Study of coronavirus variants predicts virus evolving to escape current vaccines

 A new study of the U.K. and South Africa variants of SARS-CoV-2 predicts that current vaccines and certain monoclonal antibodies may be less effective at neutralizing these variants and that the new variants raise the specter that reinfections could be more likely.

The study was published in Nature on March 8, 2021. A preprint of the study was first posted to BioRxiv on January 26, 2021.

The study's predictions are now being borne out with the first reported results of the Novavax vaccine, says the study's lead author David Ho, MD. The company reported on Jan. 28 that the vaccine was nearly 90% effective in the company's U.K. trial, but only 49.4% effective in its South Africa trial, where most cases of COVID-19 are caused by the B.1.351 variant.

"Our study and the new clinical trial data show that the virus is traveling in a direction that is causing it to escape from our current vaccines and therapies that are directed against the viral spike," says Ho, the director of the Aaron Diamond AIDS Research Center and the Clyde'56 and Helen Wu Professor of Medicine at Columbia University Vagelos College of Physicians and Surgeons.

"If the rampant spread of the virus continues and more critical mutations accumulate, then we may be condemned to chasing after the evolving SARS-CoV-2 continually, as we have long done for influenza virus," Ho says. "Such considerations require that we stop virus transmission as quickly as is feasible, by redoubling our mitigation measures and by expediting vaccine rollout."

After vaccination, the immune system responds and makes antibodies that can neutralize the virus.

Ho and his team found that antibodies in blood samples taken from people inoculated with the Moderna or Pfizer vaccine were less effective at neutralizing the two variants, B.1.1.7, which emerged last September in England, and B.1.351, which emerged from South Africa in late 2020. Against the U.K. variant, neutralization dropped by roughly 2-fold, but against the South Africa variant, neutralization dropped by 6.5- to 8.5-fold.

"The approximately 2-fold loss of neutralizing activity against the U.K. variant is unlikely to have an adverse impact due to the large 'cushion' of residual neutralizing antibody activity," Ho says, "and we see that reflected in the Novavax results where the vaccine was 85.6% effective against the U.K. variant."

Data from Ho's study about the loss in neutralizing activity against the South Africa variant are more worrisome.

"The drop in neutralizing activity against the South Africa variant is appreciable, and we're now seeing, based on the Novavax results, that this is causing a reduction in protective efficacy," Ho says.

The new study did not examine the more recent variant found in Brazil (B.1.1.28) but given the similar spike mutations between the Brazil and South Africa variants, Ho says the Brazil variant should behave similarly to the South Africa variant.

"We have to stop the virus from replicating and that means rolling out vaccine faster and sticking to our mitigation measures like masking and physical distancing. Stopping the spread of the virus will stop the development of further mutations," Ho says.

The study also found that certain monoclonal antibodies used now to treat COVID patients may not work against the South Africa variant. And based on results with plasma from COVID patients who were infected earlier in the pandemic, the B.1.351 variant from South Africa has the potential to cause reinfection.

New study contains comprehensive analysis of variants

The new study conducted an extensive analysis of mutations in the two SARS-CoV-2 variants compared to other recent studies, which have reported similar findings.

The new study examined all mutations in the spike protein of the two variants. (Vaccines and monoclonal antibody treatments work by recognizing the SARS-CoV-2 spike protein.)

The researchers created SARS-CoV-2 pseudoviruses (viruses that produce the coronavirus spike protein but cannot cause infection) with the eight mutations found in the U.K. variant and the nine mutations found in the South African variant.

They then measured the sensitivity of these pseudoviruses to monoclonal antibodies developed to treat COVID patients, convalescent serum from patients who were infected earlier in the pandemic, and serum from patients who have been vaccinated with the Moderna or Pfizer vaccine.

Implications for monoclonal antibody treatments

The study measured the neutralizing activity of 18 different monoclonal antibodies -- including the antibodies in two products authorized for use in the United States.

Against the U.K. variant, most antibodies were still potent, although the neutralizing activity of two antibodies in development was modestly impaired.

Against the South Africa variant, however, the neutralizing activity of four antibodies was completely or markedly abolished. Those antibodies include bamlanivimab (LY-CoV555, approved for use in the United States) that was completely inactive against the South Africa variant, and casirivimab, one of the two antibodies in an approved antibody cocktail (REGN-COV) that was 58-fold less effective at neutralizing the South Africa variant compared to the original virus. The second antibody in the cocktail, imdevimab, retained its neutralizing ability, as did the complete cocktail.

