Cumulative Number of Reviewed Articles Since Inception: 1127

COVID-19 Statistics: Connecticut as of September 11, 2020

Fairfield Statistics:

• Cases per 100,000 population: 2051
• Total Cases: 19360
• Current number of patients in hospitals: 11
• Deaths: 1,418
• Death Rate: 7.32%

Table of Contents

A Piece of My Mind

• The Silence and Sorrow of Miscarriage, JAMA September 8, 2020

Editorials, Perspectives, Commentaries and Reflections

• The crisis of political language, Lancet September 12, 2020
• Walking forwards, looking backwards, Lancet Planetary Health, September 2020
• Post-pandemic recovery: use of scientific advice to achieve social equity, planetary health, and economic benefits, Lancet Planetary Health, September 2020
• Targeted change making for a healthy recovery, Lancet Planetary Health, September 2020
• Responding to COVID-19 requires strong epidemiological evidence of environmental and societal determining factors, Lancet Planetary Health, September 2020
• Health Equity — Are We Finally on the Edge of a New Frontier? NEJM September 10, 2020
• “When Will We Have a Vaccine?” — Understanding Questions and Answers about Covid-19 Vaccination, NEJM September 08, 2020
• Facial Masking for Covid-19 — Potential for “Variolation” as We Await a Vaccine, NEJM September 08, 2020
• New Order, New Hope, NEJM September 09, 2020

Pathophysiology

• Trained Innate Immunity, Epigenetics, and Covid-19, NEJM September 10, 2020

Epidemiology

• Obesity and Hypertension in the Time of COVID-19, JAMA September 9, 2020
• Regardless of Age, Obesity and Hypertension Increase Risks With COVID-19, JAMA Internal Medicine September 9, 2020
• Clinical Outcomes in Young US Adults Hospitalized With COVID-19, JAMA Internal Medicine September 9, 2020
• Incidence of Nosocomial COVID-19 in Patients Hospitalized at a Large US Academic Medical Center, JAMA Network Open September 9, 2020

Clinical Manifestations

• Comparison of Clinical Features of COVID-19 vs Seasonal Influenza A and B in US Children, JAMA Network Open September 8, 2020

Diagnosis

• Covid-19 Molecular Diagnostic Testing — Lessons Learned, NEJM September 09, 2020

Prevention

• "Effect of Calcifediol Treatment and best Available Therapy versus best Available Therapy on Intensive Care Unit Admission and Mortality Among Patients Hospitalized for COVID-19: A Pilot Randomized Clinical study", Molecular Biology, 29 August 2020

Treatment

• Curing COVID-19, Lancet Infectious Disease September 10, 2020
• Immune Stimulation With Recombinant Human Granulocyte Colony–Stimulating Factor for Coronavirus Disease 2019 (COVID-19)—Beware of Blind Spots, JAMA Internal Medicine, September 10, 2020
• Effect of Recombinant Human Granulocyte Colony–Stimulating Factor for Patients With Coronavirus Disease 2019 (COVID-19) and Lymphopenia,A Randomized Clinical Trial, JAMA Internal Medicine, September 10, 2020
• COVACTA trial raises questions about tocilizumab’s benefit in COVID-19, Lancet Rheumatology September 09, 2020

Medical Education

• Can Covid Catalyze an Educational Transformation? Competency-Based Advancement in a Crisis, NEJM September 10, 2020

Miscellaneous

• Projected health-care resource needs for an effective response to COVID-19 in 73 low-income and middle-income countries: a modelling study, Lancet Global Health September 09, 2020
• Prevalence of Third-Party Tracking on COVID-19–Related Web Pages, JAMA September 8, 2020

A Piece of My Mind

JAMA September 8, 2020

The Silence and Sorrow of Miscarriage

Altaf Saadi, et al

“Immigration detention center” is really a euphemism for a prison. As a physician, I am an expert in euphemisms.

Our car ride conversation turned to the practice of mothers being separated from their children—before it had garnered media attention and become popular resistance parlance. Isn’t it symbolic, my husband would later ask, that we lost our baby in a town where immigration agents take away babies from their mothers. Yes, I thought, recognizing the symbolism in my life but, also, wondered how much harder it is to say goodbye to actual eyes and lashes and nose? Sometimes, mothers were given no opportunities for goodbyes. Children were sometimes separated under the ruse of “baths” that stretched longer and longer, until they heard, “You won’t be seeing your child again.”

Days earlier, I had read a story of a pregnant woman in an immigration detention center who began bleeding profusely. Ignored at first, she was finally taken by immigration officers to a hospital where a doctor informed her that she had miscarried. New immigration enforcement guidelines do not preclude the detention of pregnant or nursing mothers, a change from previous policy guidelines. In the first 4 months of 2017, nearly 300 pregnant women were held in Immigration and Customs Enforcement (ICE) detention centers nationwide.1 Between October 2017 and August 2018, there were a total of 1655 pregnant women booked into ICE custody. In 2018, miscarriages experienced by immigrants in detention nearly doubled. I wanted to find that woman and wrap her in a hug: how profoundly painful the isolation and fear of bleeding your fetus away without family or a partner near you, in a strange town with strange faces and strange words that your mind cannot comprehend. I was lucky to have my husband fly out to me from Los Angeles to Laredo that same evening.

“It would have been easier had I had appendicitis,” I told my husband. When people get appendicitis, there is no stigma in sharing, “I had appendicitis.” You can share the news with friends, family, and coworkers. You can receive cards that wish, “Get well soon!” Emails are easy to write. Absences are easy to explain. A hiatus for physical and emotional rest need not happen in isolation or secrecy. You say, “I had appendicitis and I have to take some time off.” You say, “I had appendicitis and I need to take it easy for a week or two.” With a miscarriage, you mute your experience. You don’t know what to say. The person who hears the news doesn’t know what to say. In conversations like that, silences are pregnant with awkwardness, but you are no longer pregnant.

Editorials, Perspectives, Commentaries and Reflections

Lancet September 12, 2020

The crisis of political language

Richard Horton

The present health and economic crises we face are compounded by a crisis of political language. Until our words are purged of duplicity, falsehood, and hypocrisy, the lessons of this pandemic will never be learned.

George Orwell, in his 1945 essay Politics and the English Language, wrote that “to think clearly is a necessary first step towards political regeneration”.

The first results of a vaccine trial were released by Russian President Vladimir Putin on Aug 13. “I know that it works quite effectively”, he said, “forms strong immunity, and I repeat, it has passed all the needed checks”. At last week's event, more big claims were made. The “poorly researched approaches” by “western” nations were criticised, and one speaker challenged western governments to respond to these alleged concerns—“would you please show your citizens” evidence about the safety of western vaccine candidates given the “poorly developed platforms” you are using, he said. “It doesn't make any sense to use poorly researched approaches”, he argued. His view was that a human adenovirus vector was safer than a chimpanzee adenovirus vector (the basis for the Oxford COVID-19 vaccine, for example). A press conference to present the results of a scientific study became the venue for renewed Cold War conflict.

