Pandemic News Links / Current News Updates

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Re: Pandemic News Links / Current News Updates

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Stigma against D.O.s had been dissipating until Trump’s doctor took the spotlight

10/9/20 ... light.aspx

Dr. Katherine Pannel was initially thrilled to see President Donald Trump's physician is a doctor of osteopathic medicine. A practicing D.O. herself, she loved seeing another glass ceiling broken for the type of doctor representing 11% of practicing physicians in the U.S. and now 1 in 4 medical students in the country.

But then, as Dr. Sean Conley issued public updates on his treatment of Trump's COVID-19, the questions and the insults about his qualifications rolled in.

"How many times will Trump's doctor, who is actually not an MD, have to change his statements?" MSNBC's Lawrence O'Donnell tweeted.

"It all came falling down when we had people questioning why the president was being seen by someone that wasn’t even a doctor," Pannel said.

The osteopathic medical field has had high-profile doctors before, good and bad. Dr. Murray Goldstein was the first D.O. to serve as a director of an institute at the National Institutes of Health, and Dr. Ronald R. Blanck was the surgeon general of the U.S. Army. Former Vice President Joe Biden, challenging Trump for the presidency, also sees a doctor who is a D.O. But another now former D.O., Larry Nassar, who was the doctor for USA Gymnastics, was convicted of serial sexual assault.

Still, with this latest example, Dr. Kevin Klauer, CEO of the American Osteopathic Association, said he's heard from many fellow osteopathic physicians outraged that Conley — and by extension, they, too — are not considered real doctors.

"You may or may not like that physician, but you don't have the right to completely disqualify an entire profession," Klauer said.

For years, doctors of osteopathic medicine have been growing in number alongside the better-known doctors of medicine, who are sometimes called allopathic doctors and use the M.D. after their names.

According to the American Osteopathic Association, the number of osteopathic doctors grew 63% in the past decade and nearly 300% over the past three decades. Still, many Americans don't know much about osteopathic doctors, if they know the term at all.

"There are probably a lot of people who have D.O.s as their primary [care doctor] and never realized it," said Brian Castrucci, president and CEO of the de Beaumont Foundation, a philanthropic group focused on community health.

So what is the difference?

Both types of physicians can prescribe medicine and treat patients in similar ways.

Although osteopathic doctors take a different licensing exam, the curriculum for their medical training — four years of osteopathic medical school — is converging with M.D. training as holistic and preventive medicine becomes more mainstream. And starting this year, both M.D.s and D.O.s were placed into one accreditation pool to compete for the same residency training slots.

But two major principles guiding osteopathic medical curriculum distinguish it from the more well-known medical school route: the 200-plus hours of training on the musculoskeletal system and the holistic look at medicine as a discipline that serves the mind, body and spirit.

The roots of the profession date to the 19th century and musculoskeletal manipulation. Pannel was quick to point out the common misconception that their manipulation of the musculoskeletal system makes them chiropractors. It's much more involved than that, she said. Dr. Ryan Seals, who has a D.O. degree and serves as a senior associate dean at the University of North Texas Health Science Center in Fort Worth, said that osteopathic physicians have a deeper understanding than allopathic doctors of the range of motion and what a muscle and bone feel like through touch.

That said, many osteopathic doctors don't use that part of their training at all: A 2003 Ohio study said approximately 75% of them did not or rarely practiced osteopathic manipulative treatments.

The osteopathic focus on preventive medicine also means such physicians were considering a patient's whole life and how social factors affect health outcomes long before the pandemic began, Klauer said. This may explain why 57% of osteopathic doctors pursue primary care fields, as opposed to nearly a third of those with doctorates of medicine, according to the American Medical Association.

Pannel pointed out that she's proud that 42% of actively practicing osteopathic doctors are women, as opposed to 36% of doctors overall. She chose the profession as she felt it better embraced the whole person, and emphasized the importance of care for the underserved, including rural areas. She and her husband, also a doctor of osteopathic medicine, treat rural Mississippi patients in general and child psychiatry.

Given osteopathic doctors' likelihood of practicing in rural communities and of pursuing careers in primary care, Health Affairs reported in 2017, they are on track to play an increasingly important role in ensuring access to care nationwide, including for the most vulnerable populations.

Stigma remains

To be sure, even though the physicians end up with similar training and compete for the same residencies, some residency programs have often preferred M.D.s, Seals said.

Traditional medical schools have held more esteem than schools of osteopathic medicine because of their longevity and name recognition. Most D.O. schools have been around for only decades and often are in Midwestern and rural areas.