"Decisions of the use of these treatments will depend heavily on the local prevalence of the South Africa and Brazil variants," Ho says, "highlighting the importance of viral genomic surveillance and proactive development of next-generation antibody therapeutics."

Reinfection implications

Serum from most patients who had recovered from COVID earlier in the pandemic had 11-fold less neutralizing activity against the South Africa variant and 4-fold less neutralizing activity against the U.K. variant.

"The concern here is that reinfection might be more likely if one is confronted with these variants, particularly the South Africa one," Ho says.

Story Source:

Materials provided by Columbia University Irving Medical Center. Note: Content may be edited for style and length.

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Journal Reference:

1. Pengfei Wang, Manoj S. Nair, Lihong Liu, Sho Iketani, Yang Luo, Yicheng Guo, Maple Wang, Jian Yu, Baoshan Zhang, Peter D. Kwong, Barney S. Graham, John R. Mascola, Jennifer Y. Chang, Michael T. Yin, Magdalena Sobieszczyk, Christos A. Kyratsous, Lawrence Shapiro, Zizhang Sheng, Yaoxing Huang, David D. Ho. Antibody Resistance of SARS-CoV-2 Variants B.1.351 and B.1.1.7. Nature, 2021; DOI: 10.1038/s41586-021-03398-2

https://www.sciencedaily.com/releases/2021/03/210308131712.htm

Sugar harms child's brain development

 Sugar practically screams from the shelves of your grocery store, especially those products marketed to kids.

Children are the highest consumers of added sugar, even as high-sugar diets have been linked to health effects like obesity and heart disease and even impaired memory function.

However, less is known about how high sugar consumption during childhood affects the development of the brain, specifically a region known to be critically important for learning and memory called the hippocampus.

New research led by a University of Georgia faculty member in collaboration with a University of Southern California research group has shown in a rodent model that daily consumption of sugar-sweetened beverages during adolescence impairs performance on a learning and memory task during adulthood. The group further showed that changes in the bacteria in the gut may be the key to the sugar-induced memory impairment.

Supporting this possibility, they found that similar memory deficits were observed even when the bacteria, called Parabacteroides, were experimentally enriched in the guts of animals that had never consumed sugar.

"Early life sugar increased Parabacteroides levels, and the higher the levels of Parabacteroides, the worse the animals did in the task," said Emily Noble, assistant professor in the UGA College of Family and Consumer Sciences who served as first author on the paper. "We found that the bacteria alone was sufficient to impair memory in the same way as sugar, but it also impaired other types of memory functions as well."

Guidelines recommend limiting sugar

The Dietary Guidelines for Americans, a joint publication of the U.S. Departments of Agriculture and of Health and Human Services, recommends limiting added sugars to less than 10 percent of calories per day.

Data from the Centers for Disease Control and Prevention show Americans between the ages 9-18 exceed that recommendation, the bulk of the calories coming from sugar-sweetened beverages.

Considering the role the hippocampus plays in a variety of cognitive functions and the fact the area is still developing into late adolescence, researchers sought to understand more about its vulnerability to a high-sugar diet via gut microbiota.

Juvenile rats were given their normal chow and an 11% sugar solution, which is comparable to commercially available sugar-sweetened beverages.

Researchers then had the rats perform a hippocampus-dependent memory task designed to measure episodic contextual memory, or remembering the context where they had seen a familiar object before.

"We found that rats that consumed sugar in early life had an impaired capacity to discriminate that an object was novel to a specific context, a task the rats that were not given sugar were able to do," Noble said.

A second memory task measured basic recognition memory, a hippocampal-independent memory function that involves the animals' ability to recognize something they had seen previously.

In this task, sugar had no effect on the animals' recognition memory.

"Early life sugar consumption seems to selectively impair their hippocampal learning and memory," Noble said.

Additional analyses determined that high sugar consumption led to elevated levels of Parabacteroides in the gut microbiome, the more than 100 trillion microorganisms in the gastrointestinal tract that play a role in human health and disease.

To better identify the mechanism by which the bacteria impacted memory and learning, researchers experimentally increased levels of Parabacteroides in the microbiome of rats that had never consumed sugar. Those animals showed impairments in both hippocampal dependent and hippocampal-independent memory tasks.

"(The bacteria) induced some cognitive deficits on its own," Noble said.

Noble said future research is needed to better identify specific pathways by which this gut-brain signaling operates.

"The question now is how do these populations of bacteria in the gut alter the development of the brain?" Noble said. "Identifying how the bacteria in the gut are impacting brain development will tell us about what sort of internal environment the brain needs in order to grow in a healthy way."

