Expansion of profibrotic monocyte-derived alveolar macrophages in patients with persistent respiratory symptoms and radiographic abnormalities after COVID-19 (preprint)

As many as 10-30% of the over 760 million survivors of COVID-19 develop persistent symptoms, of which respiratory symptoms are among the most common. To understand the cellular and molecular basis for respiratory PASC, we combined a machine learning-based analysis of lung computed tomography (CT) with flow cytometry, single-cell RNA-sequencing analysis of bronchoalveolar lavage fluid and nasal curettage samples, and alveolar cytokine profiling in a cohort of thirty-five patients with respiratory symptoms and radiographic abnormalities more than 90 days after infection with COVID-19. CT images from patients with PASC revealed abnormalities involving 73% of the lung, which improved on subsequent imaging. Interstitial abnormalities suggestive of fibrosis on CT were associated with the increased numbers of neutrophils and presence of profibrotic monocyte-derived alveolar macrophages in BAL fluid, reflecting unresolved epithelial injury. Persistent infection with SARS-CoV-2 was identified in six patients and secondary bacterial or viral infections in two others. These findings suggest that despite its heterogenous clinical presentations, respiratory PASC with radiographic abnormalities results from a common pathobiology characterized by the ongoing recruitment of neutrophils and profibrotic monocyte-derived alveolar macrophages driving lung fibrosis with implications for diagnosis and therapy.

Prolonged exposure to lung-derived cytokines is associated with inflammatory activation of microglia in patients with COVID-19 (preprint)

Neurological impairment is the most common finding in patients with post-acute sequelae of COVID-19. Furthermore, survivors of pneumonia from any cause have an elevated risk of dementia. Dysfunction in microglia, the primary immune cell in the brain, has been linked to cognitive impairment in murine models of dementia and in humans. Here, we report a transcriptional response in human microglia collected from patients who died following COVID-19 suggestive of their activation by TNF- and other circulating pro-inflammatory cytokines. Consistent with these findings, the levels of 55 alveolar and plasma cytokines were elevated in a cohort of 341 patients with respiratory failure, including 93 unvaccinated patients with COVID-19 and 203 patients with other causes of pneumonia. While peak levels of pro-inflammatory cytokines were similar in patients with pneumonia irrespective of etiology, cumulative cytokine exposure was higher in patients with COVID-19. Corticosteroid treatment, which has been shown to be beneficial in patients with COVID-19, was associated with lower levels of CXCL10, CCL8, and CCL2 - molecules that sustain inflammatory circuits between alveolar macrophages harboring SARS-CoV-2 and activated T cells. These findings suggest that corticosteroids may break this cycle and decrease systemic exposure to lung-derived cytokines and inflammatory activation of microglia in patients with COVID-19.

Risk-based prediction for optimal timing of booster vaccination for COVID-19 to prevent severe disease (preprint)

While waning protection from vaccination and natural infection against SARS-CoV-2 infection is well-documented, recent analyses have also found waning of protection against severe COVID-19. This highlights a broader need to understand the optimal timing of COVID-19 booster vaccines specific to an individual to mitigate the risk of severe COVID-19, while accounting for waning of protection and differential risk by age group and immune status. Here we show that more frequent COVID-19 booster vaccination (every 6-12 months) in older age groups and the immunocompromised population would effectively mitigate the burden of severe COVID-19, while frequent boosters in the younger population may only provide modest benefit. Analyzing United States COVID-19 surveillance and seroprevalence data in a microsimulation model, we estimated that in persons 75+ years, annual and semiannual bivalent boosters would reduce annual absolute risk of severe COVID-19 by 311 (277-369) and 578 (494-671) cases, respectively, compared to a one-time bivalent booster dose. In contrast, for persons 18-49 years, the model estimated that annual and semiannual bivalent boosters would reduce annual absolute risk of severe COVID-19 by 20 (13-26) and 37 (24-50) cases per 100,000 persons, respectively, compared to a one-time bivalent booster dose. Persons with prior infection had a much lower benefit of more frequent boosting, while immunocompromised persons had larger benefit. This study underscores the benefit of customizing timing of COVID-19 booster vaccines based on individual risk.

Outcomes in patients with large vessel occlusion strokes undergoing mechanical thrombectomy with concurrent COVID-19: a nationwide retrospective analysis.