While admission to the nation's 37 osteopathic medical schools is competitive amid a surge of applicants, the grade-point average and Medical College Admission Test scores are slightly higher for the 155 U.S. allopathic medical schools: The average MCAT was 506.1 out of 528 for allopathic medical school applicants over a three-year period, compared with 503.8 for osteopathic applicants for 2018.

Seals said prospective medical students ask the most questions about which path is better, worrying they may be at a disadvantage if they choose the D.O. route.

"I've never felt that my career has been hindered in any way by the degree," Seals said, noting that he had the opportunity to attend either type of medical school, and osteopathic medicine aligned better with the philosophy, beliefs and type of doctor he wanted to be.

Many medical doctors came to the defense of Conley and their osteopathic colleagues, including Dr. John Morrison, an M.D. practicing primary care outside of Seattle. He was disturbed by the elitism on display on social media, citing the skills of the many doctors of osteopathic medicine he'd worked with over the years."There are plenty of things you can criticize him for, but being a D.O. isn't one of them,” Morrison said.
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Re: Pandemic News Links / Current News Updates

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Study examines ways to improve prone positioning for severe ARDS during COVID-19 pandemic

10/9/20 ... demic.aspx

A new study published online in the Annals of the American Thoracic Society examines ways to increase the use of prone positioning for patients with severe acute respiratory distress syndrome (ARDS), and develops specific implementation strategies that can assist in clinicians' response to the COVID-19 pandemic.

Prone positioning has been shown to reduce mortality related to severe ARDS, yet most patients with ARDS-;up to 85 percent-;do not receive this lifesaving therapy.

In "Improving Prone Positioning for Severe ARDS during the COVID-19 Pandemic: An Implementation Mapping Approach," Meeta Prasad Kerlin, MD, MSCE, an associate professor of medicine in the Perelman School of Medicine at the University of Pennsylvania, and co-authors conducted a multifaceted study to help determine why prone positioning is rarely used as an initial therapeutic strategy for patients with ARDS, as well as ways to address these potential barriers.

First, the team conducted semi-structured interviews with a diverse, representative group of 30 clinicians who staffed 30 ICUs within the University of Pennsylvania Health System (Penn) and the University of Michigan Medical Center. They analyzed common themes arising from these interviews, using the Consolidated Framework for Implementation Research (CFIR), a systematic tool to identify factors that might influence intervention implementation and effectiveness.

They then presented their findings to focus groups of ICU leaders at Penn. Input from the focus groups was used to develop a menu of strategies to promote prone positioning implementation using the Expert Recommendations for Implementing Change (ERIC) framework.

ERIC provides a structure to help develop implementation strategies for specific practices. The implementation strategies identified through this research were adopted as part of Penn Medicine's COVID-19 response.

"Just as we use evidence-based approaches to care for patients, we sought to use evidence-based approaches to conduct this project. The advantage of all of these frameworks and the implementation mapping approach are that they provide guides for a complex process that help us to be robust and complete in identifying and assessing barriers and facilitators and in developing strategies with a stakeholder group."

- Meeta Prasad Kerlin, MD, MSCE, Associate Professor, Department of Medicine, Perelman School of Medicine, University of Pennsylvania

Based on the researchers' identification of five broad themes that determine the use of prone positioning, their task force developed five specific implementation strategies.
While they rapidly applied elements of these strategies at Penn, their intention in publishing this research was to provide potential ways for other hospitals and health systems to quickly increase the use of prone positioning for severe ARDS, both related and unrelated to COVID-19.

When the 30 interview subjects were asked about the use of prone positioning, 8 (27 percent) reported that their primary ICU used it frequently, 14 (46 percent) reported they used it sometimes and 8 (27 percent) reported using prone positioning rarely or never.

A key finding was that knowledge about prone positioning, including patient eligibility, its therapeutic value and the procedure of actually putting patients into a prone position, was integral to the use of this therapeutic strategy. Some study participants believed that prone positioning was a "last ditch" therapy, rather than an initial therapy of choice for severe ARDS. Participants identified a number of ways to effectively educate ICU staff about prone positioning.

Prone positioning requires the assistance of a number of individuals, and many interviewees stated that a lack of adequate staffing created a barrier to enacting this therapy, especially during the night. Many agreed that having a dedicated team available to provide additional staff members when needed would ensure more use of prone positioning.

Interviewed clinicians also revealed that the culture of the ICU team contributed to the use-;or lack of use-;of prone positioning. Many believed that individuals in key positions such as an ICU medical director or nurse supervisor could change ICU culture, and that team dynamics were also an important factor.

Dr. Kerlin noted, "Prior to a large randomized trial that demonstrated a benefit to early prone positioning, several studies had evaluated it as a late intervention. These early studies were largely negative, and people became aware of this as a therapy that one tries at the end, as a salvage.