The article, "Gut microbial taxa elevated by dietary sugar disrupt memory function," appears in Translational Psychiatry. Scott Kanoski, associate professor in USC Dornsife College of Letters, Arts and Science, is corresponding author on the paper.

Additional authors on the paper are Elizabeth Davis, Linda Tsan, Clarissa Liu, Andrea Suarez and Roshonda B. Jones from the University of Southern California; Christine Olson, Yen-Wei Chen, Xia Yang and Elaine Y. Hsiao from the University of California-Los Angeles; and Claire de La Serre and Ruth Schade from UGA.

Story Source:

Materials provided by University of Georgia. Original written by Cal Powell. Note: Content may be edited for style and length.

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Journal Reference:

1. Emily E. Noble, Christine A. Olson, Elizabeth Davis, Linda Tsan, Yen-Wei Chen, Ruth Schade, Clarissa Liu, Andrea Suarez, Roshonda B. Jones, Claire de La Serre, Xia Yang, Elaine Y. Hsiao, Scott E. Kanoski. Gut microbial taxa elevated by dietary sugar disrupt memory function. Translational Psychiatry, 2021; 11 (1) DOI: 10.1038/s41398-021-01309-7

https://www.sciencedaily.com/releases/2021/03/210331130910.htm

How brain cells repair their DNA reveals 'hot spots' of aging and disease

 Neurons lack the ability to replicate their DNA, so they're constantly working to repair damage to their genome. Now, a new study by Salk scientists finds that these repairs are not random, but instead focus on protecting certain genetic "hot spots" that appear to play a critical role in neural identity and function.

The findings, published in the April 2, 2021, issue of Science, give novel insights into the genetic structures involved in aging and neurodegeneration, and could point to the development of potential new therapies for diseases such Alzheimer's, Parkinson's and other age-related dementia disorders.

"This research shows for the first time that there are sections of genome that neurons prioritize when it comes to repair," says Professor and Salk President Rusty Gage, the paper's co-corresponding author. "We're excited about the potential of these findings to change the way we view many age-related diseases of the nervous system and potentially explore DNA repair as a therapeutic approach."

Unlike other cells, neurons generally don't replace themselves over time, making them among the longest-living cells in the human body. Their longevity makes it even more important that they repair lesions in their DNA as they age, in order to maintain their function over the decades of a human life span. As they get older, neurons' ability to make these genetic repairs declines, which could explain why people develop age-related neurodegenerative diseases like Alzheimer's and Parkinson's.

To investigate how neurons maintain genome health, the study authors developed a new technique they term Repair-seq. The team produced neurons from stem cells and fed them synthetic nucleosides -- molecules that serve as building blocks for DNA. These artificial nucleosides could be found via DNA sequencing and imaged, showing where the neurons used them to make repairs to DNA that was damaged by normal cellular processes. While the scientists expected to see some prioritization, they were surprised by just how focused the neurons were on protecting certain sections of the genome.

"What we saw was incredibly sharp, well-defined regions of repair; very focused areas that were substantially higher than background levels," says co-first and co-corresponding author Dylan Reid, a former Salk postdoctoral scholar and now a fellow at Vertex Pharmaceutics. "The proteins that sit on these 'hot spots' are implicated in neurodegenerative disease, and the sites are also linked to aging."

The authors found approximately 65,000 hot spots that covered around 2 percent of the neuronal genome. They then used proteomics approaches to detect what proteins were found at these hot spots, implicating many splicing-related proteins. (These are involved in the eventual production of other proteins.) Many of these sites appeared to be quite stable when the cells were treated with DNA-damaging agents, and the most stable DNA repair hot spots were found to be strongly associated with sites where chemical tags attach ("methylation") that are best at predicting neuronal age.

Previous research has focused on identifying the sections of DNA that suffer genetic damage, but this is the first time researchers have looked for where the genome is being heavily repaired.

"We flipped the paradigm from looking for damage to looking for repair, and that's why we were able to find these hot spots," Reid says. "This is really new biology that might eventually change how we understand neurons in the nervous system, and the more we understand that, the more we can look to develop therapies addressing age-related diseases."

Gage, who holds the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Disease, adds, "Understanding which areas within the genome are vulnerable to damage is a very exciting topic for our lab. We think Repair-seq will be a powerful tool for research, and we continue to explore additional new methods to study genome integrity, particularly in relation to aging and disease."

Story Source:

Materials provided by Salk Institute. Note: Content may be edited for style and length.

