Challenges in estimating waning effectiveness of two doses of BNT162b2 and ChAdOx1 COVID-19 vaccines beyond six months: an OpenSAFELY cohort study using linked electronic health records (preprint)

Quantifying the waning effectiveness of second COVID-19 vaccination beyond six months and against the omicron variant is important for scheduling subsequent doses. With the approval of NHS England, we estimated effectiveness up to one year after second dose, but found that bias in such estimates may be substantial.

Association between household composition and severe COVID-19 outcomes in older people by ethnicity: an observational cohort study using the OpenSAFELY platform (preprint)

Background Ethnic differences in the risk of severe COVID-19 may be linked to household composition. We quantified the association between household composition and risk of severe COVID-19 by ethnicity for older individuals. Methods With the approval of NHS England, we analysed ethnic differences in the association between household composition and severe COVID-19 in people aged 67 or over in England. We defined households by number of generations living together, and used multivariable Cox regression stratified by location and wave of the pandemic and accounted for age, sex, comorbidities, smoking, obesity, housing density and deprivation. We included 2 692 223 people over 67 years in wave 1 (01/02/2020-31/08/2020) and 2 731 427 in wave 2 (01/09/2020-31/01/2021). Findings Multigenerational living was associated with increased risk of severe COVID-19 for White and South Asian older people in both waves (e.g. wave 2, 67+ living with 3 other generations vs 67+ year olds only: White HR 1.61 95% CI 1.38-1.87, South Asian HR 1.76 95% CI 1.48-2.10), with a trend for increased risks of severe COVID-19 with increasing generations in wave 2. Interpretation Multigenerational living was associated with severe COVID-19 in older adults. Older South Asian people are over-represented within multigenerational households in England, especially in the most deprived settings. The number of generations in a household, number of occupants, ethnicity and deprivation status are important considerations in the continued roll-out of COVID-19 vaccination and targeting of interventions for future pandemics. Funding This research was funded in part, by the Wellcome Trust. For the purpose of open access, the author has applied a CC-BY public copyright licence to any Author Accepted Manuscript version arising from this submission.

Waning effectiveness of BNT162b2 and ChAdOx1 COVID-19 vaccines over six months since second dose: a cohort study using linked electronic health records (preprint)

Summary Background The rate at which COVID-19 vaccine effectiveness wanes over time is crucial for vaccination policies, but is incompletely understood with conflicting results from different studies. Methods This cohort study, using the OpenSAFELY-TPP database and approved by NHS England, included individuals without prior SARS-CoV-2 infection assigned to vaccines priority groups 2-12 defined by the UK Joint Committee on Vaccination and Immunisation. We compared individuals who had received two doses of BNT162b2 or ChAdOx1 with unvaccinated individuals during six 4-week comparison periods, separately for subgroups aged 65+ years; 16-64 years and clinically vulnerable; 40-64 years and 18-39 years. We used Cox regression, stratified by first dose eligibility and geographical region and controlled for calendar time, to estimate adjusted hazard ratios (aHRs) comparing vaccinated with unvaccinated individuals, and quantified waning vaccine effectiveness as ratios of aHRs per-4-week period. The outcomes were COVID-19 hospitalisation, COVID-19 death, positive SARS-CoV-2 test, and non-COVID-19 death. Findings The BNT162b2, ChAdOx1 and unvaccinated groups comprised 1,773,970, 2,961,011 and 2,433,988 individuals, respectively. Waning of vaccine effectiveness was similar across outcomes and vaccine brands: e.g. in the 65+ years subgroup ratios of aHRs versus unvaccinated for COVID-19 hospitalisation, COVID-19 death and positive SARS-CoV-2 test ranged from 1.23 (95% CI 1.15-1.32) to 1.27 (1.20-1.34) for BNT162b2 and 1.16 (0.98-1.37) to 1.20 (1.14-1.27) for ChAdOx1. Despite waning, rates of COVID-19 hospitalisation and COVID-19 death were substantially lower among vaccinated individuals compared to unvaccinated individuals up to 26 weeks after second dose, with estimated aHRs <0.20 (>80% vaccine effectiveness) for BNT162b2, and <0.26 (>74%) for ChAdOx1. By weeks 23-26, rates of SARS-CoV-2 infection in fully vaccinated individuals were similar to or higher than those in unvaccinated individuals: aHRs ranged from 0.85 (0.78-0.92) to 1.53 (1.07-2.18) for BNT162b2, and 1.21 (1.13-1.30) to 1.99 (1.94-2.05) for ChAdOx1. Interpretation The rate at which estimated vaccine effectiveness waned was strikingly consistent for COVID-19 hospitalisation, COVID-19 death and positive SARS-CoV-2 test, and similar across subgroups defined by age and clinical vulnerability. If sustained to outcomes of infection with the Omicron variant and to booster vaccination, these findings will facilitate scheduling of booster vaccination doses.

