October 2, 2020 | Case fatality rates among minorities questioned, vitamin D matters, ECMO saving lives, concerning genetic mutations, rise in anti-Asian racism, older adults excluded from trials, treatment potential of diabetes drug, rise in alcohol consumption, risks to mental health and men’s testosterone level, scary changes in care-seeking behavior, antibodies not eternal, pre-existing immunity may be widespread, younger cohorts dying in India, mostly men calling the shots, and delirium a key symptom among the elderly. Plus, a wealth of industry news that includes trials targeting nursing homes, launch of an eight-state patient data registry and an app to quantify mask-wearing behavior.

Research Updates

In a cross-sectional study of 2,595 consecutive adults tested for COVID-19 from March 12 to March 31, 2020 at Froedtert Health and Medical College of Wisconsin (Milwaukee), COVID-19 positivity was associated with Black race. Among patients with COVID-19, both race and poverty were associated with higher risk of hospitalization, but only poverty was associated with higher risk of intensive care unit admission. Results appeared in JAMA Network Open. DOI: 10.1001/jamanetworkopen.2020.21892

In a separate cohort study of 5,902 patients diagnosed with COVID-19 between March 14 and April 15, 2020, also appearing in JAMA Network Open, researchers from Montefiore Medical Center and Albert Einstein College of Medicine (Bronx, New York) found that non-Hispanic Black and Hispanic patients did not experience worse risk-adjusted survival outcomes compared with their White counterparts. This differs with observed population differences in mortality by race/ethnicity reported elsewhere, which the authors say may derive from differential testing for COVID-19 in their sample. Case fatality rates may be inflated if non-Hispanic Black and Hispanic patients are only tested when they show severe symptoms relative to White patients whose access to care permits a broader testing strategy. The association of comorbidities with mortality differed across race/ethnicity categories in this study. DOI: 10.1001/jamanetworkopen.2020.19795

Hospitalized COVID-19 patients who were vitamin D sufficient (blood level of 25-hydroxyvitamin D of at least 30 ng/mL) had a significant decreased risk for adverse clinical outcomes including becoming unconscious, hypoxia, and death, according to a study by researchers at Boston University School of Medicine that published in PLOS ONE. In addition, they had lower blood levels of an inflammatory marker (C-reactive protein) and higher blood levels of lymphocytes that help fight infection. The study involved 235 patients admitted to the hospital with COVID-19. Patients older than 40 years who were vitamin D sufficient were 51.5% less likely to die from the infection compared to patients who were vitamin D deficient or insufficient. DOI: 10.1371/journal.pone.0239799

The first nationally representative estimate of COVID-19 seroprevalence in the U.S. suggests few patients on dialysis developed SARS-CoV-2 antibodies in the first wave, finds a study by researchers from Stanford University and Ascend Clinical Laboratories that published in The Lancet. The cross-sectional analysis of more than 28,000 U.S. patients receiving dialysis finds fewer than 10% had COVID-19 antibodies by July 2020, and fewer than 10% of those with antibodies had been diagnosed by antigen or PCR testing. The study additionally shows higher COVID-19 infection rates among ethnic minorities and people living in lower-income, high-density, urban areas—underlining the need for COVID-19 public health efforts that prioritize these populations in order to prevent general community spread. Accounting for the externally validated test sensitivity, seroprevalence ranged from 8.2% to 9.4% in the sampled population compared to approximately 9.3% in the general population, with significant regional variation ranging from less than 5% in the western U.S. to greater than 25% in the northeast. By comparing seroprevalence data from their study with case counts per 100,000 population from Johns Hopkins University, researchers estimated that 9.2% of seropositive patients were diagnosed. The authors say their representative population is ideal for studying the general spread of COVID-19 in the U.S. because these patients undergo monthly, routine blood draws and represent other similar COVID-19 risk factors such as age, non-white race, and poverty. Renal disease is also a Medicare-qualifying condition, so patients don't face many of the access-to-care barriers that limit testing among the general population. DOI: 10.1016/S0140-6736(20)32009-2

Also newly appearing in The Lancet are results from an international study that suggest extracorporeal membrane oxygenation (ECMO) is saving the life of many critically ill COVID-19 patients. Among 1,035 patients in the study facing a staggeringly high risk of death (ventilators and other care failed to support their lungs), the actual death rate was less than 40% after they were placed on ECMO. That's similar to the rate for patients treated with ECMO in past outbreaks of lung-damaging viruses, and other severe forms of viral pneumonia. The study was made possible by a rapidly created international registry that has given critical care experts near real-time data on the use of ECMO in COVID-19 patients since early in the year. Data submitted by 213 hospitals on four continents is included in the registry. The study could help identify which patients will benefit most if they are placed on ECMO, based on findings that mortality risk rises significantly with patient age and that those who are immunocompromised, have acute kidney injuries, worse ventilator outcomes or COVID-19-related cardiac arrests are less likely to survive. The study used a “competing risk” approach based on in-hospital mortality (the highest-risk period) up to 90 days after the patient was put on ECMO. More than half of the patients in the study were treated in hospitals in the U.S. and Canada. Patients in the study were started on ECMO between Jan. 16 and May 1; as of Aug. 5, 380 of them had died in the hospital, most within 24 hours of a proactive decision to discontinue ECMO care because of a poor prognosis. Of the remaining patients, 57% had gone home or to a rehabilitation center (311 patients) or had been discharged to another hospital or a long-term acute care center (277 patients). The rest were still in the hospital. DOI: 10.1016/S0140-6736(20)32008-0