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Journal Reference:

1. Dylan A. Reid, Patrick J. Reed, Johannes C. M. Schlachetzki, Ioana I. Nitulescu, Grace Chou, Enoch C. Tsui, Jeffrey R. Jones, Sahaana Chandran, Ake T. Lu, Claire A. McClain, Jean H. Ooi, Tzu-Wen Wang, Addison J. Lana, Sara B. Linker, Anthony S. Ricciardulli, Shong Lau, Simon T. Schafer, Steve Horvath, Jesse R. Dixon, Nasun Hah, Christopher K. Glass, Fred H. Gage. Incorporation of a nucleoside analog maps genome repair sites in postmitotic human neurons. Science, 2021; 372 (6537): 91 DOI: 10.1126/science.abb9032

https://www.sciencedaily.com/releases/2021/04/210401151248.htm

Who Is Getting the Vaccine? Who Isn’t? And Why?

 Two things are obvious. Access to the Covid-19 vaccine has not been equal. And in many cases, the distribution is unrelated to medical need or medical risk.

According to one study, among the 23 states that report the details, Black and Latino people received far smaller shares of the vaccine than their share of cases and deaths. For instance, in Mississippi, Black people make up 38% of the population and 41% of the deaths due to COVID-19, but they’ve received just 17% of the vaccinations.

It will be many years before we know all the dimensions of unequal access to the vaccine, but I am confident that much of what we will find was entirely predictable. Why? Because we have had decades of experience with non-price rationing in health systems in cultures similar to ours and the resulting patterns are clear and unmistakable. (Note: some of what follows was previously reported in my congressional testimony.)

The British National Health Service (NHS) was established in 1948 and it has changed very little in structure in 72 years. Canada’s Medicare system was formally established in 1984 as a “single payer” system, although versions of it existed in some provinces for many years before that. 

When the NHS was founded, the most important, overriding objective was to make health care free of charge at the point of delivery. The reason: there was a widespread belief that health care should be made available on the basis of medical need and not on the basis of income, or social class, or the ability to pay. It was often said, for example, that “health care is a right.” Aneurin Bevan, father of the NHS, declared, “the essence of a satisfactory health service is that rich and poor are treated alike, that poverty is not a disability and wealth is not advantaged.” 

It was fitting therefore, that almost thirty years after the NHS establishment, a Working Group on Inequalities in Health was set up, under the chairmanship of Sir Douglas Black, to study what progress had been made. The results of the 1980 report were shocking. The Black Report found little evidence that the creation of the NHS had equalized health care access or health care outcomes at all. Here are the words of Patrick Jenkin, secretary of state for social services, in his introduction to the report: 

“It will come as a disappointment to many that over long periods since the inception of the NHS there is generally little sign of health inequalities in Britain actually diminishing, and in some cases they may be increasing. It will be seen that the Group has reached the view that the causes of health inequalities are so deep rooted that only a major and wide-ranging programme of public expenditure is capable of altering the pattern.”

In other words, 30 years after Britain had nationalized its health care system and replaced private care with public care, it appears that inequalities in access to health care and health care outcomes were not any different than if the NHS had never been established at all!

About two decades later, after politicians in both parties expressed their resolve to improve the state of affairs and vigorously pursue the original objectives of the NHS, a second study, chaired by Sir Donald Acheson (the Acheson Report) was conducted. The findings? Not only had inequalities not diminished since the publication of the Black Report, they appeared to actually have gotten worse. 

The British results are not all that unusual. In Canada, studies find that the wealthy and powerful have significantly greater access to medical specialists than less-well-connected poor people. High-profile patients enjoy more frequent services, shorter waiting times and greater choice of specialists. Moreover, among the non-elderly white population, low-income Canadians are 22% more likely to be in poor health than their U.S. counterparts.  

Note, however, that what is true in Britain and Canada is also true in other developed countries where government is heavily involved in health care delivery. For OECD countries generally, a 2008 study by health economist Sherry A. Glied found that among people with similar health conditions, “higher income people use the system more intensively and use more costly services than do lower income people.”  

Is it possible that low-income Britons and low-income Canadians might have been better off if the government had not nationalized their health care systems? Yes, that is possible. But of greater interest is to understand why inequalities persist in systems nominally dedicated to their removal. That might help us understand our own country’s response to Covid-19.

One reason is the physical distribution of health care resources. In Britain, health care access and health care outcomes are known to vary radically by postcode (the British term for the American zip code). In general, the hospitals with the largest budgets, the most modern equipment and the best doctors are located in the areas of the country where the highest-income Britons live. And that’s not an accident. Where hospital funds are spent is just as much a political decision as any other decision government makes. 