Risk of severe COVID-19 outcomes associated with immune-mediated inflammatory diseases and immune modifying therapies: a nationwide cohort study in the OpenSAFELY platform (preprint)

BackgroundIt is unclear if people with immune-mediated inflammatory diseases (IMIDs) (joint, bowel and skin) and on immune modifying therapy have increased risk of serious COVID-19 outcomes. MethodsWith the approval of NHS England we conducted a cohort study, using OpenSAFELY, analysing routinely-collected primary care data linked to hospital admission, death and previously unavailable hospital prescription data. We used Cox regression (adjusting for confounders) to estimate hazard ratios (HR) comparing risk of COVID-19-death, death/critical care admission, and hospitalisation (March to September 2020) in: 1) people with IMIDs compared to the general population; and 2) people with IMIDs on targeted immune modifying drugs (e.g., biologics) compared to standard systemic treatment (e.g., methotrexate). FindingsWe identified 17,672,065 adults; of 1,163,438 (7%) with IMIDs, 19,119 people received targeted immune modifying drugs, and 200,813 received standard systemics. We saw evidence of increased COVID-19-death (HR 1.23, 95%CI 1.20, 1.27), and COVID-19 hospitalisation (HR 1.32, 95%CI 1.29, 1.35) in individuals with IMIDs overall compared to individuals without IMIDs of the same age, sex, deprivation and smoking status. We saw no evidence of increased COVID-19 deaths with targeted compared to standard systemic treatments (HR 1.03, 95%CI 0.80, 1.33). There was no evidence of increased COVID-19-related death in those prescribed TNF inhibitors, IL-12/23, IL7, IL-6 or JAK inhibitors compared to standard systemics. Rituximab was associated with increased COVID-19 death (HR 1.68, 95%CI 1.11, 2.56); however, this finding may relate to confounding. InterpretationCOVID-19 death and hospitalisation was higher in people with IMIDs. We saw no increased risk of adverse COVID-19 outcomes in those on most targeted immune modifying drugs for IMIDs compared to standard systemics. RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed on May 19th, 2021, using the terms "COVID-19", "SARS-CoV-2" and "rheumatoid arthritis", "psoriatic arthritis" "ankylosing spondylitis", "Crohns disease" "ulcerative colitis" "hidradenitis suppurativa" and "psoriasis", to identify primary research articles examining severe COVID-19 outcome risk in individuals with immune-mediated inflammatory diseases (IMIDs) and those on immune modifying therapy. The studies identified (including matched cohort studies and studies in disease-specific registries) were limited by small sample sizes and number of outcomes. Most studies did not show a signal of increased adverse COVID-19 outcomes in those on targeted therapies, with the exception of rituximab. Additionally, disease- specific registries are subject to selection bias and lack denominator populations. Added value of the studyIn our large population-based study of 17 million individuals, including 1 million people with IMIDs and just under 200,000 receiving immune modifying medications, we saw evidence that people with IMIDs had an increased risk of COVID-19-related death compared to the general population after adjusting for potential confounders (age, sex, deprivation, smoking status) (HR 1.23, 95%CI 1.20, 1.27). We saw differences by IMID type, with COVID-19-related death being increased by the most in people with inflammatory joint disease (HR 1.47, 95%CI 1.40, 1.54). We also saw some evidence that those with IMIDs were more likely, compared to the general population, to have COVID-19-related critical care admission/death (HR 1.24, 95%CI 1.21, 1.28) and hospitalisation (HR 1.32, 95%CI 1.29, 1.35). Compared to people with IMIDs taking standard systemics, we saw no evidence of differences in severe COVID-19-related outcomes with TNF inhibitors, IL-17 inhibitors, IL-12/23 inhibitors, IL-6 inhibitors and JAK inhibitors. However, there was some evidence that rituximab was associated with an increased risk of COVID-19-related death (HR 1.68, 95%CI 1.11, 2.56) and death/critical care admission (HR 1.92, 95%CI 1.31, 2.81). We also saw evidence of an increase in COVID-19-related hospital admissions in people prescribed rituximab (HR 1.59, 95%CI 1.16, 2.18) or JAK inhibition (HR 1.81, 95%CI 1.09, 3.01) compared to those on standard systemics, although this could be related to worse underlying health rather than the drugs themselves, and numbers of events were small. This is the first study to our knowledge to use high-cost drug data on medicines supplied by hospitals at a national scale in England (to identify targeted therapies). The availability of these data fills an important gap in the medication record of those with more specialist conditions treated by hospitals creating an important opportunity to generate insights to these conditions and these medications Implications of all of the available evidenceOur study offers insights into future risk mitigation strategies and SARS-CoV-2 vaccination priorities for individuals with IMIDs, as it highlights that those with IMIDs and those taking rituximab may be at risk of severe COVID-19 outcomes. Critically, our study does not show a link between most targeted immune modifying medications compared to standard systemics and severe COVID-19 outcomes. However, the increased risk of adverse COVID-19 outcomes that we saw in people with IMIDs and those treated with rituximab merits further study.