Many people may still rely on that older belief and culture. In addition, there are those who believe strongly in an alternative therapy, extracorporeal membrane oxygenation (ECMO), and in institutions where ECMO is available, some people mentioned a strong culture around considering that first, even though there is absolutely no evidence that ECMO should come before prone positioning in the sequence of treatments."

In the first few months of the COVID-19 pandemic, it became evident to Dr. Kerlin and colleagues that there would be a major demand to scale up their practice of prone positioning across the board, and that many clinicians (doctors, nurses, respiratory therapists) who had little or no experience with prone positioning would rapidly need to get comfortable with it. As a result, the health system quickly adopted several of the strategies that were described in the paper.

Penn Medicine has an inter-hospital Critical Care Alliance, a group of ICU leaders from all six of the health system's hospitals, that led development and dissemination of educational materials (including an educational video and an infographic document) and provided guidance for the hospitals to create prone positioning teams.

One of the hospitals already had a clinical protocol and electronic health record (EHR) tools for prone positioning; these were disseminated to the other hospitals. One of the study's co-authors, Barry Fuchs, MD, had led the development of an ICU dashboard to display real-time quality metrics, and it was modified to include a prone positioning alert, which identifies eligible patients and visually displays whether or not a patient has an order for prone positioning.

"As the COVID-19 census has waned, some of the resources put towards their care, such as some of these strategies, have faded with time," said Dr. Kerlin. "In our next phase of research, we hope to conduct studies to test the effectiveness of some of these specific strategies in improving the utilization of prone positioning."
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New digital dashboard enhances the efficiency of cancer case review

10/9/20 ... eview.aspx

Multidisciplinary tumor boards are vital to cancer treatment plans, bringing together clinicians from different specialties to guide patient treatment and improve outcomes. However, compiling the relevant data for each case is time-consuming and requires contributions from multiple team members.

To optimize the process, researchers at the MU School of Medicine partnered with Roche Diagnostics to evaluate a cloud-based product called NAVIFY® Tumor Board that integrates all relevant clinical data for a tumor board into a single digital dashboard accessible to everyone.

During a 16-month clinical study of the dashboard, researchers found NAVIFY Tumor Board significantly reduced the amount of time doctors and nurses across multiple specialties spent preparing for 227 tumor board meetings involving 1866 patient cases.

" In addition to saving time, the NAVIFY digital tumor board solution resulted in less variability in preparation time. The improvements were sustained and became more significant over time, decreasing administrative burdens of meeting preparation."

-Richard Hammer, MD, Professor, Pathology, School of Medicine, University of Missouri

Hammer is also a vice chair of clinical affairs in the Dept. of Pathology and Anatomical Sciences.

Hammer evaluated case preparation time during four phases: before NAVIFY Tumor Board implementation, after manual implementation, after partial electronic medical record (EMR) integration and after a stable EMR integration phase.

The study found a 30% preparation time reduction across three cancer categories with full integration compared to pre-implementation. The biggest time savings involved the breast tumor board, where nurse navigators reduced their preparation time by 69%.

"Institutions with dedicated nurses preparing for cases will likely benefit the most," Hammer said. "This dashboard enables easy access to clinical data, which may support optimal decision-making. In addition, it reduces costs for both patients and hospitals, which is currently under analysis."

Hammer's team is also in the process of submitting data on the impact of the NAVIFY clinical decision support software on case discussion time during tumor board meetings. Future studies will investigate its impact on the quality of case discussions.

"As the first reference site for NAVIFY Tumor Board in the U.S., we are already hosting other institutional leaders to help them implement this software," Hammer said.

"This is the wave of the future, where we are using digital clinical decision support software to enhance how we care for patients, while improving efficiency, standardizing the preparation of cases and making them available to clinicians at any time."

In addition to Hammer, the study's co-authors included MU School of Medicine colleague Lincoln Sheets, MD, assistant research professor. Hammer received research funding, an honoraria and serves as an advisor for Roche.
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For this COVID-19 “long-hauler,” symptoms have persisted for months: “I’m uncomfortable literally all day long”

10/9/20 ... long-term/

Brittani Castle says she's a COVID-19 “long-hauler.” Since becoming infected with COVID-19 nearly three months ago, she continues to experience shortness of breath, digestive issues and a foggy memory — symptoms that linger even though she's tested negative for the virus.

The Houston woman is out of work and has encountered problems collecting unemployment.

In the weekend edition of The Brief podcast, listen to why she says the coronavirus has come to dominate her life.
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Coronavirus claims lives of six members of one family, infects 16 others

“We are a humble, immigrant family that came here to work hard and do better for ourselves.” said Deni Taveras, a council member in Prince George's County, Maryland.