BACKGROUND: Preliminary studies show that patients with large vessel occlusion (LVO) acute ischemic strokes have worse outcomes with concurrent COVID-19 infection. We investigated the outcomes for patients with LVO strokes undergoing mechanical thrombectomy (MT) with concurrent COVID-19 infection. METHODS: The National Inpatient Database (NIS) was used for our analysis. Patients in the year 2020 with an ICD-10 diagnosis code for acute ischemic stroke and procedural code for MT were included with and without COVID-19. Odds ratios (OR) were calculated using a logistic regression model with age, sex, stroke location, Elixhauser comorbidity score, and other patient variables deemed clinically relevant as covariates. RESULTS: Patients in the COVID-19 group were younger (64.3±14.4 vs 69.4±14.5 years, P<0.001), had a higher rate of inpatient mortality (22.4% vs 10.1%, P<0.001), and a longer length of stay (10 vs 6 days, P<0.001). Patients with COVID-19 had higher odds of death (OR 2.78, 95% CI 2.11 to 3.65) and lower odds of a routine discharge (OR 0.65, 95% CI 0.48 to 0.89). There was no difference in the odds of subsequent stroke and cerebral hemorrhage, but patients with COVID-19 had statistically significantly higher odds of respiratory failure, pulmonary embolism, deep vein thrombosis, myocardial infarction, acute kidney injury, and sepsis. CONCLUSIONS: Patients with LVOs undergoing MT within the 2020 NIS database had worse outcomes when co-diagnosed with COVID-19, likely due to non-neurological manifestations of COVID-19.

New science, drug regulation, and emergent public health issues: The work of FDA's division of applied regulatory science.

The U.S. Food and Drug Administration (FDA) Division of Applied Regulatory Science (DARS) moves new science into the drug review process and addresses emergent regulatory and public health questions for the Agency. By forming interdisciplinary teams, DARS conducts mission-critical research to provide answers to scientific questions and solutions to regulatory challenges. Staffed by experts across the translational research spectrum, DARS forms synergies by pulling together scientists and experts from diverse backgrounds to collaborate in tackling some of the most complex challenges facing FDA. This includes (but is not limited to) assessing the systemic absorption of sunscreens, evaluating whether certain drugs can convert to carcinogens in people, studying drug interactions with opioids, optimizing opioid antagonist dosing in community settings, removing barriers to biosimilar and generic drug development, and advancing therapeutic development for rare diseases. FDA tasks DARS with wide ranging issues that encompass regulatory science; DARS, in turn, helps the Agency solve these challenges. The impact of DARS research is felt by patients, the pharmaceutical industry, and fellow regulators. This article reviews applied research projects and initiatives led by DARS and conducts a deeper dive into select examples illustrating the impactful work of the Division.

The public health impact of Paxlovid COVID-19 treatment in the United States (preprint)

The antiviral drug Paxlovid has been shown to rapidly reduce viral load. Coupled with vaccination, timely administration of safe and effective antivirals could provide a path towards managing COVID-19 without restrictive non-pharmaceutical measures. Here, we estimate the population-level impacts of expanding treatment with Paxlovid in the US using a multi-scale mathematical model of SARS-CoV-2 transmission that incorporates the within-host viral load dynamics of the Omicron variant. We find that, under a low transmission scenario (Re~1.2) treating 20% of symptomatic cases with Paxlovid would be life and cost saving, leading to an estimated 0.26 (95% CrI:0.03, 0.59) million hospitalizations averted, 30.61 (95% CrI:1.69, 71.15) thousand deaths averted, and US$52.16 (95% CrI:2.62, 122.63) billion reduction in the US. Rapid and broad use of the antiviral Paxlovid could substantially reduce COVID-19 morbidity and mortality, while averting socioeconomic hardship.

Biocidal products: Opportunities in risk assessment, management, and communication.

In the coronavirus disease 2019 era, biocidal products are increasingly used for controlling harmful organisms, including microorganisms. However, assuring safety against adverse health effects is a critical issue from a public health standpoint. This study aimed to provide an overview of key aspects of risk assessment, management, and communication that ensure the safety of biocidal active ingredients and products. The inherent characteristics of biocidal products make them effective against pests and pathogens; however, they also possess potential toxicities. Therefore, public awareness regarding both the beneficial and potential adverse effects of biocidal products needs to be increased. Biocidal active ingredients and products are regulated under specific laws: the Federal Insecticide, Fungicide, and Rodenticide Act for the United States; the European Union (EU) Biocidal Products Regulation for the EU; and the Consumer Chemical Products and Biocide Safety Management Act for the Republic of Korea. Risk management also needs to consider the evidence of enhanced sensitivity to toxicities in individuals with chronic diseases, given the increased prevalence of these conditions in the population. This is particularly important for post-marketing safety assessments of biocidal products. Risk communication conveys information, including potential risks and risk-reduction measures, aimed at managing or controlling health or environmental risks. Taken together, the collaborative effort of stakeholders in risk assessment, management, and communication strategies is critical to ensuring the safety of biocidal products sold in the market as these strategies are constantly evolving.