Disrupting or reconfiguring racist narratives about Muslims? The representation of British Muslims during the Covid crisis

This article examines British newspaper coverage of Muslims during the first wave of the Coronavirus crisis. A well-established trajectory of research shows that Muslims are negativized in mainstream media representation in the UK. However, it became obvious from the outset of the pandemic, that ethnic minority key workers were disproportionately affected by Coronavirus. This, alongside high levels of support for NHS staff, had the potential to challenge and shift established narratives about Muslims as questions of structural discrimination became the subject of news media discourse. This article examines whether these events were able, even momentarily, to disrupt dominant narratives about Muslims in the UK or whether the pandemic provided further opportunity for Othering discourses to be perpetuated. In the context of a tumultuous political landscape, where the politics of immigration have been linked to the politics of austerity, Muslims have been scapegoated as a threat to the nationalist project. In this context, the identifier ?Muslim? is only deemed relevant if it signifies ?difference?, or to distinguish between good versus bad Muslim/immigrant. Hence, in the context of the reporting of Coronavirus, racist discourses have been reshaped as Muslim key workers are distinguished in the reporting from other Muslims. We examine how these representational practices play out through an analysis of four British newspapers (The Sun, Daily Mail, The Telegraph and The Mirror) over a months? coverage at the peak of the crisis (April, 2020).

OpenSAFELY: Risks of COVID-19 hospital admission and death for people with learning disabilities - a cohort study. (preprint)

ObjectivesTo assess the association between learning disability and risk of hospitalisation and mortality from COVID-19 in England among adults and children. DesignWorking on behalf of NHS England, two cohort studies using patient-level data for >17 million people from primary care electronic health records were linked with death data from the Office for National Statistics and hospitalization data from NHS Secondary Uses Service using the OpenSAFELY platform. SettingGeneral practices in England which use TPP software. ParticipantsParticipants were males and females, aged up to 105 years, from two cohorts: (1) wave 1, registered with a TPP practice as of 1st March 2020 and followed until 31st August, 2020; (2) wave 2 registered 1st September 2020 and followed until 31st December 2020 (for admissions) or 8th February 2021 (for deaths). The main exposure group was people included on a general practice learning disability register (LDR), with a subgroup of people classified as having profound or severe learning disability. We also identified patients with Down syndrome and cerebral palsy (whether or not on the learning disability register). Main outcome measures(i) COVID-19 related death, (ii) COVID-19 related hospitalisation. Non-COVID-19 related death was also explored. ResultsIn wave 1, of 14,301,415 included individuals aged 16 and over, 90,095 (0.63%) were identified as being on the LDR. 30,173 COVID-related hospital admissions, 13,919 COVID-19 related deaths and 69,803 non-COVID deaths occurred; of which 538 (1.8%), 221 (1.6%) and 596 (0.85%) were among individuals on the LDR, respectively. In wave 2, 27,611 COVID-related hospital admissions, 17,933 COVID-19 related deaths and 54,171 non-COVID deaths occurred; of which 383 (1.4%), 260 (1.4%) and 470 (0.87%) were among individuals on the LDR. Wave 1 hazard ratios for individuals on the LDR, adjusted for age, sex, ethnicity and geographical location, were 5.3 (95% confidence interval (CI) 4.9, 5.8) for COVID-19 related hospital admissions and 8.2 (95% CI: 7.1, 9.4) for COVID-19 related death. Wave 2 produced similar estimates. Associations were stronger among those classed as severe-profound and among those in residential care. Down syndrome and cerebral palsy were associated with increased hazard of both events in both waves; Down syndrome to a much greater extent. Hazards of non-COVID-19 related death followed similar patterns with weaker associations. ConclusionsPeople with learning disabilities have markedly increased risks of hospitalisation and mortality from COVID-19. This raised risk is over and above that seen for non-COVID causes of death. Ensuring prompt access to Covid-19 testing and health care and consideration of prioritisation for COVID-19 vaccination and other targeted preventive measures are warranted.