10/9/20 ... s-n1242738

A Prince George's County council member in Maryland is grappling with loss and grief after Covid-19 killed six members of her extended family and infected 16 others.

Council member Deni Taveras, who grew up in Harlem in New York City after her large, tight-knit family immigrated from the Dominican Republic, said that despite the deaths, her family is strong.

“We are a humble, immigrant family that came here to work hard and do better for ourselves,” she said. “We’ve been in this country for a long time, and we are blessed for that, but at the same time it’s sad that we couldn’t have had some of our family members even longer.”

Her half-brother,Jaimito de la Hoz, 58, and his mother, Ramona de la Hoz, 81, who lived in New York City, contracted the virus and died in March. De la Hoz likely got the virus at a hospital, where he was seeking treatment for another medical issue, and later infected his mother, who was caring for him, Taveras said.

Soon after, four of her uncles, Marcial Garcia, 83, Dario Jerez, 81, Alberto Toledo, 65, and Miguel Suazo, 65, died from Covid-19. The deceased family members lived in New York, Florida and Ecuador, and 16 others became infected but survived, she said.

Her family is supportive, especially Garcia, who encouraged her to pursue her dreams and an education, said Taveras, who attended Barnard College in New York City.

“My fondest memory of Marcial is having conversations with him about the fact that I wanted a better future for myself,” Taveras said. “I invited him to my college graduation, and I remember the pride in his face. He was the only family member, outside of my aunt, that had ever come to visit me at the university.”
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Re: Pandemic News Links / Current News Updates

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COVID-19-related social distancing measures reduce noise exposure nearly in half

10/9/20 ... -half.aspx

People's exposure to environmental noise dropped nearly in half during the early months of the coronavirus pandemic, according to University of Michigan researchers who analyzed data from the Apple Hearing Study.

Researchers at U-M's School of Public Health and Apple Inc. looked at noise exposure data from volunteer Apple Watch users in Florida, New York, California and Texas. The analysis, one of the largest to date, included more than a half million daily noise levels measured before and during the pandemic.

Daily average sound levels dropped approximately 3 decibels during the time that local governments made announcements about social distancing and issued stay-at-home orders in March and April, compared to January and February.

" That is a huge reduction in terms of exposure and it could have a great effect on people's overall health outcomes over time. The analysis demonstrates the utility of everyday use of digital devices in evaluating daily behaviors and exposures."

-Rick Neitzel, associate professor of environmental health sciences at U-M's School of Public Health

The four states reviewed in this analysis had differing COVID-19 responses in terms of stay-at-home orders, which showed through the data.

"California and New York both had really drastic reductions in sound that happened very quickly, whereas Florida and Texas had somewhat less of a reduction," Neitzel said.

Initially, the largest drop in environmental sound exposure was seen on the weekends, where nearly 100% of participants reduced their time spent above the 75 dBA threshold (a sound level roughly as loud as an alarm clock) between Friday and Sunday.

"But after the lockdowns, when people stopped physically going to work, the pattern became more opaque," Neitzel said. "People's daily routines were disrupted and we no longer saw a large distinction in exposures between the traditional five working days versus the weekend."

These data points allow researchers to begin describing what personal sound exposures are like for Americans who live in a particular state, or are of a particular age, or who have or do not have hearing loss.

"These are questions we've had for years and now we're starting to have data that will allow us to answer them," Neitzel said. "We're thankful to the participants who contributed unprecedented amounts of data. This is data that never existed or was even possible before."

The Apple Hearing Study is the first of its kind to collect data over time in order to understand how everyday sound exposure can impact hearing. The study data will also be shared with the World Health Organization as a contribution toward its Make Listening Safe initiative.

The study continues to recruit participants. To learn more about the study or to download the Research app to participate, visit Apple Hearing Study.
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Key insights into harnessing the tools of population health to combat COVID-19

10/9/20 ... ID-19.aspx

Battling the COVID-19 pandemic and preparing for the inevitable next surge requires a data-driven population health approach. A special issue of the peer-reviewed journal Population Health Management is dedicated to combatting COVID-19. It embraces systems thinking and key insights from other industries.

This series of editorials, papers, and roundtable discussions highlights the need to harness the tools of population health to successfully combat COVID-19. The authors represent some of the most important companies and organizations tackling the pandemic, including Quest Labs, Humana, Microsoft, and many provider groups too. This dedicated issue will serve as a guide as we confront the next possible surge--it should be required reading for all healthcare leaders."