US President Donald Trump routinely refers to SARS-CoV-2 as the “China virus”. He is seeking to amplify the American public's fear of China to wound his opponent in the current presidential campaign. In Latrobe, PA, on Sept 3, President Trump suggested that, “Joe Biden wants to surrender your jobs to China”. The message is clear—China is America's enemy, it is the cause of a pandemic that has destroyed the US economy, and the policies of the Democrat candidate will only strengthen America's chief international competitor. There is not one shred of evidence to support these claims. The twisting of language in public discussion of the pandemic is now standard fare. “Thanks to the efforts of Operation Warp Speed”, said President Trump in Wilmington, NC, on Sept 2, “we remain on track to deliver a vaccine very rapidly, in record time”. He has suggested a vaccine might be available by the end of October—an important claim given that the US election will take place on Nov 3. Yet there is no possibility that a COVID-19 vaccine will be ready for public use before the US election. Orwell's reflection that language is used “with intent to deceive” in “the sordid processes of international politics” could not be more apposite.

Here is Boris Johnson on June 30: “This government is committed not just to defeating coronavirus but to using this crisis to tackle this country's great unresolved challenges of the last three decades.” There is no government strategy for national revival. On July 23, while visiting Scotland, he spoke about “what we can achieve when we stand together, as one United Kingdom”. As the confused rules on quarantine show, there is no “one United Kingdom”. On July 31: “I know we are going to beat this.” Yet the virus is with us and we must learn to live with it. On Aug 13, writing in the Belfast Telegraph: “this government has an unshakable commitment to each and every person in each and every nation of our United Kingdom.” Again, where is the plan, the programme, the proof that those most severely affected by COVID-19 are being prioritised by this government? “The great enemy of clear language”, Orwell wrote, “is insincerity”. “Political language...is designed to make lies sound truthful and murder respectable.” COVID-19 is no exception.

Lancet Planetary Health, September 2020

Walking forwards, looking backwards

Editor

There are many reasons from political lobbying and disinformation campaigns, to locked in economic and political structures which favour certain types of value and extreme short-termism. Combined these seem to make long-term planning, and investment outside of existing norms politically and economically inconceivable.

If we are to do better, we need a much more forward looking and integrated and flexible approach to the future which utilises the wealth of knowledge we have, rather than waiting for predictions to come to fruition before rising to tackle them.

We are still embroiled in a pandemic, as if we could forget, the global nature of which makes almost every other event a compound one. The year opened with the tail end of the worst Australian wildfire season in documented history: a situation that had huge consequences for Australian ecosystems, infrastructure, and human health and wellbeing from smoke inhalation to post-traumatic stress and other mental health challenges. We are experiencing among the hottest average global temperatures on record, which is fuelling regional heatwaves and some of the highest temperatures ever recorded on earth. Greenland is losing record volumes of ice contributing to sea level rise. Around a third of Bangladesh has recently been affected by flooding, the fifth time floods like this have affected the region in the past 20 years. Until recently, floods of this scale were thought to be one in 20-year events. The combination of monsoon flooding and COVID-19 in the wake of super-cyclone Amphan seems particularly brutal and certainly represents a deeply challenging confluence of events for any country to manage. These events make Bangladesh an unfortunate posterchild for climate injustice, having contributed little to the greenhouse gas emissions causing the climate crisis but bearing the brunt of many of the worst impacts. Rich countries may be relatively less affected, but they are far from safe from climate change impacts, and the California wildfire season is testimony to this vulnerability. The amount of land burned in a single week in August, 2020, was more than the total burned in 2018, and double that of 2017.

A global pandemic has been warned about for decades, not least because we have experienced them before and because modern city living, and international trade and travel, are much more conducive to disease spread. Furthermore, in recent decades multiple emerging infectious diseases have avoided pandemic scale primarily because we were lucky. Expanding agriculture and habitat erosion has further accentuated the likelihood of zoonotic disease emergence. None of this should be a surprise to anyone who takes scientific knowledge seriously. The climate emergency has been predicted with remarkable consistency for decades and many impacts like wildfire and coastal flooding are equally well established. Hindsight is 20:20, but even accounting for that effect, we haven't seen anything this year that wasn't reasonably predictable. Why then were we so ill prepared?

Lancet Planetary Health, September 2020

Post-pandemic recovery: use of scientific advice to achieve social equity, planetary health, and economic benefits

Robin Fears, et al

A Communique from the InterAcademy Partnership, the global network of more than 140 academies of science, engineering, and medicine, builds on an earlier evaluation of the issues for climate change and human health to explore how science-based solutions and systemic interventions, adapted to match a country's circumstances, can help to effect a fundamental recovery transition with rapid decarbonisation. The InterAcademy Partnership's objective is to identify principles, priorities, and precepts that policy makers and other stakeholders worldwide should now take into account in designing the recovery from COVID-19 (panel).

2021 brings an unparalleled concatenation of openings for policy reform. For example, the UK hosts the United Nations Climate Change Conference COP26 and holds the presidency of the G7 group of nations, and Italy is co-host of the COP26 and chairs the G20 group of nations. The InterAcademy Partnership is striving to make the most of its participatory opportunities to help to ensure that evidence and perspectives from low-income and middle-income countries are also brought to the forefront in these events and that recovery measures intended to promote economic, environmental, and health benefits are founded on fair and equitable strategies.

Lancet Planetary Health, September 2020

Targeted change making for a healthy recovery

Courtney Howard

Global instability combined with historic public expenditures have created a generational opportunity for transformation and a global call for a healthy recovery that the planetary health community is well positioned to inform. Maximum impact will be achieved if resources are allocated to policy and advocacy, wins are communicated to facilitate hope and momentum, and a deliberate sense of solidarity is created within the planetary health community to support courageous work at the intersections of influence and power.

Evidence-informed policy goals are most resonant when contextualised as an opportunity for a given actor at a specific time. Marshall Ganz states that, “narrative is the discursive means we use to access values that equip us with the courage to make choices under conditions of uncertainty, to exercise agency.” Both data and stories can generate emotion, with individual and group-based emotions influencing actions taken. In Ganz' model, action inhibitors can be overcome by activators: inertia by urgency, apathy by anger, fear by hope, isolation by solidarity, and self-doubt by a feeling that “you can make a difference.” Where collective action is concerned, hope, anger at injustice, anticipated pride at proenvironmental behaviours, and positive emotions associated with group-based work all have shown relevance. Pictures and videos can help with story-telling, and in communicating a planetary health frame and key data points to new audiences.

Trust in leadership is key to instilling the confidence needed to make change in a situation of uncertainty. A compelling personal story of motivation can enhance trust between a leader and their audience. Message testing in target audiences is paramount, with engagement enhanced by narratives based on shared values and respect for diverse perspectives, illustrated beautifully by the Alberta Narratives Project.

A strategic target is the evidence-aligned change with the most potential to improve planetary health achievable by a given team with available resources in a specific context. Targets might be envisioned at multiple scales. Health-focused work in social accountability has been described as occurring at various levels: micro (individual or patient), meso (hospital or community), and macro (sub-national or national) levels. Global networks inclusive of a diversity of voices from high-income, middle-income, and low-income countries also make possible a meta level where international goals are developed collaboratively, and mentorship, toolkits, and other supports are offered, as appropriate, to community-centered initiatives with the goal of creating an international wave of change that influences norms and markets.

