What should you do if you’re on a flight with someone who has a highly contagious disease?

A combination of infectiousness, transmission route and flight duration influences the risk for those cooped up on a plane with someone with a contagious disease.

  • Low risk if it can be transmitted only through direct contact or through exchange of bodily fluids.
  • Variable risk is if it’s vector-borne and somehow (likely rare) the vector is also on the plane.
  • Medium risk if the organism survives long enough on intermediate surfaces (fomites) to be successfully transmitted.
  • High risk if transmission is air borne.

While risk of catching a highly contagious airborne disease from someone on a plane does sound downright scary, modern airplanes have advanced air handling systems designed to minimize such risk (1, 2). Such systems exchange cabin air many times per hour, taking in fresh air from outside the plane as well as recirculating cabin air that has been passed through a HEPA filter (see figure and text below from 3, emphasis mine).

‘The aircraft cabin environment

During flight, the aircraft cabin is a ventilated, enclosed environment that exposes passengers to hypobaric hypoxia, dry humidity, and close proximity to fellow passengers. This space is regulated by an environmental system that controls pressurisation, temperature, ventilation, and air filtration on the aircraft. Although this system is wholly automated, the number of air-conditioning packs in operation, zone temperatures, and the mixture of fresh and re-circulated air delivered to the cabin can be manipulated by the flight deck.1 When parked at the terminal, fresh air is supplied to the aircraft by auxiliary power units. During flight, fresh air is supplied into the cabin from the engines where the air is heated, compressed, cooled, and passed into the cabin to be circulated by the ventilation system.3 The outside air is assumed to be sterile at typical cruising altitudes. Air circulation patterns aboard standard commercial aircraft are side-to-side (laminar) with air entering the cabin from overhead, circulating across the aircraft, and exiting the cabin near the floor (figure 1). Little front to back (longitudinal) airflow takes place.3–9 This air circulation pattern divides the air flow into sections within the cabin, thereby limiting the spread of airborne particles throughout the passenger cabin.

Most commercial aircraft in service recirculate 50% of the air delivered to the passenger cabin for improved control of cabin circulation, humidity, and fuel efficiency.5–9 This recirculated air usually passes through high efficiency particulate air filters (HEPA) before delivery into the cabin. Normal airline cabin air exchange rates range from 15 to 20 air changes per hour compared with 12 air changes per hour for a typical office building.’

Planes carry a reported >3 billion passengers annually. Though in-flight transmission of contagious diseases is an ever-present possibility, confirmed cases are confined to a handful for flu, measles, meningococcus, norovirus, SARS, shigella, cholera and TB (4).

During the 2003 Severe acute respiratory syndrome – Wikipedia outbreak, investigations of 40 flights that carried SARS-infected passengers found evidence of on-board SARS transmission to only 37 passengers across just 5 flights. One 3 hour flight carrying 120 passengers from Hong Kong to Beijing on March 15, 2003 accounted for as many as 22 of these infections, suggesting a malfunctioning cabin filtration system may have played a role. The disease spread pattern also shows no rhyme of reason since the passengers sitting next to the index case remained uninfected (see below from 3).

In 2014, a health care worker who took care of a confirmed Ebola case and was later diagnosed with it traveled across the US on two flights while believed to have been infectious from Dallas, Texas, to Cleveland, Ohio, on October 10, 2014 and back to Texas on October 13, 2014. No one on those two flights got infected with Ebola (see figure below from 5).

In the US, the CDC uses Do Not Board lists and Public Health Border Lookout records to prevent travel within, to or from the US by someone with a contagious disease (6, 7).

Bottom-line, contagion risk on a flight is not non-existent but it isn’t panic-inducing either.

Bibliography

1. Edelson, Paul J. “Patterns of measles transmission among airplane travelers.” Travel medicine and infectious disease 10.5-6 (2012): 230-235.

2. Elmaghraby, Hossam A., Yi Wai Chiang, and Amir A. Aliabadi. “Ventilation strategies and air quality management in passenger aircraft cabins: A review of experimental approaches and numerical simulations.” Science and Technology for the Built Environment 24.2 (2018): 160-175.

3. Mangili, Alexandra, and Mark A. Gendreau. “Transmission of infectious diseases during commercial air travel.” The Lancet 365.9463 (2005): 989-996. https://pdfs.semanticscholar.org…

4. Weiss, Howard, et al. “The Airplane Cabin Microbiome.” Microbial ecology (2018): 1-9. https://link.springer.com/conten…

5. Regan, Joanna J., et al. “Public health response to commercial airline travel of a person with Ebola virus infection-United States, 2014.” MMWR. Morbidity and mortality weekly report 64.3 (2015): 63-66. https://pdfs.semanticscholar.org…

6. Centers for Disease Control and Prevention (CDC. “Control of Communicable Diseases. Final rule.” Federal register 82.12 (2017): 6890. https://www.gpo.gov/fdsys/pkg/FR…

7. Reiss, Dorit Rubinstein, and Y. Tony Yang. “CDC’s New Rule to Track and Quarantine Travellers.” Journal of Travel Medicine 24 (2017): 70. https://repository.uchastings.ed…

https://www.quora.com/What-should-you-do-if-youre-on-a-flight-with-someone-who-has-a-highly-contagious-disease/answer/Tirumalai-Kamala

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What are some great examples of overselling the microbiome?

The microbiome isn’t oversold, not if you are a mouse. It’s nothing but oversold if you are a human. Key lies in understanding why this chasm exists, which in turn requires understanding how the economy of the scientific enterprise currently operates.

Part of the difference stems from a technological difference in kind. Genetic manipulation of the mouse is relatively easy these days, giving researchers unimaginable levels of control in some aspects of mouse studies, knocking genes out or in, genetically engineering microbes, designing transgenic mice that can be induced to turn on or off specific genes in response to specific cues. Studies of causation are thus relatively straightforward using mouse models or at least they should be.

On the other hand, studies of association are the best that human studies can manage. But wait, bridging this vast gap isn’t the only problem. Separating reliable mouse data from unreliable ones has also become a hard problem. Many mouse model studies are deeply flawed, done using too few mice per group or too few experiments overall.