Second, higher-income Britons and Canadians are more likely to have a social relationship with their doctors. In both countries there are long waiting lists for hospital procedures. The patient who has dinner with her doctor at a country club is more likely to be able to jump the queue than a carpenter, bricklayer or other tradesman. 

Third, in Britain (but not in Canada) high-income patients are more likely to have a financial relationship with their doctors. The British system has a small but important private sector, where patients pay market prices for physician services and the doctors who practice in that sector also have National Health Service hospital privileges. Many employers even offer private health insurance to white-collar workers as an employee benefit. When patients receive their surgery, however, the doctor does it in an NHS hospital, with the NHS paying the bill. 

Finally, higher-income, better-educated people are almost always more successful at navigating bureaucratic systems. The British NHS is not like Walmart, which continuously monitors its sales in order to make sure it always has in stock whatever its customers want, when they want it. It’s more like a Department of Motor Vehicles, where the lives of employees are improved if the customers get tired of waiting and go home. Rationing by waiting is as much an obstacle to care as rationing by price. It seems that the talents and skills that allow people to earn high incomes in the economic marketplace are similar to the talents and skills that are useful in successfully circumventing bureaucratically managed waiting lines.

Bottom line: Decades of experience with non-price rationing of health care in countries with cultures very similar to our own provides a ton of evidence that the poor, racial minorities and other marginalized groups rarely make it to the front of the waiting lines.

But what is the alternative? John Cochrane has an excellent post explaining why price rationing is a superior way of distributing vaccines in almost every dimension. Wouldn’t that put the poor at a disadvantage? If it does, we could subsidize their purchases. But even if we don’t do that, studies show that non-market barriers to care (mainly the time cost of care) are a greater deterrent than market barriers (mainly prices) in impeding access to care for low-income families.

https://www.forbes.com/sites/johngoodman/2021/03/03/who-is-getting-the-vaccine-who-isnt-and-why

Vaccines and Rare Clotting Disorders: What's the Link?

 The possibility of a blood clot is not usually on the minds of most people when they roll up their sleeves for a vaccine, but lately that issue has been on the radar.

Recently, vaccinations with the AstraZeneca COVID-19 shot were put on hold in countries across Europe following reports of rare blood clots, low platelets, and hemorrhage. After formal review, the European Medicines Agency (EMA) and World Health Organization (WHO) both issued statements saying that the overall risk for clotting with this vaccine is no higher than in the general population, that the benefits outweigh the risks, and that vaccinations should continue. The American Society of Hematology has also said that the benefits of the AstraZeneca vaccine outweigh clotting risk.

The AstraZeneca COVID Vaccine

The EMA and WHO reviewed 18 cases of cerebral venous sinus thrombosis (CVST) following administration of over 20 million doses of the AstraZeneca vaccine. Almost all of these events happened in women under age 55. CVST refers to clots forming in veins that drain the brain, which can lead to hemorrhage and stroke. It is very rare, and normally affects about 5 people in 1 million per year.

"CVST is one of those low frequency, high morbidity conditions that attracts attention," said Rajiv Pruthi, MBBS, a hematologist at the Mayo Clinic in Rochester, Minnesota.

In its statement, the EMA said that "some concerns" remain for rare cases of specific thromboses in younger people, and that the vaccine product information should be updated to include the possibility that rare, specific thromboses may occur up to 16 days after vaccination. Both WHO and the EMA have said that further investigation is warranted.

In AstraZeneca's announcement of topline interim results from its U.S. trial, the company said it looked specifically for CVST cases among participants and there were none. About 32,500 people were in the trial, including more than 20,000 receiving the vaccine.

Clots in the U.S.

In the U.S., a Miami physician died following complications of immune thrombocytopenic purpura (ITP) after his first dose of the Pfizer COVID-19 vaccine. ITP is a rare autoimmune condition in which the body generates autoantibodies to its own platelets, resulting in low platelet counts, blood clots, and bleeding if the platelet count drops very low. About 50,000 adults are diagnosed with ITP in the U.S. per year. Risk is increased in young women and people with other autoimmune conditions.

In a case series, James Bussel, MD, and colleagues reviewed 20 reports of thrombocytopenia after receipt of the Pfizer and Moderna COVID-19 vaccines in the U.S. Bussel is professor emeritus of pediatrics at Weill Cornell Medical College in New York City who has published extensively on ITP. His group found that 17 of these patients did not have pre-existing thrombocytopenia. Patients' median age was 41 and 11 were women.