Once a target is chosen, a variety of tactics, such as sign-on letters, op-ed pieces, relationship-building with decision makers and political involvement are employed.

Lancet Planetary Health, September 2020

Responding to COVID-19 requires strong epidemiological evidence of environmental and societal determining factors

Ariana Zeka, et al

We do recognise the urgent need to understand the COVID-19 pandemic and the contribution of environmental, population, and societal aspects to this global public health emergency. Our concern, as a community of environmental epidemiology and public health researchers, is that this rapidity of publication and peer review has made possible the publication of studies that are simple to do and understand, but are inadequate at addressing the complexity, drivers, and impacts of the pandemic. Such studies have been captivating for the media and the general public, but could be considered to contribute more to noise than to a robust epidemiological evidence base. More importantly, these studies risk misinforming the public on science and policy, and could disorient public opinion on crucial issues such as global environmental health.

NEJM September 10, 2020

Health Equity — Are We Finally on the Edge of a New Frontier?

Michele K. Evans

“One true measure of a nation is its success in fulfilling the promise of a better life for each of its members. Let this be the measure of our nation.”

JFK

Our health care system is a microcosm of American society, in which power and resources are not allocated fairly among races, sexes, or classes. Social class, race, and geography are, to a large extent, destiny when it comes to health in the United States. Recent work suggests that we consider primary factors driving poor health outcomes to be the results of “political determinants of health.” Monumental political actions such as the compromise on slavery at the nation’s founding, the failure to sustain the gains of Reconstruction and its constitutional amendments, the institution of Jim Crow laws legalizing systematic racism and White supremacy, and the inability to respect Indigenous Americans’ rightful claim to their native lands have set the stage for the “social” determinants of health that promote health inequities and differential health outcomes.

Now, engulfed in the catastrophic pandemic maelstrom, we are reckoning with a deadly triad — health disparities, health inequity, and unequal health care access — quantified in a daily body count. We are obliged to acknowledge the lethal consequences of the cracks in our nation’s foundational tenets of equality, as Covid-19 exposes the cascading conglomeration of public policies reflecting toleration of underfunding of public health, undermining of equitable health care access, and the economic, educational, and judicial marginalization of minorities.

Black and Latinx Americans have consistently lower rates of insurance coverage than White Americans. Since employer-based plans provide more than half the population with insurance, the substantially higher unemployment and underemployment rates among minorities contribute to their lower coverage rates. A July 2020 report from the U.S. Bureau of Labor Statistics documents unemployment rates of 16.1% among Black Americans and 16.7% among Latinx Americans — significantly higher than the 12.0% rate among White Americans. The pandemic has amplified preexisting economic inequalities for minorities by driving up unemployment and concomitantly reducing health insurance rates, food security, housing stability, and household income.

11.9 million children in the United States live in poverty; 73% of these are children of color. In 2018, children under 19 had a lower overall health insurance rate than adults 65 or older. Uninsured children were predominantly Latinx and Black, living in low-income households in the South and in states that did not enact the Medicaid expansion provisions of the Affordable Care Act. Health insurance rates for adults were also lower in non–Medicaid-expansion states.

Systemic racism limits educational opportunities for Black Americans, resulting in inadequate diversity among health professionals. According to the Association of American Medical Colleges, 63.9% of academic medical faculty are White, 3.6% Black, and 3.2% Latinx. Although Black people make up 13.4% of the U.S. population, only 5.0% of actively practicing U.S. physicians are Black. Latinx people account for 18.3% of the population but only 5.8% of actively practicing physicians. Such unequal representation, in turn, affects health inequities, health care access, and health disparities. For example, the cancer disparities burden is exacerbated by the fact that only 2.3% of U.S. medical oncologists are Black.

NEJM September 09, 2020

“When Will We Have a Vaccine?” — Understanding Questions and Answers about Covid-19 Vaccination

Barry R. Bloom, et al

The answer to this common question is when the research studies, engagement processes, communication, and education efforts undertaken during the clinical trial stage have built trust and result in vaccination recommendations being understood, supported, and accepted by the vast majority of the public, priority and nonpriority groups alike.” Efforts to engage diverse stakeholders and communities in Covid-19 vaccination education strategies, key messages, and materials for clinicians and the public are needed now.

People's inquiry typically involves three concerns. First, when will the public be able to have confidence that available vaccines are safe and effective? Second, when will a vaccine be available to people like them? And third, when will vaccine uptake be high enough to enable a return to prepandemic conditions? Often, the inquiry is also assessing whether the biotech and vaccine companies, government agencies, and medical experts involved in developing, licensing, and recommending use of Covid-19 vaccines realize that the responses they provide now will influence what happens later.

As Covid-19 vaccines move into phase 3 clinical trials, enthusiasm about the innovative and sophisticated technologies being used needs to be replaced by consideration of the actions and messages that will foster trust among clinicians and the public.

The recently released guidelines from the Food and Drug Administration (FDA) on testing of Covid-19 vaccine candidates are scientifically sound and indicate that no compromises will be made when it comes to evaluating safety and efficacy. This commitment needs to be stated repeatedly, made apparent during the vaccine testing and approval process, and supported by transparency.

Data from antibody testing suggest that about 90% of people are susceptible to Covid-19. Accepting that 60 to 70% of the population would have to be immune, either as a result of natural infection or vaccination, to achieve community protection (also known as herd immunity), about 200 million Americans and 5.6 billion people worldwide would need to be immune in order to end the pandemic. The possibility that it may take years to achieve the vaccination coverage necessary for everyone to be protected gives rise to difficult questions about priority groups and domestic and global access.

Given public skepticism of government institutions and concerns about politicization of vaccine priorities, the recent establishment of a National Academy of Medicine (NAM) committee to formulate criteria to ensure equitable distribution of initial Covid-19 vaccines and to offer guidance on addressing vaccine hesitancy is an important step.

NEJM September 08, 2020

Facial Masking for Covid-19 — Potential for “Variolation” as We Await a Vaccine

Monica Gandhi, et al

Ultimately, combating the pandemic will involve driving down both transmission rates and severity of disease. Increasing evidence suggests that population-wide facial masking might benefit both components of the response.

Recent virologic, epidemiologic, and ecologic data have led to the hypothesis that facial masking may also reduce the severity of disease among people who do become infected. This possibility is consistent with a long-standing theory of viral pathogenesis, which holds that the severity of disease is proportionate to the viral inoculum received.

As proof of concept of viral inocula influencing disease manifestations, higher doses of administered virus led to more severe manifestations of Covid-19 in a Syrian hamster model of SARS-CoV-2 infection.

Masking might reduce the inoculum that an exposed person inhales. If this theory bears out, population-wide masking, with any type of mask that increases acceptability and adherence, might contribute to increasing the proportion of SARS-CoV-2 infections that are asymptomatic. The typical rate of asymptomatic infection with SARS-CoV-2 was estimated to be 40% by the CDC in mid-July, but asymptomatic infection rates are reported to be higher than 80% in settings with universal facial masking, which provides observational evidence for this hypothesis.