David Nash, MD, MBA, Editor-in-Chief of Population Health Management and Founding Dean Emeritus and Dr. Raymond C. and Doris N. Grandon Professor, Jefferson College of Population Health, Philadelphia, PA

Point-of-view, original research, and two roundtable articles comprise the special issue. Included in the issue are the following articles:

If Aviation Were in Control of the COVID-19 Response
A Simple Algorithm for Return to Workplace Employer Antibody Testing
Health Inequalities in the Use of Telehealth in the United States in the Lens of COVID-19
We Know Health Is Not Elective: Impacts of COVID-19
Changes in Health Care Following COVID-19


Mary Ann Liebert, Inc.
Journal reference:

Nash, D.B., (2020) Population Health and the Pandemic: Emerging Stronger Next Time. Population Health Management.
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Exuberant activation of immune cells in severe COVID-19 resembles lupus

10/9/20 ... lupus.aspx

In severe cases of COVID-19, Emory researchers have been observing an exuberant activation of immune cells, resembling acute flares of systemic lupus erythematosus (SLE), an autoimmune disease.

Their findings point towards tests that could separate some COVID-19 patients who need immune-calming therapies from others who may not. They also may begin to explain why some people infected with SARS-CoV-2 produce abundant antibodies against the virus, yet experience poor outcomes.

The results were published online on Oct. 7 in Nature Immunology.

The Emory team's results converge with recent findings by other investigators, who found that high inflammation in COVID-19 may disrupt the formation of germinal centers, structures in lymph nodes where antibody-producing cells are trained. The Emory group observed that B cell activation is moving ahead along an "extrafollicular" pathway outside germinal centers - looking similar to they had observed in SLE.

B cells represent a library of blueprints for antibodies, which the immune system can tap to fight infection. In severe COVID-19, the immune system is, in effect, pulling library books off the shelves and throwing them into a disorganized heap.

Before the COVID-19 pandemic, co-senior author Ignacio (Iñaki) Sanz, MD and his lab were focused on studying SLE and how the disease perturbs the development of B cells.

Sanz is head of the division of rheumatology in the Department of Medicine, director of the Lowance Center for Human Immunology, and a Georgia Research Alliance Eminent Scholar. Co-senior author Frances Eun-Hyung Lee, MD is associate professor of medicine and director of Emory's Asthma/Allergy Immunology program.

" We came in pretty unbiased. It wasn't until the third or fourth ICU patient whose cells we analyzed, that we realized that we were seeing patterns highly reminiscent of acute flares in SLE."

- Ignacio (Iñaki) Sanz, MD, co-senior author

In people with SLE, B cells are abnormally activated and avoid the checks and balances that usually constrain them. That often leads to production of "autoantibodies" that react against cells in the body, causing symptoms such as fatigue, joint pain, skin rashes and kidney problems. Flares are times when the symptoms are worse.

Whether severe COVID-19 leads to autoantibody production with clinical consequences is currently under investigation by the Emory team. Sanz notes that other investigators have observed autoantibodies in the acute phase of the disease, and it will be important to understand whether long-term autoimmune responses may be related to the fatigue, joint pain and other symptoms experienced by some survivors.

"It's an important question that we need to address through careful long-term follow-up," he says. "Not all severe infections do this. Sepsis doesn't look like this."

In lupus, extrafollicular B cell responses are characteristic of African-American patients with severe disease, he adds. In the new study, the majority of patients with severe infection were African-American. It will be important to understand how underlying conditions and health-related disparities drive the intensity and quality of B cell responses in both autoimmune diseases and COVID-19, Sanz says.

The study compared 10 critically ill COVID-19 patients (4 of whom died) admitted to intensive care units at Emory hospitals to 7 people with COVID-19 who were treated as outpatients and 37 healthy controls.

People in the critically ill group tended to have higher levels of antibody-secreting cells early on their infection. In addition, the B cells and the antibodies they made displayed characteristics suggesting that the cells were being activated in an extrafollicular pathway. In particular, the cells underwent fewer mutations in their antibody genes than seen in a focused immune response, which is typically honed within germinal centers.

The Nature Immunology paper was the result of a collaboration across Emory. The co-first authors are Matthew Woodruff, PhD, an instructor in Sanz's lab, and Richard Ramonell, MD, a fellow in pulmonary and critical care medicine at Emory University Hospital.

Ramonell notes that the patients studied were treated early during the COVID-19 pandemic. It was before the widespread introduction of the anti-inflammatory corticosteroid dexamethasone, which has been shown to reduce mortality.

The team's findings could inform the debate about which COVID-19 patients should be given immunomodulatory treatments, such as dexamethasone or anti-IL-6 drugs. Patients with a greater expansion of B cells undergoing extrafollicular activation also had higher levels of inflammatory cytokines, such as IL-6.