"It is not surprising that 17 possible de novo cases would be detected among the well over 20 million people who have received at least one dose of these two vaccines in the United States as of February 2, 2021," they wrote in the American Journal of Hematology. "The incidence of an immune‐mediated thrombocytopenia post SARS‐CoV‐2 vaccination appears either less than or roughly comparable to what would be seen if the cases were coincidental following vaccination, perhaps enhanced somewhat by heightened surveillance of symptomatic patients."

However, they note that "all but one" of these cases occurred after the first dose of the Pfizer or Moderna vaccine.

"One would assume that if the vaccination was unrelated to development of ITP, case occurrences would divide more evenly between the two doses," they write. "...[W]e cannot exclude the possibility that the Pfizer and Moderna vaccines have the potential to trigger de novo ITP (including clinically undiagnosed cases), albeit very rarely."

Clots After Other Vaccines

ITP has been reported after natural infection with viruses like HIV and hepatitis C. As well, "ITP has been reported after other vaccines, albeit not at high enough numbers to warrant concern," Alfred Lee, MD, PhD, a hematologist and associate professor of medicine at Yale School of Medicine told MedPage Today.

Much of the information about ITP and vaccines relies on small numbers of case reports. The condition has been reported in about 1 to 3 children out of every 100,000 after receiving the MMR vaccine, a rate that is significantly lower than reported after natural infection with these viruses, according to one review. Other cases of ITP -- mostly mild -- have been reported after vaccination for flu, varicella-zoster, and hepatitis B, as well as with the diphtheria/tetanus/pertussis (DTP), diphtheria/tetanus/acellular pertussis (DTaP), and Shingrix zoster vaccines.

It's important to remember that rare adverse events like these rely on voluntary reporting to the CDC's Vaccine Adverse Event Reporting System, which could be biased. The key is to look at the observed incidence following the vaccine compared to the expected incidence in the general population, according to the Mayo Clinic's Pruthi.

"Severe autoimmune thrombocytopenia is really rare," he said.

What's Going On?

Still, scientists are generating hypotheses.

For cases of CVST linked to the AstraZeneca vaccine in Europe, the leading hypothesis is that these few patients may be experiencing an autoimmune reaction. Two teams of researchers in Germany and Norway said they had identified an autoantibody called heparin platelet factor 4 antibody that may be involved in CVST's development. The group, which includes Andreas Greinacher, MD, of the Medical University of Greifswald in Germany, who is well known in the field, issued a statement about their preliminary data (though no formal publication or preprint manuscript). The statement offers guidance on diagnosing and treating this condition if it develops after the AstraZeneca vaccine.

Heparin platelet 4 antibody causes heparin-induced thrombocytopenia (HIT), in which heparin paradoxically activates platelets, leading to platelet depletion and clotting. HIT is a well-known but rare complication of heparin use that develops in about 1%-2% of patients. Some patients who have never been exposed to heparin can also have this autoantibody.

Moreover, this antibody has been linked previously to rare cases of CVST -- about 20 have been reported in the literature, according to Pruthi.

"This is a unique situation because the German and Norwegian researchers actually found a unique antibody for which there's no other explanation than the vaccine," he said. "Although the observed incidence of CVST with the AstraZeneca vaccine does not appear to be higher than expected in the population, I think this deserves further study."

Are the European and U.S. Cases Linked?

Whether these rare clotting events in Europe and the ITP cases in the U.S. bear anything in common is anyone's guess right now.

One hypothesis is that the mRNA vaccines (Pfizer, Moderna) and those using adenoviruses (AstraZeneca, Johnson & Johnson) could induce synthesis of the COVID spike protein within platelets, which may then trigger autoimmune reactions against platelets, Hamid Merchant, PhD, of the University of Huddersfield in England, wrote in a letter to The BMJ.

"COVID genetic vaccines may have a direct role in spurring an autoimmune response against platelets that may clinically manifest in thrombocytopenia, hemorrhage, and blood clots. Clotting risks may be equally possible with all genetic COVID vaccines, and may not be limited only with the AstraZeneca/Oxford vaccine," he told MedPage Today.

Pruthi said ITP related to vaccination is probably a separate process involving a different autoantibody than the HIT reaction linked to the European CVST cases. The important point is that healthcare providers recognize the possibility that platelet factor 4 antibody could be involved in very rare cases of CVST after vaccination for COVID-19.