Preliminary evidence suggests that children have a lower susceptibility to SARS-CoV-2 infection compared with adults, but the role that children and adolescents play in transmission of this virus remains unclear, according to a systematic review and meta-analysis of 32 studies by an international team of researchers that published in JAMA Pediatrics. Children and adolescents younger than 20 years had 44% lower odds of secondary infection with SARS-CoV-2 compared with adults 20 years and older; this finding was most marked in those younger than 10 to 14 years. Data were insufficient to conclude whether transmission of SARS-CoV-2 by children is lower than by adults. DOI: 10.1001/jamapediatrics.2020.4573

More than 10% of young and healthy people who develop severe COVID-19 have misguided antibodies that attack not the virus, but the immune system itself, and at least another 3.5% percent carry a specific kind of genetic mutation. In both groups, the upshot is basically the same: The patients lack type I interferon, a set of 17 proteins crucial for protecting cells and the body from viruses. Those were the findings of a pair of papers, published in Science, which could help explain why some people develop a more severe course of the disease than others in their age group as well as provide the first molecular explanation for why more men than women die from COVID-19. At least in theory, such interferon problems could be treated with existing medications and interventions. The findings are the first results being published out of the COVID Human Genetic Effort, an ongoing international project spanning over 50 sequencing hubs and hundreds of hospitals around the world, co-led by researchers at The Rockefeller University and the National Institute of Allergy and Infectious Diseases. In one study, researchers genetically analyzed blood samples from more than 650 patients who had been hospitalized for life-threatening pneumonia due to SARS-CoV-2, 14% of whom had died, as well as samples from another group of over 530 people with asymptomatic or benign infection. A significant number of people with severe disease carried rare variants in the 13 genes governing type 1 interferons, and more than 3% of them were in fact missing a functioning gene. Further experiments showed that immune cells from these patients did not produce any detectable type I interferons in response to SARS-CoV-2. The team then examined 987 patients with life-threatening COVID-19 pneumonia and found that more than one in 10 had autoantibodies against interferons at the onset of their infection and most of them (95%) were men. These autoantibodies seem to be rare in the general population (only four out of 1,227 randomly selected healthy people were found to have them). DOI:10.1126/science.abd4570 and DOI: 10.1126/science.abd4585

Tel Aviv University researchers have found that carriers of the genetic mutations PiZ and PiS appear to be at high risk for severe illness and even death from COVID-19. These mutations lead to deficiency in the alpha1-antitrypsin protein, which protects lung tissues from damage in case of severe infections. Previous studies have associated deficiency in this protein with inflammatory damage to lung function in other diseases. Findings were based on an analysis of data from 67 countries on all continents, and a highly significant positive correlation between the prevalence of the two mutations in the population and COVID-19 mortality rates was seen in many countries, including the U.S., U.K., Belgium, Spain and Italy. Conversely, in many countries in Africa and South East Asia as well as in Japan, Korea, Taiwan, Thailand, Vietnam and Cambodia where these mutations are relatively rare, COVID-19 mortality rates have been correspondingly low.  The authors propose that their findings be corroborated by clinical trials and, if validated, should lead to population-wide screening for detecting mutation carriers and prioritizing them for vaccination once COVID-19 vaccines have been approved. Results published in the FASEB Journal. DOI: 10.1096/fj.202002097

Black, South Asian and Aboriginal populations from disadvantaged socioeconomic backgrounds in Canada are nearly four times more likely to have three or more medical conditions that have been identified as risk factors for severe illness from COVID-19, finds a study by a University of Toronto researcher that published in The Gerontologist. The study compared 1,102 racialized immigrants and 338 Aboriginal Canadians with 23,802 Canadian-born Whites, aged 45 and older, using population-based data from the baseline Canadian Longitudinal Study on Aging (2012-2015). Nine medical conditions were examined: diabetes, asthma, cancer, previous heart attack or myocardial infarction, kidney disease, cardiovascular disease, hypertension, chronic obstructive pulmonary disease and obesity. The multimorbidity differences associated with these populations were enhanced for older adults (aged 66 to 85) compared to their middle-aged counterparts (aged 45-65). Additional identified risk factors included being male, experiencing chronic pain, having a physical impairment, living without partners, and a lifetime of smoking. DOI: 10.1093/geront/gnaa143

A pandemic-driven rise in anti-Asian racism has become so pronounced that it was described as a “secondary contagion” threatening this population in a commentary published by experts at Massachusetts General Hospital and Brigham and Women’s Hospital in the American Journal of Public Health. In the U.S., Asians of all ethnicities have been scapegoated, verbally attacked with racial slurs, coughed at, spat on, and physically assaulted, they report. The authors provide an overview of the history of anti-Asian discrimination in this country, reviewing associations between discrimination and health, describing the associated public health implications of the COVID-19 pandemic, and reviewing evidence from previous disasters in U.S. history that were "racialized." Asian Americans are projected to become the largest immigrant group in the U.S. by 2055. The website Stop AAPI Hate that tracks attacks against Asian Americans received 1,135 reports nationwide within two weeks of launching in March 2020. DOI: 10.2105/AJPH.2020.305858

Members of the National Institutes of Health COVID-19 Treatment Guidelines Panel provide their views regarding the use of convalescent plasma for treating COVID-19 and explain why the currently available data are insufficient for them to recommend for or against it. Adequately powered randomized controlled trials (RCTs) of convalescent plasma in the U.S. have been slow to enroll patients. Retrospective, indirect evaluations of the efficacy of convalescent plasma by the FDA and the Mayo Clinic using Expanded Access Program data were sufficient to meet the “may be effective” criterion for Emergency Use Authorization issuance, but not to establish its efficacy or safety because of the lack of an untreated control group. The authors point to two trials—Adaptive COVID-19 Treatment Trial (ACTT) and Randomized Evaluation of COVID-19 Therapy (RECOVERY), which demonstrated the efficacy of remdesivir and dexamethasone, respectively—as evidence that well-controlled, adequately powered RCTs are possible. Their analysis published in Annals of Internal Medicine. DOI: 10.7326/M20-6448

