical

Onchocerciasis (video notes)

Caused by Onchocerca volvulus, a nemotode or round worm found near rivers #1 cause of blindness in the developing world 18 million infected worldwide 99% of cases are found in Zaire and Nigeria Female black fly transmits larvae (microfilariae) into the host skin Humans are only known definitive host Larvae become adults in 6-12 months, and subsequent fibrosis around the adult worms results in subcutaneous nodules which protect the parasite from the host's immune system Parasites mate in the system producing microfilariae, which can migrate to they eye, where they cause keratitis and subsequent sclerosis Skin biopsy, slit-lamp examination, serlogic tests can help diagnose Ivermectin is effective against the larvae and must be given every 6-12 months until asymptomatic; can also surgically remove

Symptoms suggesting TB*

Cough for longer than 3 week Fever and night sweats for longer than 3 weeks Involuntary weight loss Coughing blood Lung lesions

Most common symptom of TB

Coughing, because it accumulates abundantly in the lungs, but it can harm other organs as well

Mindu Dam (Tanzania)

Dams bring electricity and provide fish for fishermen and women, but they also change ecosystems This dam slowed water flow and brought schistosomiasis to Tanzania It's mostly the poor who feel the negative impact of development projects

Prehistory of schistosomiasis

Dates back about 10,000 years to the Neolithic Era First Epidemiologic Transition

DDT

Developed in Pacific in WWII "Aerial bombing" of mosquito breeding swamps and ponds Spraying within houses About 500 million people, 1/3 of all victims worldwide, malaria-free by 1970 Globally, from the 1940s onward

Malaria challenges*

Drug-resistant strains of Plasmodium Insecticide-resistant strains of mosquitoes Weak public health infrastructure Profound poverty

Smallpox*

Easy to diagnose Causes time-limited, visible illness Needs only a one-time vaccination

Causes of Death (reading notes)

Elderly gentlemen & ladies worldwide die of very similar causes, notably cardiovascular disease Girls & boys also succumb to a similar set of illnesses, mostly infectious diseases Yet the death differences are pronounced for young & middle-aged women & men, Women are more likely to die from TB, diarrhea, respiratory illnesses & nutritional deficiencies Men perish from substance abuse, injuries, self-harm & violence As with so many issues related to the sexes, cause of death is determined much more by social factors than by biology Compared with worldwide averages, many more women & men die of disease in countries with a depressed socio demographic index (SDI), a combo of low income & education levels & high fertility rate More women & men die from injuries & violence in countries with an elevated SDI, high income/education & low fertility Cause of death diverges most between women & men aged 15 to 45 The disparity is largely driven by mortality rates in underdeveloped countries; differences in developed countries are much less pronounced

Malaria prognosis*

Fewer than 1% die, mostly young children Survivors develop immunity, especially if bitten with malaria-infected mosquitoes hundreds of times a year, but they may have serious permanent damage

T/F HIV is spread through casual contact

False

T/F P. falciparum, the main malaria strain that infects humans, evolved from chimps

False (actually gorillas) Original thought: "P. falciparum evolved from another version of the parasite, P. reichenowi, which currently infects chimpanzees; it happened a mere 10,000 years ago, a moment in evolutionary terms" "Until recently, researchers thought falciparum had jumped into humans from chimps, but in September, a team from Alabama showed that all falciparum parasites are descended from a single lineage that jumped from gorillas millions of years ago; since then, the parasite has been furiously evolving, & drug resistance is part of that" See hypothetical evolutionary model of host-switch events from Plasmodium falciparum-like malaria parasites (infecting African nonhuman primates) to P. falciparum (infecting humans)

T/F Many past eradication campaigns have succeeded

False... many have failed, though smallpox succeeded (completely eradicated in 1979) and guinea worm is close (possibly this year)

T/F Malaria parasite needs only humans to propagate (breed) itself

False... needs both humans and mosquitoes

Trachoma's lifecycle

Flies carrying the microorganism land on children's eyes to feed on discharge -> women who take care of the children also get the infection (family contact) -> flies that breed in human feces spread the disease to others Dirty hands or face cloths also spread the disease

Influenza (reading notes)

For a disease that can resemble the common cold, influenza packs a powerful & sometimes lethal punch; up to half-a-million people worldwide die annually from flu The culprit is a virus that mutates to evade our immune systems, leaving vaccines & therapies scrambling to keep up In some years, a mutation creates a pathogen that's particularly nasty, resulting in pandemic flu (i.e. 1918 Spanish flu pandemic killed at least 50 million people worldwide) In 2009, another pandemic swept across the world at frightening speed, & in 2017-18 so-called seasonal flu (not considered a pandemic) hit hard in the US Vaccines are the 1st line of defence against flu, & researchers have made it a top priority to develop a vaccine that protects against as many strains of the virus as possible Because speed is of the essence in mounting a response to flu, new methods are being pursued to speed up vaccine production If prevention fails, there's only a limited arsenal of antiviral drugs to treat flu, but researchers are working to develop more It's a never-ending battle, as the wily virus mutates its way to resistance Treatment of course depends on diagnosis For patients, molecular tests can now give conclusive results more quickly than older methods, but adoption of the new tests has been slow, partly due to their high cost On a public-health level, it's important to know when & where an outbreak is under way; a task made easier by information technology Because some of the most dangerous flu viruses make the leap from animals to humans, researchers are studying how to monitor the disease on farms & in wild bird populations A better understanding of the immune response to influenza is driving progress towards vaccines that protect against both seasonal & pandemic flu strains Flu shots can be hard to sell to the public Even a run-of-the-mill influenza infection can be debilitating to otherwise healthy people, & lethal to those who are elderly or frail, so vaccinations are important The problem is that flu vaccines deliver inconsistent performance In a good season, they're up to 60% effectiveness, but in bad, mismatched years it can be as low as 10-20%, Current flu vaccines provide protection only against the strains they've been matched to, so a universal flu vaccine that provides broader protection against most influenza viruses has been a long-standing dream The 2009 swine-flu pandemic, which caught the public-health community off guard & claimed the lives of up to half-a-million people worldwide, gave the issue new urgency The 2009 pandemic made it clear we didn't have good enough solutions for influenza vaccines; we knew the virus, but weren't able to make enough vaccine quickly enough More-effective manufacturing is one solution but a single vaccine that protects against both seasonal & emerging strains would have much greater impact Fortunately, the timing of the pandemic coincided with great progress in the development of technologies for investigating the human response to influenza Around 2008 or 2009, people started finding a few broadly neutralizing antibodies against the influenza virus; once people started looking, many more were discovered Now, after the Spanish flu pandemic of 1918 that killed about 50 million people, multiple universal-vaccine programmes are demonstrating promise in testing, but it remains to be seen whether any will ultimately deliver the broad protection that clinicians seek Peter Palese believes today's flu vaccines come in for too much criticism: they're good but not perfect; the main problem is they elicit a focused immune response against a moving target Humans are affected by 2 main types of influenza: influenza A and B can both contribute to seasonal flu, but some influenza A subtypes preferentially infect animal hosts Sometimes these subtypes abruptly acquire the ability to infect humans, leading to pandemics such as the one in 2009 Each year the seasonal flu vaccine is designed to cover 2 strains each of influenza A & B, based on the public health community's best informed guess about which strains will be dominant that year Every influenza virus is studded with hundreds of molecular structures formed by haemagglutinin, a multifunctional protein that helps the virus bind & penetrate host cells; it comprises a bulky head attached to the virus by a slender stalk Most of the immune response is targeted at the head because it's highly exposed, but there's also evidence that the head contains features that preferentially elicit a strong antibody response Influenza A viruses are particularly diverse; they're classified by #s based on the subtype of haemagglutinin (H) protein & a second viral protein known as neuraminidase (N), with even greater strain variation observed among those subtypes For example, the 2009 pandemic arose from a new strain of the H1N1 subtype The extent of haemagglutinin variability means that poor strain selection can leave recipients largely unprotected; & even a good vaccine offers limited protection against future strains Further complicating the quest for a universal flu vaccine is the fact our immune system is strongly biased by its earliest encounters with influenza through a phenomenon called imprinting (aka original antigenic sin); individuals have a strong antibody response to viruses with molecular features shared by the strain encountered during their first exposure, but they essentially start from scratch when exposed to distantly related strains for the first time Imprinting is a double-edged sword because early exposure to the right strain could theoretically produce far-reaching and vigorous protection in response to vaccination, but if a child's first influenza encounter is with a relatively unusual or atypical strain, vaccination might prove less effective in terms of rousing broadly protective immunity A vaccine that focuses the immune response on a more stable target on the virus could overcome the problem of viral diversity In 1983, it was determined that the haemagglutinin stalk domain is so similar between strains that antibodies can recognize specific physical features (epitopes) of haemagglutinin proteins from multiple influenza subtypes; unfortunately, the stalk is something of an immunological wallflower, overshadowed by the influence of the head We've engineered epitopes into the stalk and the same epitopes into the head, and we get a much better response to epitopes in the head, but immunity can still emerge naturally in some cases, and a series of stalk-specific antibodies were isolated from human donors in 2008 and 2009 More recently, several research groups have devised multiple vaccine strategies for selectively provoking a stem-specific response; i.e. Graham's team at NIAID undertook a painstaking process of protein engineering a standalone version of the stem from an H1 influenza virus This vaccine design is now undergoing a phase I clinical trial and could in principle confer protection against many of the most prominent pandemic virus subtypes A newer haemagglutinin stem construct developed by NIAID could lead to even broader protection against the remaining subtypes An alternative approach generated multiple influenza viruses with chimaeric haemagglutinin proteins in which the same stalk domain is paired with various exotic head domains from virus subtypes that primarily infect birds & are therefore unlikely to trigger an imprinting-biased response in humans If you then revaccinate with a vaccine that has the same stalk but a completely different head, the immune memory against the stalk could be boosted This approach uses the entire virus particle, creating the potential to elicit parallel immune recognition of other influenza antigens Inspired by the discovery of cross-protective stalk antibodies in the wild, some research groups have been casting the net wider to find more such molecules After isolating the antibody-producing B cells from donors, researchers can profile the specific influenza targets that elicit a natural immune response & identify antibodies that might have broad infection-neutralizing capabilities These studies have revealed that even in the variable head domain of haemagglutinin there are structural elements that are consistent across influenza subtypes In 2012, researchers identified an antibody (CR9114) which exhibited unprecedented breadth of recognition; it could actually bind to both influenza A and influenza, & it's now being used to identify target epitopes on haemagglutinin that can be exploited to achieve far-reaching virus neutralization for both prevention and treatment In some cases these searches have revealed unexpected vulnerabilities in the virus Haemagglutinin normally assembles into highly stable complexes of three closely coupled molecules, but it was discovered this year that these trimers occasionally open up to expose a weak point to which antibodies can bind, potentially thwarting infection by a wide range of influenza A viruses Much of the variability between influenza viruses is only skin deep; probe more deeply within the virus particle & you find greater similarity in the essential proteins These are beyond the reach of antibodies but they can be recognized by T cells, an element of the immune system that can target and eliminate influenza-infected cells, which present peptide signatures of their viral intruders So far, antibodies have been the primary focus of the vaccine community because they represent a crucial first line of defence against circulating virus particles, but T cells provide critical protection by containing infection once it is under way. People get exposed and infected every 2-3 years on average; the vast majority of these infections are either asymptomatic or mild, & the reason is that people have a T-cell response that's strong enough to protect them In general, eliciting a truly protective T-cell response entails reawakening memory T cells that were formed in the aftermath of a previous exposure Gilbert's team uses a crippled vaccinia virus that can infect human cells & synthesize 2 different immunity-stimulating influenza proteins but is incapable of further replication With a single dose, we saw a boost in pre-existing T-cell responses of between eight- and tenfold in humans; the target proteins are 90% identical across influenza A viruses, offering the potential for broad protection against pandemic strains Gilbert's vaccine is undergoing two phase II trials A potent T-cell response also seems to contribute to the apparent cross-protection offered by a replication-defective flu vaccine from FluGen, which has reported success in a recent phase II clinical trial Even with several promising series of human trials under way, the road to the clinic remains fraught with difficulties Mice are often used for early studies of vaccine preclinical development but they aren't a natural reservoir for the influenza virus; many researchers therefore quickly switch to using ferrets to test their vaccine candidates, since they're broadly susceptible to influenza & are physiologically more like humans; however, both species are short-lived, making it difficult to study vaccine effects over many rounds of influenza exposure Gilbert has started working on pigs, a long-lived species that could serve as both a useful test case & an important beneficiary for vaccines; their large size though makes them difficult to use routinely in research Some hesitant about drawing too many conclusions from any animal model The ultimate proof for any flu vaccine is protection against disease in clinical trials, but for a putative universal vaccine, such testing is more complicated A growing # of groups are using 'human challenge' trials, in which healthy volunteers are deliberately exposed to a particular influenza strain after vaccination; this approach allows for faster trials with smaller cohorts & defined exposure conditions (lowering the trial cost) & it also lets researchers hand-pick the viruses they wish to protect against But challenge trials also have their critics: "It's not a natural infection; you have to inoculate people with a million or even 10 million virus particles, & it doesn't seem to work like a natural infection" Trials also leave out very young/old people, which are the groups most vulnerable to flu Another problem is that the FDA still requires a real-world trial before giving approval, & these are difficult and costly They require thousands of participants to ensure that a sufficient # of people are exposed to flu, & they must span several seasons to demonstrate efficacy against multiple virus strains or subtypes Many academic researchers say that even embarking on a clinical trial can pose a nearly insurmountable challenge, because it requires access to sophisticated production facilities that meet the high bar of good manufacturing standards At least a year to make it & a cost of approximately $1-2 million A few major companies have made these investments, but obtaining that much funding from either public or private bodies is far from easy More investment may be on the way from NIAID, the US Biomedical Advanced Research and Development Authority, and the Gates Foundation The vaccines now being developed promise much broader protection than current seasonal shots but fall well short of being truly universal The WHO still sees considerable value in such vaccines, & has called for 1 that prevents severe disease from all forms of influenza A by 2027, which would prevent pandemics But Krammer points out that seasonal influenza B infections can also inflict a serious death toll, and both he and Palese have focused their sites on true universality Universal protection need not entail eliminating all traces of influenza virus but simply providing sufficient immunity to minimize the symptoms of infection Even achieving that more modest goal will probably require a multipronged attack Gilbert is exploring the potential of a broader immunological assault that melds the Mount Sinai group's chimaeric stem vaccine with her team's vaccinia technique A greater understanding of the human immune system & its response to infection could inform smarter vaccination strategies In May 2019, the NIH awarded $35 million to an international team of researchers to profile the immunity of young children in the years after their initial exposure to influenza, providing the deepest insights yet into the imprinting process Their findings could help vaccine designers figure out the best way to rewire the immune system while it remains malleable, which could be a game-changer