"Generally when patients develop CVST, the first thing you do is give them heparin. In this situation, that would be the worst thing to do. You would need to avoid heparin and use a different nonheparin anticoagulant," he said. "Hence the importance of making the diagnosis. Providers need to be vigilant to this phenomenon, to make sure they get the right tests, diagnose it quickly, and consult a coagulation expert."

https://www.medpagetoday.com/special-reports/exclusives/91813

Revolution Underway in Alzheimer's: Not All Good

 The biomarker revolution has changed the way people look at Alzheimer's disease -- and that has its downsides, says Jason Karlawish, MD, co-director of the Penn Memory Center at the University of Pennsylvania in Philadelphia.

"Over a fairly short period of time, we've had a revolutionary redefinition about what we talk about when we talk about Alzheimer's," Karlawish said in an interview with MedPage Today. "This is really made possible by two events: one is the discovery of biomarkers, and the other is the discovery of the idea of mild cognitive impairment."

In the field of Alzheimer's disease, science often collides with politics. Battle lines are drawn over cure versus care. More than six million Americans live with Alzheimer's, and many more provide unpaid care for patients. And decades after scientists first realized they could clear the brain of amyloid plaques -- a hallmark of the disease, along with tau tangles -- people with Alzheimer's have no effective treatments.

This is the backdrop for Karlawish's new book, The Problem of Alzheimer's: How Science, Culture, and Politics Turned a Rare Disease Into a Crisis and What We Can Do About It. MedPage Today senior staff writer Judy George spoke with Karlawish to learn more about the complexity of Alzheimer's disease in today's society.

George: Let's start with the biomarker revolution. We now can image amyloid and tau in people's brains, and blood tests for Alzheimer's are on the horizon.

Karlawish: When I started out, patients had to have dementia to be diagnosed with Alzheimer's. It was a sort of Gothic horror story; I couldn't tell you what was wrong with you until you died and until then, it was at most a probable diagnosis.

Biomarkers have made what was invisible visible. But the biomarker revolution will not be without challenges. One is the pushing of the Alzheimer's diagnosis into milder and milder and even unimpaired states of being -- persons who are not impaired, or at most are mildly cognitively impaired.

This certainly creates opportunities for early diagnosis and treatment. But it presents real challenges to people in terms of their identity, autonomy, and threats that come from stigma and the need for monitoring and therefore intrusion into their privacy.

George: What kind of stigma?

Karlawish: There are three kinds of stigma with Alzheimer's disease. There's self stigma -- the stigma an individual feels when they can't do things. There's public stigma -- the world around them thinks less of them. And there's stigma that people around the patient or family members may feel, a distancing from others.

I cite a story in the book about Ronald Reagan. His ambassador to the White House and the U.K., Walter Annenberg, was quoted as saying that he preferred to remember Reagan as a vigorous fellow. He didn't want to see him with Alzheimer's because he was just "out of it." He was essentially saying, "I'm staying away from Ronald Reagan, I'm distancing myself from him," which meant he was distancing himself from Nancy Reagan as well, I assume. To me, that is a very poignant example of stigma.

The ground zero of stigma expression in Alzheimer's disease is what I call the "z" word -- namely, that we cultivate this rhetoric of death before death or the living dead, that people become zombies.

George: You've mentioned the Alzheimer's field has an "odd pitting of care versus cure." How did this emerge?

Karlawish: It's wrapped up in a number of events. The Alzheimer's field struggled to gain legitimacy, and focusing on topics other than "let's figure out how to diagnose and cure this disease" was perceived as a distraction from that mission.

When the Alzheimer's Association was founded in 1980, there was no debate that cancer was a disease; cancer had been recognized for centuries. There was no debate that cardiovascular disease was a disease. Yet in 1980, there was vast ignorance about the legitimacy of Alzheimer's as a disease.

We support research to discover a cure, but we don't agree on how to care for people with Alzheimer's disease. Care has become caught up in contentious political debates around the role of the state for long-term care services and support and ideological battles about the role of the family.

In the 1990s, one party in America said absolutely no increases in taxes, no expansion of federal programs beyond defense and some related things, and had a deep skepticism about feminism and creating equal opportunity for women. While none of those positions were articulated to specifically harm or otherwise hurt persons living with dementia or their caregivers, they did just that because they thwarted a coherent national conversation about how we should provide care.

You have to build infrastructure for care -- for long-term services and support, not just diagnosis and treatment. I consider it basic infrastructure that allows the American family to function, like roads and traffic lights: we don't question those as being what we need.

George: The FDA will decide the fate of aducanumab soon. What can we expect from drugs like aducanumab?

Karlawish: Aducanumab is part of the story of amyloid, which is interesting. Right around the turn of the century, studies first appeared using a very novel method that cleared transgenic mice of amyloid. Researchers were thinking they might have to find a new line of work because Alzheimer's would be solved.

