Evaluation of S/F94 as a proxy for COVID-19 severity

Optimising statistical power in early-stage trials and observational studies accelerates discovery and improves the reliability of results. Ideally, intermediate outcomes should be continuously distributed and lie on the causal pathway between an intervention and a definitive outcome such as mortality. In order to optimise power for an intermediate outcome in the RECOVERY trial, we devised and evaluated a modification to a simple, pragmatic measure of oxygenation function - the SaO2/FIO2 (S/F) ratio. We demonstrate that, because of the ceiling effect in oxyhaemoglobin saturation, S/F ceases to reflect pulmonary oxygenation function at high values of SaO2. Using synthetic and real data, we found that the correlation of S/F with a gold standard (PaO2/FIO2, P/F ratio) improved substantially when measurements with SaO2 [≥] 0.94 are excluded (Spearman r, synthetic data: S/F : 0.31; S/F94: 0.85). We refer to this measure as S/F94. In order to test the underlying assumptions and validity of S/F94 as a predictor of a definitive outcome (mortality), we collected an observational dataset including over 39,000 hospitalised patients with COVID-19 in the ISARIC4C study. We first demonstrated that S/F94 is predictive of mortality in COVID-19. We then compared the sample sizes required for trials using different outcome measures (S/F94, the WHO ordinal scale, sustained improvement at day 28 and mortality at day 28) ensuring comparable effect sizes. The smallest sample size was needed when S/F94 on day 5 was used as an outcome measure. To facilitate future study design, we provide an online user interface to quantify real-world power for a range of outcomes and inclusion criteria, using a synthetic dataset retaining the population-level clinical associations in real data accrued in ISARIC4C https://isaric4c.net/endpoints. We demonstrated that S/F94 is superior to S/F as a measure of pulmonary oxygenation function and is an effective intermediate outcome measure in COVID-19. It is a simple and non-invasive measurement, representative of disease severity and provides greater statistical power to detect treatment differences than other intermediate endpoints.

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

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, analysingroutinely-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.

Analysis of severe outcomes associated with the SARS-CoV-2 Variant of Concern 202012/01 in England using ICNARC Case Mix Programme and QResearch databases.

BackgroundA new, more transmissible variant of SARS-CoV-2, variant of concern (VOC) 202012/01 or lineage B.1.1.7, has emerged in the UK. We estimate the risk of critical care admission, mortality in critical ill patients, and overall mortality associated with VOC B.1.1.7 compared with the original variant. We also compare clinical outcomes between these variants groups. MethodsWe linked a large primary care (QResearch), the national critical care (ICNARC CMP) and the COVID-19 testing (PHE) database and extracted two cohorts. The first was used to explore the association between VOC B.1.1.7 and critical care admission and 28-day mortality. The second to determine the risk of mortality in critically ill patients with VOC B.1.1.7 compared to those without. We used Royston-Parmar models adjusted for age, sex, region, other socio-demographics and comorbidities (asthma, COPD, type I and II, hypertension). We reported information on types and duration of organ supports for the two variants groups. FindingsThe first cohort included 198,420 patients. Of these, 80,494 had VOC B.1.1.7, 712 were critically ill and 630 died by 28 days. The second cohort included 3432 critically ill patients. Of these, 2019 had VOC B.1.1.7 and 822 died at the end of critical care. Using the first cohort, we estimated adjusted hazard ratios for critical care admission and mortality to be 1.99 (95% CI: 1.59, 2.49) and 1.59 (95% CI: 1.25-2.03) for VOC B.1.1.7 compared with the original variant group, respectively. The adjusted hazard ratio for mortality in critical care, estimated using the second cohort, was 0.93 (95% CI 0.76-1.15) for patients with VOC B.1.1.7, compared to those without. InterpretationVOC B.1.1.7 appears to be more severe. Patients with VOC B.1.1.7 are at increased risk of critical care admission and mortality compared with patients without. For patients receiving critical care, mortality appears independent of virus strain. RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSA new variant of the SARS-CoV-2 virus, variant of concern (VOC) 202012/01, or lineage B.1.1.7, was detected in England in September 2020. The characteristics and outcomes of patients infected with VOC B.1.1.7 are not yet known. VOC B.1.1.7 has been associated with increased transmissibility. Early analyses have suggested infection with VOC B.1.1.7 may be associated with a higher risk of mortality compared with infection with other virus variants, but these analyses had either limited ability to adjust for key confounding variables or did not consider critical care admission. The effects of VOC B.1.1.7 on severe COVID-19 outcomes remain unclear. Added value of this studyThis study found a 60% higher risk of 28-day mortality associated with infection with VOC B.1.1.7 in patients tested in the community in comparison with the original variant, when adjusted for key confounding variables. The risk of critical care admission for those with VOC B.1.1.7 is double the risk associated with the original variant. For patients receiving critical care, the infecting variant is not associated with the risk of mortality at the end of critical care. Implications of all the available evidenceThe higher mortality and rate of critical care admission associated with VOC B.1.1.7, combined with its known increased transmissibility, are likely to put health care systems under further stress. These effects may be mitigated by the ongoing vaccination programme.