Modern history of TB: death rates and interventions

From 1838 until the 1880s (when tubercle bacillus was identified), deaths per million fell considerably From the 1880s until around 1950 (when chemotherapy was introduced), deaths per million kept declining Even until the 1950s, when the BCG vaccination was introduced, deaths per million kept declining (and of course thereafter as well) ... Death rates from TB fell before BCG or therapies such as isoniazid and streptomycin were available Similar declines were observed for the other common infectious diseases; likely due to improvement in food supplies and nutrition; nutritional improvement in developing countries is causing similar trends today despite little/no access to medical services

Current polio eradication challenges

Funding shortfalls threaten eradication in Africa/Asia The spread has never stopped in Afghanistan/Pakistan, the latter of which has had particularly lousy vaccination campaigns, with mothers not trusting vaccinators

Retroviruses

Genomes consist of 2 RNA strands RNA strands are reverse-transcribed into DNA•Rely on three enzymes-Reverse transcriptase-Integrase-Protease•Significant in mammalian evolution-8% of the human genome consists of integrated retroviral DNA

Malaria vaccine

Ghana, Kenya, and Malawi will pilot the world's first malaria vaccine from 2018, offering it for babies and children in high-risk areas as part of real-life trials The injectable vaccine (RTS,S or Mosquirix) was developed by a British drug maker to protect children from the most deadly form of Malaria in Africa In clinical trials it proved only partially effective, and it needs to be given in a 4-dose schedule, but is the first regulator-approved vaccine against the mosquito-borne disease

Hawaii TB Patient Forced Into Quarantine (video notes)

Honolulu police and the health department worked together to forcibly quarantine a Hawaiian man with TB who has TB and has been refusing treatment Being used to protect both the public and the patient 47-year-old resisted health workers who were bringing him his daily medicine He needs 5 more months of treatment and could've become contagious again without medication "For his own good"

Ebola War (reading notes)