Case fatality risk of the SARS-CoV-2 variant of concern B.1.1.7 in England (preprint)

The B.1.1.7 variant of concern (VOC) is increasing in prevalence across Europe. Accurate estimation of disease severity associated with this VOC is critical for pandemic planning. We found increased risk of death for VOC compared with non-VOC cases in England (HR: 1.67 (95% CI: 1.34 - 2.09; P

­­The Impact of a National Cash Transfer Programme on Reducing Suicide: A Study Using the 100 Million Brazilian Cohort (preprint)

Background: Socio-economic factors have been consistently associated with suicide, and economic recessions are linked to rising suicide rates. This study investigates the effect of the world`s largest conditional cash transfer (CCT) programme on suicide rates in a cohort of half the Brazilian population. Methods: We used data from the 100 Million Brazilian Cohort, covering a 12-year period (2004 to 2015). It comprises socio-economic and demographic information on 114,008,317 individuals, linked to the “Bolsa Família” programme (BFP) payroll database, and nationwide death registration data. We fitted Poisson models to estimate the incidence rate ratios for suicide, associated with exposure to the BFP and Propensity Score (PS) to group BFP beneficiaries and non-beneficiaries. We estimated the PS through multiple logistic regression using baseline socio-demographic and economic characteristics and year of registration, and ran Kernel matching analysis and several sensitivity tests. Results: In the main analysis, 33,281 suicide cases occurred among the 69,707,312 individuals followed for 305,229,883 person-years at risk. Suicide rates among beneficiaries and non-beneficiaries were 5.5 (95%CI=5.44, 5.61) and 11.1 (95%CI=10.41, 11.81) in the matched cohort and 5.4 (95%CI=5.32, 5.47) and 10.7 (95%CI=10.51, 10.87) per 100,000 individuals, in the original cohorts. BFP beneficiaries had a 61% lower suicide rate than non-beneficiaries (IRR=0.39, 95%CI=0.37,0.41) in the main analysis and similar results in all sensitivity analyses. This effect was higher among women (IRR=0.35, 95%IC=0.31,0.39), and younger individuals (IRR=0.40, 95%IC=0.37,0.44). Interpretation: CCT programs play an important role in poverty reduction and well-being improvement for beneficiaries. We have also demonstrated that it contributes towards reduced suicide rates. Targeting social determinants, using cash transfer programmes, could be important tools to limit suicide, predicted to rise in the aftermath of the economic recession, consequent to the Covid-19 pandemic.Funding Statement: The authors received no direct financial support for this article. During the study DBM held a research associate scholarship from Wellcome Trust (202912/Z/16/Z) and CIDACS has received support from the Department of Science and Technology, from the Brazilian Ministry of Health; National Research Council (CNPq), Brazil; Bill and Melinda Gates Foundation (CHAMADA MCTI/CNPq/MS/SCTIE/Decit/Fundação Bill e Melinda Gates N o 47/2014); Health Surveillance Secretariat, Ministry of Health, Brazil; Fundação de Apoio a Pesquisa do Estado da Bahia (FAPESB); Financiadora de Estudos e Projetos (FINEP); Secretaria de Ciência e Tecnologia do Estado da Bahia (SECTI), and Wellcome Trust.Declaration of Interests: All authors have no competing interests.Ethics Approval Statement: This study was approved by the two research ethics committees of the: (i) Federal University of Bahia (application number: 1023107) and (ii) London School of Hygiene & Tropical Medicine (application number: 11581).