Community incidence patterns drive the risk of SARS-CoV-2 outbreaks and alter intervention impacts in a high-risk institutional setting.

Optimization of control measures for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in high-risk institutional settings (e.g., prisons, nursing homes, or military bases) depends on how transmission dynamics in the broader community influence outbreak risk locally. We calibrated an individual-based transmission model of a military training camp to the number of RT-PCR positive trainees throughout 2020 and 2021. The predicted number of infected new arrivals closely followed adjusted national incidence and increased early outbreak risk after accounting for vaccination coverage, masking compliance, and virus variants. Outbreak size was strongly correlated with the predicted number of off-base infections among staff during training camp. In addition, off-base infections reduced the impact of arrival screening and masking, while the number of infectious trainees upon arrival reduced the impact of vaccination and staff testing. Our results highlight the importance of outside incidence patterns for modulating risk and the optimal mixture of control measures in institutional settings.

Demise of the USMLE Step-2 CS exam: Rationalizing a way forward.

The COVID-19 pandemic has compelled rethinking and changes in medical education, the most controversial perhaps being the cancelation of USMLE Step-2 Clinical Skills exam (Step-2 CS). What started in March of 2020 as suspension of this professional licensure exam, because of concerns about infection risk for examinees, standardized patients (SPs), and administrators, soon became permanent cancelation in January 2021. Expectedly, it triggered debate in medical education circles. Positively, however, the USMLE regulatory agencies (NBME and FSMB) saw an opportunity to innovate an exam tainted with perceptions of validity deficits, cost, examinee inconvenience, and worries about future pandemics; they therefore called for a public debate to fashion a way forward. We have approached the issue by defining Clinical Skills (CS), exploring its epistemology and historic evolution, including assessment modalities from Hippocratic times to the modern era. We defined CS as the art of medicine manifest in the physician-patient encounter as history taking (driven by communication skills and cultural competence) and physical examination. We classified CS components into knowledge and psychomotor skill domains, established their relative importance in the physician process (clinical reasoning) of diagnosis, thus establishing a theoretical framework for developing valid, reliable, feasible, fair, and verifiable CS assessment. Given the concerns for COVID-19 and future pandemics, we established that CS can largely be assessed remotely, and what could not, can be assessed locally (school/regional consortia level) as part of a USMLE-regulated/supervised assessment regimen with established national standards, thus maintaining USMLE's fiduciary responsibilities. We have suggested a national/regional program for faculty development in CS curriculum development, and assessment, including standard setting skills. This pool of expert faculty will form the nucleus of our proposed USMLE-regulated External Peer Review Initiative (EPRI). Finally, we suggest that CS evolves into an academic discipline/department of its own, rooted in scholarship.

Debates, tensions, and alternatives in health promotion education from south-north and south-south cooperation: The health promotion and social development master experience

This chapter covers the experience of the iPROMS, Master's Degree in Health Promotion and Social Development, as well as the learnings gathered from its implementation, offered since 2013 and provided in Spanish in an online platform by ISPED at the Universite de Bordeaux, France, and the Faculty of Health Sciences at the UPNA, Spain. This experience was shaped as a triangular prism involving faculty members from the UPNA, the ISPED, and Latin America. The co-production of this chapter took place within the context of the COVID-19 pandemic, a social and health emergency with global and differential impacts aggravating pre-existing structural inequalities, an integrated and critical approach intended to break with the northern hemisphere hegemony in the field of public health and health promotion. We also understand the importance of interdisciplinary, intercultural lenses and seek to integrate diverse professional voices and trajectories, resulting in a perspective that reflects the complexity of the health promotion field. The first section describes the main features of the processes that shaped the Masters experience. The second section explains the key components of the pedagogical proposal, in particular the challenge of pursuing an academic relationship integrating the experience of the Southern hemisphere, avoiding hegemonic positions and based on mutual respect and creative dialogue. The last section introduces some of the lessons learned as well as pending challenges and opportunities for scaling up the experience in alternative scenarios. Within the last section, the following aspects were highlighted according to their pedagogical relevance: academic training (academic oriented) vs. professional training (practice oriented), questioning hegemonic approaches and confronting teaching models, learning achievements, and, finally, thinking in terms of community. © The Author(s), under exclusive license to Springer Nature Switzerland AG 2022. All rights reserved.