How the largest outbreak on record jump-started the development of 2 experimental vaccines & a couple of promising treatments As long as Ebola outbreaks remained small & sporadic, there was little real chance researchers could test & distribute vaccines or better treatments The current outbreak in West Africa (the largest on record) has changed the odds, focusing new attention & resources to fighting this relentless killer Researchers are rushing to test a few experimental treatments & potential vaccines, hoping to prevent thousands more deaths ... Researchers often talk about a race between the Ebola virus and the people it infects A patient wins the race only if the immune system manages to defeat the virus before it destroys most of his/her organs A community wins the race if it can isolate the 1st few patients before the disease spreads Humanity will win the race if it develops treatments & ultimately a vaccine before the virus gains a permanent toehold in the cities of the globe For years Ebola held a natural advantage; outbreaks were too small (typically fewer than 100 people) and too short-lived (less than 5 months) to give researchers the chance to test potential therapies By the time they could've put a clinical trial in place, the threat would have passed Pharmaceutical companies & research groups found it difficult to justify spending $ on a disease that, as horrible as it was, had taken 40 years to dispatch its first 1,600 victims Other diseases seemed far more worrisome: malaria, TB & HIV killed more than 3 million people in 2013; that steely calculus changed with the current, extraordinary Ebola outbreak in West Africa, the largest & longest on record By mid-January at least 21,000 people had acquired Ebola in Sierra Leone, Liberia & Guinea, and more than 8,500 deaths could be attributed to the disease International health leaders, realizing further inaction might let the virus spread well beyond the outbreak zone, called for a massive international response to identify & isolate those possibly coming down with it, build & staff dozens of emergency treatment centers to care for the sick, & recruit enough burial teams to safely dispose of the dead For the first time ever, scientists had an Ebola outbreak large/long enough to allow intensive clinical trials aimed at finding better treatments, 1 that might be impossible to stop without developing vaccines & new drug; they also won, for the first time, widespread agreement to test some of these experimental therapies in the field The unprecedented effort may prove more useful in tackling the next outbreak than in reducing the ongoing epidemic; but if researchers are successful this time around, they may ensure it never has the upper hand for long when it attacks humans again (& it will) As startling as it might seem, given the tsunami of cases over the past 15 months, much remains unknown about the Ebola virus: where it lives, how it comes to occasionally attack humans & why more people don't become infected when it starts spreading (each individual transmits the virus to 1-2 others, unlike highly contagious illnesses such as measles, where each case typically infects 18 others) Although it's not the most contagious of viruses, it's an exquisitely effective killer of humans & primates; as of the end of 2014, an estimated 70% of the people infected in West Africa had succumbed to the illness, usually within a matter of days, & often beyond the view of health authorities How quickly & completely Ebola overwhelms an individual depends on at least 2 factors: the amount of virus involved & how it first enters the body After the first few viruses have jumped the species barrier, presumably from fruit bats to people, it doesn't take much to keep the chain of transmission going Many victims become infected after preparing an infected relative's corpse for burial Wiping the vomit from a patient's chin or cleaning up after an infected child's bout of diarrhea can also transmit the virus, which gains entry into people's bodies after caregivers touch their own eyes, lips, nose or mouth with their now contaminated hands If many viruses are injected directly into the bloodstream, as with an accidental needle stick injury, you're unlikely to be saved Autopsies &pathology reports offer some of the best ways to learn about how viruses spread inside the body, but few have been conducted on Ebola victims because of the high risk of accidental infection to the people performing the necessarily invasive procedures A recent scientific review identified only 29 human cases where an autopsy or postmortem biopsy had been performed in the disease's nearly 40-year history Nevertheless, animal and pathology studies conducted so far show Ebola viruses make a devastating first strike on the immune system Like other viruses, Ebola must harness the machinery of cells it infects to make more copies of itself Among the initial targets are the so-called dendritic cells, which typically act as all-purpose sentries patrolling the tissues of the body, & macrophages, which consume damaged cells Rather than trying to avoid these first responders, Ebola viruses actually seek them out and begin reproducing inside of them This bold attack accomplishes 2 things: the viruses disrupt the cells' normal ability to jump-start the rest of the immune system, & they hitch a ride inside the cells, traveling unmolested to the lymph nodes, liver, spleen and other areas of the body if such guerilla tactics were not enough, Ebola employs another trick to hide its presence: it puts up a decoy to distract the immune system. The virus forces the cells it infects to manufacture and release into the bloodstream large amounts of a substance called secreted glycoprotein, or sGP, which looks a lot like a crucial molecule (known as GP) that sticks out of the viruses' outer covering. Ordinarily the immune system would target the GP—and thereby kill the virus to which it is attached. By fooling the immune system into also attacking the sGP (which, of course, is not attached to the virus), Ebola further undermines the body's ability to mount an e ective defense. NEW TREATMENTS THE RECENT EBOLA OUTBREAK has taught doctors and health workers some practical ways of overcoming the virus. It has long been known that despite the early setbacks, the immune system can rally to defeat the virus if it is given enough time. Health care workers have confi rmed in the current epidemic that they can buy their patients some of that time if they start giving them intravenous fl uids soon after the fi rst symptoms appear. The World Health Organization has okayed treating at least some patients with blood from survivors, which, by defi nition, must include plenty of antibodies, although no one knows whether the treatment works. The risky decision to support an untested therapy showed how desperate the situation had grown in West Africa. The approach at least makes theoretical sense, however. Convalescent serum was successfully used in response to polio from the 1920s to the 1950s and to fl u during the 1918 pandemic. The Bill & Melinda Gates Foundation has begun funding clinical trials of anti-Ebola serums in hard-hit Guinea. Of course, thanks to the biotech revolution, scientists can now manufacture the necessary antibodies artifi cially and have done so in a preparation called ZMapp, which is made up of three so-called monoclonal antibodies that target the Ebola virus. ZMapp gained nearly mythical status last summer when Kent Brantly, an American missionary doctor who was infected with Ebola in Liberia, became the fi rst person to receive the treatment. Media reports suggest that Brantly, gravely ill when his fi rst transfusion started, improved rapidly, getting up to shower the next day. There were fewer than a dozen courses of treatment in existence when Brantly was treated (three transfusions equal one course); within a couple of weeks even this small supply was exhausted. ZMapp was in the early stages of development— undergoing tests in animals—and commercial-scale production had not yet begun when the outbreak began. Manufacturing has since been geared up in the hopes that clinical trials in West Africa can start in the fi rst quarter of 2015. But even if the drug proves to be e ective, there is no hope that there will be enough ZMapp for all who might need it in the foreseeable future. Physicians would not have had even this much material to work with had governments not started spending money trying to develop antidotes in case Ebola was ever turned into a bioweapon. Scientists at Canada's National Microbiology Laboratory and the U.S. National Institute of Allergy and Infectious Diseases (NIAID) researched and developed the antibodies in the cocktail and then licensed their production to Mapp Biopharmaceutical, which in turn depends on Kentucky BioProcessing to grow the antibodies in genetically modified tobacco plants. Kentucky BioProcessing can produce enough antibodies for between 17 and 25 treatment courses per batch; it takes 12 weeks to grow the plants and a couple more to process the material. Efforts are afoot to try to substantially ramp up ZMapp output. The U.S. government—under its public health emergency authority—is considering bringing another producer onboard in a move that could potentially increase ZMapp output fourfold or fivefold. In addition, researchers are conducting studies in nonhuman primates to determine whether the number or volume of the infusions in a treatment course could be reduced, allowing supplies to be stretched. VACCINE NEEDED So much time was lost early on in recognizing the true extent of Ebola's spread through West Africa that the epidemic has now fractured into dozens of different micro outbreaks, with varying epidemiological characteristics. Health care workers, military personnel and local communities are making heroic efforts to save lives and contain the disease. But experts worry that the longer the epidemic continues, the greater the risk that the world could face ongoing transmission of Ebola in pockets of West Africa. In addition, the paralyzing effect the virus has had on the health care systems of the affected countries could open the door to other public health crises, such as outbreaks of measles or even the resurgence of polio. One of the best ways to forestall this grim future is to develop, test and distribute a successful vaccine—something that was impossible during previous smaller, shorter outbreaks. As case numbers in Guinea, Liberia and Sierra Leone exploded in late summer, the agencies guiding the international response determined that an effective vaccine might be the only way to halt the epidemic. Safety studies of the two leading experimental vaccines— dubbed cAd3-EBO and rVSV-ZEBOV—were conducted on several hundred volunteers in the U.S., Canada, Europe and various unaffected African countries toward the end of 2014. Larger studies with thousands more people were to begin earlier this year in Liberia and Sierra Leone; trials in Guinea will follow. The pace is unprecedented: a job that normally takes five to 10 years—the testing and scaled-up production of vaccine—is happening in less than a year. And yet, as the overall rate of new infections started to drop in Liberia toward the end of 2014, another wrinkle cropped up: Would there be enough sick people to determine if the vaccines were working? No one involved in the Ebola response wants to see more cases. But the reality of vaccine research is that you can only find out if these experimental preparations work in settings where the targeted pathogen is spreading. If infection rates drop too low, the clinical study slated to enroll 27,000 people in Liberia will have to be expanded—adding to the cost, complexity and time it will take to get to the answers. Organizers are still hoping to avoid that, says Charles Link, Jr., CEO of NewLink Genetics, an Iowa-based biotech company that is developing rVSV-ZEBOV in partnership with pharmaceutical giant Merck. The plan is to focus on the parts of Liberia where the infection rate is greater than average. Nothing is easy about the Ebola vaccines project, Link says: "The complexities are off the chart." The NewLink vaccine was designed by scientists at the Public Health Agency of Canada. It is composed of a modified live virus (vesicular stomatitis virus, or VSV) that is coupled with a portion of the primary protein found on the Ebola virus's surface. VSV sickens some livestock but is harmless to people; the virus generates a low-grade infection that provokes the immune system to pump out antibodies against the Ebola protein. But the vaccine cannot trigger the disease itself. The other vaccine, cAd3-EBO, was originally developed by scientists at niaid. GlaxoSmithKline acquired the rights to it when it bought Swiss vaccine developer Okairos in 2013. It is an inactivated (killed) vaccine that uses a genetically modified chimp adenovirus to present the key surface protein from the Ebola virus to the immune system. Both experimental vaccines have pros and cons. The GlaxoSmithKline vaccine started off with more advanced testing than the NewLink vaccine. But the VSV vaccine is easier to make, and many more doses were available by late last December. Just how many depends on what preliminary studies show is needed to generate good levels of antibodies. There are concerns that the GlaxoSmithKline vaccine might not be able to protect with a single dose. A two-dose delivery regimen—especially one that uses different vaccines for priming and boosting—would be phenomenally difficult, given the statof the health care infrastructure in the affected countries. It is expected that the NewLink vaccine will require only one shot, but it may induce mild (though nonetheless confusing) side effects such as low-grade fever, chills, muscle aches or headaches—in other words, precisely the same cluster of symptoms that foretell Ebola's arrival. In a world that uses those symptoms to detect Ebola infections, this will make sorting the sick from the well in the outbreak zone more challenging. The Liberian trial is designed to contain three arms. Some recipients are receiving the GlaxoSmithKline vaccine, some are receiving the NewLink vaccine, and some are getting a placebo, perhaps a flu shot or a hepatitis B vaccine. A number of prominent scientists have argued in the pages of the Lancet and elsewhere that placebo-controlled trials in this situation are unethical. But the U.S. Food and Drug Administration, which would need to approve any preparation used by U.S. military or health organizations, has pushed for placebo-controlled trials. "We need to learn what helps and what hurts at the soonest possible time and in the most definitive way," says Luciana Borio, who is leading the fda's Ebola response. "It's going to be important for generations to come, and we have to get this right." Jeremy Farrar, director of British charity foundation Wellcome Trust, which is funding a number of drug and vaccine trials, had been hoping for more innovative approaches—trials employing what is known as step-wedge and cluster-randomized designs—that allow everyone to get the active vaccine eventually. Still, he can live with a placebo-controlled trial. "I'm not absolutely comfortable with it," he says. "But with a vaccine, which you are giving to healthy people when you don't know its safety profile and you don't know its efficacy, I actually can ac - cept either a cluster-randomized or step-wedge design or a placebo-controlled design." Meanwhile a step-wedge trial will take place in Sierra Leone. That trial design uses the fact that it is impossible to vaccinate everyone at once to create a control group; you compare the rate of new infections in areas that have already received the vaccine with those in places where rollout has not yet taken place. The benefit: everyone gets vaccine; the disadvantage: it may take longer to determine if a vaccine works. Guinea, too, will see some type of trial, although it is likely to be less ambitious. The infrastructure of the country is in worse shape than those of its neighbors, making operating clinical trials an even more difficult task. Marie-Paule Kieny, who is the WHO's point person in the international effort to develop Ebola vaccines and drugs, says the Guinean trial will vaccinate health care workers in an observational study that does not include a placebo arm. In addition, the Gates Foundation may fund a trial to see whether ring vaccination—vaccinating around a known case to try to prevent onward transmission—would be effective. (Ring vaccination is what finally vanquished smallpox in the 20th century.) A series of other experimental vaccines are at different stages of development. Some of them are thought to be at least as promising as the GlaxoSmithKline and NewLink products. One made by Johnson & Johnson started safety trials in early January. But those that are trailing behind the GlaxoSmithKline and NewLink vaccines face a tough economic reality. In the race to de - feat the deadly virus, fourth or fifth place is not likely to count. The future market for Ebola vaccines will be limited. Either the WHO or GAVI (the Vaccine Alliance) will most likely stockpile the product for use in future outbreaks. And some affluent countries will surely buy supplies as a shield against bioterrorism. But the market is un - likely to be much bigger. So unless one of the front-runners falters, those at the back of the pack may fall away. "The ones that come af - ter the two first, they have a place only if the first two fail," Kieny says. Of course, the possibility that the entire vaccine effort might fail is never far from the minds of Ebola researchers and health care workers. Although the epidemic is no longer growing exponentially—as it was last September—the outbreak is still not under control. The number of new cases has fallen in large parts of Liberia, but disease transmission remains intense in the western and northern districts of Sierra Leone. Until the number of new cases drops to zero, however, the possibility of renewed resurgence and spread remains all too real. Thousands of people died in 2014. Even with the continued efforts of many health care workers, burial teams and other volunteers, hundreds and possibly thousands more will, unfortunately, die in 2015. But the world will have a much better sense in the coming months of just how much farther and faster we need to run to finally outpace this dastardly virus Early in the course of infection, the virus delivers a lethal one-two punch, targeting key aspects of both the immune system & the circulatory system The crippling attack on the body's defenses lets the pathogen reproduce in explosive #s in other cells throughout the body, while the collapse of the vascular system & subsequent loss of blood provide new opportunities for the pathogen to infect other people Ebola is a member of the Filoviridae family of viruses & consists of a single strand of RNA & associated proteins, wrapped in a fatty membrane Scientists have so far isolated 2 members of the family, Ebola and Marburg viruses, and grown them in culture Genes from a third member, Lloviu virus, have been sequenced, but the virus hasn't yet been fully characterized in a lab Of the 5 known strains of Ebola, Reston is the only one that apparently doesn't cause disease in infected people Substances called glycoproteins stick out of the fatty outer membrane & help the virus latch on to host cells Much remains unknown about exactly how the Ebola virus infects cells, but research on nonhuman primates suggests the virus targets the immune system's first lines of defensive cells, disabling them & thereby crippling the rest of the immune system As the viruses reproduce and their #s mount, they attack the body's blood vessels & various organs as well Among the first immune cells to be infected by Ebola are the dendritic cells, which patrol the body's tissues looking for microscopic invaders, & the macrophages, which help spread the alarm about the presence of pathogens by, among other things, producing various inflammatory molecules called cytokines By targeting cells that travel throughout the body, the Ebola virus quickly spreads to (&reproduces in) the liver, spleen & other major organs Disabling this early line of defense also triggers an avalanche of problems in the immune system that the virus takes advantage of to rapidly grow and divide Once inside a host cell, the viral RNA is duplicated using both viral proteins & the cell's own machinery Currently the best line of defense is to prevent infection from happening in the first place: clinicians must wear protective clothing that covers the entire body, including the face; community workers need to identify &, if necessary, isolate anyone who's been exposed to an infected person before they can spread the illness, & burial teams must dispose of infected corpses safely Providing intravenous fluids early in the course of infection may help some patients survive More targeted strategies now being developed include the injection of antibodies, from survivors or engineered antibody drugs such as ZMapp, antiviral drugs & vaccines The Ebola virus crosses the physical barrier of the skin via cuts, contaminated needles or the mucosal surfaces of the eyes, nose and throat; from this point on, the virus is hard to stop Infected immune cells transport virus into lymph nodes then blood vessels Immune cells are distracted by decoys For complex reasons, the overproduction of cytokines leads, among other things, to the overproduction of clotting factors in the blood; too many clots form in some areas, and excessive bleeding occurs in others Leaky blood vessels can't supply enough blood to the organs, causing them to fail; also, the now damaged blood vessels may allow bacteria from the gut to slip into the bloodstream, causing a life-threatening condition known as sepsis As chaos reigns throughout the immune system, viral reproduction grows dramatically in liver cells & other tissues The overproduction of cytokines prompts the death of many other immune cells, including some of the ones that manufacture antibodies that could ultimately neutralize the Ebola virus The virus forces infected cells to manufacture substances, called soluble glycoproteins, that look like the glycoproteins found on the virus's outer coat, which help the virus gain entry into host cells The soluble proteins may act as decoys that fool the immune system into releasing antibodies against the wrong target, further undermining the body's counterattack