People with bone, joint and muscle pain saw their symptoms worsen during lockdown, according to research at the University of East Anglia (U.K.). Those who experienced the most social isolation and loneliness were also less likely to access healthcare. Findings were based on an online survey in late April of 678 patients across the country with a range of musculoskeletal diseases, just over 53% of whom reported worsened symptoms. One-third of patients reported needing to access either their general practitioner or hospital rheumatology department, and 44% said they needed assistance to access medications. Results appeared in Rheumatology Advances in Practice. DOI: 10.1093/rap/rkaa047

Among 54 COVID-19 patients hospitalized at Beaumont Health (Royal Oak, Michigan) there was a 100% mortality rate following cardiopulmonary resuscitation (CPR) for cardiac arrest, according to a study that published in JAMA Open Network. The high mortality, which has also been reported elsewhere, is likely multifactorial in this population and warrants further investigation given that CPR generates aerosols that may place healthcare personnel at a higher risk of contracting the virus. DOI: 10.1001/jamainternmed.2020.4796

Older adults are likely to be excluded from more than 50% of COVID-19 clinical trials and 100% of vaccine trials, limiting the ability to evaluate the efficacy, dosage, and adverse effects of the intended treatments. That’s the conclusion of researchers after reviewing 847 COVID-19 trials posted on ClinicalTrials.gov. Even without stated age-based exclusions, several recently published clinical trials of COVID-19 treatments had no or few participants over age 75. Broad, non-specified exclusions (vaccine trials) and exclusions preferentially affecting older adults (treatment trials) were major factors. It is imperative that older adults be included in vaccine trials because of the high level of immunity (67%) needed to achieve herd immunity and the fact that many settings such as nursing homes are comprised nearly exclusively of older adults. Study results appeared in JAMA Internal Medicine. DOI: 10.1001/jamainternmed.2020.5084

Findings of a multicenter observational study in Italy, led by an investigator at Boston Children's Hospital, suggest that sitagliptin, a drug to lower blood sugar in type 2 diabetes, also improves survival in diabetic patients hospitalized with COVID-19. Patients given sitagliptin in addition to insulin had a mortality rate of 18%, compared to 37% in matched patients receiving only insulin. Patients treated with sitagliptin were less likely to need mechanical ventilation, intensive care and have an increase in their clinical severity score and more likely to have at least a 2-point drop on a 7-point scale of disease severity. The study, which published in Diabetes Care, involved 338 patients at seven Italian hospitals during the first surge of COVID cases last spring. Results have sparked a new randomized, placebo-controlled trial of sitagliptin that is preparing to enroll patients in Europe. The drug lowers blood sugar by blocking the receptor for the enzyme DPP-4 (aka CD26), causing an increase in insulin production. Recent studies suggest that DPP-4 may also help SARS-CoV-2 get into respiratory cells. Sitagliptin additionally has anti-inflammatory effects, reducing the production of the cytokine IL-6 that contributes to the cytokine storm that can cause organ complications in COVID-19. Its third potential benefit is keeping blood sugar down; previous studies have shown that diabetic patients with worse glycemic control have worse COVID-19 outcomes. DOI: 10.2337/dc20-1521

A survey conducted by researchers at the University of Minnesota School of Public Health and completed by 1,007 adults conducted who are members of AmeriSpeak—a probability-based panel designed to be representative of the U.S. household population—indicates a high willingness to allocate a SARS-CoV-2 vaccine preferentially to front-line medical workers (91.6%), high-risk children (81%), and high-risk older adults (80.6%). Respondents also reported priority for middle-aged people with higher risk (75.2%) and for essential nonmedical workers (72%); fewer reported high priority for pregnant people (64%). While respondents ranked people with moderate mortality risk the lowest, they were more likely to give higher priority to children than adults (39.2% vs. 29%). Respondents’ age, race and ethnicity, and self-reported health status impacted ratings in different ways. Overall, the study found that preferences were consistent with experts’ emergent recommendations for priority populations for vaccination, suggesting the public would support guidelines that offer vaccine priority to groups defined by age, risk of dying, and employment type. Findings appeared in JAMA Open Network. DOI: 10.1001/jamanetworkopen.2020.23020

A RAND Corporation study finds American adults have sharply increased their consumption of alcohol during the shutdown triggered by the coronavirus pandemic, with women increasing their heavy drinking episodes (four or more drinks within a couple of hours) by 41%. Based on a national survey conducted in the spring of 2020 and completed by 1,540 adults who are members of the RAND American Life Panel—a nationally representative internet panel—the overall frequency of alcohol consumption increased by 14% among adults over age 30, compared to the same time last year. The increase was 19% among all adults aged 30 to 59, 17% among women and 10% among for non-Hispanic White adults. The results published in JAMA Network Open. DOI: 10.1001/jamanetworkopen.2020.22942