Ethnic differences in COVID-19 infection, hospitalisation, and mortality: an OpenSAFELY analysis of 17 million adults in England

Background: COVID-19 has had a disproportionate impact on ethnic minority populations, both in the UK and internationally. To date, much of the evidence has been derived from studies within single healthcare settings, mainly those hospitalised with COVID-19. Working on behalf of NHS England, the aim of this study was to identify ethnic differences in the risk of COVID-19 infection, hospitalisation and mortality using a large general population cohort in England. Methods: We conducted an observational cohort study using linked primary care records of 17.5 million adults between 1 February 2020 and 3 August 2020. Exposure was self-reported ethnicity collapsed into the 5 and 16 ethnicity categories of the English Census. Multivariable Cox proportional hazards regression was used to identify ethnic differences in the risk of being tested and testing positive for SARS-CoV-2 infection, COVID-19 related intensive care unit (ICU) admission, and COVID-19 mortality, adjusted for socio-demographic factors, clinical co-morbidities, geographic region, care home residency, and household size. Results: A total of 17,510,002 adults were included in the study; 63% white (n=11,030,673), 6% south Asian (n=1,034,337), 2% black (n=344,889), 2% other (n=324,730), 1% mixed (n=172,551), and 26% unknown (n=4,602,822). After adjusting for measured explanatory factors, south Asian, black, and mixed groups were marginally more likely to be tested (south Asian HR 1.08, 95%CI 1.07-1.09; black HR 1.08; 95%CI 1.06-1.09, mixed HR 1.03, 95%CI 1.01-1.05), and substantially more likely to test positive for SARS-CoV-2 compared with white adults (south Asian HR 2.02. 95% CI 1.97-2.07; black HR 1.68, 95%CI 1.61-1.76; mixed HR 1.46, 95%CI 1.36-1.56). The risk of being admitted to ICU for COVID-19 was substantially increased in all ethnic minority groups compared with white adults (south Asian HR 2.22, 95%CI 1.96-2.52; black HR 3.07, 95%CI 2.61-3.61; mixed HR 2.86, 95%CI 2.19-3.75, other HR 2.86, 95%CI 2.31-3.63). Risk of COVID-19 mortality was increased by 25-56% in ethnic minority groups compared with white adults (south Asian HR 1.27, 95%CI 1.17-1.38; black HR 1.55, 95%CI 1.38-1.75; mixed HR 1.40, 95%CI 1.12-1.76; other HR 1.25, 95%CI 1.05-1.49). We observed heterogeneity of associations after disaggregation into detailed ethnic groupings; Indian and African groups were at higher risk of all outcomes; Pakistani, Bangladeshi and Caribbean groups were less or equally likely to be tested for SARS-CoV-2, but at higher risk of all other outcomes, Chinese groups were less likely to be tested for and test positive for SARS-CoV-2, more likely to be admitted to ICU, and equally likely to die from COVID-19. Conclusions: We found evidence of substantial ethnic inequalities in the risk of testing positive for SARS-CoV-2, ICU admission, and mortality, which persisted after accounting for explanatory factors, including household size. It is likely that some of this excess risk is related to factors not captured in clinical records such as occupation, experiences of structural discrimination, or inequitable access to health and social services. Prioritizing linkage between health, social care, and employment data and engaging with ethnic minority communities to better understand their lived experiences is essential for generating evidence to prevent further widening of inequalities in a timely and actionable manner.