American Endemic (reading notes)

Resurgent infectious diseases outbreaks are sickening thousands, and the causes are societal Rising rates of hepatitis A, Legionnaires' disease &other scourges carried by viruses, bacteria & parasites are scarring US cities Infectious diseases, once thought to be on the decline, are making a comeback, driven by widening economic inequality & microbe-vulnerable buildings Not only the poor but the well off are at risk, as disease transmission crosses lines of health & wealth ... Sustained person-to-person spread of hepatitis A, is rare, & the severity of this epidemic also stands out Other infections have also been tearing through US cities (i.e. legionnaires' disease in NYC, gonorrhea in San Fran, & other STIS throughout the country) These surging infections in the US aren't what the medical world expected Infectious diseases are less of a threat in this country than they were a century ago, thanks to mass vaccination, improved sanitation, & scientific advances in diagnostics, treatment & epidemiology Rates of HIV and tuberculosis are still continuing to decline overall But some infections are making a strong comeback in America, & researchers worry the effects of the diseases could be more devastating now since the country has a more aged, chronically ill & vulnerable population Infections rarely seen in the US are also ripe for emergence & a handful of parasitic diseases are becoming established—yet are underdiagnosed There are many causes for these rising infectious tides, but researchers agree a major driver is the country's ever-worsening income inequality The disparity between America's highest & lowest earners exceeds that of almost every other developed country, & it's still widening People on the bottom rungs of society live in crowded, unclean conditions, have limited health care & poor nutrition, must work when sick, experience debilitating stress, & are more likely to abuse drugs/alcohol—all known infection risk factors What makes for large outbreaks, however, is that when illnesses start spreading through America's urban poor, they don't stay there Large urban population increase; crowding facilitates transmission More city-dwelling Americans take public transportation & travel now than ever before, too, turning the nation into the equivalent of a crowded, germ-trading global market Historically, the US has done a good job of controlling infections; but recently, new cases of certain ailments have gone up, & scientists attribute the rise to growing poverty & increasingly vulnerable populations Newly diagnosed cases of STDs have increased; chlamydia, gonorrhea and syphilis have all spiked; legionnaires' disease & hepatitis C have been climbing as well Some childhood diseases like whooping cough, for which there are vaccines, appear to rise & then drop Outbreaks of infectious diseases are rising around the world, but deaths are dropping Recently in the US, the # of people getting sick from certain ailments has risen Worldwide, the # of people killed from many types of infections has decreased over the long term, but the trend varies at different economic levels Overall, disease outbreaks, a measure that includes both sickness & death, have become more frequent, with more varied causes Global mortality drops but differs by economy When the countries of the world are divided by economy type, some distinctions in death rates stand out Low- & lower-middle-income countries, like Haiti & India, started high & showed a steep drop in mortality during the first 15 years of this century; the wider availability of medical care, as well as drugs to combat infections, played an important role HIV/AIDS deaths declined dramatically after 2005, coinciding with a US-led initiative to provide care, including antiretroviral medication, to poorer countries Upper-middle- and high-income countries, like China & Germany, began with better care & thus did not show a sharp drop in deaths Even so, well-off countries have had a difficult time controlling respiratory diseases like pneumonia, which hits hard among the elderly & people with weakened immune systems Global outbreaks rise The # of infectious disease outbreaks worldwide rose steadily during the 30 years following 1980; the variety of outbreak-causing diseases also went up Viruses & bacteria were the most common causes of disease during those three decades, & the # of outbreaks driven by both person-to-person transmission & vectors such as insects climbed Epidemics from zoonotic diseases increased over time, slightly more so than did human-specific illnesses Most of these zoonotic outbreaks were traced to a few familiar causes Although outbreaks are on the upswing, the actual # of people infected as a % of the total world population declined as the international community increased epidemic containment efforts for diseases like Ebola & influenza Infectious Disease: illness caused by microorganisms, such as bacteria, viruses, parasites or fungi, that can spread from one person to another or from an animal to a person Endemic: describes the baseline level of a disease usually present in a community Epidemic or outbreak: an increase, often sudden, in the # of cases of a disease above normal levels in a region; an outbreak sometimes refers to an increase in a smaller geographical area Pandemic: an epidemic that's spread across several countries or continents & usually affects a large # of people Zoonosis: a type of infectious disease that originates in vertebrate animals & moves to people; can be spread by direct contact or carried from animals to humans by a vector like a biting insect Mortality: # of deaths caused by a disease in a population at a particular time Incidence: # of new cases of a disease in a population at a particular time

Transmission of chagas disease

Insect takes a blood meal and defecates (poops) Feces contain parasite

First XDR-TB patient successfully completes treatment in Kenya (video notes)

Late 2013, Elizabeth started treatment for MDR-TB 5 months later, her treatment wasn't having any effect and she was diagnosed with a more serious form of the disease, XDR-TB This was the first case in Kenya's MSF program (diagnosing XDR-TB), shocking the care facility and patient She was put under new drug, Bedaquilline, becoming the first patient in Kenya to receive the XDR-TB drug These drugs needed cross-monitoring for side effects, adverse effects because they'd never used the treatment before Her treatment lasted 24 months Elizabeth's son was being treated for MDR-TB at the same clinic; they both suffered constraints and side effects of their treatment The child was taking 7-8 pills daily & an injection almost every day; the mother took 15 pills plus injections Nausea, nightmares, joint pains, vomiting effects

A small but increasingly influential group of investigators believes ____________ may have evolved along an unexpected and particularly dangerous path. They discovered that TB can be divided into ________ families of genetically related strains, at least ___________ of which is surprisingly virulent, prone to drug resistance and very well suited to spreading disease in our increasingly interconnected, densely populated world. Efforts to develop new therapies and diagnostic tests may be doomed to fail.