The economic landscape in which researchers operate explains a great deal of this surprising conundrum.

  • As the scientific workforce expanded greatly in recent decades, glut of academics means they need to fight more vigorously and frequently for a smaller slice of an insufficiently expanding funding pie.
  • As funding for scientific research thus becomes more precarious, researchers are pressured to publish more frequently to remain competitive in the academic market.
  • No surprise then that dubious use of statistics is rampant in biomedical research.
  • A Replication crisis – Wikipedia is thus no surprise.
  • Animal husbandry costs consume a disproportionately large share of a research lab’s funding. This key aspect of poorly replicating mouse model studies explains why so many labs use small mouse numbers per group and don’t repeat experiments sufficiently, and is one that solutioneers of the replication crisis seem to studiously ignore.

The ensuing culture rewards incrementally novel outcomes. Being inherently far riskier, groundbreaking ideas stand far less chance of ever getting funded. Any wonder then if economists find an inverse relationship between scientific workforce and productivity across both academia and industry (see below from 1)?

Meantime, technology now enables researchers to generate ‘Big data – Wikipedia‘ fairly easily. When the prevailing scientific culture artificially fosters a dearth of good ideas and rewards less risky incrementalism, technological solutionism becomes an easy crutch and ‘big data’ has stepped in as though the secrets of nature can be unraveled simply by throwing a surplus of data on a wall and seeing what sticks. If that’s the way to great science, Darwin would surely be spinning in his grave in sheer envy though I’m fairly certain he is resting entirely in peace.

In my opinion the economic pressures under which scientific enterprise currently operates is why association studies of the microbiome in humans have become the norm, why insight into causation remains meager and why the microbiome or anything else in biomedical research is easily oversold.

Bibliography

  1. Bloom, Nicholas, et al. Are ideas getting harder to find?. No. w23782. National Bureau of Economic Research, 2017. http://eprints.lse.ac.uk/86588/1…

https://www.quora.com/What-are-some-great-examples-of-overselling-the-microbiome/answer/Tirumalai-Kamala

What do professors think about the idea that graduate students are exploited cheap labor in the lab?

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Asking a professor whether they think graduate students are exploited as cheap labor in the lab is akin to expecting a potential suspect to voluntarily confess, not because any given professor is necessarily in the wrong but because whether they like it or not or acknowledge it or not, they operate within an entrenched hierarchy designed for their benefit, one where in the decades since WWII, universities and the scientific enterprise they support evolved to indeed subject graduate students and later post-docs as well to work conditions rather akin to indentured labor.

Rather than asking professors, examining independent analyses of the scientific enterprise and of graduate student efforts to unionize provides better understanding, and this US- and biomedical research-specific answer draws on such material.

A tenured professor (or principal investigator) typically operates with unquestioning authority as the head of a lab or lab section. Though it’s a work environment with quite the extreme power asymmetry, academia runs on the principle that tenured professors self-regulate but we know from Wall Street and Silicon Valley that self-regulation simply doesn’t work.

In recent decades, some changes and trends in academia further exacerbated this power asymmetry in the US.

Research by tenured professors yields manifold economic and other benefits to the university that employs them,

  • Grant money.
  • Prestige.
  • Fees from increased student enrollment using names of star academics as recruiting tools.
  • Potential revenue from patents, licensing fees, biotech and other commercial spin-offs, partnerships and the like.

The passage of the Bayh–Dole Act – Wikipedia in 1980 codified and spurred the expansion of such commercial aspects of federally funded university research. Thus motivated, universities expanded their research activities and, generously subsidized by federal monies, tenured professors eagerly and successfully recruited more students to their labs. Research labs thus expanded and even more so during the late Clinton-early Bush II years when the NIH budget ~doubled over a mere handful of years.

Problem is while faculty were thus incentivized to churn out more and more Masters and PhDs, faculty positions remained largely stagnant even as mandatory faculty retirement got abolished in 1994. This intensified academic competition, exacerbated the supply-demand gap between eligible candidates and available faculty positions, and increased the pressure to publish research papers within shorter time frames.

Too Many Graduate Students, Backbone of Academic Labor; Too Few Faculty Positions

US universities evolved to staff labs not with a full-time workforce on the university payroll with the benefits and protections that accompany such a designation but with a constantly churning temporary labor force in the form of graduate students and post-docs funded through fellowships, grants, scholarships, teaching or research assistantships (1, 2).

  • Notice how the position of the post-doc barely existed pre-WW II and has ballooned since the 1980s. The post-doc is a purely made-up temporary position whose very existence exemplifies an artificially created supply-demand problem between a glut of PhDs and lack of faculty positions that can absorb them into academia, even as it conveniently offers a steady pipeline of well-trained, cheap labor.
  • Paternalistically labeling graduate students’ work products euphemisms such as ‘labor of love‘ or ‘intellectual pursuit‘ cannot mask the ugly reality that an inherently asymmetric relationship leaves them little or no recourse against discrimination, exploitation or harassment, all of which are pervasive and massively under-reported across academia (3, 4, 5, 6, 7, 8, 9, 10).
  • Meantime, universities and graduate student advisors have consistently fallen short in managing student expectations, woefully failing to train and prepare them for alternate career choices. Some of this may stem from a classic frog-in-the-well mindset. After all, a typical academic best knows how to be an academic and can likely offer little or no guidance about other career options.
  • In the meantime, since the 1980s, an immigrant student population, *cough* workforce, began swelling the ranks of undergraduate and graduate (Masters, PhD) students as well as post-docs (11). Coming in on temporary student visas with little parity or bargaining power with respect to the professors who sponsor their higher studies, such students are the very definition of a captive workforce.
  • The abrupt squeeze on federal research funds in the wake of the Great Recession was a tremendous shock wave to this gussied up system, akin to a pin abruptly and sharply pushed into a tightly inflated balloon. Its aftermath only further exacerbated an already obscene gap between a supply glut and an even further cratering demand.

The terms of the exchange are a graduate student’s labor in the lab and increasingly, in the classroom as well, in exchange for a degree. Problem is this phony paternalistic mindset deliberately devalues academic labor (1, see below from 2, emphasis mine).