Some COVID-19 patients have been given drugs that push back against IL-6, but results have been mixed in clinical trials. Patients with markers of unregulated immune responses may be appropriate candidates for treatment with anti-inflammatory drugs that target the corresponding pathways, Sanz suggests.


Emory Health Sciences
Journal reference:

Woodruff, M.C.., et al. (2020) Extrafollicular B cell responses correlate with neutralizing antibodies and morbidity in COVID-19. Nature Immunology.
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Analysis of existing comorbidities and COVID-19 mortality

10/11/20 ... ality.aspx

As the COVID-19 pandemic continues to spread, and research related to potential risk factors for COVID-19 mortality continues, it is becoming clear that individuals with underlying comorbidities have a greater risk of death from COVID-19. The exact contribution of different comorbidities is unclear, however. Now, a new study published in the journal PLOS ONE dissects this topic and may help to quantify the risk posed by specific conditions and offer help with the prognosis.

Earlier Studies Yield Contradictory Results

With many different studies coming up, the contradictions multiply. While some say chronic disease increases the risk of COVID-19 and its severity, others disagree. The differences may arise because of the small number of studies, the variety of methods used, and the sources of bias. There is no doubt that the locales with the highest mortality rates are those regions with the highest prevalence of chronic illnesses.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters and infects human host cells using angiotensin-converting enzyme 2 (ACE2), an enzyme and receptor found in many tissues, such as the heart, kidney, and type II pneumocytes. Some researchers suggest that the use of angiotensin II type 1 receptor blockers (ARBs) may enhance the expression of ACE2 on the cell membranes and thus render the individual more susceptible to the infection and at a higher risk of developing progressive and severe disease. This would include people with hypertension and chronic cardiac failure who are being treated with ARBs.

Most studies carried out in this area so far have covered only certain countries, some of the research, and specific conditions. The presence of significant bias from various sources prevents their conclusions from gaining complete acceptance. To address this bias, the current study adopted a panoramic view of most major pre-existing chronic illnesses.

These include hypertension, cardiovascular disease, chronic kidney disease, chronic liver disease, cancer, asthma, chronic obstructive pulmonary disease, asthma, and HIV/AIDS. The researchers estimated the risk of dying from COVID-19-related conditions in individuals with these illnesses.

The researchers found 25 studies suitable for quantitative analysis, including ~65,500 patients. Almost four-fifths of the studies were from China. The median patient age was 61 years, and 57% of the patients were male. The study also had a median score of 7, indicating a reasonable quality standard.

Cardiovascular Disease and Mortality in COVID-19

In half the studies that reported this risk, there was a significant negative or positive association, with the estimated risk of mortality being anywhere from ~30% less to ~9 times higher than expected in an uninfected population. The pooling of the studies showed an overall doubling of the risk of death.

Other Chronic Illnesses and COVID-19 Mortality

The researchers showed that the risk of death was ~80% higher in patients with hypertension, 1.5 times higher in diabetics and cancer patients, doubled in those with congestive heart failure, and threefold in patients with chronic kidney disease. Other conditions were not linked to a higher risk of death in COVID-19.

Sources of Bias

The researchers suspect the presence of publication bias for some conditions, notably cerebrovascular disease, cancer, and hypertension, with these receiving more attention compared to others. However, even after adjustment for this, hypertension remains a risk factor for mortality, but not cancer.

The findings of various studies diverged significantly as to whether these conditions were or were not linked to a high risk of mortality. However, examining only those conditions which were implicated in more than 10 studies, they found that neither age nor male sex was associated with a higher risk.

The risk that any single study might have an undue influence on the risk estimate was also ruled out by removing them one by one from the meta-analysis, which failed to show any significant change in the pooled risk.

The researchers, therefore, concluded that the presence of pre-existing cardiovascular disease, hypertension, diabetes, congestive heart failure, chronic kidney disease, and cancer in patients with COVID-19 who are hospitalized confer a higher risk of death from the infection. This agrees with earlier studies showing that individuals with cardiovascular disease, chronic kidney disease, and cancer have a higher mortality risk with COVID-19.

However, the risk with cerebrovascular disease was not significantly raised, unlike the conclusion of an earlier study. This may be because of the larger size of the sample in this study, as well as the opportunity to use the data from recent studies.

Why this effect?

The researchers think these chronic illnesses may be related to a higher risk of mortality because the body’s functioning is already under stress from the pre-existing illness. The body’s endocrine system is in disarray and the sympathetic nervous system and immune system. Since these are responsible for homeostasis, chronic stress on them causes a slow and progressive wearing down of regulatory capability.