Universal masking seems to reduce the rate of new infections; thus by reducing the viral inoculum, it would also increase the proportion of infected people who remain asymptomatic.

In an outbreak on a closed Argentinian cruise ship, for example, where passengers were provided with surgical masks and staff with N95 masks, the rate of asymptomatic infection was 81% (as compared with 20% in earlier cruise ship outbreaks without universal masking). In two recent outbreaks in U.S. food-processing plants, where all workers were issued masks each day and were required to wear them, the proportion of asymptomatic infections among the more than 500 people who became infected was 95%, with only 5% in each outbreak experiencing mild-to-moderate symptoms. Case-fatality rates in countries with mandatory or enforced population-wide masking have remained low, even with resurgences of cases after lockdowns were lifted.

Variolation was a process whereby people who were susceptible to smallpox were inoculated with material taken from a vesicle of a person with smallpox, with the intent of causing a mild infection and subsequent immunity. Variolation was practiced only until the introduction of the variola vaccine, which ultimately eradicated smallpox.

Reinfection with SARS-CoV-2 seems to be rare, despite more than 8 months of circulation worldwide and as suggested by a macaque model. Promising data have been emerging in recent weeks suggesting that strong cell-mediated immunity results from even mild or asymptomatic SARS-CoV-2 infection, so any public health strategy that could reduce the severity of disease should increase population-wide immunity as well.

To test if population-wide masking is one of those strategies, we need further studies comparing the rate of asymptomatic infection in areas with and areas without universal masking. To test the variolation hypothesis, we will need more studies comparing the strength and durability of SARS-CoV-2–specific T-cell immunity between people with asymptomatic infection and those with symptomatic infection, as well as a demonstration of the natural slowing of SARS-CoV-2 spread in areas with a high proportion of asymptomatic infections.

NEJM September 09, 2020

New Order, New Hope

Andrew L. Tambyraja

Surgeons, by nature, are addicted to being decisive, to keeping up with busy practices, to caring for critically ill patients, and to the craft of surgery itself; and now we are being made to go cold turkey. The sudden loss of purpose, the transition from omnipotent to impotent, has left my surgical colleagues and me in an unfamiliar state akin to grief. We scrape the barrel for ways to demonstrate our value, in search of just one more fix. Taking the emergency calls, being asked for a consult from another specialty, any sort of time-critical operation — never have these had so much appeal. Orthopedics teams creatively offer their brains and brawn to the physical effort of positioning multiple ventilated patients each day (from prone to supine and back again) — small crumbs of comfort in a famine. In times of such trouble, solace may even be found by withdrawing to neglected paperwork and administrative responsibilities. Anything to quell tongue-in-cheek rumormongering that surgical staff may need to suffer the further ignominy of being placed on furlough.

In the Covid-19-and-beyond landscape of hospital medicine, all doctors’ own hitherto irrefutable self-worth is very much open to question. The saying “Idle hands are the devil’s workshop” has never seemed more true. From all the adversity that this novel virus brings springs the unquenchable hope of opportunity. Society and doctors alike will have to evolve to negotiate this latest trial that nature has placed in front of us. Many doctors have a catalyst to find ways in which we can work with more agility and patient focus, build a foundation of truly value-based health care, and perhaps most important, be reminded of the virtues of humility and the pursuit of the greater good.

Pathophysiology

NEJM September 10, 2020

Trained Innate Immunity, Epigenetics, and Covid-19

Alberto Mantovani and Mihai G. Netea

Myeloid cells are central players in innate immunity: they produce effector molecules and contribute to the activation, orientation, and regulation of adaptive immune responses. Diversity and plasticity are fundamental properties of myeloid cells, particularly macrophages. To some extent, these properties are imprinted through ontogenetic origin (embryonal vs. adult bone marrow), but they are also influenced by environmental cues in the tissue. Moreover, in response to microbial molecules, metabolic products, or cytokines, macrophages increase effector function (“activation”), are primed for short-term responses (“priming”), or become unresponsive (“tolerance”). Microbial components can also cause long-term imprinting (“training”) of innate immunity and myeloid-cell function (Figure 1). (This type of imprinting is distinct from genomic imprinting whereby methyl groups are added to DNA in or near specific genes.)

Some epidemiologic studies suggest that BCG has a pleiotropic effect that decreases the incidence of other infections. Several trials to determine whether BCG can help prevent Covid-19 are under way; findings from these trials could reinforce a role of trained immunity in illness prevention or amelioration (the second author of this article is leading two of them). The use of BCG in the prophylaxis or treatment of Covid-19 outside of controlled clinical trials is, of course, not recommended.

Epidemiology

JAMA September 9, 2020

Obesity and Hypertension in the Time of COVID-19

Griffin P. Rodgers and Gary H. Gibbons

The devastating effects of COVID-19 on communities of color is tightly related to this same intersectionality between race and class that increases exposure to the COVID-19 pandemic related to employment in essential service sectors and limited capacity to physically distance in crowded housing conditions. Addressing these complex drivers of health disparities will necessitate an approach that recognizes the multidimensional nature of contextual factors that led to structural racism, and advances the understanding of how these social factors promote comorbidities such as obesity and hypertension.

In addition to race/ethnicity and health care use, geographic location (eg, the stroke belt in the Southeastern US), rurality, and low socioeconomic status are also associated with increased risk of obesity and poor control of cardiovascular disease risk factors. What brings these disparities into sharper focus, and provides increased urgency for addressing them, is the ongoing severe acute respiratory syndrome coronavirus 2 pandemic and the risk for potentially life-threatening outcomes from coronavirus disease 2019 (COVID-19).

If the US is committed to changing the trend line of health disparities in obesity and hypertension, it is critical to acknowledge the important contributions of systemic racism and the social determinants of health in the context of the current COVID-19 crisis. It will take a collective, committed effort at every level, including policy makers, frontline community organizations, health care workers at safety-net clinics, and those conducting behavioral and biomedical scientific research, to address these potentially remediable contributors to some of the nation’s most complex health challenges. Only then will it be possible to achieve a vision of health equity in which each child born in the US is destined to live a full and healthy life regardless of their family’s zip code.

JAMA Internal Medicine September 9, 2020

Regardless of Age, Obesity and Hypertension Increase Risks With COVID-19

Mitchell H. Katz

While young adults are much less likely than older persons to become seriously ill, if they reach the point of hospitalization, their risks are substantial. Obesity, hypertension, and male sex put patients of all ages at greater risk. COVID-19 is a life-threatening disease in people of all ages and that social distancing, facial coverings, and other approaches to prevent transmission are as important in young adults as in older persons.

Unfortunately, as shown by Cunningham et al in this issue of JAMA Internal Medicine, COVID-19 does not spare young people. Using a national all-payer hospital database, the investigators identified 3222 nonpregnant adults aged 18 to 34 years who were admitted to US hospitals for COVID-19. Morbidity was substantial: 21% required intensive care, and 2.7% died. Mortality was higher among those who had obesity, hypertension, and male sex, as has been noted in general adult populations.