The troubles plaguing academic science — including fierce competition for funding, dismal career opportunities for young scientists, overdependence on soft money, excessive time spent applying for grants, and many more — do not arise, Stephan suggests, from a shortage of funds. In 2009, she notes, the United States spent nearly $55 billion on university- and medical school–based research and development, far more than any other nation.

The problems arise, Stephan argues, from how that money is allocated: who gets to spend it, where, and on what. Unlike a number of other countries, the United States structures university-based research around short-term competitive grants to faculty members. The incentives built into this system lead universities to behave “as though they are high-end shopping centers,” she writes. “They turn around and lease the facilities to faculty in [exchange for] indirect costs on grants and buyout of salary. In many instances, faculty ‘pay’ for the opportunity of working at the university, receiving no guarantee of income if they fail to bring in a grant.” Those who land funding staff their labs with students enrolled in their department’s graduate program, or with postdocs. Paid out of the faculty member’s grant, both types of workers depend on the primary investigator’s (PI’s) continued success in the tournament.

Universities, however, also face considerable risks. They must, for example, provide large start-up packages to outfit new faculty members for the competition. Newcomers generally have about 3 years to establish a revenue stream — to start winning “the funding to stay in business,” Stephan says. The need to reduce risk explains universities’ growing penchant for hiring faculty members off the tenure track and using adjuncts for teaching. “Medical schools have gone a step further,” Stephan notes, “employing people, whether tenured or nontenured, with minimal guarantees of salary.” Where tenure once constituted a pledge to pay a person’s salary for life, it now constitutes, in the acerbic definition I’ve heard from some medical school professors, a mere “license to go out and fund your own salary.”

Risk avoidance has scientific as well as financial consequences. “The system … discourages faculty from pursuing research with uncertain outcomes,” which may endanger future grants or renewals. This peril is “particularly acute for those on soft money.” Experimental timidity produces “little chance that transformative research will occur and that the economy will reap significant returns from investments in research and development.”

As in all financial ventures, cost determines much of what goes on in the laboratory. “Cost plays a role in determining whether researchers work with male mice or female mice (females, it turns out, can be more expensive), whether principal investigators staff their labs with postdoctoral fellows (postdocs) or graduate students, and why faculty members prefer to staff labs with ‘temporary’ workers, be they graduate students, postdocs, or staff scientists, rather than with permanent staff.” Postdocs often are a PI’s best staffing buy, Stephan writes, because their excellent skills come with no requirement to pay tuition, which at top private institutions can run $30,000 a year or more. Overall, the need to reduce risk and cost in the grant-based system produces “incentives … to get bigger and bigger” by winning the maximum number of grants and, because grad students and postdocs do the actual bench work, to “produce more scientists and engineers than can possibly find jobs as independent researchers.

Many universities, meanwhile, took out large loans during flush times to finance buildings and equipment intended to give them an edge in attracting grants. They find their fiscal stability “severely threatened when funding from grants plateaus, or does not grow sufficiently to keep pace with the expansion. They face even more serious prospects when budgets decline in real terms.” The nation’s enormous investment in biomedical research has also “created a lobbying behemoth composed of universities and nonprofit health advocacy groups that constantly remind Congress of the importance of funding health-related research,” Stephan adds. This gives rise to unceasing claims that no amount of science funding is ever enough.

Although one topflight report described this setup as “ ‘incredibly successful’ from the perspective of faculty,” Stephan observes, “it is the Ph.D. students and postdocs who are bearing the cost of the system — and the U.S. taxpayers — not the principal investigators.” Undergraduates also carry an increasing share of the load, she adds: Their tuition, often paid with student loans, rises as more funds go to research. Their teachers, meanwhile, increasingly are cut-rate adjuncts rather than the famous professors the recruiting brochures boast about.’

This decision to greatly expand graduate student enrollment and use them as poorly paid, poorly protected, temporary academic labor in a greatly expanding academic research landscape has fueled years-long demands for unionization across the US university landscape.

‘The National Labor Relations Board issued a 3-1 decision in Columbia University that student assistants working at private colleges and universities are statutory employees covered by the National Labor Relations Act. The Graduate Workers of Columbia-GWC, UAW filed an election petition seeking to represent both graduate and undergraduate teaching assistants, along with graduate and departmental research assistants at the university in December 2014. The majority reversed Brown University (342 NLRB 483) saying it “deprived an entire category of workers of the protections of the Act without a convincing justification.”

For 45 years, the National Labor Relations Board has exercised jurisdiction over private, nonprofit universities such as Columbia. In that time, the Board has had frequent cause to apply the Act to faculty in the university setting, which has been upheld by the Supreme Court.

Federal courts have made clear that the authority to define the term “employee” rests primarily with the Board absent an exception enumerated within the National Labor Relations Act. The Act contains no clear language prohibiting student assistants from its coverage. The majority found no compelling reason to exclude student assistants from the protections of the Act.’

  • This groundbreaking decision will surely reverberate across US academia. For example, in April 2018, Harvard graduate students voted 1931 to 1523 to join the United Auto Workers (15, 16).

Bibliography

1. How Economics Shapes Science: Paula Stephan: 9780674088160: Amazon.com: Books

2. Academia’s Crooked Money Trail

3. The Pyramid Problem

4. Moss-Racusin, Corinne A., et al. “Science faculty’s subtle gender biases favor male students.” Proceedings of the National Academy of Sciences 109.41 (2012): 16474-16479. http://www.pnas.org/content/pnas…

5. Clancy, Kathryn BH, et al. “Survey of academic field experiences (SAFE): Trainees report harassment and assault.” PLoS One 9.7 (2014): e102172. Survey of Academic Field Experiences (SAFE): Trainees Report Harassment and Assault

6. Better advice for ‘Bothered’

7. Sexual harassment is rife in universities, but complaining means risking your career

8. It’s Time for the ‘Harvey Effect’ to Reach Academia

9. SEXUAL HARASSMENT OF WOMEN: Climate, Culture, and Consequences in Academic Sciences, Engineering, and Medicine, The National Academies of Sciences, Engineering, Medicine, 2018. Sexual Harassment of Women

10. Why science breeds a culture of sexism

11. The 2018 Science & Engineering Indicators published by the National Science Board (NSF). https://www.google.com/url?sa=t&…

12. https://www.google.com/url?sa=t&…

13. Grad-Student Unions

14. Board: Student Assistants Covered by the NLRA

15. Harvard graduate students vote to form a union

16. Harvard agrees to negotiate a contract with graduate-student union

https://www.quora.com/What-do-professors-think-about-the-idea-that-graduate-students-are-exploited-cheap-labor-in-the-lab/answer/Tirumalai-Kamala

If antigens and pathogens can both stimulate/induce the immune system, what makes them different from one another?

