Mucosal and systemic immune dynamics associated with COVID-19 outcomes: a longitudinal prospective clinical study (preprint)

Rationale: COVID-19 severity varies widely; children and African Americans have low and high risk, respectively. Mechanistic data from these groups and the mucosa is lacking. Objectives: To quantify mucosal and systemic viral and immune dynamics in a diverse cohort to identify mechanisms underpinning COVID-19 severity and outcome predictors. Methods: In this prospective study of unvaccinated children and adults COVID-19 outcome was based on an ordinal clinical severity scale. We quantified viral RNA, antigens, antibodies, and cytokines by PCR, ELISA, and Luminex from 579 longitudinally collected blood and nasal specimens from 78 subjects including 45 women and used modeling to determine functional relationships between these data. Measurements and Main Results: COVID-19 induced unique immune responses in African Americans (n=26) and children (n=20). Mild outcome was associated with more effective coordinated responses whereas moderate and severe outcomes had rapid seroconversion, significantly higher antigen, mucosal sCD40L, MCP-3, MCP-1, MIP-1, and MIP-1{beta}, and systemic IgA, IgM, IL-6, IL-8, IL-10, IL-15, IL-1RA, and IP-10, and uncoordinated early immune responses that went unresolved. Mucosal IL-8, IL-1{beta}, and IFN-{gamma} with systemic IL-1RA and IgA predicted COVID-19 outcomes. Conclusions: We present novel mucosal data, biomarkers, and therapeutic targets from a diverse cohort. Based on our findings, children and African Americans with COVID-19 have significantly lower IL-6 and IL-17 levels which may reduce responsiveness to drugs targeting IL-6 and IL-17. Unregulated immune responses persisted indicating moderate to severe COVID-19 cases may require prolonged treatments. Reliance on slower acting adaptive responses may cause immune crisis for some adults who encounter a novel virus.

Application of the PHENotype SIMulator for rapid identification of potential candidates in effective COVID-19 drug repurposing

The current, rapidly diversifying pandemic has accelerated the need for efficient and effective identification of potential drug candidates for COVID-19. Knowledge on host-immune response to SARS-CoV-2 infection, however, remains limited with few drugs approved to date. Viable strategies and tools are rapidly arising to address this, especially with repurposing of existing drugs offering significant promise. Here we introduce a systems biology tool, the PHENotype SIMulator, which -by leveraging available transcriptomic and proteomic databases-allows modeling of SARS-CoV-2 infection in host cells in silico to i) determine with high sensitivity and specificity (both>96%) the viral effects on cellular host-immune response, resulting in specific cellular SARS-CoV-2 signatures and ii) utilize these cell-specific signatures to identify promising repurposable therapeutics. Powered by this tool, coupled with domain expertise, we identify several potential COVID-19 drugs including methylprednisolone and metformin, and further discern key cellular SARS-CoV-2-affected pathways as potential druggable targets in COVID-19 pathogenesis. Graphical abstract Application of the PHENotype SIMulator: By modeling human host-cell infection with a pathogen in silico - in this case SARS-CoV-2 - we can acquire a cell-specific viral signature and formulate multiple drug repurposing hypotheses;(I) logFold Changes (logFCs) of Differentially Expressed Genes (DEGs) arising from transcriptomic genome wide expression analysis of infected vs. baseline uninfected cells are used to represent a virus in the meta-pathway;(II) we run the PHENSIM simulation by upregulating the viral node and collect all perturbation values computed by PHENSIM for pathway endpoints to define a cell-specific pathogen signature. (III) The same process is applied to expression data arising from whole transcriptome-wide expression analysis of drug treated vs. mock-treated cell lines, yielding a cell-specific drug signature. This process is iterated for each drug we wish to test and collected in a database of drug signatures. (IV) Finally, a Pearson correlation analysis between the pathogen and each drug signature is utilized to score repurposing candidates.Image 1

Eliciting Opinions on Health Messaging During the COVID-19 Pandemic: Qualitative Survey Study.