Mucosa-associated invariant T (MAIT) cells, which account for a small fraction of T cells in the blood of healthy people, are strongly activated in people with moderate to severe COVID-19 disease, according to a study by researchers at Karolinska Institute (Sweden) that published in Science Immunology. MIAT cells are primarily important for controlling bacteria but can also be recruited by the immune system to fight some viral infections. Study results indicate that the number of MAIT cells in the blood of 24 patients with moderate to severe COVID-19 disease sharply decline and the remaining cells in circulation are highly activated—suggesting they are engaged in the immune response against SARS-CoV-2. Pro-inflammatory MAIT cells also accumulated in the airways of COVID-19 patients to a larger degree than in healthy people (14 individuals), which partly explains the reduced number of MAIT cells in their blood. In convalescent patients (45 individuals), the number of MAIT cells in the blood recovered at least partially in the weeks after disease and, among four patients who had died, the MAIT cells tended to be extremely activated with lower expression of the receptor CXCR3 than in those who survived. DOI: 10.1126/sciimmunol.abe1670

A study published in The Aging Male suggests that COVID-19 might deteriorate men's testosterone levels. Researchers from the University of Mersin and the Mersin City Education and Research Hospital (Turkey) found that as men's testosterone level at baseline decreases, the probability for them to be in the intensive care unit (ICU) significantly increases. Over half of the 232 males with laboratory-confirmed SARS-CoV-2 were found to have below-normal testosterone levels and, even among the 46 asymptomatic patients, about 65% had a loss of libido. This could help explain why the prognosis for men is worse than for women and possible improvement in clinical outcomes using testosterone-based treatments. Testosterone is associated with the immune system of respiratory organs and low levels have been associated with infection-related hospitalizations and all-cause mortality in males in the ICU. DOI: 10.1080/13685538.2020.1807930

Long after a COVID-19 vaccination is developed and the coronavirus death toll is tallied, the impact on mental health will continue to inflict damage if not addressed, according to University of Houston researchers in a paper published in Psychiatry Research. The impact of COVID-19 on psychological symptoms and disorders, addiction and health behavior are substantial, they write, and will put people at greater risk for chronic illness and drug addiction. Those who have mental health vulnerabilities or disorders will be disproportionately affected. Their study finds that worry and fear about the pandemic may be risk factors for substance use initiation (worry is specifically related to using substances to cope during the pandemic) and psychological factors may require specific clinical attention. DOI: 10.1016/j.psychres.2020.113407

A major study in Heart has identified 2,085 excess deaths in England and Wales due to heart disease and stroke during the peak of the COVID-19 pandemic—an average of 17 deaths per day over four months that probably could have been prevented. The scientists, led by academics at the University of Leeds, believe the excess deaths were caused by people not seeking emergency hospital treatment for a heart attack or other acute cardiovascular illness requiring urgent medical attention, either because they were afraid of contracting COVID-19 or were not referred for treatment. Findings were based on an analysis of information contained on death certificates. Between March 2 and June 30, 2020, there were 28,969 cardiovascular deaths, 8% higher than the average number of deaths seen for the same period over each of the previous six years. Proportionately fewer deaths happened in hospital (53.4% vs. 63%) and more happened at home (30.9% vs. 23.5%) and care homes: (15.7% vs 13.5%). Excess deaths were also disproportionately happening at home and in care homes. DOI: 10.1136/heartjnl-2020-317912

Researchers from the Perelman School of Medicine at the University of Pennsylvania found no difference in COVID-19 infection rates among healthcare workers who took a daily regimen of hydroxychloroquine versus those taking a placebo. Infection levels were low among the participants, which they believe points to the effectiveness of other prevention measures in the health system. The study, the first randomized trial of hydroxychloroquine's prophylactic effect for those not yet exposed to COVID-19, published in JAMA Internal Medicine. Roughly half of the 125 participants received a substantial dose of hydroxychloroquine—600 milligrams daily for two months. At the end of the study, 6.3% of those who took the hydroxychloroquine had tested positive for COVID-19 while 6.6% of those who took the placebos were positive. None required hospitalization. Additionally, there was no difference detected in the heart rhythms between those in either arm of the study. DOI: 10.1001/jamainternmed.2020.6319

In patients with symptomatic severe aortic stenosis, deferral of aortic valve replacement (AVR) due to COVID-19 was associated with an increased risk of hospitalization for valve-related symptoms or worsening heart failure, according to cardiologists at Bern University Hospital (Switzerland) in a research letter that published in JAMA Open Network. An additional finding is that patients with symptomatic severe aortic stenosis in combination with relevant multivalvular disease may particularly benefit from expedited AVR. A total of 71 patients were enrolled in the study between March 20 and April 26, 2020, 25 of whom were allocated to expedited AVR and 46 patients who were allocated to deferred AVR, according to a prespecified algorithm that is similar to the triage recommendation from the American College of Cardiology and Society for Cardiovascular Angiography & Interventions consensus statement. DOI: 10.1001/jamanetworkopen.2020.20402

Cardiologists affiliated with the Icahn School of Medicine at Mount Sinai in New York separately write in a JAMA Open Network research letter that vigilance is needed during the pandemic for patients with aortic stenosis (AS) awaiting transcatheter aortic valve replacement (TAVR) because 10% of their patients experienced a cardiac event during the first month, and 35% did so over the course

of the next three months. The decision to intervene needs to consider the additional risks for both patients and the heart team, they say, and required interventions should resume after the initial peak of COVID-19 hospitalizations has passed and healthcare resources become available. This was a single-center cohort study of 77 patients with severe AS undergoing evaluation for TAVR before the COVID-19 pandemic.  DOI: 10.1001/jamanetworkopen.2020.19801