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An Antigen – Wikipedia is any molecule capable of inducing an immune response. Source of antigens are many, ranging from pathogens to any manner of other microbes as well as other humans, animals, and plants.

  • For example, antigens derived from tissues from other humans can drive such potent immune responses that a transplant can be rejected. Minimizing such risk of rejection is why tissue matching and immunosuppression are standard operating procedures for Allotransplantation – Wikipedia. Similar principles are at play with animal-to-human transplants, Xenotransplantation – Wikipedia.
  • Similarly, plant-derived antigens can drive intense immune responses, even potentially fatal Anaphylaxis – Wikipedia, in sensitized people who suffer from allergies, Peanut allergy – Wikipedia being case in point.

Thus, antigens derived from pathogens are just one among many types of antigens that the immune system can respond to.

A helpful way to visualize the world of antigens is as a Venn diagram – Wikipedia with a given individual at the center of it. The greater the overlap in sequence similarity of a molecule with one expressed by that individual, lower the chance s/he would make an immune response to it.

Lower and not remove the chance because rather than black and white, immune responsiveness spans a spectrum as Autoimmune disease – Wikipedia indicate. While antigen is important, the context in how it is presented is also critical in triggering an immune response.

https://www.quora.com/If-antigens-and-pathogens-can-both-stimulate-induce-the-immune-system-what-makes-them-different-from-one-another/answer/Tirumalai-Kamala

What are the health benefits of activated charcoal?

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Activated charcoal is an ancient medicinal remedy. In 1999, the American Academy of Clinical Toxicology concluded (see below from 1, emphasis mine),

‘In conclusion, based on experimental and clinical studies, multiple-dose activated charcoal should be considered only if a patient has ingested a life-threatening amount of carbamazepine, dapsone, phenobarbital, quinine, or theophylline.’

Thus, activated charcoal is an antidote with an enviable track record of saving lives in cases of accidental poisoning. However, all manner of health fads are a moneymaking goldmine these days for a whole bunch of gifted marketers. Inevitably, activated charcoal got co-opted into the detox trend (Detoxification (alternative medicine) – Wikipedia) and charcoal lattes, juices, croissants and even pills sprouted across fashionable watering holes in recent years.

However, activated charcoal has no part in daily food intake and could be dangerously counter-productive since it’s indiscriminate in what it adsorbs. Nutrients, medications, vitamins, minerals, antioxidants, etc. could thus be prevented from being absorbed by the body. Rather than promoting health, such effects are adverse. Something medically useful isn’t necessarily helpful as part of daily diet.

As an article in The Conversation points out (see below from 2),

‘Everyone is looking for a quick fix to wellness, and while we are all struggling with maintaining our energy levels, eating well and exercising while living busy lives, it is easy to be sucked in by clever marketing and celebrity endorsements.

The detox market is huge and highly misleading. While the common perception is that our daily lives and dietary habits (including alcohol intake) cause a build up of “toxins” in our system, there are no products or diets that will impact on this, regardless of their marketing budget or how many “influencers” tell you otherwise. We are often sold the idea that our diets are somehow “toxic” when the reality is that, aside from ingesting poison, even fast food doesn’t contain anything toxic.

You already have the means to detoxify your body (your liver and your kidneys do a fine job of this), so don’t waste your money. The last thing you want to do is make your food less nutritious by adding an unnecessary, indigestible compound.’

Who needs activated charcoal to routinely detoxify their body? Someone without a liver and kidneys, i.e., no one (see below from 3).

Brief History of Medicinal & Public Health Uses of Charcoal

An Egyptian papyrus from 1550 BCE is supposed to describe the medicinal use of different types of charcoal while Hippocrates and Pliny are reported to have used wood charcoal to treat a variety of conditions ranging from epilepsy to anthrax (4).

Carl Wilhelm Scheele – Wikipedia is considered to have discovered the property of Adsorption – Wikipedia in the 18th century. How charcoal works to detoxify poisons helped regularize its use , and in the process, in a small but tangible way, helped create the modern world. For example, Paris, France, was a pioneer in developing modern municipal water treatment plants and its earliest systems used filters containing different types of sand and charcoal to filter the water (5).

In 1813, a French chemist named Michel Bertrand dramatically demonstrated the life-saving antidote ability of charcoal by swallowing a teaspoon of it mixed with 5 grams of arsenic trioxide, a 150X lethal dose of arsenic (see below from 6).

‘Two European scientists, in heroic experiments, publicly demonstrated its protective properties. A French chemist, M. Bertrand, first experimented with charcoal in animals. Then in 1813 he survived without ill effect after he swallowed lethal dose of arsenic mixed with charcoal.

Then in 1830, P. F. Touery, a French pharmacist, swallowed with impunity 10 lethal doses of strychnine in a demonstration before the French Academy of Medicine.’

Over the centuries, doctors began to better understand charcoal’s antidote effect. While it has decent adsorption ability, treating it in specific ways converts it to ‘activated’ charcoal, which has strikingly superior adsorption capability. In the early 20th century, Raphael Ostrejko patented processes for enhancing charcoal’s adsorption ability by treating it with superheated steam or carbon dioxide (7, 8). These days charcoal is usually heated in the absence of oxygen and under pressure. This creates millions of gaps between the carbon atoms that make it a sponge that can effectively adsorb toxins.

Bibliography

1. American Academy of Clinical Toxicology, European Association of Poisons Centres and Clinical Toxicologists. “Position statement and practice guidelines on the use of multi-dose activated charcoal in the treatment of acute poisoning.” Journal of Toxicology: Clinical Toxicology 37.6 (1999): 731-751.