BACKGROUND: Effective public health messaging has been necessary throughout the COVID-19 pandemic, but stakeholders have struggled to communicate critical information to the public, especially in different types of locations such as urban and rural areas. OBJECTIVE: This study aimed to identify opportunities to improve COVID-19 messages for community distribution in rural and urban settings and to summarize the findings to inform future messaging. METHODS: We purposively sampled by region (urban or rural) and participant type (general public or health care professional) to survey participants about their opinions on 4 COVID-19 health messages. We designed open-ended survey questions and analyzed the data using pragmatic health equity implementation science approaches. Following the qualitative analysis of the survey responses, we designed refined COVID-19 messages incorporating participant feedback and redistributed them via a short survey. RESULTS: In total, 67 participants consented and enrolled: 31 (46%) community participants from the rural Southeast Missouri Bootheel, 27 (40%) community participants from urban St Louis, and 9 (13%) health care professionals from St Louis. Overall, we found no qualitative differences between the responses of our urban and rural samples to the open-ended questions. Participants across groups wanted familiar COVID-19 protocols, personal choice in COVID-19 preventive behaviors, and clear source information. Health care professionals contextualized their suggestions within the specific needs of their patients. All groups suggested practices consistent with health-literate communications. We reached 83% (54/65) of the participants for message redistribution, and most had overwhelmingly positive responses to the refined messages. CONCLUSIONS: We suggest convenient methods for community involvement in the creation of health messages by using a brief web-based survey. We identified areas of improvement for future health messaging, such as reaffirming the preventive practices advertised early in a crisis, framing messages such that they allow for personal choice of preventive behavior, highlighting well-known source information, using plain language, and crafting messages that are applicable to the readers' circumstances.

Application of the PHENotype SIMulator for rapid identification of potential candidates in effective COVID-19 drug repurposing.

The current, rapidly diversifying pandemic has accelerated the need for efficient and effective identification of potential drug candidates for COVID-19. Knowledge on host-immune response to SARS-CoV-2 infection, however, remains limited with few drugs approved to date. Viable strategies and tools are rapidly arising to address this, especially with repurposing of existing drugs offering significant promise. Here we introduce a systems biology tool, the PHENotype SIMulator, which -by leveraging available transcriptomic and proteomic databases-allows modeling of SARS-CoV-2 infection in host cells in silico to i) determine with high sensitivity and specificity (both>96%) the viral effects on cellular host-immune response, resulting in specific cellular SARS-CoV-2 signatures and ii) utilize these cell-specific signatures to identify promising repurposable therapeutics. Powered by this tool, coupled with domain expertise, we identify several potential COVID-19 drugs including methylprednisolone and metformin, and further discern key cellular SARS-CoV-2-affected pathways as potential druggable targets in COVID-19 pathogenesis.

Impact of the COVID-19 pandemic on breast, colorectal, lung, and prostate cancer stage at diagnosis according to race.

PURPOSE: To determine if the COVID-19 pandemic has further exacerbated racial disparities in late-stage presentation of breast, colorectal, lung, and prostate cancers. METHODS: We conducted a registry-based retrospective study of patients with newly reported diagnoses of breast, colorectal, lung, and prostate cancers between March 2019-June 2019 (pre-COVID-19) and March 2020-June 2020 (early-COVID-19). We compared the volume of new diagnoses and stage at presentation according to race between both periods. RESULTS: During the study period, a total of 3528 patients had newly diagnosed cancer; 3304 of which had known disease stages and were included in the formal analyses. 467 (14.1%) were Blacks, and 2743 were (83%) Whites. 1216 (36.8%) had breast, 415 (12.6%) had colorectal, 827 (25%) had lung, and 846 (25.6%) had prostate cancers, respectively. The pre-COVID-19 period included 2120 (64.2%), and the early-COVID-19 period included 1184 (35.8%), representing a proportional 44.2% decline in the volume of new cases of breast, colorectal, lung, and prostate cancers, p < 0.0001. Pre-COVID-19, 16.8% were diagnosed with metastatic disease, versus 20.4% early-COVID-19, representing a proportional increase of 21.4% in the numbers of new cases with metastatic disease, p = 0.01. There was a non-significant proportional decline of 1.9% in Black patients diagnosed with non-metastatic breast, colorectal, lung, and prostate cancers early-COVID-19 (p = 0.71) and a non-significant proportional increase of 7% in Black patients diagnosed with metastatic disease (p = 0.71). Difference-in-difference analyses showed no statistically significant differences in metastatic presentation comparing Black to White patients. CONCLUSION: While we identified substantial reductions in the volume of new cancer diagnoses and increases in metastatic presentations due to the COVID-19 pandemic, the impact was similar for White and Black patients.