Well, here we are 21 years later and it's not solved, and at best we have a treatment that's controversial. Even the most optimistic take on aducanumab is that the drug has some effect on slowing the rate of progression.

A word that's whispered at meetings is "heterogeneity" -- that we really should think of this not so much as Alzheimer's disease, but Alzheimer's diseases. I think a very plausible future is that there will be druggable forms, not so-druggable forms, and potentially untreatable forms of Alzheimer's. The stories of multiple sclerosis tell us that; the stories of many cancers tell us that.

The implication is we really need to think about how we're going to live with this disease. We're not going to drug our way out of the problem. Banking on a cure for all causes of late-life disabling cognitive impairments is like planning your retirement with lottery tickets: you may win and win big, but odds are you're not going to.

George: Given Alzheimer's many dimensions, what do we need to pay attention to next?

Karlawish: We're beginning to face an enormous irony in the field of Alzheimer's. The reason why Alzheimer's is a disease is because of its relentless assault on our autonomy and self-determination. Alzheimer's keeps people from living their life the way they want to live their life. That's what makes it a disease, fully, completely -- along with amyloid, tau, and neurodegeneration.

The irony is that the biomarker transformation poses threats to the very same autonomy we're trying to preserve. We can address those threats, but we have to organize ourselves as a society to do that.

Our approach to dealing with this disease needs to emphasize helping persons living with it to maintain autonomy and identity, even in the face of disabling cognitive impairments.

That needs to be the way we frame our strategy as a country in terms of the support we provide people, the way we talk about the disease, and the language and images we use.

https://www.medpagetoday.com/neurology/alzheimersdisease/91927

1/5 in US Give to Medical Crowdfunding Campaigns

 Despite the financial hardships that many Americans experienced during the COVID-19 pandemic, 45 million still donated to medical crowdfunding campaigns last year, survey results suggested.

Among more 1,000 members of a population-representative panel, 18% reported donating to a crowdfunding campaign raising money for a medical bill or treatment, reported Susan Cahn, DrPH, and Mollie Hertel, AM, MPP, of the National Opinion Research Center (NORC) at the University of Chicago.

The average number of donations per donor was about 1.4; 28% of donors contributed to two or more efforts.

Nearly 40% of people who donated to a medical crowdfunding campaign were from households with annual income less than $60,000. Of those who donated, 36% were not working (either unemployed or retired) and 6% had no health insurance at the time the survey was taken.

Among individuals who contributed funds to medical crowdfunding, 52% reported donating to raise money for a friend. Around 30% donated to someone they didn't know personally, 22% donated to an acquaintance, 14% donated to a relative, and 8% donated to a co-worker.

"This demonstrates that even during the pandemic, Americans continued to try to help their friends, families, and strangers pay for medical care and treatment," Cahn told MedPage Today. Cahn added that continued trends of medical crowdfunding donations across the last year was striking, as many people were faced with financial challenges including paying for their own medical expenses and losing access to insurance.

Many people have turned to crowdfunding campaigns to help them afford rising out-of-pocket medical costs, via websites such as Indiegogo, Kickstarter, and GoFundMe. In 2019, the CEO of GoFundMe said one-third of all donations to the site were for medical expenses.

Survey results from NORC last year showed nearly identical participation in medical crowdfunding. While the researchers expected that figure to fluctuate during the pandemic due to financial challenges, that metric remained consistent.

For the current report, surveyors interviewed 1,028 members of NORC's AmeriSpeak probability-based panel. All of the survey respondents were interviewed in December 2020, were 18 years or older, and spoke English.

Cancer was the most common condition for which people supported crowdfunding campaigns, with 39% donating funds to this cause. Additionally, 35% contributed to expenses for accidents or workplace injuries, 19% for heart disease, and 11% for mental illnesses such as depression, bipolar disorder, or schizophrenia.

Among those who started a medical crowdfunding campaign, nearly one-third sought to raise money for someone with COVID-19. Approximately 21% of people who started a campaign did so for accidents and injuries, 20% for cancer, and 10% for diabetes. The report gave no estimates for dollar amounts donated, however, either overall or for specific conditions or types of expenses.

Cahn said that while crowdfunding is not a systemic solution to unaffordable healthcare, it's popular because "Americans know that there are gaps in insurance and people have really significant needs."

"While Americans continue to donate to help friends and family and strangers, they think that the government and healthcare providers have a great deal of responsibility to deal with healthcare affordability," she said.

https://www.medpagetoday.com/special-reports/exclusives/91925