2. Activated charcoal doesn’t detox the body – four reasons you should avoid it

3. sciencesense

4. Cooney, David O. Activated Charcoal: Antidote, Remedy and Health Aid. TEACH Services, Inc., 2016.

5. Mays, L. W., M. Sklivaniotis, and A. N. Angelakis. Water for human consumption through history. IWA Publishing, London, UK, 2012.

6. CHARCOAL POWDER TERMED ANTIDOTE

7. US739104A – Process of obtaining carbon of great decolorizing power. – Google Patents

8. GB106089A – Improvements in the Production of Decolourizing Charcoal. – Google Patents

https://www.quora.com/What-are-the-health-benefits-of-activated-charcoal/answer/Tirumalai-Kamala

Besides X-linked agammaglobulinemia (which selectively crippled the B cell immunity), are there other genetic defects that affect a very specific part of the immune system?

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Yes indeed. At present mutations on >120 separate genes are implicated with ~150 different primary immunodeficiencies identified thus far.

Many of these mutations affect multiple cell types but some don’t.

One of the most famous and in my opinion most consequential are mutations in the FOXP3 – Wikipedia gene, which specifically impair Regulatory T cell – Wikipedia. Why so consequential? Because impairment of just this one rather small subset of CD4 T cells causes one of the severest and deadliest immunodeficiencies ever observed, IPEX syndrome – Wikipedia.

This only serves to highlight how extremely critical this T cell subset is for entire immune function. No surprise then that even 17 years after FoxP3 was identified, regulatory T cells continue to mystify and much of what’s known about their function is a mishmash of contradictory observations. At this juncture, immunology can’t make real progress without a proper understanding of regulatory T cell function.

Some other mutations that affect largely one specific aspect of the immune system are,

There are obviously many many more but listing them out one by one would be rather boring. Instead check out the 2015 report from the International Union of Immunological Societies – Wikipedia, which lists the major mutations in 9 large tables: Picard, Capucine, et al. “Primary immunodeficiency diseases: an update on the classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015.” Journal of clinical immunology 35.8 (2015): 696-726. Primary Immunodeficiency Diseases: an Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015

https://www.quora.com/Besides-X-linked-agammaglobulinemia-which-selectively-crippled-the-B-cell-immunity-are-there-other-genetic-defects-that-affect-a-very-specific-part-of-the-immune-system/answer/Tirumalai-Kamala

Is there a blood test to see if the immune system is showing inflammation that could cause atherosclerosis?

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Short answer: Some blood tests such as for C-reactive protein – Wikipedia (CRP) can help diagnose atherosclerosis partially, not fully, since it could be elevated in some other diseases as well while not all atherosclerosis patients have elevated CRP at all times. This is why definitive diagnosis might require Functional imaging – Wikipedia or structural imaging as well.

Slightly longer answer

Historically, atherosclerosis was considered a lipid storage disease. However, hypercholesterolemia isn’t present in all patients while inflammation is present in many more. This helped establish the link between unresolved inflammation and atherosclerosis. Lipids don’t get deposited mechanically onto the inner lining of an artery in the form of an atherosclerotic lesion. Rather an inflammatory process consisting of many stages eventually results in plaque deposition.

Inflammation doesn’t cause atherosclerosis. Rather, its improper initiation and persistence indicates an underlying problem is stoking it. Earliest changes are in blood vessel cells which get inflamed and recruit leukocytes to the site. Persisting inflammation retains them there, eventually leading to plaque formation. What causes such changes in blood vessel cells in the first place isn’t fully understood yet (1, 2).

CRP aka Pentraxin 1 is now a well-recognized, sensitive and systemic marker of inflammation and tissue damage. At present CRP is the most well-established biomarker of inflammation used to monitor cardiovascular disease. It’s a small (~23kDa) acute-phase protein produced by the liver and its levels are low most of the time. More importantly, some large-scale prospective studies found CRP levels to be independently and strongly predictive of major cardiovascular problems such as myocardial infarction, ischemic stroke, coronary artery disease, and sudden cardiac death, which are various manifestations of atherosclerosis. Most useful tests are those that look for what is called high-sensitivity CRP (3, 4, 5).

Main hallmarks of CRP are

  • Normal circulation levels of 0.1 to 0.3 mg/L.
  • Can increase 1000X during an acute phase response.
  • Activates complement.
  • Binds to very low density lipoprotein (VLDL) and low density lipoprotein (LDL).
  • Gets deposited in atherosclerotic lesions.
  • <1mg/L CRP is considered low risk for cardiovascular disease while >3mg/L is considered high risk.

Several problems limit the practical utility of CRP levels in preemptively diagnosing every single atherosclerosis patient,

  • CRP is also high in infections such as sepsis and pneumonia as well as in autoimmune diseases.
  • Some people with low or very low levels of high-sensitivity CRP may still have acute coronary syndrome. The fact that both environmental (age, gender, blood pressure, obesity) and genetic factors equally influence CRP levels (6) explains how that could be the case.
  • Some patients could have high circulating levels of myeloperoxidase instead. A type of immune cell called polymorphonuclear cell or PMN secretes MPO.
  • CRP increases in acute conditions while atherosclerosis is chronic so how best to use CRP levels to accurately assess risk is challenging and not yet fully worked out.
  • This is why functional imaging is also required to differentially diagnose atherosclerosis.
  • Some patients present no signs of systemic inflammation and structural imaging is needed for their diagnosis.

Bibliography

1. Hansson, Göran K., and Peter Libby. “The immune response in atherosclerosis: a double-edged sword.” Nature Reviews Immunology 6.7 (2006): 508.

2. Liuzzo, Giovanna, et al. “Inflammation and Atherothrombosis.” Clinical Immunology (Fifth Edition). 2019. 935-946.

3. Biasucci, Luigi M., et al. “How to use C-reactive protein in acute coronary care.” European heart journal 34.48 (2013): 3687-3690. How to use C-reactive protein in acute coronary care | European Heart Journal | Oxford Academic

4. Zimmermann, Oliver, et al. “C-reactive protein in human atherogenesis: facts and fiction.” Mediators of inflammation 2014 (2014). C-Reactive Protein in Human Atherogenesis: Facts and Fiction

5. Fan, Jianglin, Jifeng Zhang, and Yuqing Eugene Chen. “C‐Reactive Protein and its Pathophysiological Roles in Atherosclerosis.” Atherosclerosis: Risks, Mechanisms, and Therapies (2015): 247.