Factors Associated With the Intention to Receive the COVID-19 Vaccine: Cross-sectional National Study.

BACKGROUND: The COVID-19 pandemic is an unprecedented public health crisis, and vaccines are the most effective means of preventing severe consequences of this disease. Hesitancy regarding vaccines persists among adults in the United States, despite overwhelming scientific evidence of safety and efficacy. OBJECTIVE: The purpose of this study was to use the Health Belief Model (HBM) and reasoned action approach (RAA) to examine COVID-19 vaccine hesitancy by comparing those who had already received 1 vaccine to those who had received none. METHODS: This study examined demographic and theory-based factors associated with vaccine uptake and intention among 1643 adults in the United States who completed an online survey during February and March 2021. Survey items included demographic variables (eg, age, sex, political ideology), attitudes, and health belief variables (eg, perceived self-efficacy, perceived susceptibility). Hierarchical logistic regression analyses were used for vaccine uptake/intent. The first model included demographic variables. The second model added theory-based factors to examine the association of health beliefs and vaccine uptake above and beyond the associations explained by demographic characteristics alone. RESULTS: The majority of participants were male (n=974, 59.3%), White (n=1347, 82.0%), and non-Hispanic (n=1518, 92.4%) and reported they had already received a COVID-19 vaccine or definitely would when it was available to them (n=1306, 79.5%). Demographic variables significantly associated with vaccine uptake/intent included age (adjusted odds ratio [AOR] 1.05, 95% CI 1.04-1.06), other race (AOR 0.47, 95% CI 0.27-0.83 vs White), and political ideology (AOR 15.77, 95% CI 7.03-35.35 very liberal vs very conservative). The theory-based factors most strongly associated with uptake/intention were attitudes (AOR 3.72, 95% CI 2.42-5.73), self-efficacy (AOR 1.75, 95% CI 1.34-2.29), and concerns about side effects (AOR 0.59, 95% CI 0.46-0.76). Although race and political ideology were significant in the model of demographic characteristics, they were not significant when controlling for attitudes and beliefs. CONCLUSIONS: Vaccination represents one of the best tools to combat the COVID-19 pandemic, as well as other possible pandemics in the future. This study showed that older age, attitudes, injunctive norms, descriptive norms, and self-efficacy are positively associated with vaccine uptake and intent, whereas perceived side effects and lack of trust in the vaccine are associated with lower uptake and intent. Race and political ideology were not significant predictors when attitudes and beliefs were considered. Before vaccine hesitancy can be addressed, researchers and clinicians must understand the basis of vaccine hesitancy and which populations may show higher hesitancy to the vaccination so that interventions can be adequately targeted.

Lactate Dehydrogenase is Associated with Hemorrhagic Stroke During Extracorporeal Membrane Oxygenation for COVID-19

Background: Hemorrhagic stroke (HS) is a devastating complication during extracorporeal membrane oxygenation (ECMO), but markers for risk stratification are unknown. Lactate dehydrogenase (LDH) is a readily available biomarker of global tissue injury and permeability. We sought to determine whether an elevated LDH at baseline is related to eventual HS during ECMO for COVID-19. Method(s): A multicenter, retrospective study was conducted. Adult patients with COVID-19 requiring ECMO between March 2020 and February 2022 were included. LDH values prior to ECMO were captured. Patients were categorized into high (>750 U/L) or low (<=750 U/L) LDH groups. Result(s): There were 520 patients (47+/-11 years old) that underwent ECMO placement in 17 centers and 384 had an available LDH. In this cohort, 122 (32%) had a high LDH. Forty (10%) patients required venoarterial ECMO, while the remaining 344 (90%) received venovenous support only. Twenty-one out of 122 (17%) patients with a high LDH had a HS in comparison to 21 out of 262 (8%) with a low LDH. At 100 days, the probability of a HS was 40% in the high LDH group and 23% in those with a low LDH, p=0.002. After adjustment for age, sex and antecedent cardiopulmonary resuscitation, high LDH was associated with subsequent HS (aHR: 2.73, 95% CI 1.46-5.12). Findings were similar when restricting to patients supported by venovenous ECMO only. Conclusion(s): Elevated LDH prior to ECMO is associated with a HS during device support. LDH can risk stratify cases for impending cerebral bleeding during ECMO.