The eventual outcome of dysregulated metabolism is the build-up of pro-inflammatory cytokines, which triggers an abnormal immune response. This is widely held to be responsible for the severe complications that are called severe or critical COVID-19, as observed before with the flu, SARS, and MERS.

The study concludes that patients with COVID-19 with six specific pre-existing chronic conditions are at a greater risk of death from this disease compared to those who do not. This may indicate the role of sheltering such individuals and targeted treatment early in the course of infection, or preferential administration of a vaccine, for this high-risk group.

Implications for research and clinical practice

Renin-angiotensin-aldosterone system (RAAS) blockers are used by most patients with heart or vascular disease, hypertension, diabetes, chronic kidney disease, and congestive cardiac failure. These have not been found to increase the proportion of COVID-19 patients who die of the disease, even though experiments have shown that they may increase the levels of the host receptor molecule ACE2. Thus, these drugs remain an optimal choice for treating high blood pressure and other cardiovascular conditions, even with COVID-19.

The current study, therefore, shows the need to prioritize vaccinations when a vaccine becomes available, in order to reduce the mortality rate. This has been termed targeted vaccination and is a strategy supported by history, especially concerning the flu. Similar to this latter illness, SARS-CoV-2 may become a seasonal virus requiring annual vaccinations, predict some researchers.

Journal reference:

Ssentengo, P. et al. (2020). Association of Cardiovascular Disease And 10 Other Pre-Existing Comorbidities With COVID-19 Mortality: A Systematic Review and Meta-Analysis. PLOS ONE. ... ne.0238215
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Lab-Made ‘Miniproteins’ Could Block the Coronavirus from Infecting Cells

Synthetic peptides that mimic human antibodies for COVID-19 could be cheaper and easier to produce

10/12/20 ... ing-cells/

While the world waits for a COVID-19 vaccine, many researchers are focused on developing effective therapeutics that can be rolled out quickly and cheaply. Monoclonal antibodies—a potentially promising laboratory-manufactured therapy modeled on antibodies extracted from the blood of recovering patients—made headlines recently when President Trump received a not-yet-approved antibody cocktail made by the company Regeneron. And pharmaceutical giant Eli Lilly recently announced that its monoclonal antibody reduced the risk of hospitalization in 300 people who had mild or moderate symptoms of COVID-19, in a small clinical trial.

But David Baker, a biochemist at the University of Washington’s Institute for Protein Design, and his colleagues think they can produce an even better therapy. They have designed a synthetic peptide—a short string of amino acids, the building blocks of proteins—20 times smaller than a monoclonal antibody that is designed to bind to the infamous “spike” protein on the surface of the SARS-CoV-2 virus particle. Doing so would directly block the virus from binding to the ACE-2 receptors on human cells, functioning much like an antibody produced by an infected person’s immune system. Baker and his colleagues described these “miniprotein inhibitors” in September in Science. Although the study only tested these synthetic proteins in the lab, mixing viral particles with monkey cells in vitro, he says that unpublished data show they can protect mice and hamsters from SARS-CoV-2 infection.

“We built these [tiny proteins] from scratch based on ‘first principles,’ using computers to model all the biochemical details of a theoretical protein that could stick to the virus,” explains Baker, who was awarded a $3 million Breakthrough Prize earlier in September for his decades of work pioneering the field of synthetic protein design. His team used computers to digitally design more than two million candidate “miniproteins,” crunched the data using algorithms, sifted out 118,000 candidate genes that encode these proteins, manufactured the proteins from scratch, and tested them directly against the virus in the lab—finding that seven designs could effectively bind to and thus disable the virus.

Over the course of 3.5 billion years evolution has produced an incredible array of proteins and peptides. In recent years biochemists have tracked down and used some of these to create new drugs, such as Eptifibatide, an antiplatelet drug administered to prevent heart attacks whose active ingredient is extracted from the venom of the southern pygmy rattlesnake. The Protein Data Bank, an online repository of protein sequences and educational tools, contains the amino acid sequences and full 3-D structures for more than 160,000 peptides and proteins—but the natural world contains hundreds of millions of proteins.

“It’s very challenging to discover in nature a peptide that does exactly what you want it to do,” explains Gaurav Bhardwaj, also a biochemist at the Institute for Protein Design, but who was not involved in the Science study. He is trying to design a bespoke peptide that would prevent SARS-CoV-2 from replicating within human cells. “Now we can computationally explore the possible design configurations for a peptide in order to perform the exact functions that we want.”