OpenSAFELY: impact of national guidance on switching from warfarin to direct oral anticoagulants (DOACs) in early phase of COVID-19 pandemic in England (preprint)

BackgroundEarly in the COVID-19 pandemic the NHS recommended that appropriate patients anticoagulated with warfarin should be switched to direct acting oral anticoagulants (DOACs), requiring less frequent blood testing. Subsequently, a national safety alert was issued regarding patients being inappropriately co-prescribed two anticoagulants following a medication change, and associated monitoring. ObjectiveTo describe which people were switched from warfarin to DOACs; identify potentially unsafe co-prescribing of anticoagulants; and assess whether abnormal clotting results have become more frequent during the pandemic. MethodsWorking on behalf of NHS England we conducted a population cohort based study using routine clinical data from >17 million adults in England. Results20,000 of 164,000 warfarin patients (12.2%) switched to DOACs between March and May 2020, most commonly to edoxaban and apixaban. Factors associated with switching included: older age, recent renal function test, higher number of recent INR tests recorded, atrial fibrillation diagnosis and care home residency. There was a sharp rise in co-prescribing of warfarin and DOACs from typically 50-100 per month to 246 in April 2020, 0.06% of all people receiving a DOAC or warfarin. INR testing fell by 14% to 506.8 patients tested per 1000 warfarin patients each month. We observed a very small increase in elevated INRs (n=470) during April compared with January (n=420). ConclusionsIncreased switching of anticoagulants from warfarin to DOACs was observed at the outset of the COVID-19 pandemic in England following national guidance. There was a small but substantial number of people co-prescribed warfarin and DOACs during this period. Despite a national safety alert on the issue, a widespread rise in elevated INR test results was not found. Primary care has responded rapidly to changes in patient care during the COVID-19 pandemic.

Quality of life and depressive symptoms among Peruvian university students during the COVID-19 pandemic (preprint)

ObjectivesCharacterize the quality of life and depressive symptoms of university students in Peru during the COVID-19 pandemic and to determine the associated factors. MethodsMulti-centre study in 1634 university students recruited by convenience sampling. Quality of life (QoL) was assessed with the European Quality of Life-5 Dimensions at three levels (EQ-5D-3L) and depressive symptoms with the Patient Health Questionarie-9 (PHQ-9). To evaluate factors associated with QoL and depressive symptoms, linear and adjusted regressions were used, with robust variance reporting coefficients ({beta}). ResultsThe percentage of participants most affected by QoL dimension was: anxiety/depression (47.2%) and pain/discomfort (35.6%). Regarding the Visual Analog Scale (EQ-VAS) of QoL, the score was 76.0 + 25.6. Those who had family economic decline during quarantine ({beta}=-3.4, IC95%=-6.5 to -0.3) or family with chronic diseases ({beta}=-3.7, IC95%=-6.1 to -1.4) presented significantly lower scores in their QoL. Regarding depressive symptomatology, the university students reported a moderate to severe level (28.9%). A higher risk of depressive symptoms was found in residents of Ayacucho ({beta}=0.8, IC95%=0.1 to 1.5), those who were released from quarantine ({beta}=0.7, IC95%=0.2 to 1.2) and those who had a family member with chronic disease ({beta}=1.5, IC95%=1.0 to 2.1). ConclusionsAlmost half and one third of participants reported anxiety/depression, and pain/discomfort in their QoL respectively. Nearly a third presented moderate and severe depressive symptoms. The deterioration of QoL was worse in those who had a decrease in income and a family member with chronic illness. The presence of depressive symptoms was found in students in Ayacucho, those who left home during quarantine and those who had a family member with chronic diseases.