6. Casas, J. P., et al. “C‐reactive protein and coronary heart disease: a critical review.” Journal of internal medicine 264.4 (2008): 295-314. C‐reactive protein and coronary heart disease: a critical review

https://www.quora.com/Is-there-a-blood-test-to-see-if-the-immune-system-is-showing-inflammation-that-could-cause-atherosclerosis/answer/Tirumalai-Kamala

Why is Shingrix vaccination so much more effective at preventing shingles than the older Zostavax vaccine? In other words, why is an inactivated recombinant vaccine more effective than a live attenuated vaccine?

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It is too early to definitively conclude Shingrix prevents shingles more effectively in the long-term compared to Zostavax since there is as yet no immune marker for protection against herpes zoster and results of longer follow-up studies aren’t yet out. In practical terms, this means longer post-marketing studies that compare incidence rates between those vaccinated or not with Shingrix will yield clearer evidence, same as was the case for Zostavax.

Some of the problems with Zostavax were

  • Studies showed protection waned with time, typically by ~7 years post-vaccination.
  • It doesn’t seem to be as protective in those >/= 70 years of age as in younger age groups.
  • Being a live attenuated vaccine, it cannot be given to those with immunodeficiencies or immunosuppression, both of which are more likely among the aged, the main target population for a herpes zoster vaccine.

These reasons made a different vaccine a worthwhile goal. A landmark Shingles Prevention Study led to Zostavax approval by the FDA in May 2006. That placebo-controlled study in >38,500 volunteers found in a subset of patients that decline not of circulating antibodies but rather of T cell immunity correlated with severity of herpes zoster as well as post-herpetic neuralgia, i.e., shingles complications (1). This suggested T cell – Wikipedia were more critical for herpes zoster control and made them the focus of new vaccine development that led to Shingrix.

Shingrix contains only one varicella-zoster virus (VZV) antigen, namely, VZV glycoprotein E (gE) plus a new Immunologic adjuvant – Wikipedia, AS01B. Though Zostavax should also have the gE antigen, the results with Shingrix imply the following non-mutually exclusive possibilities,

  • gE in the Shingrix formulation may be getting better presented to T cells and/or,
  • The adjuvant in Shingrix may be able to more effectively engage the Innate immune system – Wikipedia to better activate gE-specific T cells or better drive the establishment of gE-specific memory T cells, which are presumably a critical component in conferring long-term protection against herpes zoster.

At the time Shingrix was approved, a study showed circulating gE-specific CD4 T cells persisted at ~4X higher numbers ~3 years later compared to their levels pre-vaccination (2). That combined with the fact that it is a subunit (non-live) vaccine suggests Shingrix can overcome some of Zostavax’s inherent limitations from the get go.

When compared with historical Zostavax studies, at 3 to 4 years post-vaccination, Shingrix has higher and more long-lasting efficacy against herpes zoster, even in those >/= 70 years of age (3, 4). What remains to be seen is whether gE-specific T cell immunity alone is both necessary and sufficient to maintain long-lasting (>7 years) protection against herpes zoster and other complications.

Bibliography

1. Oxman, M. N., et al. “A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults.” New England Journal of Medicine 352.22 (2005): 2271-2284. https://www.nejm.org/doi/pdf/10….

2. Chlibek, Roman, et al. “Long-term immunogenicity and safety of an investigational herpes zoster subunit vaccine in older adults.” Vaccine 34.6 (2016): 863-868. https://ac.els-cdn.com/S0264410X…

3. Lal, Himal, et al. “Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults.” New England Journal of Medicine 372.22 (2015): 2087-2096. https://www.nejm.org/doi/pdf/10….

4. Cunningham, Anthony L., et al. “Efficacy of the herpes zoster subunit vaccine in adults 70 years of age or older.” New England Journal of Medicine 375.11 (2016): 1019-1032. https://www.nejm.org/doi/pdf/10….

https://www.quora.com/Why-is-Shingrix-vaccination-so-much-more-effective-at-preventing-shingles-than-the-older-Zostavax-vaccine-In-other-words-why-is-an-inactivated-recombinant-vaccine-more-effective-than-a-live-attenuated-vaccine/answer/Tirumalai-Kamala

How would medicine need to change to become a “hard” science?

This answer was inspired by a quote attributed to G.K Chesterton,

‘The things we see every day are the things we never see at all.’

If medicine isn’t a ‘hard’ science in that it lacks requisite methodological rigor, it stands to reason to not assume modern medicine as it exists today could have emerged. With that the premise, let’s take a brief, hair-raising, scary journey into an alternative bizzaro world to see how our life would unfold without modern medicine.

  • Rabies: Start to present symptoms after being bit by a possibly rabid wild animal? Celsus – Wikipedia recommended throwing such a person into a pond without warning and holding their head down until they swallowed water. There’s also the famous ‘hair of the dog‘, swallow a hair of the rabid dog that bit the person or lay the hair down on the bite. Unlike rabies vaccine plus immunoglobulin, such treatments don’t work but effective or not, they’re what’s on offer if medicine isn’t a ‘hard’ science.
  • Bacterial infections: Pray, perform bloodletting. Repeat in no particular order. Would they work as well as antibiotics? Certainly not but whether they work or not isn’t the deciding factor if medicine isn’t a ‘hard’ science. Also no preventative vaccines.
  • HIV: Used to be a death sentence. Now, with treatment, it’s a chronic disease.
  • Deep wounds: No vaccines or antibiotics. Soldiers, farmers, athletes, construction & factory workers, cooks, hobbyists and just about anyone else really should just accept loss of limb or life from tetanus, gangrene or gas gangrene as par for the course.
  • Acute trauma: Victims of car crashes, gunshot wounds, severe falls, combat injuries, burns, and the like, all lost causes.
  • Blood transfusion: No chance it would have come into existence.
  • Diabetes: Little chance of timely diagnosis, let alone treatments to keep the condition in check. After all even diagnosis could do little to help as English king Charles I’s physician Thomas Willis – Wikipedia advised, ‘Taste thy patient’s urine. If it be sweet like honey, he will waste away, grow weak, fall into sleep and die’.
  • Heart attacks, hypertension & other cardiovascular diseases: Accept as near fatal in the near-term. No heart or cholesterol medications, no defibrillators or atrial fibrillators, no open-heart surgeries, no angioplasty to remove vessel blockages, no stents, no valve replacements, no bypass, certainly no transplants. Pediatric heart patients? Lost cause.
  • Chronic & end stage organ disease: Pray for a quick, merciful end. Certainly no dialysis, inhalers, nebulizers, bronchodilators, steroids or other palliative measures to keep patients alive for years. Also, certainly no transplants.
  • Operable tumors: Chances of getting diagnosed before it’s too late would be non-existent. Need to reconcile to either dying from them or dying from secondary infections from getting them removed without sterile techniques and antibiotics.
  • Infertility: Sorry, no chance of having biological children.
  • Pregnancy: No contraceptives so little chance of preventing or timing it.
  • Pre-term births: Little to no chance of survival.