Patients with a prior psychiatric diagnosis while hospitalized for COVID-19 had a higher mortality rate compared those without a psychiatric condition and it is unclear why, according to researchers at Yale University School of Medicine in JAMA Open Network. Previous studies have similarly found that individuals with concurrent psychiatric and medical diagnoses have poorer outcomes and higher mortality. Possibly, psychiatric symptoms arise as a marker of systemic pathophysiologic processes, such as inflammation, which in turn predispose to mortality. They may also augment systemic inflammation and compromise the function of the immune system. This study enrolled 1,685 patients hospitalized with COVID-19 at the five-hospital Yale New Haven Health System between Feb. 15 and April 25, 2020, 473 (28%) of whom received psychiatric diagnoses prior to hospitalization. Patients with psychiatric diagnoses were significantly older and more likely to be female, white, and non-Hispanic and have medical comorbidities. Their two-weekly were also more likely to die (two-week mortality of 35.7% vs. 14.7%; three-week mortality of 40.9% vs. 22.2%, and four-week mortality of 44.8% vs. 31. 5%). DOI: 10.1001/jamanetworkopen.2020.23282

New research suggests that the earlier plasma is collected after the donor's recovery from COVID-19, the better, as antibodies start to disappear after three months of symptom onset. The results may also have implications for vaccine design and for prevalence studies in communities trying to gauge how many people have recovered from the virus, say the study’s authors from Héma-Québec blood center (Canada). Findings appeared in Blood. The small study followed 15 adult plasma donors who were diagnosed with and subsequently recovered from COVID-19. While symptoms ranged from mild to severe, none of the donors were hospitalized for their COVID-19 infection. Participants each donated their plasma between four and nine times with the first donation occurring between 33 and 77 days after symptom onset and the last donation between 66 and 114 days. The decline in antibodies over time appears unrelated to the number of times someone donated blood plasma. All 15 donors showed decreases in antibodies at the same time, around 88 days, and half of the detectable antibodies decreased within 21 days afterward. The research team focused on antibodies to one target for the virus—the receptor binding domain. DOI: 10.1182/blood.2020008367

In a Policy Forum that published in Science, legal experts argue that current interpretations of the General Data Protection Regulation (GDPR) overly limit data sharing outside of the EU, which has hampered global biomedical research—including essential efforts to address COVID-19. They propose amendments for consideration by the EU Commission in its upcoming review of GDPR and urge the European Data Protection Board, the GDPR's governing body, to reevaluate recent guidance on COVID-19 related research. The existing GDPR approach fails to recognize that personal data is typically used in biomedical research to derive generalized knowledge that benefits society and is applied in ways that pose negligible privacy risks to data subjects, unlike commercial and marketing endeavors that seek to create profiles of individuals and their behaviors. DOI: 10.1126/science.abd2499

Research by infectious disease experts at the University of Rochester Medical Center suggests that past colds may provide some protection from COVID-19. In fact, immunity to COVID-19 is likely to last a long time—maybe even a lifetime. Their study, published in mBio, is the first to show that SARS-CoV-2 induces memory B cells to create antibodies to destroy the viral pathogen and remember it in the future, clearing infection before it starts. The study is also the first to report cross-reactivity of memory B cells, which could mean that anyone who has been infected by a common coronavirus—which is nearly everyone—may have some degree of pre-existing immunity to COVID-19. Findings are based on a comparison of blood samples from 26 people who were recovering from mild to moderate COVID-19 and 21 healthy donors whose samples were collected six to 10 years ago, specifically levels of memory B cells and antibodies that target specific parts of the spike protein (S2 subunits) common to all coronaviruses. DOI: 10.1128/mBio.01991-20

In Molecular Frontiers Journal, researchers from the Boston-based technology startup Sensory Cloud report on their discovery of a more effective way to eliminate airborne particles from the airways using nasal calcium-rich salts called FEND, which have potential applications in the fight against COVID-19. Lead authors of the paper hail from Harvard University and Massachusetts Institute of Technology. Ninety-two men, women and children were observed in separate studies showcasing the use of FEND in the workplace, quarantining at home, and in comparison to cloth face masks. Results showed a reduction of exhaled aerosol particles of up to 99%, with an overall reduction of exhaled particles in the largest cohort of human subjects (76 workers) of around 75%, suggesting a nasal filter to protect at-risk populations from viral carrying aerosols is possible. DOI: 10.1142/S2529732520400040

Cardiac arrest is common in critically ill patients with COVID-19 and is associated with poor survival, particularly among patients aged 80 or older, finds a study published by The BMJ that could help guide end-of-life care discussions. Results are based on data for 5,019 critically ill patients (aged 18 years or over) with COVID-19 admitted to ICUs at 68 hospitals across the U.S. Overall, 14% had in-hospital cardiac arrest within 14 days of ICU admission, of whom only 57% received CPR. Patients who had in-hospital cardiac arrest were older, had more comorbidities, and were more likely to be admitted to a hospital with fewer ICU beds. Importantly, this suggests that hospital resources, staffing, expertise, strain, or other factors not captured in the study could have had a major impact. Among patients who received CPR, who were younger than those who did not, only 12% survived to hospital discharge and 7% did so with normal or mildly impaired neurological status. DOI: 10.1136/bmj.m3513

In Tamil Nadu and Andhra Pradesh—two states in India that account for 10% of the country’s population—COVID-19 cases and deaths have been more heavily concentrated in younger cohorts than is seen in high-income countries, researchers report in Science. Results are based on surveillance and contact tracing data; epidemiological data and laboratory test results were available from 575,071 tested contacts of 84,965 confirmed cases. The findings may indicate the identification of less-severe infections through active case-finding, they say. Same-age contacts were associated with the greatest infection risk, a pattern strongest among children ages 0-14 years and among adults older than 65 years. Case-fatality ratios spanned 0.05% at ages 5-17 years to 16.6% at ages exceeding 85. The authors note that estimates of time-to-death in both states is rapid compared to what has been observed internationally. The most prevalent conditions among those who died were diabetes, sustained hypertension, coronary artery disease, and renal disease, with at least one comorbid condition noted among 62.5% of fatalities versus 22% of fatalities in the U.S. Only 17.9% of COVID-19 deaths occurring on or before Aug. 1, 2020 were among people older than 75, compared with 58.1% of COVID-19 deaths in the U.S. DOI: 10.1126/science.abd7672