A Universal Travel Risk Assessment Questionnaire: Travel Assessment During COVID-19 Pandemic and Endemicity.

INTRODUCTION: Throughout the Coronavirus Disease 2019 (COVID-19) pandemic, military commanders have been challenged with providing appropriate travel guidance for their military and civilian personnel and dependents. This guidance, where promulgated, lacks uniformity. Travel aids and computer applications similarly differ and are not updated as often as jurisdictional travel health guidance is changed. Given the ever-evolving Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variants with differing degrees of infectivity, COVID-19 travel guidance will remain relevant for military travelers during the transition from pandemic to endemic phases and for the foreseeable future. MATERIALS AND METHODS: We reviewed all germane travel guidance promulgated by the U.S, Department of Defense; the U.S. Centers for Disease Control and Prevention; and other federal, state, and international agencies. From these materials, we identified and delineated applicable universal components for COVID-19 travel risk and created a universal Travel Risk Assessment Questionnaire (TRAQ). RESULTS: We present a universal TRAQ that identifies and allows for a graded most-appropriate response to known travel risk assessment factors including travel restrictions, travel mode, travel time, travel party size, trip duration, COVID-19 incidence rate at travel destination, lodging, planned activities, personal interaction level, vaccination coverage at destination, travel location, traveler's vaccination status, previous COVID-19 infection, mask wear compliance, mask type, and work environment, along with additional considerations and post-travel COVID-19 questions. We provide examples of the use of this questionnaire that describe low, medium, and high risk to the traveler for contracting COVID-19. CONCLUSION: Our TRAQ provides an easy-to-use format that can enable military, business, or personal travelers to more completely assess their likelihood of COVID-19 exposure and help them to reduce their potential for contracting COVID-19 during travel and subsequently transmitting it to others upon return. It should help commanders and traveling personnel to better assess COVID-19 travel risks through application of known travel risk factors.

What Cuts in Federal COVID-19 Funding Could Mean for Rural Communities.

The COVID-19 pandemic has widened the health disparities between urban and rural communities as rural populations face more limited health care capacities and worse COVID-19 outcomes than their urban counterparts. When this article was written, congress was debating continuing federal funds for free COVID-19 testing, vaccines, and treatment. In this article, we discuss the potential consequences rural communities may experience should such funding fail to be approved. Peer-reviewed literature and our research indicate these budget cuts could harm rural communities' financial distress, risk of severe disease outcomes, and trust in health care systems, making continued funding for public health resources critical for vulnerable rural communities.

Examining resilience of individuals living with sickle cell disease in the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic has impacted the physical and mental health of people worldwide including those living with genetic conditions. Sickle cell disease (SCD) is a hematologic chronic disease that causes multisystem damage and morbidity. Individuals living with SCD have had to continue managing their care for their chronic disease while following public health measures to protect against infection with COVID-19. Promoting resilience has been posited as being psychologically protective for those living with SCD. This study examines changes in resilience over time in a SCD population in the context of the COVID-19 pandemic. METHODS: Ninety-seven adults living with SCD completed two parent studies: (1) The INSIGHTS Study, a cross-sectional natural history study conducted from 2014-2019 and (2) The Living with SCD in COVID-19 Pandemic Study, an online survey conducted in 2020. Changes over time in resilience, perceived stress, emotional distress, and physical and mental health were analyzed in multivariable repeated measures model. RESULTS: Results showed that the psychological resilience of our study cohort had significantly decreased (0.19, p=0.01) over time. Resilience during the pandemic was associated with better mental health and physical health and lower perceived stress and emotional distress. In addition, results showed that marital status, education level, and employment were significantly associated with the psychological resilience of study participants. CONCLUSION: Resilience declined during the COVID-19 pandemic but was still associated with better physical and mental health outcomes. Future studies should investigate the relationship between resilience and sociodemographic factors.