JAMA Internal Medicine September 9, 2020

Clinical Outcomes in Young US Adults Hospitalized With COVID-19

Jonathan W. Cunningham, et al

Young adults age 18 to 34 years hospitalized with COVID-19 experienced substantial rates of adverse outcomes: 21% required intensive care, 10% required mechanical ventilation, and 2.7% died. This in-hospital mortality rate is lower than that reported for older adults with COVID-19, but approximately double that of young adults with acute myocardial infarction. Morbid obesity, hypertension, and diabetes were common and associated with greater risks of adverse events. Young adults with more than 1 of these conditions faced risks comparable with those observed in middle-aged adults without them. More than half of these patients requiring hospitalization were Black or Hispanic, consistent with prior findings of disproportionate illness severity in these demographic groups.

JAMA Network Open September 9, 2020

Incidence of Nosocomial COVID-19 in Patients Hospitalized at a Large US Academic Medical Center

Chanu Rhee, et al

In this cohort study of patients in a large academic medical center with rigorous infection control measures, nosocomial COVID-19 was rare during the height of the pandemic in the region. These findings may inform practices in other institutions and provide reassurance to patients concerned about contracting COVID-19 in hospitals.

Some patients are avoiding essential care for fear of contracting coronavirus disease 2019 (COVID-19) in hospitals. There are few data, however, on the risk of acquiring COVID-19 in US hospitals.

This cohort study included all patients admitted to Brigham and Women’s Hospital (Boston, Massachusetts) between March 7 and May 30, 2020. Follow-up occurred through June 17, 2020. Medical records for all patients who first tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by reverse-transcription polymerase chain reaction (RT-PCR) on hospital day 3 or later or within 14 days of discharge were reviewed.

Over the 12-week period, 9149 patients (mean [SD] age, 46.1 [26.4] years; median [IQR] age, 51 years [30-67 years]; 5243 female [57.3%]) were admitted to the hospital, for whom 7394 SARS-CoV-2 RT-PCR tests were performed; 697 COVID-19 cases were confirmed, translating into 8656 days of COVID-19–related care. Twelve of the 697 hospitalized patients with COVID-19 (1.7%) first tested positive on hospital day 3 or later (median, 4 days; range, 3-15 days). Of these, only 1 case was deemed to be hospital acquired, most likely from a presymptomatic spouse who was visiting daily and diagnosed with COVID-19 before visitor restrictions and masking were implemented. Among 8370 patients with non–COVID-19–related hospitalizations discharged through June 17, 11 (0.1%) tested positive within 14 days (median time to diagnosis, 6 days; range, 1-14 days). Only 1 case was deemed likely to be hospital acquired, albeit with no known exposures.

The present findings differ from the results of a recent review that suggested that up to 44% of COVID-19 infections may be nosocomial. However, that review was limited to case series conducted early in the outbreak in Wuhan, China, before recognition of the virus and the institution of infection control practices and PPE. In contrast, hospitals in Hong Kong cared for 42 patients with COVID-19 and reported no nosocomial transmission during the first 6 weeks after the virus was first discovered in China. Of note, their report encompassed a smaller number of patients compared with the present series.

An important theme that emerged from our case reviews was the need to conduct serial testing of patients with clinical syndromes highly suspicious for COVID-19. At least 3 patients with concerning syndromes initially tested negative for SARS-CoV-2 but had positive results on repeat testing. Other researchers have also documented that repeat RT-PCR testing can yield positive results for patients with initial negative results, albeit at relatively low rates. On the basis of our early experience, we instituted a protocol requiring at least 2 negative RT-PCR test results for symptomatic patients before discontinuing isolation.

Another observation that emerged was that several patients were only tested for the first time 3 or more days after hospitalization, sometimes because of atypical symptoms that were initially attributed to non-COVID conditions. These cases highlight the importance of implementing universal testing on admission, and we observed fewer late-onset cases after this intervention. However, universal testing is not infallible because several patients initially tested negative while asymptomatic and then tested positive after symptoms began several days later. This underscores the lower sensitivity of RT-PCR early in the course of infection.

Clinical Manifestations

JAMA Network Open September 8, 2020

Comparison of Clinical Features of COVID-19 vs Seasonal Influenza A and B in US Children

Xiaoyan Song, et al

In this cohort study of 315 children with COVID-19 and 1402 children with seasonal influenza, there were no statistically significant differences in the rates of hospitalization, admission to the intensive care unit, and mechanical ventilator use between the 2 groups. More patients with COVID-19 than with seasonal influenza reported fever, diarrhea or vomiting, headache, body ache, or chest pain at the time of diagnosis.

This retrospective cohort study included children who were diagnosed with laboratory-confirmed COVID-19 between March 25 and May 15, 2020, and children diagnosed with seasonal influenza between October 1, 2019, and June 6, 2020, at Children’s National Hospital in the District of Columbia.

No patients in this cohort were hospitalized with coinfection of both COVID-19 and seasonal influenza. During this study period, testing for influenza remained available for patients when clinically indicated, but a sharp decrease of influenza was detected at our facility after local school closures took place on March 15, 2020, followed by the activation of stay-at-home orders by local authorities on April 1, 2020. The positive detection rate for influenza decreased from 22% in the week ending on March 21, 2020, to 0.3% between March 22 and June 6, 2020, with only 1 influenza case detected.

Two patients with influenza A died. No deaths were observed among patients with COVID-19 or influenza B.

Patients hospitalized with COVID-19 (median age, 9.7 years [range, 0.06-23.2]) were older than those hospitalized with seasonal influenza (median age, 4.2 years [range, 0.04-23.1]). Patients older than 15 years accounted for 37% of those with COVID-19, in contrast to 6% in those with influenza (OR, 25.8; 95% CI, 14.2-48.5; P < .001)

Of patients hospitalized with COVID-19, 35 [65%] had at least 1 underlying medical condition, significantly higher than the 121 [42%] observed in those hospitalized with influenza (OR, 2.6; 95% CI, 1.4-4.7; P = .002). Neurological issues owing to global developmental delay or seizures were the most often identified underlying condition and were present in 11 patients (20%) hospitalized with COVID-19 compared with 24 patients (8%) hospitalized with influenza (OR, 2.8; 95% CI, 1.3-6.2; P = .002). There was no statistically significant difference in patients reporting a history of asthma, cardiac, hematologic, and oncologic conditions in those with COVID-19 vs those with influenza.

Diagnosis

NEJM September 09, 2020

Covid-19 Molecular Diagnostic Testing — Lessons Learned

Jeffrey Shuren, et al

We need common approaches to validating test design and performance, regardless of whether there is an emergency. The U.S. government should work with international partners to establish a plan for sharing clinical specimens as soon as a public health threat emerges. When a public health threat warrants large-scale testing, it would be more effective to authorize a small number of well-designed, well-developed, and validated tests run on common high-throughput platforms, followed by a few point-of-care tests, all of which are manufactured in large quantities, than to simultaneously develop and authorize scores of diagnostics.