First-described recently discovered non-toxic vegetal-derived furocoumarin preclinical efficacy against SARS-CoV-2: a promising antiviral herbal drug. (preprint)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the aetiology of coronavirus disease 2019 (COVID19) pandemic. ICEP4 purified compound (ICEP4) is a recently discovered furocoumarin-related purified compound derived from the roots and seeds of Angelica archangelica (herbal drug). ICEP4-related herbal preparations have been extensively used as active herbal ingredients in traditional medicine treatments in several European countries. Extraction method of patent pending ICEP4 (patent application no. GB2017123.7) has previously shown strong manufacturing robustness, long-lasting stability, and repeated chemical consistency. Here we show that ICEP4 presents a significant in vitro cytoprotective effect in highly virulent-SARS-CoV-2 challenged Vero E6 cellular cultures, using doses of 34.5 and 69 M. No dose-related ICEP4 toxicity was observed in Vero E6 cells, M0 macrophages, B, CD4+ T and CD8+ T lymphocytes, Natural Killer (NK) or Natural Killer T (NKT) cells. No dose-related ICEP4 inflammatory response was observed in M0 macrophages quantified by IL6 and TNF release in cell supernatant. No decrease in survival rate was observed after either 24 hr acute or 21-day chronic exposure in in vivo toxicity studies performed in C. elegans. Therefore, ICEP4 toxicological profile has demonstrated marked differences compared to others vegetal furocoumarins. Successful ICEP4 doses against SARS-CoV-2-challenged cells are within the maximum threshold of toxicity concern (TTC) of furocoumarins as herbal preparation, stated by European Medicines Agency (EMA). The characteristic chemical compounding of ICEP4, along with its safe TTC, allow us to assume that the first-observation of a natural antiviral compound has occurred. The potential druggability of a new synthetic ICEP4-related compound remains to be elucidated. However, well-established historical use of ICEP4-related compounds as herbal preparations may point towards an already-safe, widely extended remedy, which may be ready-to-go for large-scale clinical trials under the EMA emergency regulatory pathway. To the best of the authors knowledge, ICEP4-related herbal drug can be postulated as a promising therapeutic treatment for COVID19.

Elevated temperature inhibits SARS-CoV-2 replication in respiratory epithelium independently of the induction of IFN-mediated innate immune defences (preprint)

The pandemic spread of SARS-CoV-2, the etiological agent of COVID-19, represents a significant and ongoing international health crisis. A key symptom of SARS-CoV-2 infection is the onset of fever, with a hyperthermic temperature range of 38 to 41{degrees}C. Fever is an evolutionarily conserved host response to microbial infection and inflammation that can influence the outcome of viral pathogenicity and regulation of host innate and adaptive immune responses. However, it remains to be determined what effect elevated temperature has on SARS-CoV-2 tropism and replication. Utilizing a 3D air-liquid interface (ALI) model that closely mimics the natural tissue physiology and cellular tropism of SARS-CoV-2 infection in the respiratory airway, we identify tissue temperature to play an important role in the regulation of SARS-CoV-2 infection. We show that temperature elevation induces wide-spread transcriptome changes that impact upon the regulation of multiple pathways, including epigenetic regulation and lncRNA expression, without disruption of general cellular transcription or the induction of interferon (IFN)-mediated antiviral immune defences. Respiratory tissue incubated at temperatures >37{degrees}C remained permissive to SARS-CoV-2 infection but severely restricted the initiation of viral transcription, leading to significantly reduced levels of intraepithelial viral RNA accumulation and apical shedding of infectious virus. To our knowledge, we present the first evidence that febrile temperatures associated with COVID-19 inhibit SARS-CoV-2 replication. Our data identify an important role for temperature elevation in the epithelial restriction of SARS-CoV-2 that occurs independently of the induction of canonical IFN-mediated antiviral immune defences and interferon-stimulated gene (ISG) expression.

Botanical Drugs and Supplements Affecting the Immune Response in the Time of COVID-19: Implications for Research and Clinical Practice (preprint)

In times of health crisis, including the current COVID-19 pandemic, the potential benefit of botanical drugs and supplements emerges as a focus of attention, although controversial efficacy claims are rightly a concern. Phytotherapy has an established role in everyday selfcare and health care, and since botanical preparations contain many chemical constituents rather than single compounds, challenges arise in demonstrating efficacy and safety. However, there is ample traditional, empirical and clinical evidence that botanicals can offer some protection and alleviation of disease symptoms as well as promoting general well-being. Newly emerging viral infections, specifically COVID-19, represent a unique challenge in their novelty and absence of established antiviral treatment or immunization. We discuss here the roles and limitations of phytotherapy in helping to prevent and address viral infections, and specifically regarding their effects on immune response. Botanicals with a documented immunomodulatory, immunostimulatory, and anti-inflammatory effect include adaptogens, Boswellia spp., Curcuma longa, Echinacea spp., Glycyrrhiza spp., medicinal fungi, Pelargonium sidoides, salicylate-yielding herbs, and Sambucus spp. We further provide a clinical perspective on applications and safety of these herbs in prevention, onset, progression, and convalescence from respiratory viral infections.