Royal Society of Medicine, Colt Foundation Research & Clinical Innovation Meeting 2022

Correspondence to Wg Cdr Robert M Barker-Davies, Academic Department of Military Rehabilitation, Defence Medical Rehabilitation Centre Stanford Hall, Loughborough, LE12 5BR, UK;Robert.barker-davies@nhs.net The Royal Society of Medicine (RSM–Military Medicine Section), Colt Foundation Research & Clinical Innovation Meeting has been at the core of Defence Medical Services (DMS) academic activity since its inception in 2007. Initially, the meeting sought submissions from medical officers, typically undertaking higher degrees, but in recent years the scope of the meeting has been broadened to include all healthcare professional disciplines.1 2 This reflects the strategic directions of both UK Healthcare and the DMS towards greater interdisciplinary healthcare delivery models and integrated research3 in which shared role understanding and supportive team structures have been identified as themes that promote collaborative success in military medical teams.4 The top six s for the Colt Research prize, published here in BMJ Military Health, reflect this diversity as they span several disciplines and both academic and Defence institutions. [...]we heard from Captain Kat Matthews, army physiotherapist and professional triathlete.

Cardiopulmonary, functional, cognitive and mental health outcomes post covid, across the range of severity of acute illness, in a physically active working age population: baseline findings from the MCOVID study

BackgroundThe medium-long impact of coronavirus disease 2019 (COVID-19) on active populations is yet to be fully understood, with potential individual and operational impact on military service personnel (SP). The M-COVID study was established to investigate cardiopulmonary, functional, cognitive, and mental health post-COVID-19 SP outcomes, across the spectrum of acute COVID-19 severity.MethodObservational four-cohort study;hospitalised, community-based illness with on-going symptoms (communitysymptomatic), community-based illness now recovered (community-recovered) and age, sex, job-role matched control. Participants underwent extensive clinical assessment involving cardiopulmonary imaging, submaximal and maximal exercise testing, pulmonary function, cognitive assessment, blood tests, electrocardiogram and questionnaires on mental health and physical function.Results113 participants (aged 39±9, 86% male) were recruited;Hospitalised (n=35), community-symptomatic (n=34), community-recovered (n=18) and control (n=26), 159±72 days following acute illness. Hospitalised and community-symptomatic groups were older (p=0.003), with a higher body mass index (p<0.001), and worse mental health (anxiety,p=0.011;depression,p<0.001;post-traumatic stress, p<0.001), fatigue (p<0.001), and quality of life scores (p=0.001), with a mean of 2±2 and 2±1 symptoms, respectively. Hospitalised and community-symptomatic participants also performed less well on sub-maximal (p<0.001) and maximal exercise testing, with hospitalised individuals displaying impaired ventilatory efficiency (p<0.001), less work at the anaerobic threshold and at peak (both p<0.001), and significantly reduced forced vital capacity (p=0.004). Clinically significant abnormal cardiopulmonary imaging findings were present in 6% of hospitalised participants, lower than those seen in other studies. Those who recovered from communitybased, mild-moderate COVID-19 had no significant differences from controls on any parameter.ConclusionsRecovered SP who suffered mild-moderate COVID-19 do not differ from an age, sex and job-role matched controls. This is reassuring for the vast majority of individuals who have had acute COVID-19 not requiring hospital management. Individuals who were hospitalised or continue to suffer symptoms may require a specific, comprehensive clinical and occupational assessment prior to a full return to duty.

Efficient and effective large-scale vaccine distribution

The goal of pandemic response is to provide the greatest protection, for the most people, in the least amount of time. Short response times minimize both current and future health impacts for evolving pathogens that pose global threats. To achieve this goal, efficient and effective systems are needed for distributing and administering vaccines, a cornerstone of pandemic response. COVID-19 vaccines were developed in record time in the U.S. and abroad, but U.S. data shows that they were not distributed efficiently and effectively once available. In an effort to "put vaccines on every corner”, pharmacies and other small venues were a primary means for vaccinating individuals, but daily throughput rates at these locations were very low. This contributed to extended times from manufacture to administration. An important contributing factor to slow administration rates for COVID-19 was vaccine transport and storage box size. In this paper, we establish a general system objective and provide a computationally tractable approach for allocating vaccines in a rolling horizon manner optimally. We illustrate the consequences of both box size and the number and capacity of dispensing locations on achieving system objectives. Using U.S. CDC data, we demonstrate that if vaccines are allocated and distributed according to our proposed strategy, more people would have been vaccinated sooner in the U.S. Many additional days of protection would have occurred, meaning there would have been fewer infections, less demand for healthcare resources, lower overall mortality, and fewer opportunities for the evolution of vaccine-evading strains of the disease.