MTB; 7; 1

Chronic schistosomiasis

May appear months to years after exposure: Bloody diarrhea Abdominal pain, right upper quadrant (RUQ) pain, cramping Bloody urine or painful urination Portal hypertension Pulmonary hypertension Seizures/mental status changes (brain damage) Paralysis (spinal cord damage)

Anopheles (mosquito)

Most active at dawn and dusk, but also during the night Malaria (gambiae and stephensi)

Culex (mosquito)

Most active at dawn and dusk, but also during the night West Nile virus Culex quinquefaciatus

Falciparum malaria

Most severe form Case fatality: 20% 1-2,000,000 deaths/year Cerebral malaria, hypoglycemia; severe anemia; respiratory distress, renal failure

Read me (polio)

Motor neurons that control voluntary muscle movement have their cell bodies in the spinal cord and long axons that extend to groups of muscles (i.e. in the arm) Sprouts near the end of each axon innervate individual muscle cells Some motor neurons infected by polio survive, but others die, leaving paralyzed muscle cells Recovered (alive) motor neurons develop new terminal axon sprouts that reinnervate orphaned muscle cells A single motor neuron may grow sprouts to innervate 5-10x more muscle cells than it did originally, creating a giant motor unit The adaptation isn't static: in a process called remodeling, the motor unit is constantly losing old sprouts and growing new ones After many years of functional stability, enlarged motor units begin to break down, causing new muscle weakness 2 types of degeneration have been proposed A progressive lesion is produced when normal regeneration of the axon sprouts no longer keeps pace with dying or malfunctioning sprouts A fluctuating lesion occurs when there's a faulty synthesis or release of the neurotransmitter acetylcholine ... Normal activity of acetylcholine leads to muscle contraction When acetylcholine is released from an axon into a synaptic cleft, it binds to receptors on the muscle, causing it to contract An enzyme spits the remaining acetylcholine into choline and acetate, which are reabsorbed by the axon and resynthesized into new acetylcholine Chronic disruption of this cycle may result in progressive muscle weakness

TB vaccine research

Pre-exposure vaccination (10 in clinical trials), for children Postexposure vaccination (1 prepared for clinical trial), for latent infection Therapeutic vaccination (2 in clinical trials), for active TB Latent infection (2 billion individiuals) -> sterile Mtb eradication (cure) or active TB (10 million annually, look into ways to prevent active) -> death and/or transmission (2 million annually) -> latent or cure (prevent Mtb infection)

What does it mean that TB germs do not spread in a vacuum?

People with TB might also be malnourished or alcoholic or might avoid taking medication Not just HIV but also diabetes seems to interact synergistically with the organism

Hidden and Dangerous (reading notes)

Polio could soon be wiped out, but only if scientists can track down the last carriers Global eradication of polio has been the ultimate game of Whack-a-Mole for the past decade; when it seems the virus has been beaten into submission in a final refuge, up it pops in a new region Now, as vanquishing polio worldwide appears again within reach, another insidious threat may be in store from infection sources hidden in plain view Polio's latest redoubts are "chronic excretors," people with compromised immune systems who, having swallowed weakened polioviruses in an oral vaccine as children, generate & shed live viruses from their intestines & upper respiratory tracts for years Healthy children react to the vaccine by developing antibodies that shut down viral replication, thus gaining immunity to infection; but chronic excretors can't quite complete that process & instead churn out a steady supply of viruses The oral vaccine's weakened viruses can mutate & regain wild polio's hallmark ability to paralyze the people it infects After coming into wider awareness in the mid-1990s, the condition shocked researchers Wild polioviruses stop circulating & countries cut back on vaccination efforts, but a chronic excreter kisses an unvaccinated baby, the baby goes to daycare, & then it's all over the place, with babies drooling all over each other Polio could come back from a developed country & even in the developing world Although it was once thought immuno-compromised individuals couldn't survive for long in lower-income countries, circumstances are changing as those countries improve their health care systems In 2009 an immunodeficient 11-year-old Indian boy was paralyzed by polio, 5 years after swallowing a dose of oral vaccine; it was only then researchers recognized him as a chronic excreter Chronic excretors are generally only discovered when they develop polio after years of secretly spreading the virus; thankfully, such cases are rare The Global Polio Eradication Initiative is pushing for the development of drugs that could turn off vaccine virus shedding; a few promising options are in the pipeline Drugs can only solve the problem if chronic excretors are identified, & that's no easy task For years scientists in Finland, Estonia & Israel monitored city sewers, watching for signs of shedders' presence; in many samples, they've found the telltale viruses from chronic excretors, but they've failed to locate any of the individuals These stealthy shedders may not be classic immunodeficient patients traceable through visits to immunologists; instead they may be people who don't know they have an immunity problem at all & are under no specialized medical care

What Is Polio (reading notes)