Commentary: University Technology Transfer Has Made a Significant Contribution to Fighting COVID-19 while Ensuring Global Access.

This paper reviews the response by public sector research organizations and their technology transfer offices to the COVID-19 pandemic. It shows that leading universities and technology transfer associations quickly enacted licensing principles for the duration of the pandemic to maximize availability and minimize delays in translating public sector research institutes' (PSRIs') COVID-19 inventions to the public - in both the developed and the developing world - while waiving payment of royalties. It discusses examples of vaccines, drugs, diagnostics and personal protective equipment that were developed in PSRIs and swiftly deployed throughout the world on socially responsible terms. It reviews the case cited by Herder et al. (2022) and concludes that their proposed mandates are unnecessary and may inhibit the free flow of healthcare innovation from bench to bedside.

Commentary: University Technology Transfer Has Made a Significant Contribution to Fighting COVID-19 while Ensuring Global Access Commentaire: Le transfert de technologie universitaire a apporté une importante contribution à la lutte contre la COVID-19 tout en garantissant l'accès universel

This paper reviews the response by public sector research organizations and their technology transfer offices to the COVID-19 pandemic. It shows that leading universities and technology transfer associations quickly enacted licensing principles for the duration of the pandemic to maximize availability and minimize delays in translating public sector research institutes' (PSRIs’) COVID-19 inventions to the public – in both the developed and the developing world – while waiving payment of royalties. It discusses examples of vaccines, drugs, diagnostics and personal protective equipment that were developed in PSRIs and swiftly deployed throughout the world on socially responsible terms. It reviews the case cited by Herder et al. (2022) and concludes that their proposed mandates are unnecessary and may inhibit the free flow of healthcare innovation from bench to bedside.

Changes and differences in school food standards (2010-2021) and free school meal provision during COVID-19 across the UK: Potential implications for children's diets.

This paper explores changes to school food standards from 2010, free school meal provision during the COVID-19 pandemic across the UK and potential implications for children's diets. To obtain information on UK school food policies and free school meal provision methods we reviewed several sources including news articles, policy documents and journal articles. School food is an important part of the UK's health agenda and commitment to improving children's diets. Each UK nation has food-based standards implemented, however, only Scotland and Wales also have nutrient-based standards. School food standards in each nation have been updated in the last decade. Universal free school meals are available for children in the first 3 years of primary school in England and the first 5 years of primary school in Scotland, with plans announced for implementation of free school meals for all primary schoolchildren in Scotland and Wales. There is a lack of consistent monitoring of school food across the UK nations, and a lack of reporting compliance to the standards. Each nation differed in its response and management of free school meals during COVID-related school closures. Further, there are issues surrounding the monitoring of the methods to provide free school meal support during school closures. The role of school food has been highlighted during COVID-19, and with this, there have been calls for a review of free school meal eligibility criteria. The need for improved and consistent monitoring of school food across the UK remains, as does the need to evaluate the impact of school food on children's diets.

Sex-Specific Effects of Plastic Caging in Murine Viral Myocarditis.

BACKGROUND: Myocarditis is an inflammatory heart disease caused by viral infections that can lead to heart failure, and occurs more often in men than women. Since animal studies have shown that myocarditis is influenced by sex hormones, we hypothesized that endocrine disruptors, which interfere with natural hormones, may play a role in the progression of the disease. The human population is exposed to the endocrine disruptor bisphenol A (BPA) from plastics, such as water bottles and plastic food containers. METHODS: Male and female adult BALB/c mice were housed in plastic versus glass caging, or exposed to BPA in drinking water versus control water. Myocarditis was induced with coxsackievirus B3 on day 0, and the endpoints were assessed on day 10 post infection. RESULTS: We found that male BALB/c mice that were exposed to plastic caging had increased myocarditis due to complement activation and elevated numbers of macrophages and neutrophils, whereas females had elevated mast cell activation and fibrosis. CONCLUSIONS: These findings show that housing mice in traditional plastic caging increases viral myocarditis in males and females, but using sex-specific immune mechanisms.