And beyond medicine itself,

  • Food supply: Forget about the modern-day food chain. Without sterilization, preservative techniques, and microbiological and biochemical quality control at every step of the food processing process, one should get used to the pre-industrial era of rampant food adulteration, contamination and poisoning.

https://www.quora.com/How-would-medicine-need-to-change-to-become-a-hard-science/answer/Tirumalai-Kamala

Is there a racial bias in clinical trial enrollment?

These days clinical trials are a global endeavor spanning 204 countries, according to Home – ClinicalTrials.gov (1), something that should make accusations of racial bias harder to substantiate. However, the crux of the matter is who participates in clinical trials within a given country.

Briefly,

  • Diversity mandates do little when mechanisms to enforce them are left unstated. In such a vacuum, individual biases and structural barriers drive the process.
  • The US has a bleak history of unethical medical experimentation on minorities that has left them with a persistent and deep mistrust of the medical establishment.
  • Meantime, being largely white, US clinical trial organizers don’t reflect the ethnic diversity of the population at large. Such a decision-making silo inadvertently de-prioritizes clinical trial recruitment of minorities.

Diversity mandates do little when mechanisms to enforce them are left unstated

After clinical trials became the norm for new drug approvals post- WWII, white males remained over-represented in them for several decades. In response, the US National Institutes of Health Revitalization Act of 1993 mandated women and minorities be represented in NIH-funded research. Enforcing a mandate is easier said than done especially when mechanisms to do so are left unstated. Not surprising then that biases and structural barriers take hold and drive the process in such a vacuum.

  • As recently as 2015, though blacks and Latinos make up ~30% of the US populations, a study found they accounted for just ~6% of participants in federally funded clinical trials (2).
  • Another US study found <2% of cancer clinical trials focused on the health needs of racial/ethnic minorities (3).
  • Even though African Americans are >30% more likely to have asthma and even >3X more likely to die from it, a study found <5% of federally funded lung disease studies in the US focused on them between 1993 and 2013 (4).
  • Even Precision medicine – Wikipedia, the notion that medical treatment could be tailored to an individual’s variations in genes, environment and lifestyle, leaves minorities far behind. As of 2011, ~96% of participants in >1000 Genome-wide association study – Wikipedia (GWAS) were of European descent (5).
  • Since some minorities tend to be poorer and to live in places far from large reputed medical centers that conduct clinical trials, practical constraints such as time and money needed to travel to a study site may hamper their participation.
  • Diversity mandates on federally funded trials don’t apply to the pharmaceutical industry which is today the biggest funder of clinical trials. For such trials, only something like a diversity mandate enforceable by the FDA during its review process of product approval could make a dent (6).

The US has a bleak history of unethical medical experimentation on minorities that has left them with a persistent and deep mistrust of the medical establishment

In the US, the Tuskegee syphilis experiment – Wikipedia looms large in collective consciousness as a constant reminder of the lengths to which racial animus could infect a clinical study design in that the study doctors knowingly and wantonly withheld treatment from syphilis-infected poor, uneducated, rural black men not for a year or two but for a whopping 40 years. Any wonder then that studies (7, 8) continue to find the African American community mistrust of the medical establishment?

Given such a bleak history, where African Americans are concerned, racial bias in US clinical trial enrollment is best viewed as a two-way street with low black (and other minority) participation explainable two ways,

  • one, implicit bias of trial researchers may play a considerable role in restricting minority enrollment. Some recent studies found a profound degree of implicit bias in medical doctors on matters of race. It stands to reason to assume such bias might well bleed into clinical trial enrollment processes as well.
    • A 2016 study found substantial numbers of white medical students continue to hold false beliefs about biological differences between black and white people, (see below from 9),

‘blacks have thicker skin than do white people or that black people’s blood coagulates more quickly than white people’s blood.’

    • Another 2016 study found (see below from 10, emphasis mine),

‘…significant racial-ethnic disparities, with non-Hispanic Blacks being less likely (adjusted odds ratio ranging from 0.56–0.67, p value < 0.05) to receive opioid prescription at discharge during ED visits for back pain and abdominal pain, but not for toothache, fractures and kidney stones, compared to non-Hispanic whites after adjusting for other covariate.’

    • Indeed, such implicit bias has been used to explain the far lower rates of prescription opioid abuse among African Americans and Hispanics in the early years of the ongoing opioid crisis (11, 12).
  • two, blacks, especially black males, have for long actively avoided participating in clinical trials due to their understandable deep-rooted mistrust of the medical establishment (7, 8). Some other minorities also avoid them due to lingering mistrust engendered by a past history of trust abuse.
    • Apparently so hard-wired is this mistrust that as recently as 2014, a severe TB outbreak in the small rural Alabama town of Marion went unchecked because those affected chose not to go to a doctor (13).
    • Bad acts and actors in US biomedical research didn’t magically end with Tuskegee. In 1989, Arizona State University researchers collaborated with the Havasupai Tribe on a type II diabetes project. In 2003, Carletta Tiousi, a trial participant, found out that blood samples taken during this trial had been used without her and other participants’ consent for testing schizophrenia, migration and inbreeding (14). A lawsuit led to an out of court settlement and the tribe members received funds for a school and clinic, and return of their samples.