Findings of a phase 1 trial of the investigational mRNA-1273 vaccine to prevent SARS-CoV-2 infection, described in the New England Journal of Medicine, show the vaccine is well tolerated and generates a strong immune response in older adults. The vaccine was co-developed by researchers at the National Institute of Allergy and Infectious Diseases (NIAID) and Moderna. The trial, initiated on March 16, was conducted at Kaiser Permanente Washington Health Research Institute (Seattle), Emory University (Atlanta), and NIAID’s Vaccine Research Center clinic at the NIH Clinical Center (Bethesda). In its expansion in April to include older adults, the trial enrolled 40 healthy volunteers—20 ages 56 to 70 years, and 20 ages 71 years and older. Ten volunteers in each age group received a lower dose of the vaccine (25 µg), and 10 volunteers in each age group received a higher dose (100 µg). After approximately one month, volunteers then received a second dose of the same vaccine at the same dosage. The blood of vaccinated volunteers exhibited a good immune response with robust binding and neutralizing antibodies against SARS-CoV-2, comparable to that seen in younger age groups. The study will continue to follow the older volunteers for approximately a year to monitor the long-term effects of the vaccine. The phase 1 trial results further support testing of the investigational vaccine in older adults in a large ongoing phase 3 trial. DOI: 10.1056/NEJMoa2028436

Men predominate in more than 85% of COVID-19 decision-making and key advisory bodies globally, a “disturbingly accepted pattern" of health governance that ultimately costs lives, warn authors in an article appearing in BMJ Global Health. They collected information through June 2020 on the membership, leadership and areas of expertise of COVID-19 global and national decision-making and expert bodies for 193 UN Member States, which they note was neither easily accessible nor publicly available. Their analysis included 115 COVID-19 expert groups and task forces from 87 countries, among which 11.5% were predominantly comprised of women and 3.5% had gender parity. Expert groups more often had higher proportions of women or gender parity than decision-making committees, most likely a reflection of potential societal biases and gender stereotyping around leadership, they say. Women have been hit harder than men socially and economically by COVID-19 as a result of extended and unpaid caring responsibilities, heightened risk of domestic and sexual violence, and loss of access to maternal and reproductive health services during lockdown. They propose a new “default” mode of diverse and intersectional governance. DOI: 10.1136/bmjgh-2020-003549

The COVID-19 pandemic has created a flood of potentially substandard research amid the rush to publish, with a string of papers retracted or under a cloud and a surge in submissions to pre-print servers where fewer quality checks are made, a leading ethicist from Bond University (Australia) has warned in the Journal of Medical Ethics. As of May 7, 2020, 1,221 studies on COVID-19 were registered on the international clinical trial registry site, ClinicalTrials.gov, and as of July 31, 2020, 19 published articles and 14 preprints about COVID-19 have been retracted, withdrawn, or had serious doubts raised about the integrity of their data. Most of these papers came from Asia (57.5%), with over half coming from China (58%). The reason for known in three of the 33 cases that have come under scrutiny—unverifiable data (common across publications) and undisclosed conflict of interest. The authors also offer suggestions for remedying the situation. DOI: 10.1136/medethics-2020-106494

Researchers at King's College London have analyzed data from the COVID Symptom Study app (535 users reporting a positive test result), and 322 COVID-positive patients aged 65 or over admitted to St Thomas' Hospital in London to show delirium is a key symptom of COVID-19 in frail, older people. The older hospitalized adults classified as frail (per Clinical Frailty Scale, or CFS) were more likely to have had delirium as one of their symptoms than people of the same age who were not classed as frail. Delirium, along with tiredness and breathlessness, were also more common among frailer users (per questionnaire based on the CFS) of the COVID Symptom Study app compared with fitter people of the same age. One-third of app users experiencing delirium did not report suffering classic COVID-19 symptoms, while delirium was the only symptom for around one in five of the hospitalized patients. Findings published in Age and Ageing. DOI: 10.1093/ageing/afaa223

Patients with human immunodeficiency virus (HIV) are not only susceptible to COVID-19, but certain factors increase their risk of hospitalization and death, researchers report in Clinical Infectious Diseases. They analyzed data on 286 adult patients with HIV who were diagnosed with COVID-19 across 36 institutions in 21 states. Within 30 days of COVID-19 diagnosis, 57% of the patients required hospitalization, 16% required ICU admission and 9% did not survive. Notably, more than 94% of patients were actively taking HIV medication. Clinical trials are testing whether medications that treat HIV can also treat COVID-19, leading some patients with HIV wrongly believe they might be protected against the coronavirus. The study also found that patients with low immunity uncontrolled HIV or newly diagnosed HIV are at a higher risk of hospitalization or death, as are people with HIV older than 60 and those with chronic health issues. DOI: 10.1093/cid/ciaa1339