We need common approaches to validating test design and performance, regardless of whether there is an emergency. Then Covid-19 highlights the need for a common legislative framework to ensure that all clinical tests are accurate and reliable.

No test is 100% accurate, and performance can vary within populations. Covid-19 diagnostic tests may be less accurate in asymptomatic or low-risk populations and in persons who shed little virus or are early or late in the course of illness. Even if a test were 98% sensitive and 99% specific, it would still produce a false negative result in 2 of every 100 people infected. If we test 5 million Americans daily and only 1% of them have Covid-19, a total of 1000 positive cases will be missed, which increases the risk of spread, and another 49,500 people will receive false positive results. False positive results can be burdensome to public health officials who are tasked with contact tracing and other public health activities, and many people may be unnecessarily quarantined. An understanding of the positive and negative predictive value of a test should be factored into clinical decision making and patient counseling. To mitigate the impact of false results, all Covid-19 tests authorized to date have been made available only by prescription, so that clinicians can interpret results for patients. However, several nonprescription tests are currently under development.

Prevention

Molecular Biology, 29 August 2020

"Effect of Calcifediol Treatment and best Available Therapy versus best Available Therapy on Intensive Care Unit Admission and Mortality Among Patients Hospitalized for COVID-19: A Pilot Randomized Clinical study"

Marta Entrenas Castillo, et al

This pilot study demonstrated that administration of a high dose of Calcifediol or 25-hydroxyvitamin D, a main metabolite of vitamin D endocrine system, significantly reduced the need for ICU treatment of patients requiring hospitalization due to proven COVID-19. Calcifediol seems to be able to reduce severity of the disease, but larger trials with groups properly matched will be required to show a definitive answer.

It has been proposed that the activation of the vitamin D receptor (VDR) signaling pathway may generate beneficial effects in ARDS by decreasing the cytokine/chemokine storm, regulating the renin‑angiotensin system, modulating neutrophil activity and by maintaining the integrity of the pulmonary epithelial barrier, stimulating epithelial repair and tapering down the increased coagulability. Recently, two ecological studies have reported inverse correlations between national estimates of vitamin D status and the incidence and mortality of IDOC-19 in European countries; lower concentrations of circulating 25 (OH) D have also been reported to be associated with susceptibility to SARS-CoV-2 infection and the severity of the evolution of COVID-19. Vitamin D deficiency is frequent in wintertime even in Southern Spain and even more so in patients requiring ICU treatment.

Calcifediol can rapidly increase serum 25OHD concentration. The authors therefore evaluated the effect of calcifediol treatment, on Intensive Care Unit Admission and Mortality rate among Spanish patients hospitalized for COVID-19.

Pilot Covidiol was a parallel pilot randomized open label, double-masked clinical study aiming to assess whether calcifediol can reduce the need for admission to ICU, and related death. This pilot trial was conducted at Reina Sofia University Hospital, Cordoba Spain.

Treatment

Lancet Infectious Disease September 10, 2020

Curing COVID-19

Editor

Randomised controlled trials (RCTs) in hospitalised patients have shown no effect of hydroxychloroquine in reducing mortality. One RCT hinted at an effect when used as post-exposure prophylaxis, but this was not statistically significant. Unless new, high-quality evidence emerges, the aminoquinolines appear to have no future in the management of COVID-19. Remdesivir, an antiviral, was also the subject of White House fanfare. The US Government has attempted to corner the market for this costly drug but results of clinical trials are ambiguous. One review concluded that remdesivir may reduce time to clinical improvement and decrease mortality but had no effect on need for invasive ventilation or length of hospital stay. A subsequent RCT found no effect on mortality. Although approved to treat COVID-19 in the USA and Europe, conclusive evidence to support remdesivir is lacking. For other antivirals, there is no good evidence for efficacy of favipiravir, although it has been approved in Russia, and the lopinavir/ritonavir combination showed no clinical benefit in the UK RECOVERY RCT.

Immunomodulators to treat COVID-19 are being widely tested in clinical trials. Among the front-runners, evidence to support use of tocilizumab, a monoclonal antibody against interleukin-6 receptors, comes largely from observational studies. Roche, the manufacturer, has announced that the drug did not improve clinical status in a phase 3 RCT among patients with severe COVID-19-associated pneumonia. Similarly, good quality evidence on the use of convalescent plasma is still awaited. Immunomodulators that do work are the corticosteroids. In the dexamethasone group of RECOVERY, deaths were reduced by 35% in ventilated patients and by 20% among those receiving oxygen only compared with those in the standard care group. An RCT of dexamethasone done in Brazil further supports the beneficial effect of the drug. The REMAP-CAP RCT of hydrocortisone—another corticosteroid—versus placebo in patients with severe COVID-19 showed a 93% improvement in the intervention group in days when organ support was not needed. Based on these findings, WHO guidelines recommend corticosteroids in patients with severe and critical COVID-19.

Where there has been a resurgence of COVID-19 cases to levels at least as high as when the pandemic first struck in the spring, such as in the USA, France, and Spain, it has not been followed by a comparable increase in deaths, nor of people requiring admission to hospital. Possible explanations for the recent disparity in cases and deaths include more widespread testing, meaning that the number of cases being detected is closer to the true burden of infection, whereas the accuracy of counting deaths remains unchanged; lower viral load at the point of transmission, and hence less severe disease, because of non-pharmaceutical measures such as mask wearing; and changes in the distribution of cases towards younger age groups. Data from England show that until recently cases have been fairly evenly distributed across all ages from 20 years upwards, but by the last 2 weeks of August cases in people aged 20–39 were about ten times the number in those aged 70 or more. Risk of COVID-19 death in young people is tiny compared with the elderly. However, cases in the young might yet spill over into older people, and the long-term consequences of non-fatal disease are unknown.

All hospitalized patients received as best available therapy the same standard care, (per hospital protocol), of a combination of hydroxychloroquine (400 mg every 12 hours on the first day, and 200 mg every 12 hours for the following 5 days), azithromycin (500 mg orally for 5 days) and for patients with pneumonia and NEWS score≥5, a broad spectrum antibiotic (ceftriaxone2 g intravenously every 24 hours for 5 days) was added to hydroxychloroquine and azithromycin.

Of 50 patients treated with calcifediol, one required admission to the ICU (2%), while of 26 untreated patients, 13 required admission (50%) p value X2 Fischer test p < 0.001. Of the patients treated with calcifediol, none died, and all were discharged, without complications. The 13 patients not treated with calcifediol, who were not admitted to the ICU, were discharged. Of the 13 patients admitted to the ICU, two died and the remaining 11 were discharged.

JAMA Internal Medicine, September 10, 2020

Immune Stimulation With Recombinant Human Granulocyte Colony–Stimulating Factor for Coronavirus Disease 2019 (COVID-19)—Beware of Blind Spots

Nuala J. Meyer, et al

Lymphopenia during infection, and particularly during sepsis, is not unique to COVID-19, nor even to viral illness. In studies of hospitalized patients with positive blood cultures, most had lymphopenia, and persistent lymphopenia was associated with mortality. However, during many acute viral respiratory infections, lymphopenia is transient and coincident with peak symptoms but then rapidly resolves as the patient improves. The severity, and in some cases persistence, of lymphopenia in patients with COVID-19 is different. As patients with sepsis have concomitant inflammation and features of immune exhaustion, an attractive strategy might augment specific immune responses, particularly if it could be predicted which patients would be most likely to benefit.