Being largely white, clinical trial organizers don’t reflect the ethnic diversity of the population at large. Such a decision-making silo inadvertently de-prioritizes recruitment of minorities

Minority participation in US clinical trials could be increased through concerted effort on fairly simple, practical steps (15, 16, 17, 18, 19),

  • Situate clinical trials where minorities tend to live.
  • Provide low income participants travel assistance back and forth to trial sites.
  • Focus on recruitment efforts in places such as churches and barbershops where minorities tend to congregate.
  • Employ minority recruitment staff to serve as outreach partners to engage with potential minority participants in their own languages.
  • Advertise clinical trials within ethnic communities using culturally appropriate informational material clarifying purpose of the trial, and how data will be collected and used.

Nothing new about any of these suggestions. They’ve floated around for years and yet little changes. Bias in clinical trial recruitment, as in any aspect of human life, need not always occur deliberately. They can and often are the result of blinkered thinking that easily takes root in silos. When a particular majority has the power, the decisions it makes reflect that.

Minority researchers would be more likely to focus on issues of health disparities in minority populations and yet even after controlling for other variables such as education, training and experience, one study found that they were ~half as likely to get NIH grants (20).

Racially homogenous make-up of clinical trial participants reflect the racially homogenous make-up of clinical trial decision makers. Seats at the table; changes in clinical trial participants will occur lockstep with changes in clinical trial organizers, when trials are conducted not by largely white doctors but by a healthy mix of white, black, Hispanic and other minority doctors who better represent their distribution in the US population at large.

Bibliography

1. Studies on Map – ClinicalTrials.gov

2. Oh, Sam S., et al. “Diversity in clinical and biomedical research: a promise yet to be fulfilled.” PLoS medicine 12.12 (2015): e1001918. http://journals.plos.org/plosmed…

3. Chen, Moon S., et al. “Twenty years post‐NIH Revitalization Act: Enhancing minority participation in clinical trials (EMPaCT): Laying the groundwork for improving minority clinical trial accrual.” Cancer 120.S7 (2014): 1091-1096. Twenty years post‐NIH Revitalization Act: Enhancing minority participation in clinical trials (EMPaCT): Laying the groundwork for improving minority clinical trial accrual – Chen – 2014 – Cancer – Wiley Online Library

4. Burchard, Esteban G., et al. “Moving toward true inclusion of racial/ethnic minorities in federally funded studies. A key step for achieving respiratory health equality in the United States.” American journal of respiratory and critical care medicine 191.5 (2015): 514-521. https://www.atsjournals.org/doi/…

5. Bustamante, Carlos D., M. Francisco, and Esteban G. Burchard. “Genomics for the world.” Nature 475.7355 (2011): 163. https://www.igb.illinois.edu/sit…

6. Wilder, Julius M. “Scientific and Ethical Considerations for Increasing Minority Participation in Clinical Trials.” (2018). https://cdn.intechopen.com/pdfs/…

7. Alsan, Marcella, and Marianne Wanamaker. “Tuskegee and the Health of Black Men.” The Quarterly Journal of Economics 133.1 (2017): 407-455. https://economics.stanford.edu/s…

8. Wong, Kristin X. “The Pivotal Role that Race Plays in Medical Research: The Tuskegee Syphilis Study.” (2018). https://pdxscholar.library.pdx.e…

9. Hoffman, Kelly M., et al. “Racial bias in pain assessment and treatment recommendations, and false beliefs about biological differences between blacks and whites.” Proceedings of the National Academy of Sciences 113.16 (2016): 4296-4301. http://www.pnas.org/content/pnas…

10. Singhal, Astha, Yu-Yu Tien, and Renee Y. Hsia. “Racial-ethnic disparities in opioid prescriptions at emergency department visits for conditions commonly associated with prescription drug abuse.” PLoS One 11.8 (2016): e0159224. http://journals.plos.org/plosone…

11. Meghani, Salimah H., Eeeseung Byun, and Rollin M. Gallagher. “Time to take stock: a meta-analysis and systematic review of analgesic treatment disparities for pain in the United States.” Pain Medicine 13.2 (2012): 150-174. https://academic.oup.com/painmed…

12. Finding Good Pain Treatment Is Hard. If You’re Not White, It’s Even Harder.

13. In Rural Alabama, a Longtime Mistrust of Medicine Fuels a Tuberculosis Outbreak

14. Havasupai Tribe and the lawsuit settlement aftermath

15. Galsky, Matthew D., et al. “GEographic accessibility to clinical trials for advanced cancer in the United States.” JAMA internal medicine 175.2 (2015): 293-295. Accessibility to US Clinical Trials for Cancer

16. Tanner, Andrea, et al. “Communicating effectively about clinical trials with African American communities: A comparison of African American and White information sources and needs.” Health promotion practice 17.2 (2016): 199-208. https://www.researchgate.net/pro…

17. Wallington, Sherrie F., et al. “Enrolling minority and underserved populations in cancer clinical research.” American journal of preventive medicine 50.1 (2016): 111-117. https://www.ncbi.nlm.nih.gov/pmc…

18. Konkel, Lindsey. “Racial and ethnic disparities in research studies: the challenge of creating more diverse cohorts.” Environmental health perspectives 123.12 (2015): A297. https://www.ncbi.nlm.nih.gov/pmc…

19. Graham, Louis F., et al. “Outreach Strategies to Recruit Low-Income African American Men to Participate in Health Promotion Programs and Research: Lessons From the Men of Color Health Awareness (MOCHA) Project.” American journal of men’s health (2018): 1557988318768602. http://journals.sagepub.com/doi/…

20. Ginther, Donna K., et al. “Race, ethnicity, and NIH research awards.” Science 333.6045 (2011): 1015-1019. Race, Ethnicity, and NIH Research Awards

https://www.quora.com/Is-there-a-racial-bias-in-clinical-trial-enrollment/answer/Tirumalai-Kamala