Feasibility Study of Assessing the Preclinical Alzheimer Cognitive Composite (PACC) Score via Videoconferencing (preprint)

Background: Identifying mild cognitive impairment (MCI) at early stages is of importance both for research and for clinical practice. The Preclinical Alzheimer Cognitive Composite (PACC) is a composite score which can detect the first signs of cognitive impairment. It is designed to be administered in person, by a trained research psychologist or nurse, however, in-person assessments are costly, and are difficult during the current COVID-19 pandemic. The aims of this study are to assess the feasibility of performing the PACC assessment with videoconferencing, and to compare the validity of this remote PACC score with the in-person PACC score obtained previously.Methods: Participants from the HEalth and Ageing Data IN the Game of football (HEADING) Study who had already undergone an in-person assessment were re-contacted and re-assessed remotely. The correlation between the two PACC scores was estimated. The difference between the two PACC scores was calculated and used in multiple linear regression to assess which variables were associated with a difference in PACC scores.Findings: Of the 43 participants who were invited to this external study, 28 were re-assessed. The median duration in days between the in-person and the remote assessments was 236·5 days (7·9 months) (IQR 62·5). There was a strong positive correlation between the two assessments for the PACC score, with a Spearman correlation coefficient of 0·75 (95% CI 0·56, 0·95). The multiple linear regression found that the only predictor of the PACC difference was the time between assessments.Interpretation: This study provides evidence on the feasibility of performing cognitive tests online, with all four tests comprising the PACC being successfully administered through videoconferencing. This is relevant, especially during times when face-to-face assessments cannot be performed.Funding Statement: This study was funded by the Drake Foundation as part of the BRAIN study funded to London School of Hygiene and Tropical Medicine (EPMSZO61) in collaboration with Queen Mary University of London and the Institute of Occupational Health.Declaration of Interests: We declare that we have no conflict of interests. Ethics Approval Statement: The HEADING Study was approved by the London School of Hygiene & Tropical Medicine’s Ethical Committee (16282).

OpenSAFELY: Do adults prescribed Non-steroidal anti-inflammatory drugs have an increased risk of death from COVID-19? (preprint)

Importance: There has been speculation that non-steroidal anti-inflammatory drugs (NSAIDs) may negatively affect coronavirus disease 2019 (COVID-19) outcomes, yet clinical evidence is limited. Objective: To assess the association between NSAID use and deaths from COVID-19 using OpenSAFELY, a secure analytical platform. Design: Two cohort studies (1st March-14th June 2020). Setting: Working on behalf of NHS England, we used routine clinical data from >17 million patients in England linked to death data from the Office for National Statistics. Participants: Study 1: General population (people with an NSAID prescription in the last three years). Study 2: people with rheumatoid arthritis/osteoarthritis. Exposures: Current NSAID prescription within the 4 months before 1st March 2020. Main Outcome and Measure: We used Cox regression to estimate hazard ratios (HRs) for COVID-19 related death in people currently prescribed NSAIDs, compared with those not currently prescribed NSAIDs, adjusting for age, sex, comorbidities and other medications. Results: In Study 1, we included 535,519 current NSAID users and 1,924,095 non-users in the general population. The crude HR for current use was 1.25 (95% CI, 1.07-1.46), versus non-use. We observed no evidence of difference in risk of COVID-19 related death associated with current use (HR, 0.95, 95% CI, 0.80-1.13) in the fully adjusted model. In Study 2, we included 1,711,052 people with rheumatoid arthritis/osteoarthritis, of whom 175,631 (10%) were current NSAID users. The crude HR for current use was 0.43 (95% CI, 0.36-0.52), versus non-use. In the fully adjusted model, we observed a lower risk of COVID-19 related death (HR, 0.78, 95% CI, 0.65-0.94) associated with current use of NSAID versus non-use. Conclusion and Relevance: We found no evidence of a harmful effect of NSAIDs on COVID-19 related deaths. Risks from COVID-19 do not need to influence decisions about therapeutic use of NSAIDs.