Early Adoption of Longitudinal Surveillance for SARS-CoV-2 among Staff in Long-Term Care Facilities: Prevalence, Virologic and Sequence Analysis.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in 2019 and has become a major global pathogen in an astonishingly short period of time. The emergence of SARS-CoV-2 has been notable due to its impacts on residents in long-term care facilities (LTCFs). LTCF residents tend to possess several risk factors for severe outcomes of SARS-CoV-2 infection, including advanced age and the presence of comorbidities. Indeed, residents of LTCFs represent approximately 40% of SARS-CoV-2 deaths in the United States. Few studies have focused on the prevalence and transmission dynamics of SARS-CoV-2 among LTCF staff during the early months of the pandemic, prior to mandated surveillance testing. To assess the prevalence and incidence of SARS-CoV-2 among LTCF staff, characterize the extent of asymptomatic infections, and investigate the genomic epidemiology of the virus within these settings, we sampled staff for 8 to 11 weeks at six LTCFs with nasopharyngeal swabs from March through June of 2020. We determined the presence and levels of viral RNA and infectious virus and sequenced 54 nearly complete genomes. Our data revealed that over 50% of infections were asymptomatic/mildly symptomatic and that there was a strongly significant relationship between viral RNA (vRNA) and infectious virus, prolonged infections, and persistent vRNA (4+ weeks) in a subset of individuals, and declining incidence over time. Our data suggest that asymptomatic SARS-CoV-2-infected LTCF staff contributed to virus persistence and transmission within the workplace during the early pandemic period. Genetic epidemiology data generated from samples collected during this period support that SARS-CoV-2 was commonly spread between staff within an LTCF and that multiple-introduction events were less common. IMPORTANCE Our work comprises unique data on the characteristics of SARS-CoV-2 dynamics among staff working at LTCFs in the early months of the SARS-CoV-2 pandemic prior to mandated staff surveillance testing. During this time period, LTCF residents were largely sheltering-in-place. Given that staff were able to leave and return daily and could therefore be a continued source of imported or exported infection, we performed weekly SARS-CoV-2 PCR on nasal swab samples collected from this population. There are limited data from the early months of the pandemic comprising longitudinal surveillance of staff at LTCFs. Our data reveal the surprisingly high level of asymptomatic/presymptomatic infections within this cohort during the early months of the pandemic and show genetic epidemiological analyses that add novel insights into both the origin and transmission of SARS-CoV-2 within LTCFs.

Sentiments Regarding COVID-19 Vaccination among Graduate Students in Singapore.

As the COVID-19 pandemic rages unabated, and with more infectious variants, vaccination may offer a way to transit out of strict restrictions on physical human interactions to curb the virus spread and prevent overwhelming the healthcare system. However, vaccine hesitancy threatens to significantly impact our progress towards achieving this. It is thus important to understand the sentiments regarding vaccination for different segments of the population to facilitate the development of effective strategies to persuade these groups. Here, we surveyed the COVID-19 vaccination sentiments among a highly educated group of graduate students from the National University of Singapore (NUS). Graduate students who are citizens of 54 different countries, mainly from Asia, pursue studies in diverse fields, with 32% expressing vaccine hesitancy. Citizenship, religion, country of undergraduate/postgraduate studies, exposure risk and field of study are significantly associated with vaccine sentiments. Students who are Chinese citizens or studied in Chinese Universities prior to joining NUS are more hesitant, while students of Indian descent or studied in India are less hesitant about vaccination. Side effects, safety issues and vaccine choice are the major concerns of the hesitant group. Hence, this study would facilitate the development of strategies that focus on these determinants to enhance vaccine acceptance.

Group IIA secreted phospholipase A2 is associated with the pathobiology leading to COVID-19 mortality.