Polio, or poliomyelitis, is a disabling & life-threatening disease caused by the poliovirus The virus spreads from person to person & can infect a person's spinal cord, causing paralysis (can't move parts of the body) Most people who get infected with poliovirus (72/100) won't have any visible symptoms About 1/4 people with poliovirus infection will have flu-like symptoms that may include: sore throat, fever, tiredness, nausea, headache, stomach pain; these symptoms usually last 2-5 days, then go away on their own A smaller proportion of people with poliovirus infection will develop other, more serious symptoms that affect the brain and spinal cord: paresthesia (feeling of pins & needles in the legs), meningitis (infection of the covering of the spinal cord &/or brain; occurs in 1/25 people with poliovirus infection), paralysis (can't move parts of the body; or weakness in the arms, legs, or both; occurs in 1/200 people) Paralysis is the most severe symptom associated with polio, since it can lead to permanent disability & death Between 2-10 out of 100 people who have paralysis from poliovirus infection die, since the virus affects the muscles that help them breathe Even children who seem to fully recover can develop new muscle pain, weakness, or paralysis as adults, 15-40 years later (post-polio syndrome) Poliomyelitis (polio for short) is defined as the paralytic disease, so only people with the paralytic infection are considered to have the disease Poliovirus is very contagious & spreads via person-to-person contact It lives in an infected person's throat & intestines Poliovirus only infects people It enters the body through the mouth & spreads through: contact with the feces of an infected person, droplets from a sneeze or cough of an infected person (less common) You can get infected with poliovirus if: you have feces on your hands, & touch your mouth; you put in your mouth objects like toys contaminated with feces An infected person may spread the virus to others immediately before & up to 2 weeks after symptoms appear The virus can live in an infected person's feces for many weeks; it can contaminate food & water in unsanitary conditions People who don't have symptoms can still pass the virus to others & make them sick There are 2 types of vaccine that can prevent polio: - Inactivated poliovirus vaccine (IPV) given as an injection in the leg or arm, depending on the patient's age; only IPV has been used in the US since 2000 - Oral poliovirus vaccine (OPV) is still used throughout much of the world Polio vaccine protects children by preparing their bodies to fight the poliovirus Almost all children (99/100) who get all the recommended doses of the inactivated polio vaccine will be protected from polio Thanks to a successful vaccination program, the US has been polio-free since 1979, but poliovirus is still a threat in some countries Get your child vaccinated on schedule & be part of the success story Polio was once one of the most feared diseases in the US In the early 1950s, before polio vaccines were available, polio outbreaks caused more than 15,000 cases of paralysis each year Following introduction of vaccines (specifically, trivalent IPV in 1955 & trivalent OPV in 1963) the # of polio cases fell rapidly to less than 100 in the 1960s & fewer than 10 in the 1970s In the late 1940s, polio outbreaks in the US increased in frequency & size, crippling an average of more than 35,000 people each year Parents were frightened to let their children go outside, esp in the summer when the virus seemed to peak Travel & commerce between affected cities were sometimes restricted Public health officials imposed quarantines (used to separate & restrict the movement of well people who may have been exposed to a contagious disease to see if they become ill) on homes & towns where polio cases were diagnosed Thanks to the polio vaccine, dedicated health care professionals, & parents who vaccinate their children on schedule, polio's been eliminated in this country for over 30 years, meaning there's no year-round transmission of poliovirus in the US Since 1979, no cases of polio have originated in the US, but the virus has been brought into the country by travelers with polio (the last time this happened was in 1993.) It takes only 1 traveler with polio to bring the disease into the US People most at risk are: those who never had polio vaccine, those who never received all the recommended vaccine doses, those traveling to areas that could put them at risk for getting polio The best way to keep the US polio-free is to maintain high immunity (protection) against polio in the population through vaccination For the best protection, children should get 4 doses of polio vaccine, which is given as a shot in the arm or leg & is very safe. Ideally, your child should receive a dose at ages: 2 months, 4 months, 6-18 months, & then a booster dose at age 4-6 years Inactivated polio vaccine (IPV) may sometimes be given in the same shot with other vaccines (a combination vaccine), so discuss this option with your child's doctor Getting the recommended doses of polio vaccine is an important part of keeping the US polio-free. Polio has been eliminated from most of the world, but the disease still exists in a few countries in Asia & Africa Even if you were previously vaccinated, you may need a one-time booster shot before you travel anywhere that could put you at risk for getting polio A booster is an additional dose of vaccine to ensure the original vaccine series remains effective Make sure you get your travel vaccination(s) well before your departure date to ensure complete protection Polio, or poliomyelitis, has been eliminated from most of the world, but it is still a threat in some countries Even if you were previously vaccinated, you may need a one-time booster shot before traveling to a country where the risk of getting polio is greater People who plan to travel internationally should make sure they're fully vaccinated against polio before departure When visiting one of the higher polio risk countries, you may be required by the government of the country to show proof of polio vaccination CDC recommends all infants and children in the US are vaccinated against polio with 4 doses of the IPV vaccine given at 2 months, 4 months, 6-18 months, & 4-6 years Infants & children traveling to areas where the risk of getting polio is greater should complete the routine series before departure If a child can't complete the routine series before departure, an accelerated schedule is recommended as follows: first dose at age 6 weeks or older, a second dose 4 or more weeks after the first dose, a third dose 4 or more weeks after the second dose, a fourth dose 6 or more months after the third dose If the accelerated schedule can't be completed before leaving, remaining doses should be given in the affected country, or upon return home, at the intervals recommended in the accelerated schedule Children completing the accelerated schedule should still receive a dose of IPV at 4 years old or older, as long as it's been at least 6 months after the previous dose Adults traveling to areas with increased risk of polio & who are unvaccinated, incompletely vaccinated, or whose vaccination status is unknown should receive a series of 3 doses: 2 doses separated by 1-2 months, & a third dose 6-12 months after the second dose. Adults who completed the polio vaccine series as children & are traveling to areas with increased risk of polio should receive a 1-time booster dose of vaccine (IPV) Post-polio syndrome (PPS) is a condition that can affect polio survivors decades after they recover from their initial poliovirus infection Unlike poliovirus, PPS isn't contagious. PPS affects between 25-40/100 polio survivors Starting about 15 -40 years after the initial infection, people affected by PPS can begin experiencing a set of health problems such as: muscle weakness, feeling tired (mental & physical fatigue), joint pain Some people with PPS have only minor symptoms, while others develop more visible muscle weakness & atrophy (a decrease in muscle size) PPS is rarely life-threatening, but the symptoms can make it difficult for an affected person to function independently While poliovirus is no longer endemic in the US, it's important healthcare professionals rule out poliovirus infection in cases of unexplained acute flaccid paralysis (AFP) that are clinically compatible with polio, esp those with anterior myelitis, to ensure that any importation of poliovirus is quickly identified and investigated There hasn't been a case of wild polio acquired in the US since 1979; the last imported case of wild polio was in 1993 However, polio is still a threat in other parts of the world & could easily be brought into the US from countries where wild poliovirus is circulating In the last decade, at least 40 polio-free countries have been affected through international travel Poliovirus Poliovirus causes polio, or poliomyelitis, a highly infectious disease There are 3 poliovirus serotypes (PV1, PV2, & PV3) with minimal heterotypic immunity between them; immunity to 1 serotype doesn't produce significant immunity to the other serotypes Poliovirus is spread by fecal-oral & respiratory routes Infection is more common in infants & young children Polio occurs at an earlier age among children living in poor hygienic conditions In temperate climates, poliovirus infections are most common during summer & autumn In tropical areas, the seasonal pattern is less pronounced Most people infected with poliovirus (72%) will not have any visible symptoms About 1/4 people will have flu-like symptoms, which usually last 2-5 days, then go away on their own About 1% of people will have weakness or paralysis in their arms, legs, or both The paralysis can lead to permanent disability & death About 2-10% of people who have paralysis from polio die, because the virus affects the muscles that help them breathe The incubation period of nonparalytic poliomyelitis is 3-6 days For the onset of paralysis in paralytic poliomyelitis, the incubation period usually is 7-21 days Polio vaccine provides the best protection PPS is characterized by slow & irreversible exacerbation of weakness often in those muscle groups involved during the original infection Muscle & joint pain also are common manifestations The prevalence & incidence of PPS is unclear; studies estimate 25%-40% of polio survivors suffer from PPS A probable polio case is defined as an acute onset of flaccid paralysis of 1 or more limbs with decreased or absent tendon reflexes in the affected limbs, without other apparent cause, & without sensory or cognitive loss Paralysis usually begins in the arm or leg on one side of the body (asymmetric) & then moves towards the end of the arm or leg (progresses to involve distal muscle groups); descending paralysis Many patients with AFP will have a lumbar puncture & analysis of cerebrospinal fluid (CSF) performed as part of their evaluation Detection of poliovirus in CSF from confirmed polio cases is uncommon, & a negative CSF test result can't be used to rule out polio Consider polio in patients with polio-like symptoms, esp if the person is unvaccinated & recently traveled abroad to a place where polio still occurs, or was exposed to a person who recently traveled to one of these areas If you suspect polio: promptly isolate the patient to avoid disease transmission, immediately report the suspected case to the health departmen, obtain specimens for diagnostic testing for poliovirus detection (polymerase chain reaction), viral isolation & intratypic differentiation as early in the course of illness as possible, including 2 stool specimens and two throat swab specimens at least 24 hours apart, ideally within 14 days of symptom onset The rapid investigation of suspected polio cases is critical to identifying possible poliovirus transmission and implementing proper control measures, allowing specimen collection for poliovirus isolation to confirm whether a case of AFP may be the result of wild or vaccine-related poliovirus infection Paralytic polio has been classified as "Immediately notifiable, Extremely Urgent," which requires that local & state health departments contact CDC within 4 hours Non-paralytic polio has been classified as "Immediately notifiable, Urgent," which requires that local & state health departments contact CDC within 24 hours. CDC will provide consultation Poliovirus can be detected in specimens from the throat, feces (stool), & occasionally cerebrospinal fluid (CSF) by isolating the virus in cell culture or by etecting the virus by polymerase chain reaction (PCR) CDC laboratories conduct testing for poliovirus, including: culture, intratypic differentiation, genome sequencing, serology Virus isolation in culture is the most sensitive method to diagnose poliovirus infection Poliovirus is most likely to be isolated from stool specimens; it may also be isolated from pharyngeal swabs; isolation is less likely from blood or CSF To increase the probability of isolating poliovirus, collect at least 2 stool specimens 24 hours apart from patients with suspected poliomyelitis; these should be collected as early in the course of disease as possible (ideally within 14 days after onset) Real-time reverse transcription PCR is used to differentiate possible wild strains from vaccine-like strains ("intratypic differentiation"), using virus isolated in culture as the starting material Partial genome sequencing is used to confirm the poliovirus genotype and determine its likely geographic origin Serology may be helpful in supporting the diagnosis of paralytic poliomyelitis, esp if a patient is known or suspected to not be vaccinated An acute serum specimen should be obtained as early in the course of disease as possible, & a convalescent specimen should be obtained at least 3 weeks later. Detection of poliovirus in CSF is uncommon; CSF usually contains an increased number of leukocytes & a mildly elevated protein Specimen type: stool, sereum, sespiratory (nasopharyngeal/oropharyngeal swab), CSF Polio (or poliomyelitis) is a disease caused by poliovirus; It can cause lifelong paralysis (can't move parts of the body), & it can be deadly Initial symptoms of polio are: fever, fatigue, headache, vomiting, stiffness in the neck, pain in the limbs Polio mainly affects children under 5 years of age Poliovirus enters the body through the mouth, in water or food that's been contaminated with fecal material from an infected person The virus multiplies in the intestine & is excreted by the infected person in feces, which can pass on the virus to others An infected person may spread the virus to others immediately before and usually 1-2 weeks after developing symptoms The virus may live in an infected person's stool for many weeks; he or she can contaminate food & water when they touch it with unwashed hands Polio doesn't respect borders: any unimmunized child is at risk For every case of paralysis there are between 200-1000 children infected without symptoms, so it's hard to detect polio & hard to prevent the virus from travelling Children living in areas where immunity levels are low are particularly vulnerable The best defense against polio importations is to eradicate the virus; only then will all children be safe No, there is no cure for polio Polio vaccine is the only protection against polio Safe and effective vaccines exist: OPV & IPV OPV is administered orally & can be given by volunteers; protects both the individual & the community; it's essential to stop wild poliovirus (WPV) transmission IPV is given by injection & needs to be administered by a trained health worker; extremely effective in protecting children from polio, but can't stop the spread of virus in a community To stop polio we need to: - Engage entire societies in the effort to reach every last child - Make special plans to reach children from mobile and migrant populations, in conflict zones, or in remote regions - Strengthen routine immunization, which is the best national defense against polio - Improve surveillance in high-risk areas - Encourage governments to reach out to the poorest people with other public services - Continue to receive the highest level of political commitment from national governments and multilateral institutions - Ensure the needed financial resources are in place to finish the job

5 elements of Directly Observed Treatment, Short-Course (DOTS)

Political commitment Microscopy services Drug supplies Surveillance and monitoring systems Highly effective regimes with direct observation of treatment

Classify the NTDs we studied as either protozoan, bacterial, helminth, or a virus