Every protein’s function depends on its structure. Interactions between the atoms of the protein’s amino acids cause these chains to self-assemble in less than a second into a complex array of spirals and pleats. As the chain of amino acids grows, these helices and rippled sheets stack on top of and around one another into a dizzyingly complex series of folds, and it is these folds that give proteins their shape and function. Yet figuring out how one amino acid sequence turns into a specific fold has been a torturously difficult task, and it was only in the 1990s—with ever expanding databases of protein information—that scientists could begin to link sequence to form.

“We can make up completely new proteins that have never been seen in nature because we now understand the nature of protein folding,” Baker says. “Our ability to use computers to design ‘de novo’ proteins has really only come into its own in the last few years–we might not have been able to apply ourselves to COVID-19 if the pandemic had happened five years ago.”

Many organizations, including the Gates Foundation, the Open Philanthropy Foundation, and most recently, the committee of the Breakthrough Prize, have supported this work. Although monoclonal antibodies for SARS-CoV-2 are already in clinical trials, Baker says his miniprotein inhibitors have even greater potential to tackle the pandemic because they are 20 times smaller and thus would be cheaper to produce quickly and consistently.

Synthetic peptides show enormous potential to be scaled up at low cost to produce robust, bespoke treatments, says Sarel Fleishman of the Weizmann Institute of Science in Israel, who was not involved in the study. But they are still in uncharted territory, putting them at a disadvantage in the race for a cure, he says. “The major advantage of monoclonal antibody treatments is that they are completely ‘human,’ meaning they are already compatible with our immune systems. So they carry a lot less risk than synthetic proteins,” he says. Crossing regulatory hurdles will be a lot more straightforward with monoclonal antibodies, he says, because regulators will already understand what they are dealing with compared with a new and unproven technology.

Although synthetic peptides have enormous potential, we need to be cautious about being overly optimistic, adds biochemist Erik Procko of the University of Illinois, who worked as a postdoctoral researcher in Baker’s team, but was not part of this specific study. “The pharmacokinetics of miniproteins”—the ways the human body can metabolize, absorb and excrete them—“will be a barrier to their usefulness as drugs,” Procko says. “Eli Lily’s antibody drug persists in the body for a month; it will be challenging for a small designed miniprotein to match that stability in the blood.”

Baker acknowledges that both Fleishman and Procko are correct: “our miniproteins will have to go through the same scrutiny of clinical trials as monoclonal antibodies,” he says, “though it is worth noting that regulatory bodies like the FDA have vast experience with all sorts of drug and therapeutic modalities.”

Both Procko and Baker note that miniproteins will very likely need to be administered directly to the lungs by inhalation. Researchers at the University of California, San Francisco, have designed just such an aerosol formulation. The technology, called “AeroNabs,” would be administered by an inhaler or nasal spray. Roughly three times larger than Baker’s miniproteins, the U.C.S.F. ones are modeled on “nanobody” particles found in the immune systems of animals such as llamas, and function similarly: they bind to SARS-CoV-2’s “spike” protein and prevent it from fusing with the ACE-2 receptor on human cells.

“Monoclonal antibodies are unlikely to reach the airway spaces of the lungs when given as an injectable drug,” explains Aashish Manglik of U.C.S.F., part of the team that developed AeroNabs. He and his colleagues described their innovation in the preprint database bioRxiv in August. Only 2 percent of monoclonal antibodies injected into the bloodstream tend to reach the pulmonary spaces, the regions of the lungs through which the virus gains entry in most people—but a drug delivered via aerosol would be able to reach these air sacs, and thus could serve both as a therapeutic and a prophylactic, Manglik says. “We see this as being useful with patients who are in the early stages of infection, or with people at high risk of becoming infected, such as frontline and healthcare workers,” he says. “However, from a technical perspective, what Baker has been able to pull off—designing everything prospectively and not based on an existing structure in nature—is just phenomenal. It’s an exciting time in protein science.”

Beat Christen of the Institute of Molecular Systems Biology in Zurich, who was not involved in Baker’s or Manglik’s research, agrees it is an exciting time. “Synthetic biology is progressing very fast in developing vaccines and therapeutics—in a very short time frame we have seen many things pushed to the forefront, and the corporate world is reacting with many spinoffs and startups that have pivoted to this field,” he says.

With an increase in corporate interest, however, may come a decrease in public trust—as happened with genetically modified food two decades ago. The technology was largely seen as expensive and unnecessary, driven by corporate profit motives rather than public need. Synthetic peptides—many entirely “unnatural” and “never seen before on earth”—risk falling into the same trap.

“But with COVID-19, there is a clear, huge challenge facing humanity,” Christen says, “and if synthetic biology can contribute with new solutions and new therapies, people will easily see the need for it.”
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