There is an urgent need to identify the cellular and molecular mechanisms responsible for severe COVID-19 that results in death. We initially performed both untargeted and targeted lipidomics as well as focused biochemical analyses of 127 plasma samples and found elevated metabolites associated with secreted phospholipase A2 (sPLA2) activity and mitochondrial dysfunction in patients with severe COVID-19. Deceased COVID-19 patients had higher levels of circulating, catalytically active sPLA2 group IIA (sPLA2-IIA), with a median value that was 9.6-fold higher than that for patients with mild disease and 5.0-fold higher than the median value for survivors of severe COVID-19. Elevated sPLA2-IIA levels paralleled several indices of COVID-19 disease severity (e.g., kidney dysfunction, hypoxia, multiple organ dysfunction). A decision tree generated by machine learning identified sPLA2-IIA levels as a central node in the stratification of patients who died from COVID-19. Random forest analysis and least absolute shrinkage and selection operator-based (LASSO-based) regression analysis additionally identified sPLA2-IIA and blood urea nitrogen (BUN) as the key variables among 80 clinical indices in predicting COVID-19 mortality. The combined PLA-BUN index performed significantly better than did either one alone. An independent cohort (n = 154) confirmed higher plasma sPLA2-IIA levels in deceased patients compared with levels in plasma from patients with severe or mild COVID-19, with the PLA-BUN index-based decision tree satisfactorily stratifying patients with mild, severe, or fatal COVID-19. With clinically tested inhibitors available, this study identifies sPLA2-IIA as a therapeutic target to reduce COVID-19 mortality.

An urgent call to raise the bar in oncology.

Important breakthroughs in medical treatments have improved outcomes for patients suffering from several types of cancer. However, many oncological treatments approved by regulatory agencies are of low value and do not contribute significantly to cancer mortality reduction, but lead to unrealistic patient expectations and push even affluent societies to unsustainable health care costs. Several factors that contribute to approvals of low-value oncology treatments are addressed, including issues with clinical trials, bias in reporting, regulatory agency shortcomings and drug pricing. With the COVID-19 pandemic enforcing the elimination of low-value interventions in all fields of medicine, efforts should urgently be made by all involved in cancer care to select only high-value and sustainable interventions. Transformation of medical education, improvement in clinical trial design, quality, conduct and reporting, strict adherence to scientific norms by regulatory agencies and use of value-based scales can all contribute to raising the bar for oncology drug approvals and influence drug pricing and availability.

The Food provision, cUlture and Environment in secondary schooLs (FUEL) study: protocol of a mixed methods evaluation of national School Food Standards implementation in secondary schools and their impact on pupils' dietary intake and dental health.

INTRODUCTION: Excess free sugar intake is associated with obesity and poor dental health. Adolescents consume substantially more free sugar than is recommended. National (UK) School Food Standards (SFS) are in place but are not mandatory in all schools, and their impact on the diets of secondary school pupils is unknown. We aim to evaluate how SFS and wider healthy eating recommendations (from the national School Food Plan (SFP)) are implemented in secondary schools and how they influence pupils' diets and dental health. METHODS AND ANALYSIS: Secondary-level academies/free schools in the West Midlands, UK were divided into two groups: SFS mandated and SFS non-mandated. Using propensity scores to guide sampling, we aim to recruit 22 schools in each group. We will compare data on school food provision and sales, school food culture and environment, and the food curriculum from each group, collected through: school staff, governor, pupil, parent surveys; school documents; and observation. We will explore the implementation level for the SFS requirements and SFP recommendations and develop a school food typology. We aim to recruit 1980 pupils aged 11-15 years across the 44 schools and collect dietary intake (24-hour recall) and dental health data through self-completion surveys. We will compare free sugar/other dietary intake and dental health across the two SFS groups and across the identified school types. School type will be further characterised in 4-8 case study schools through school staff interviews and pupil focus groups. Evaluation of economic impact will be through a cost-consequence analysis and an exploratory cost-utility analysis. ETHICS AND DISSEMINATION: Ethical approval was obtained from the University of Birmingham Ethical Review Committee (ERN_18-1738). Findings will be disseminated to key national and local agencies, schools and the public through reports, presentations, the media and open access publications. TRIAL REGISTRATION NUMBER: ISRCTN 68757496 (registered 17 October 2019).