Specifically reversing sepsis-associated lymphopenia has been the focus of immunoadjuvant trials of recombinant human interleukin-7 (rhIL-7), a cytokine favoring lymphocyte survival and proliferation. In a small phase IIb trial of patients with septic shock, rhIL-7 increased lymphocyte cell counts and was well tolerated, although no effect on mortality was seen. RhIL-7 has also been administered to a small series of 12 critically ill patients with COVID-19; the lymphocyte cell count increased, although changes in inflammatory cytokines or survival were not seen.

Cheng et al report an open-label randomized trial of recombinant human granulocyte colony-stimulating factor (rhG-CSF) compared with usual care in 200 hospitalized adults with COVID-19, pneumonia, and lymphopenia (absolute lymphocyte count, ≤ 800/μL [to convert to ×109/μL, multiply by 0.001]). Patients with preexisting conditions, baseline leukocytosis, and those requiring invasive mechanical ventilation at the time of screening were excluded. The patients in the treatment arm received 3 daily doses of subcutaneous rhG-CSF, 5 μg/kg. Usual care included oxygen, assisted ventilation if needed, and antibiotics or adjuvant therapies (corticosteroids, lopinavir-ritonavir, arbidol, or inhaled α-interferon) at the discretion of the treating physician.

The primary outcome was the time to clinical improvement of at least 1 point on a 7-point ordinal scale of clinical and respiratory severity ranging from not hospitalized with normal activities to death. The treatment groups were reasonably well balanced at enrollment, with a slightly more participants in the usual care arm receiving high-flow oxygen and adjuvant therapies before randomization. There was no difference in the primary outcome by treatment group. Treatment with rhG-CSF increased lymphocyte and leukocyte cell counts by day 5. Participants randomized to receive rhG-CSF were less likely to progress to invasive ventilation or shock and exhibited lower 21-day mortality. Both of these secondary end points were statistically significant.

Cheng et al tested for heterogeneity of rhG-CSF treatment effect by patient factors, including degree of lymphopenia, degree of baseline oxygen support, age, and sex. They detected significant interaction between the effect of rhG-CSF and the degree of lymphopenia, stratifying at a lymphocyte cell count of 400 or less per μL, with the participants with more severe lymphopenia exhibiting greater improvement. In contrast, for the roughly 50% of the study population with a lymphocyte cell count more than 400 per μL, no effect of rhG-CSF was observed. Similarly, Cheng et al report a significant interaction between the level of oxygen support and the rhG-CSF effect. Participants requiring high-flow oxygen or noninvasive ventilation at enrollment demonstrated a significant improvement in the primary outcome. In contrast, those requiring low-flow oxygen or no supplemental oxygen did not manifest a benefit.

Although the subgroup analyses suggesting a heterogeneous effect of rhG-CSF on COVID-19 recovery are provocative, caution should be exercised in interpreting these data, as the findings could be biased. For example, the stratification threshold for lymphopenia (≤400/μL) is not validated. These and other stratified results should be viewed as hypothesis-generating; they require prospective testing before they should influence clinical care. Also, it is not clear whether the administration of adjuvant therapies without a proven benefit for patients with COVID-19 affected the trial results. The more frequent use of these agents in the usual care arm suggests that clinicians viewed patients in this group as having greater illness severity or higher risk, perhaps explaining the higher proportion with worse outcomes.

The trial of rhG-CSF conducted by Cheng et al was relatively small, excluded patients with comorbidities, and was conducted early during the COVID-19 pandemic. Moreover, since this trial was conducted, the standard of care for hospitalized patients with COVID-19 has evolved considerably to include the use of remdesivir and dexamethasone. It is unclear how receipt of these medications in a uniform manner might influence the effects of rhG-CSF. Important next steps in determining the role of rhG-CSF or other medications that target lymphopenia in patients with COVID-19 are larger trials that incorporate the evolving standard of care into the control arm and the inclusion of patients with comorbidities.

JAMA Internal Medicine, September 10, 2020

Effect of Recombinant Human Granulocyte Colony–Stimulating Factor for Patients With Coronavirus Disease 2019 (COVID-19) and Lymphopenia,A Randomized Clinical Trial

Lin-ling Cheng, et al

In this open-label, randomized clinical trial of 200 Chinese patients with COVID-19, lymphopenia, and no comorbidities, rhG-CSF treatment did not accelerate clinical improvement, but the number of patients progressing to critical illness or death may have been reduced, without an increased risk of serious adverse events.

Between February 18 and April 10, 2020, we conducted an open-label, multicenter, randomized clinical trial at 3 participating centers in China. The main eligibility criteria were pneumonia, a blood lymphocyte cell count of 800 per μL (to convert to ×109/L, multiply by 0.001) or lower, and no comorbidities. Severe acute respiratory syndrome coronavirus 2 infection was confirmed with reverse-transcription polymerase chain reaction testing.

Exposures

Usual care alone, or usual care plus 3 doses of recombinant human granulocyte colony-stimulating factor (rhG-CSF, 5 μg/kg, subcutaneously at days 0-2).

The primary endpoint was the time from randomization to improvement of at least 1 point on a 7-category disease severity score.

Of 200 participants, 112 (56%) were men and the median (interquartile range [IQR]) age was 45 (40-55) years. There was a random assignment of 100 patients (50%) to the rhG-CSF group and 100 (50%) to the usual care group. Time to clinical improvement was similar between groups (rhG-CSF group median of 12 days (IQR, 10-16 days) vs usual care group median of 13 days (IQR, 11-17 days); hazard ratio, 1.28; 95% CI, 0.95-1.71; P = .06). For secondary endpoints, the proportion of patients progressing to acute respiratory distress syndrome, sepsis, or septic shock was lower in the rhG-CSF group (rhG-CSF group, 2% vs usual care group, 15%; difference, −13%; 95%CI, −21.4% to −5.4%). At 21 days, 2 patients (2%) had died in the rhG-CSF group compared with 10 patients (10%) in the usual care group (hazard ratio, 0.19; 95%CI, 0.04-0.88). At day 5, the lymphocyte cell count was higher in the rhG-CSF group (rhG-CSF group median of 1050/μL vs usual care group median of 620/μL; Hodges-Lehmann estimate of the difference in medians, 440; 95% CI, 380-490). Serious adverse events, such as sepsis or septic shock, respiratory failure, and acute respiratory distress syndrome, occurred in 29 patients (14.5%) in the rhG-CSF group and 42 patients (21%) in the usual care group.

This study has limitations. First, it was limited by its small size and the observational time frame of 21 days, within which discharge from hospital or death might not have been documented. Second, the open-label trial design might have affected the outcome measures. Third, the authors did not exclude patients who had received antiviral therapy or systemic corticosteroids before enrollment, which could have confounded the findings. Finally, they excluded patients who had comorbidities to minimize the potential adverse effects of other comorbidities on the immune responses of patients and also the potential for adverse events related to rhG-CSF treatment.