In a study focused on the unborn children of pregnant women with COVID-19, and the factors affecting their outcomes, an international team of researchers observed miscarriage, stillbirth or death within the first 28 days after birth. The rate of child mortality among the pregnancies was approximately 4%, mainly related to premature births. The incidence of poor fetal outcomes was significantly higher when COVID-19 infection occurred in the first three months of pregnancy, children had lower birth weight, and when mothers were so ill that they required oxygen treatment. Strikingly, only one baby in the study tested positive for the disease and was asymptomatic, suggesting that transmission from mother to baby is very rare. Findings were based on 388 pregnancies in 22 different countries, making it the largest study of pregnant mothers with COVID-19 published to date. The study appeared in the Journal of Perinatal Medicine. DOI: 10.1515/jpm-2020-0355

Industry Updates

The C.S. Mott Children's Hospital National Poll on Children's Health at Michigan Medicine (University of Michigan) reveals that one-third of parents plan to skip flu shots for their kids during COVID-19 pandemic—most commonly because of concerns about side effects or beliefs that it isn't necessary or effective—while an equal proportion believe it’s more important for children to get vaccinated this year. Intentions to vaccine align with whether they had their kids vaccinated last year. Less than half of the parents say their child's regular healthcare provider strongly recommends vaccination this year (possibly due to fewer in-person visits), which correlates with their likelihood to do so. The findings heighten concerns about how the onset of flu season may compound challenges in managing COVID-19. Influenza has led to between 9 to 45 million illnesses, 140,000 to 810,000 hospitalizations and 12,000 to 61,000 deaths a year since 2010, according to estimates by the Centers for Disease Control and Prevention (CDC). During the 2019-2020 flu season, the CDC reported 188 pediatric flu deaths. The Mott Poll report includes 1,992 responses from parents of children age 2-18 years who were surveyed in August. Press release.

Among many research abstracts presented at the recent ESCMID (European Society of Clinical Microbiology and Infectious Diseases) Conference (ECCVID) on Coronavirus Diseases was one suggesting that the higher risk of poor COVID-19 outcomes in men could be explained by differences in circulating proteins and immune system cells compared with women, and that immune mediators that contribute to a more severe infection are already intrinsically higher in males. Press release. Another study abstract presented at ECCVID indicated that around half of roughly 3,000 frontline responders (police, fire and healthcare workers) in the U.K. with self-reported symptoms of COVID-19 did not test positive for antibodies to the disease and therefore probably did not have the disease. Press release. A third study abstract showed that the severe COVID-19 immunological profile, represented by changes in cell populations and 28 circulating inflammatory proteins, is already partly present in older healthy individuals. That study looked at two cohorts of healthy Western European individuals, 776 in all ranging in age from 18 to 75. Press release. A fourth abstract shows emergence of SARS-CoV-2 was associated with a large drop in circulation of other common respiratory viruses during the first wave. Press release. A fifth found that a shorter time from symptom onset to hospitalization is associated with more serious disease and death in patients with COVID-19. Press release.

Russia biotechnology company BIOCAD has announced that it will mass produce the two-component Sputnik V vaccine developed by the Gamalei Institute, allowing scientists to complete the third stage of clinical trials that will involve many volunteers in and outside the country. In addition to the production of the liquid vaccine, the partners are planning to organize the production of a lyophilized (powder form) version of vaccine. Dry vaccine does not require special storage conditions during transportation, which is the main advantage. With last month’s launch of a high-tech production complex in Zelenograd, BIOCAD now has nine of the newest manufacturing plants in Russia, four of which are in or near Moscow. This is the company’s fourth vaccine development project. Press release.

In Sweden, SciLifeLab (one of the largest molecular biology research laboratories in Europe) and the Visualization Center (research and science center) are collaborating to set up an interactive exhibition about COVID-19. The project is designed to facilitate communication about complex data to the public in an attractive and educational fashion using interactive multi-touch display tables and 3D technology of Interspectral AB. The visualization combines four different types of research datasets on COVID-19: the SARS-CoV-2 virus architecture, the atomic structure of the spike protein, influenced human lungs, and global aspects of the pandemic. Press release.

West Virginia University (WVU) will head a multi-state consortium for a centralized, national data resource that it hopes will help researchers uncover the best treatment options for COVID-19 patients. The West Virginia Clinical and Translational Science Institute (WVCTSI), headquartered at WVU, will work with Delaware, Louisiana, Maine, Mississippi, Nebraska, Oklahoma, Rhode Island and West Virginia in compiling a large, granular dataset that can examine associations of improved outcomes with various treatments. The effort is being funded by a $1.5 million grant from the National Institutes of Health (NIH) and the consortium will feed into the National COVID Cohort Collaborative, the national COVID data source being developed by the NIH. The registry will give investigators answers to important research questions relevant to patients in their geographic area and builds on a COVID-19 patient data registry developed by WVCTSI in early spring 2020. The WVCTSI registry alone now contains data on more than 60,000 individuals tested through the WVU Medicine system. Press release.

Researchers at the University of Texas Health Science Center at Houston have launched a trial of a combination antibody treatment for preventing COVID-19 illness in individuals who have had sustained exposure to someone with the virus. The phase III, randomized, double-blinded, placebo-controlled trial will help determine if the laboratory-made dual-antibody treatment, REGN-COV2, can prevent SARS-CoV-2 infection in individuals who share a home with someone with a confirmed infection. REGN-COV2 is a combination of two monoclonal antibodies that target two different sites of the spike protein found on the surface of SARS-CoV-2. Asymptomatic individuals who have had at least 48 hours of sustained exposure to an index case are being enrolled at Harris Health System's Lyndon B. Johnson Hospital and must be randomized within 96 hours of the index case's diagnosis. Trial participants must live in the same household as the index case patient for 29 days during the study. The study period will last 32 weeks; on day one of enrollment, patients will receive four subcutaneous injections of either the trial agent or a placebo and will be tested for COVID-19 weekly during the first month. Regeneron Pharmaceuticals is sponsoring the trial. Press release.