Protozoan: chagas Bacterial: trachoma Helminth: river blindness, schistosomiasis, hookworm, dracunculiasis, guinea-worm Virus (smaller than bacteria): chikungunya

HIV classifications*

Retrovirus, specifically a lentivirus (long incubation) Two types: HIV-1 and HIV-2 HIV-2 progression to AIDS is slower and concentrated in West Africa There are many strains evolving in different places

OPV

Sabin's oral polio vaccine, introduced in 1962 Weakened live virus, taken orally Live-attenuated vaccine

Article's description of schistosomiasis cycle

Schistosome eggs produced in infected individuals enter freshwater in urine or feces -> snail-invading larvae called miricadia hatch from the eggs -> larvae in snails reproduce & morph repeatedly, ultimately into a human-infecting form -> released larvae (cercariae) swim to a new victim, usually emerging in midday to maximize the chance of finding a host -> cercariae bore through the skin (despite being toothless), transform into schistosomula & enter veins -> schistosomula float to the liver circulation, where they pair up & mature into adults -> worm pairs migrate (against the flow of blood) to distant sites to lay eggs -> eggs lodge in the intestines or bladder & enter feces or urine, restarting the cycle

Malaria

Serious, sometimes fatal, disease you get from a mosquito bite Fever and flu-like aches, followed by nausea, jaundice, and worse Over a million people die from malaria every year, many of them are children Very widespread: over 40% of the world's people are at risk for malaria, and there are 300-500 million cases every year

Whitehall studies

Show that low-ranked British officers (officer messengers and other support staff) are almost twice as likely to die from heart disease as administrators of the same age Differences in risk (i.e. higher smoking rates among the support staff) account for less than HALF the gap in mortality rates

?????????

Sickle cells bind to blood vessel lining & activate it Activated blood vessel lining attracts other cells, gook, and a "cloud" of inflammation chemicals This attracts smooth muscle cells, which form a layer of increasing thickness These build up, narrow the channel .& block the channel, causing oxygen starvation downstream (e.g. a stroke)

UNICEF: eradicating polio

Since the momentous launch of the Global Polio Eradication Initiative in 1988 during the World Health Assembly in Geneva, nearly five million children, who otherwise would've been paralyzed and incapacitated by polio, are walking, able and symptoms-free

Malarial fever symptoms

Sometimes (often not) very well for days in between ferbile (feverish) episodes: - Shivering stage: cold, violent shivering (half or 1 hour) - Hot stage: malaise, headache, prostration, anorexia, vomiting (2-6 hours) Drenching sweat stage (half hour)

Put the following malaria lifecycle steps in order: Oocyst, merozoite, RBCs, fertilization, sporozoite, liver cells, zygote, gametes, gametocytes, liver cells, meiosis

Sporozoite -> liver and liver cells -> merozoites (rupture) -> RBCs -> gametocytes (rupture) -> gametes (in mosquito) -> fertilization -> zygote -> meiosis -> oocyst (burst) -> sporozoite

3 stages and vaccine targets of malaria

Sporozoite: the goal of sporozoite vaccines is to block parasites from entering/growing within human liver cells Merozoite: Vaccines based on merozoite antigens lessen malaria's severity by hobbling the invasion of new generations of red blood cells or by reducing complications Gametocyte: So-called altruistic gametocyte-based vaccines don't affect human disease but are designed to evoke human antibodies that derail parasite development within the mosquito

How did Japan eradicate schistosomiasis?

Switched from water buffalo to horses (less susceptible host) Removed vegetation from the sides of irrigation canals Good sanitary practices to control human excrement Mainly, political will: stable government coordinated control programs, and enough funding for success

Award-Winning Photos Highlight Drug-Resistant Tuberculosis (video notes)

TB is preventable and usually treatable, but it continues to afflict nearly 9 million people each year, and kills 1 person every 20 seconds Because of decades of neglect, TB has now developed into newer, deadlier strains, some of which are extremely drug-resistant Even though this disease kills nearly 2 million people a year and is the biggest killer of people with AIDS Half a million cases of drug-resistant TB estimated every year, and this issue is receiving very little attention Can be treated with powerful drugs, but many poor countries lack the techniques to detect the disease The newest TB drug is 40 years old, there was no effective vaccine for adults, and diagnosing the newer strains is more difficult In most of the developing world, the diagnostic test is over 100 years old, so while it can detect standard TB, it can't detect drug resistance & is harder to detect TB in people that are HIV positive In countries with a poor medical infrastructure, experts say it's difficult to make sure patients continue taking their medications for the minimum 6 months Many people who are diagnosed don't get the treatment or don't stay on the treatment; it can take 2 years to treat them, so it's difficult to have expectations for someone in a poor country with pretty bad health facilities is going to be able to continue treatment for a 2 year period and that means they're gonna die

Diseases of poverty

Tropical diseases like schistosomiasis are underfunded for research, prevention, and control They remain endemic despite inexpensive treatment and prevention

T/F Different drugs and drug combinations are needed for different Plasmodium species and different stages of the illness, because they act at different points in the parasite's life cycle

True

T/F During polio epidemics, communities attempted to deny entry to children who might've been exposed to the polio virus; quarantine was common

True

T/F Health professionals should always know their limitations, assuming there is someplace to refer the patient to

True

T/F In 1988, 70 million people were infected worldwide, and 350,000 were paralyzed; by 2002, only 1,919 cases were identified

True

T/F In the vast majority of cases, a poliovirus infection is harmless; however, if it makes its way into your brain or spinal cord, it can cause paralysis, and even death

True

T/F P. falciparum can make its human host more attractive to Anopheles mosquitoes, boosting its chances of being transferred to another host

True... the "bite me" signal is sent out only when parasites are in the gametocyte stage, ready to be picked up by a mosquito Parasite presumably triggers changes in breath or body odors

Tertiary prevention for malaria*

Try to prevent worsening of the disease and life-threatening complications I.e. help a child with kidney failure caused by malaria

Basic TB Facts (reading notes)