Lancet Rheumatology September 09, 2020

COVACTA trial raises questions about tocilizumab’s benefit in COVID-19

Bryant Furlow

The randomised controlled COVACTA trial failed to meet its primary endpoint of improved clinical status, the company announced on July 29. Nor did tocilizumab improve patient mortality, although tocilizumab-treated patients spent roughly a week less in hospital compared with those given placebo, which could have a meaningful clinical impact in the face of surging capacity during a pandemic. Full results of the trial have not yet been published.

Another IL-6 antagonist, sarilumab, showed early promise in retrospective studies, only to see a prospective, randomised phase 3 study suspended for futility.

Tocilizumab's potential as a COVID-19 therapy has been controversial from the start, partly because IL-6 has both pro-inflammatory and anti-inflammatory effects and is also involved in antiviral responses. Like glucocorticoids, IL-6 blockade can increase patients' risks of secondary infections. But retrospective studies have suggested an association between tocilizumab and reduced hospital mortality, particularly in patients in intensive care units, as well as evidence that baseline C-reactive protein concentrations (controlled in part by IL-6) predict benefit.

COVACTA's failure raises doubts about these earlier associations, but researchers are awaiting the full trial data, including those on SARS-CoV-2 viral loads and inflammatory marker trends over the entire study period.

For the time being, glucocorticoids will “likely save the day” for the global COVID-19 response because of their ready availability and low expense, Cron said. Dexamethasone is the only drug thus far to have shown a mortality benefit for patients with COVID-19.

But here too, timing could be crucial. The RECOVERY trial results show a clear benefit of dexamethasone in patients who require respiratory support but not in patients who do not require respiratory support.

Any benefit of anti-inflammatory treatments would likely be observed only in patients who progress to an inflammatory state, which usually happens around one week into illness.

Medical Education

NEJM September 10, 2020

Can Covid Catalyze an Educational Transformation? Competency-Based Advancement in a Crisis

Mary Ellen J. Goldhamer, et al

Because Covid’s disruption to GME may continue — and because CB-TV GME has been a goal for educational reform — we should use this unexpected, uncontrolled experiment as an opportunity to learn how best to implement CB-TV GME. Studying outcomes of physicians who graduate without fulfilling case quotas or time requirements, and investing in evidence-based methods to assess physician competence, will help in charting the course ahead. In these ways, we hope that the Covid crisis will be used to capitalize on prior work and catalyze planning for a robust system of CB-TV GME, achieving sustainable improvement in how we train physicians.

Historically, GME relied on immersion in patient care with informal supervision and assessment; residents graduated if they completed the prescribed duration of training without evidence of significant shortcomings. In 1999, the Accreditation Council for Graduate Medical Education (ACGME), which accredits training programs, articulated six core competencies, establishing a more structured and deliberate approach to physician training and thereby paving the way for the development of competency-based program curricula and assessment. Subsequent delineation of entrustable professional activities and specialty-specific milestones have advanced a framework for assessing physician competency.

The next logical step in this evolution is a transition from time-based to competency-based, time-variable (CB-TV) GME, in which each physician graduates from residency (or fellowship) to unsupervised practice when — and only when — the necessary competencies are achieved. Canada has launched a nationwide transition to CB-TV GME across all specialties, after completing pioneering pilot work in orthopedics.

The United States, however, is still tethered to time- and case-volume–based training requirements, as evidenced by ACGME and specialty-board certification standards (see table). Several factors impede implementation of CB-TV GME, including heavy reliance on residents and fellows to deliver care, lack of confidence in our assessment of trainees, regulatory requirements that constrain innovation, scarce funding for medical education research, and complacency about the status quo.

Covid may propel us over the threshold to CB-TV GME.

Indeed, the competency-based, time-variable approach to GME presumes that some people will need less than the standard volume of experience or time in training and others will need more. Our accelerated foray into CB-TV GME will have to tackle the challenge of requiring and providing extended training for those who need it.

Miscellaneous

Lancet Global Health September 09, 2020

Projected health-care resource needs for an effective response to COVID-19 in 73 low-income and middle-income countries: a modelling study

Tessa Tan-Torres Edejer, et al

This Article discusses the costs of pandemic preparedness if current COVID-19 transmission levels are maintained or scenarios where transmission is increased or decreased by 50%. The modelling study projected the number of COVID-19 cases for 73 LMICs for each scenario for both 4 and 12-week timeframes. The cost estimate for the COVID-19 response if transmission levels are maintained is US$52∙45 billion over 4 weeks. For decreased or increased transmission scenarios, the total is US$33∙08 billion and US$61∙92 billion respectively, with costs tripling under the 12 weeks scenarios. The main cost drivers were clinical case management (54%), maintaining essential services (21%), rapid response and case investigation (14%), and infection prevention and control (9%). The authors assert that sizeable costs of a COVID-19 response in the health sector will escalate, particularly if transmission increases, highlighting the importance of working to reduce virus transmission and contain costs.

JAMA September 8, 2020

Prevalence of Third-Party Tracking on COVID-19–Related Web Pages

Matthew S. McCoy, et al

This study found that 99% of COVID-19–related web pages included a third-party data request, and 89% included a third-party cookie. By comparison, a prior study of 1 million popular web pages found that 91% included a third-party data request and 70% included a third-party cookie.

Third-party tracking was pervasive even among government and academic COVID-19–related web pages, on which visitors might reasonably expect greater privacy protections. Decision-makers at these institutions may be unaware of third-party tracking on their websites because they do not realize that tools used to monitor website traffic transmit data to third parties.

Amid debate and legislative activity focused on the privacy implications of COVID-19 contact-tracing apps, these findings suggest that attention should also be paid to privacy risks of online information seeking.

Online information seeking related to COVID-19 may carry privacy risks. Prior research has shown that web pages visited by individuals seeking health information frequently contain code that initiates data transfers to third parties, such as online advertisers. These transfers often include URLs of visited pages and users’ IP addresses. When third parties have code on multiple web pages, they can build detailed profiles of specific individuals’ browsing behaviors and interests. This practice, known as “web tracking,” can reveal sensitive information about individuals’ health conditions and concerns to parties who wish to profit from it.

To better understand the privacy risks of online information seeking related to COVID-19, the authors assessed the prevalence and characteristics of web tracking on COVID-19–related web pages.

Overall, 535 of 538 (99%; 95% CI, 98%-100%) unique web pages included a third-party data request, with no significant differences by website type, while 477 (89%; 95% CI, 86%-91%) included a third-party cookie. Compared with commercial web pages, third-party cookies were slightly less common, although still highly prevalent, among government and academic web pages. However, the median numbers of third-party data requests and third-party cookies per page were both higher on commercial web pages (77 requests; 130 cookies) than on government (8 requests; 4 cookies), nonprofit (16 requests; 7 cookies), or academic (14 requests; 10 cookies) web pages.

Most (95%; 95% CI, 93%-97%) web pages included a data request from a third-party domain owned by Google, while 7 other companies received data from at least 40% of web pages studied.