University of Minnesota Medical School researchers are initiating research on the widely used diabetes medication, metformin, available globally as an inexpensive generic drug for prevention and treatment for COVID-19. They submitted an investigational new drug application with the FDA on August 12 and received some initial funding from the California-based Parsemus Foundation. The team has the next few weeks to secure additional funding. Metformin has a little-known past as an antiviral and TNFα and mTOR are among the proposed pathways, but a RCT is needed to be sure the association is truly cause and effect. Several observational studies in the U.S. and around the world have shown an association between outpatient metformin use and reduced mortality and hospitalizations for COVID-19. The team previously examined de-identified data from UnitedHealthcare and found that women already taking metformin who were diagnosed with COVID-19 had about 25% reduced risk of mortality. Preliminary data from another observational study of patients with non-alcoholic fatty liver disease showed that treatment for metabolic disease, including taking metformin, was associated with a lower likelihood of being hospitalized due to COVID-19. Press release.

Care Access Research has announced that it is collaborating with Eli Lilly and Company on a first-of-its-kind system of decentralized, mobile COVID-19 clinical trials that involve the simultaneous deployment of traveling teams of trucks, RVs and personnel. The mobile research teams will be providing the in-person patient care—including infusions—and have access to a fully functioning lab fitted with centrifuges, lab kits, and medical supplies to the help at-risk nursing home residents and staff participate in the BLAZE-2 phase III trial of Lilly's monoclonal antibody (LY-CoV555). The unique and scalable model is expected to enroll over 2,000 participants in a matter of months. Press release.

MaskCount, a new web app developed at the Regenstrief Institute (Indianapolis, Indiana), will allow citizen scientists document the number of people they see wearing or not-wearing masks without having to identify anyone. Users simply and discreetly tap or swipe on their screens to capture counts, and can enter the information as frequently as they choose. Submitted information will be combined for display and analyzed with other COVID-19 data, such as case counts and hospitalizations, to better understand outbreaks. MaskCount is free, available in 15 languages, and can run across platforms (e.g., Apple, Android, and other smart devices). Press release.

Thanks to a $2.3 million grant from the National Institutes of Health, Case Western Reserve University researchers will try to better understand how COVID-19 ravaged America’s nursing homes and ways to identify its presence earlier. Stemming nursing home infections could in turn reduce COVID-19's spread in communities across the country. The plan is to look at the magnitude of the problem and how long-term care residents transmit and cope with the disease. The three main areas of focus are epidemiology, transmission, and immunity and biomarkers. Press release.

Organicell Regenerative Medicine has announced that FDA has granted expanded access for an intermediate size population, allowing its proprietary therapeutic Zofin to be used for the treatment of COVID-19. The expanded access protocol will provide access to the investigational product for patients in outpatient and inpatient facilities who have mild to moderate COVID-19, or who are judged by a healthcare provider to be at high risk of progression to moderate disease. Aside from convalescent plasma, Zofin is the first reported acellular therapy available through the agency’s expanded access program. Zofin is manufactured to retain naturally occurring microRNAs, without the addition of any other substance or diluent. Organicell is now enrolling patients into its phase I/II placebo-controlled clinical trial to evaluate the safety and potential efficacy of Zofin. Press release.

People have short-lived immunity to seasonal coronaviruses, writes Dr. Francis Collins in his NIH Director’s Blog, meaning the best course of action until a COVID-19 vaccine is developed is to follow the standard advice: maintain social distancing, wear a mask, avoid crowded indoor gatherings, and wash your hands. He cites two recent studies to back his case. A study in Nature Medicine (DOI: 10.1038/s41591-020-1083-1) looking at the historic behavior of four less life-threatening members of the coronavirus family found that immunity tends to be short-lived, with reinfections often happening within 12 months if not sooner. Another new study has similarly found that reinfections by four common coronaviruses happen most frequently about a year after a previous infection, and that infection rates are lower during the summer months. Annual reinfections are consistent with evidence that antibodies against SARS-CoV-2 decrease within two months of infection, he adds, as recently reported in the New England Journal of Medicine (DOI: 10.1056/NEJMc2025179). Blog.

An industry report newly issued by Arkivum (U.K.) finds that 74% of surveyed life science professionals expect that COVID-19 will continue to compromise their ability to deliver on clinical trial objectives for the next six to 12 months, and nearly as many say the pandemic has triggered a change in the way studies will be conducted moving forward. Interoperability between eClinical applications used in trials remains a major challenge, and current archiving of clinical trial data is not always fit for purpose. All the 200 respondents surveyed were either directly or indirectly involved with the management of clinical trial data and the trial master file. More than half (51%) call for more diversification of patient enrollment and report the need for more virtual trials, incorporating telemedicine, remote monitoring of patients, wearable technologies, and mobile apps and devices. Press release.

Researchers at the University of Oxford (U.K.) are starting a new study to explore the effectiveness of the anti-tumor necrosis factor (anti-TNF) drug adalimumab as a treatment for patients with COVID-19 in the community, especially care homes. The AVID-CC trial, which will be conducted by Oxford Clinical Trials Research Unit, will enroll up to 750 patients from community care settings throughout the country. Recent studies of patients with COVID-19 have shown that patients already taking anti-TNF drugs for inflammatory bowel disease and inflammatory arthritis are less likely to be admitted to hospital. The study will be delivered by established hospital-based teams that specialize in delivering more complex treatment interventions in the community. It is the first drug trial designed for the university’s Acute Hospital at Home services. Press release.