Tuberculosis (TB) is caused by a bacterium called Mycobacterium tuberculosis The bacteria usually attack the lungs, but TB bacteria can attack any part of the body like the kidney, spine, & brain Not everyone infected with TB bacteria becomes sick -> 2 TB-related conditions exist: latent TB infection (LTBI) and TB disease If not treated properly, TB disease can be fatal TB bacteria are spread through the air from one person to another The TB bacteria are put into the air when a person with TB disease of the lungs or throat coughs, speaks, or sings People nearby may breathe in these bacteria & become infected TB is NOT spread by handshaking, sharing food or drink, touching bed linens or toilet seats, sharing toothbrushes, or kissing When a person breathes in TB bacteria, the bacteria can settle in the lungs & begin to grow; from there, they can move through the blood to other parts of the body, like the kidney, spine, & brain TB disease in the lungs or throat can be infectious, meaning the bacteria can be spread to other people TB in other parts of the body, like the kidney or spine, isn't usually infectious People with TB disease are most likely to spread it to people they spend time with every day, including family members, friends, & coworkers or schoolmates Latent TB Infection: TB bacteria can live in the body without making you sick In most people who breathe in TB bacteria & become infected, the body is able to fight the bacteria to stop them from growing (Latent) People with latent TB infection: have no symptoms, don't feel sick, can't spread TB bacteria to others, usually have a positive TB skin test reaction or positive TB blood test, may develop TB disease if they don't receive treatment for latent TB infection Many people who have latent TB infection never develop TB disease; in these people, the TB bacteria remain inactive for a lifetime without causing disease In other people, esp people who have a weak immune system, the latent bacteria become active, multiply, & cause TB disease TB Disease: TB bacteria become active if the immune system can't stop them from growing; when TB bacteria are active (multiplying in your body) People with TB disease are sick; they may also be able to spread the bacteria to people they spend time with every day Many people who have latent TB infection never develop TB disease Some people develop TB disease soon after becoming infected (within weeks) before their immune system can fight the TB bacteria Other people may get sick years later when their immune system becomes weak for another reason For people with weak immune systems, esp those with HIV infection, the risk of developing TB disease is much higher than for people with normal immune systems A person with Latent TB Infection: has no symptoms, doesn't feel sick, can't spread TB bacteria to others, usually has a skin test or blood test result indicating TB infection, has a normal chest x-ray & a negative sputum smear, needs treatment for latent TB infection to prevent TB disease A Person with TB Disease: has symptoms that may include a bad cough that lasts 3 weeks or longer, chest pain, coughing up blood or sputum, weakness or fatigue, weight loss, no appetite, chills, fever, night sweating; usually feels sick; may spread TB bacteria to others; usually has a skin test or blood test result indicating TB infection; may have an abnormal chest x-ray, or positive sputum smear or culture; needs treatment to treat TB disease Symptoms of TB disease depend on where in the body the TB bacteria are growing TB bacteria usually grow in the lungs (pulmonary TB) TB disease in the lungs may cause symptoms like a bad cough that lasts 3 weeks or longer, chest pain, coughing up blood or sputum (phlegm from deep inside the lungs) Other symptoms of TB disease are weakness or fatigue, weight loss, no appetite, chills, fever, night sweating Symptoms of TB disease in other parts of the body depend on the area affected People who have latent TB infection don't feel sick, don't have any symptoms, & can't spread TB to others Some people develop TB disease soon after becoming infected (within weeks) before their immune system can fight the TB bacteria; other people may get sick years later, when their immune system becomes weak for another reason About 5-10% of infected persons who don't receive treatment for latent TB infection will develop TB disease at some time in their lives For persons with weak immune systems, esp those with HIV infection, the risk of developing TB disease is much higher than for persons with normal immune systems Generally, persons at high risk for developing TB disease fall into 2 categories: persons who've been recently infected with TB bacteria & persons with medical conditions that weaken the immune system Persons who have been Recently Infected with TB Bacteria includes: close contacts of a person with infectious TB disease, persons who've immigrated from areas of the world with high rates of TB, children less than 5 years of age who have a positive TB test, groups with high rates of TB transmission (homeless, injection drug users, HIV infection), persons who work or reside with people who're at high risk for TB in facilities or institutions like hospitals, homeless shelters, correctional facilities, nursing homes, & residential homes for those with HIV Persons with Medical Conditions that Weaken the Immune System include babies and young children (who often have weak immune systems); possibly those with HIV infection (virus that causes AIDS), substance abuse, silicosis, diabetes mellitus, severe kidney disease, low body weight, organ transplants, head & neck cancer, medical treatments like corticosteroids or organ transplant, specialized treatment for rheumatoid arthritis or Crohn's disease You may be exposed to TB bacteria if you spent time near someone with the disease The TB bacteria are put into the air when a person with active TB disease of the lungs or throat coughs, sneezes, speaks, or sings You can't get TB from clothes, drinking glass, eating utensils, handshake, toilet If you think you've been exposed to someone with TB disease, you should contact your doctor or local health department about getting a TB skin test or a special TB blood test Tell the doctor or nurse when you spent time with the person who has TB disease A person exposed to TB bacteria isn't able to spread the bacteria to other people right away; only persons with active TB disease can spread TB bacteria to others Before you're able to spread TB to others, you'd have to breathe in TB bacteria & become infected; then the active bacteria would have to multiply in your body & cause active TB disease, & at this point, you could possibly spread TB bacteria to others Some people develop TB disease soon (within weeks) after becoming infected, before their immune system can fight the TB bacteria Other people may get sick years later, when their immune system becomes weak Those at high risk for developing TB disease include: people with HIV infection, people who became infected with TB bacteria in the last 2 years, babies and young children, people who inject illegal drugs, people sick with other diseases that weaken the immune system, elderly people, & people who weren't treated correctly for TB in the past If you have latent TB infection & you're in one of these high-risk groups, you should take medicine to keep from developing TB disease There are several treatment options for latent TB infection If you take your medicine as instructed, it can keep you from developing TB disease Because there are less bacteria, treatment for latent TB infection is much easier than treatment for TB disease A person with TB disease has a large amount of TB bacteria in the body Several drugs are needed to treat TB disease In many countries, TB is much more common than in the United States Travelers should avoid close contact or prolonged time with known TB patients in crowded, enclosed enviros (ie clinics, hospitals, prisons, or homeless shelters) While multidrug-resistant (MDR) & extensively drug-resistant (XDR) TB are occurring globally, they're still rare HIV-infected travelers are at greatest risk if they come in contact with a person with MDR or XDR TB Air travel itself carries a relatively low risk of infection with TB of any kind Travelers who'll be working in clinics, hospitals, or other health care settings where TB patients are likely to be encountered should consult infection control or health experts & ask about procedures for preventing TB exposure Travelers who anticipate possible prolonged exposure to people with TB should have a TB skin test or a TB blood test before leaving the US If the test reaction is negative, they should have a repeat test 8-10 weeks after returning to the US Annual testing may be recommended for those who anticipate repeated or prolonged exposure or an extended stay over a period of years Since people with HIV infection are more likely to have an impaired response to TB tests, travelers who are HIV positive should tell physicians about their HIV infection status Bacille Calmette-Guérin (BCG) is a vaccine for TB disease that's not widely used in the US but often given to infants & small children in other countries where TB is common; BCG doesn't always protect people from getting TB In the US, BCG should be considered for only very select people who meet specific criteria Health care providers who are considering BCG vaccination for their patients are encouraged to discuss this intervention with the TB control program in their area BCG vaccination should only be considered for children who have a negative TB test & who are continually exposed, & can't be separated from adults who: are untreated or ineffectively treated for TB disease, & the child can't be given long-term primary preventive treatment for TB infection; or have TB disease caused by strains resistant to isoniazid & rifampin BCG vaccination of healthcare workers should be considered on an individual basis in settings in which: a high % of TB patients are infected with TB strains resistant to both isoniazid & rifampin; there's ongoing transmission of drug-resistant TB strains to health care workers and subsequent infection is likely; or comprehensive TB infection-control precautions have been implemented, but haven't been successful Health care workers considered for BCG vaccination should be counseled regarding the risks/benefits associated with both BCG vaccination & treatment of latent TB infection Many people born outside of the US have been BCG-vaccinated People previously vaccinated with BCG may receive a TB skin test to test for TB infection Vaccination with BCG may cause a positive reaction to a TB skin test; a positive reaction to a TB skin test may be due to the BCG vaccine itself or infection with TB bacteria TB blood tests (IGRAs), unlike the TB skin test, aren't affected by prior BCG vaccination & aren't expected to give a false-positive result in people who've received BCG For children under the age of 5, the TB skin test is preferred over TB blood tests A positive TB skin test or TB blood test only tells that a person's been infected with TB bacteria; it doesn't tell whether they have latent TB infection or progressed to TB disease Other tests, like a chest x-ray & a sample of sputum, are needed to see if the person has TB disease TB is a serious health threat, esp for people living with HIV (who are more likely than others to become sick with TB) Worldwide, TB is one of the leading causes of death among people living with HIV Without treatment, as with other opportunistic infections, HIV & TB can work together to shorten lifespan Someone with untreated latent TB infection & HIV infection is much more likely to develop TB disease during his or her lifetime than someone without HIV Among people with latent TB infection, HIV infection is the strongest known risk factor for progressing to TB disease A person who has both HIV infection & TB disease has an AIDS-defining condition People infected with HIV who also have either latent TB infection or TB disease can be effectively treated The first step is to ensure people living with HIV are tested for TB infection; if found to have TB infection, further tests are needed to rule out TB disease; the next step is to start treatment for latent TB infection or TB disease based on test results Untreated latent TB infection can quickly progress to TB disease in people living with HIV since the immune system is already weakened; & without treatment, TB disease can progress from sickness to death Fortunately, there are a number of treatment options for people living with HIV who also have either latent TB infection or TB disease Diabetes is a chronic (long-lasting) disease affecting how the body turns food into energy TB is a serious health threat, esp for people living with diabetes 2 TB-related conditions exist: latent TB infection & TB disease People with latent TB infection aren't sick since the body is able to fight the bacteria to stop them from growing People with TB disease are sick & have active TB since the body can't stop the bacteria from growing People living with diabetes who are also infected with TB are more likely to develop TB disease & become sick with TB Someone with untreated latent TB infection & diabetes is more likely to develop TB disease than someone without diabetes Without proper treatment, diabetes & TB can increase health complications In 2018, 9,029 new TB cases were reported in the US In 2017, 20% of persons with TB in the US also had diabetes In the last 20 years, the 3 of adults diagnosed with diabetes has more than tripled Untreated latent TB infection can progress to TB disease TB disease, without treatment, can progress from sickness to death Treatment options are available for people with diabetes who also have either latent TB infection or TB disease If a person is diagnosed with TB infection, further testing is required to rule out TB disease; people with either latent TB infection or TB disease can be effectively treated Before beginning treatment for TB disease or for latent TB infection, TB patients should talk to their doctor about any other meds they're taking, including for diabetes

Malaria parasite's lifecycle*

Very complex, involving many stages As the mosquito feeds, malaria sporozoites (which have protective coating) enter into the human blood stream They quickly make their way to the liver and infect liver cells With the help of the circumsporozoite protein The parasite develops into mature schizonts, creating tens of thousands merozoites, which burst out of the cell and journey back toward the bloodstream They then infect healthy red blood cells, reproducing and eventually rupturing the cell, liberating more merozoite, which in turn go to infect other cells, leading the massive destruction of red blood cells A few of the infected cells develop into gametocytes, which can remain in the blood stream for several days, and may be ingested by another mosquito during a subsequent feeding Inside the mosquito, the gametocytes develop into new sporozoites, so now the human has infected the mosquito; the life cycle comes full circle and continues

Polio

Very contagious Causes irreversible crippling nerve damage Typically strikes children May be eradicated soon

Why do so many US women die giving birth? (video notes)

While progress has been made to curb death rates among women in other countries, the US has seen an increase since the year 2000 As the rate of mothers dying has decreased across the developed world, it's gone up dramatically in the US America's numbers are bad even compared to some in the developing world A lot of campaigners feel that access to medical care is a big part of the problem The state that has the highest rate of maternal mortality is also the state with the highest proportion of people without health insurance (Texas) Texas is the uninsured capital of the nation, so from the very beginning we know that many of our residents don't have health care Some government officials don't accept this and say the underlying trend for increasing chronic disease in this country is the same one increasing maternal morbidity and mortality across the nation A huge racial disparity is going on: 13 maternal deaths per 100,000 white vs. 44 black African-American women are dying at 3x the rate We have to look at what it is about this group specifically People want to talk about how we're post-racial, but our #s aren't bearing that out There's not a sense of urgency, and yet it's an easy fix We have to sit down with the people who need the help and ask what they need, and there seems to be this unwillingness to do that The fear is that without a sense of urgency, many more American women will die before there's even a plan in place to address the problem

From a public health perspective, there can be no let-up in malaria control activities; otherwise, malaria will _____________________. This is what happened from the 1970s to the 1990s, when malaria-control activities declined in the aftermath of the failed global eradication effort and resistance spread to antimalarial agents (chloroquine) and insecticides (DDT). An increase in _______________________ in Africa and ___________________________ in Asia do not bode well for the future. Preventing malaria during pregnancy in areas where drug resistance is increasing and where transmission rates are low and unstable remains a serious challenge

return with a vengeance. resistance to pyrethroid insecticides in Africa and uncontained artemisinin resistance in Asia