Characterizing the most Popular Tinnitus Inquiries: Is Tinnitus Incidence on the Rise Since COVID-19?

OBJECTIVE: Approximately 50 million US adults experience chronic tinnitus, yet search behaviors and topics of concern to these patients have not been investigated on a national level. STUDY DESIGN: Observational. SETTING: Online database and tertiary otology clinic. PATIENTS: Nationwide and institutional samples. INTERVENTIONS: None. MAIN OUTCOME MEASURE: A search engine optimization tool was utilized to extract metadata on "People Also Ask" (PAA) questions pertaining to tinnitus. Website quality was assessed using JAMA benchmark criteria. Search volume trends were investigated along with institutional-level data on tinnitus incidence. RESULTS: Of the 500 PAA questions assessed, the majority (54.0%) contained value-type content. The most popular question categories pertained to tinnitus treatment (29.3%), alternative treatment approaches (21.5%), technical details (16.9%), and timeline of symptoms (13.4%). Patients were most interested in treatment with wearable masking devices and most commonly searched for tinnitus as being attributable to a neurologic etiology. Online searches pertaining to unilateral tinnitus symptoms have increased >3-fold since the onset of the COVID-19 pandemic. Likewise, review of patient encounters at our tertiary otology clinic revealed a nearly 2-fold increase in tinnitus consultations since 2020. CONCLUSIONS: Topics of interest and concern identified herein may inform the development of patient education materials and help guide clinical practice. Online search data suggest an increase in tinnitus searches since the onset of COVID-19, which did correlate clinically with an increase in tinnitus consultations at our institution.

An aluminum hydroxide:CpG adjuvant enhances protection elicited by a SARS-CoV-2 receptor binding domain vaccine in aged mice.

Global deployment of vaccines that can provide protection across several age groups is still urgently needed to end the COVID-19 pandemic, especially in low- and middle-income countries. Although vaccines against SARS-CoV-2 based on mRNA and adenoviral vector technologies have been rapidly developed, additional practical and scalable SARS-CoV-2 vaccines are required to meet global demand. Protein subunit vaccines formulated with appropriate adjuvants represent an approach to address this urgent need. The receptor binding domain (RBD) is a key target of SARS-CoV-2 neutralizing antibodies but is poorly immunogenic. We therefore compared pattern recognition receptor (PRR) agonists alone or formulated with aluminum hydroxide (AH) and benchmarked them against AS01B and AS03-like emulsion-based adjuvants for their potential to enhance RBD immunogenicity in young and aged mice. We found that an AH and CpG adjuvant formulation (AH:CpG) produced an 80-fold increase in anti-RBD neutralizing antibody titers in both age groups relative to AH alone and protected aged mice from the SARS-CoV-2 challenge. The AH:CpG-adjuvanted RBD vaccine elicited neutralizing antibodies against both wild-type SARS-CoV-2 and the B.1.351 (beta) variant at serum concentrations comparable to those induced by the licensed Pfizer-BioNTech BNT162b2 mRNA vaccine. AH:CpG induced similar cytokine and chemokine gene enrichment patterns in the draining lymph nodes of both young adult and aged mice and enhanced cytokine and chemokine production in human mononuclear cells of younger and older adults. These data support further development of AH:CpG-adjuvanted RBD as an affordable vaccine that may be effective across multiple age groups.

Social and moral psychology of COVID-19 across 69 countries.

The COVID-19 pandemic has affected all domains of human life, including the economic and social fabric of societies. One of the central strategies for managing public health throughout the pandemic has been through persuasive messaging and collective behaviour change. To help scholars better understand the social and moral psychology behind public health behaviour, we present a dataset comprising of 51,404 individuals from 69 countries. This dataset was collected for the International Collaboration on Social & Moral Psychology of COVID-19 project (ICSMP COVID-19). This social science survey invited participants around the world to complete a series of moral and psychological measures and public health attitudes about COVID-19 during an early phase of the COVID-19 pandemic (between April and June 2020). The survey included seven broad categories of questions: COVID-19 beliefs and compliance behaviours; identity and social attitudes; ideology; health and well-being; moral beliefs and motivation; personality traits; and demographic variables. We report both raw and cleaned data, along with all survey materials, data visualisations, and psychometric evaluations of key variables.