Protocol for the development and evaluation of a tool for predicting risk of short-term adverse outcomes due to COVID-19 in the general UK population (preprint)

Introduction: Novel coronavirus 2019 (COVID-19) has propagated a global pandemic with significant health, economic and social costs. Emerging emergence has suggested that several factors may be associated with increased risk from severe outcomes or death from COVID-19. Clinical risk prediction tools have significant potential to generate individualised assessment of risk and may be useful for population stratification and other use cases. Methods and analysis: We will use a prospective open cohort study of routinely collected data from 1205 general practices in England in the QResearch database. The primary outcome is COVID-19 mortality (in or out-of-hospital) defined as confirmed or suspected COVID-19 mentioned on the death certificate, or death occurring in a person with SARS-CoV-2 infection between 24th January and 30th April 2020. Our primary outcome in adults is COVID-19 mortality (including out of hospital and in hospital deaths). We will also examine COVID-19 hospitalisation in children. Time-to-event models will be developed in the training data to derive separate risk equations in adults (19-100 years) for males and females for evaluation of risk of each outcome within the 3-month follow-up period (24th January to 30th April 2020), accounting for competing risks. Predictors considered will include age, sex, ethnicity, deprivation, smoking status, alcohol intake, body mass index, pre-existing medical co-morbidities, and concurrent medication. Measures of performance (prediction errors, calibration and discrimination) will be determined in the test data for men and women separately and by ten-year age group. For children, descriptive statistics will be undertaken if there are currently too few serious events to allow development of a risk model. The final model will be externally evaluated in (a) geographically separate practices and (b) other relevant datasets as they become available. Ethics and dissemination: The project has ethical approval and the results will be submitted for publication in a peer-reviewed journal.

OpenSAFELY: factors associated with COVID-19-related hospital death in the linked electronic health records of 17 million adult NHS patients. (preprint)

Background Establishing who is at risk from a novel rapidly arising cause of death, and why, requires a new approach to epidemiological research with very large datasets and timely data. Working on behalf of NHS England we therefore set out to deliver a secure and pseudonymised analytics platform inside the data centre of a major primary care electronic health records vendor establishing coverage across detailed primary care records for a substantial proportion of all patients in England. The following results are preliminary. Data sources Primary care electronic health records managed by the electronic health record vendor TPP, pseudonymously linked to patient-level data from the COVID-19 Patient Notification System (CPNS) for death of hospital inpatients with confirmed COVID-19, using the new OpenSAFELY platform. Population 17,425,445 adults. Time period 1st Feb 2020 to 25th April 2020. Primary outcome Death in hospital among people with confirmed COVID-19. Methods Cohort study analysed by Cox-regression to generate hazard ratios: age and sex adjusted, and multiply adjusted for co-variates selected prospectively on the basis of clinical interest and prior findings. Results There were 5683 deaths attributed to COVID-19. In summary after full adjustment, death from COVID-19 was strongly associated with: being male (hazard ratio 1.99, 95%CI 1.88-2.10); older age and deprivation (both with a strong gradient); uncontrolled diabetes (HR 2.36 95% CI 2.18-2.56); severe asthma (HR 1.25 CI 1.08-1.44); and various other prior medical conditions. Compared to people with ethnicity recorded as white, black people were at higher risk of death, with only partial attenuation in hazard ratios from the fully adjusted model (age-sex adjusted HR 2.17 95% CI 1.84-2.57; fully adjusted HR 1.71 95% CI 1.44-2.02); with similar findings for Asian people (age-sex adjusted HR 1.95 95% CI 1.73-2.18; fully adjusted HR 1.62 95% CI 1.43-1.82). Conclusions We have quantified a range of clinical risk factors for death from COVID-19, some of which were not previously well characterised, in the largest cohort study conducted by any country to date. People from Asian and black groups are at markedly increased risk of in-hospital death from COVID-19, and contrary to some prior speculation this is only partially attributable to pre-existing clinical risk factors or deprivation; further research into the drivers of this association is therefore urgently required. Deprivation is also a major risk factor with, again, little of the excess risk explained by co-morbidity or other risk factors. The findings for clinical risk factors are concordant with policies in the UK for protecting those at highest risk. Our OpenSAFELY platform is rapidly adding further NHS patients' records; we will update and extend these results regularly. Keywords COVID-19, risk factors, ethnicity, deprivation, death, informatics.