Associations between COVID-19 infection, tobacco smoking and nicotine use, common respiratory conditions and inhaled corticosteroids: a prospective QResearch-Case Mix Programme data linkage study January-May 2020

IntroductionEpidemiological and laboratory research seems to suggest that smoking and perhaps nicotine alone could reduce the severity of COVID-19. Likewise, there is some evidence that inhaled corticosteroids could also reduce its severity, opening the possibility that nicotine and inhaled steroids could be used as treatments. MethodsIn this prospective cohort study, we will link English general practice records from the QResearch database to Public Health Englands database of SARS-CoV-2 positive tests, Hospital Episode Statistics, admission to intensive care units, and death from COVID-19 to identify our outcomes: hospitalisation, ICU admission, and death due to COVID. Using Cox regression, we will perform sequential adjustment for potential confounders identified by separate directed acyclic graphs to: O_LIAssess the association between smoking and COVID-19 disease severity, and how that changes on adjustment for smoking-related comorbidity. C_LIO_LIMore closely characterise the association between smoking and severe COVID-19 disease by assessing whether the association is modified by age (as a proxy of length of smoking), gender, ethnic group, and whether people have asthma or COPD. C_LIO_LIAssess for evidence of a dose-response relation between smoking intensity and disease severity, which would help create a case for causality. C_LIO_LIExamine the association between former smokers who are using NRT or are vaping and disease severity. C_LIO_LIExamine whether pre-existing respiratory disease is associated with severe COVID-19 infection. C_LIO_LIAssess whether the association between chronic obstructive pulmonary disease (COPD) and asthma and COVID-19 disease severity is modified by age, gender, ethnicity, and smoking status. C_LIO_LIAssess whether the use of inhaled corticosteroids is associated with severity of COVID-19 disease. C_LIO_LITo assess whether the association between use of inhaled corticosteroids and severity of COVID-19 disease is modified by the number of other airways medications used (as a proxy for severity of condition) and whether people have asthma or COPD. C_LI ConclusionsThis representative population sample will, to our knowledge, present the first comprehensive examination of the association between smoking, nicotine use without smoking, respiratory disease, and severity of COVID-19. We will undertake several sensitivity analyses to examine the potential for bias in these associations.

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

BackgroundEstablishing 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 sourcesPrimary 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. Population17,425,445 adults. Time period1st Feb 2020 to 25th April 2020. Primary outcomeDeath in hospital among people with confirmed COVID-19. MethodsCohort 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. ResultsThere 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 1.431.82). ConclusionsWe 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.

Behavioral and cognitive impulsivity in obsessive-compulsive disorder and eating disorders.

This study compared self-reported impulsivity and neurocognitively assessed response inhibition in obsessive-compulsive disorder (OCD), eating disorder (ED), and healthy control participants. Participants completed the Barratt Impulsiveness Scale (BIS-11), stop-signal reaction time task, and measures of OCD and ED symptomatology (Yale-Brown Obsessive-Compulsive Scale and Eating Disorders Examination-Questionnaire). Compared to controls, both clinical groups reported higher levels of impulsivity on the BIS-11 however; only the OCD demonstrated increased stop-signal reaction time. Heightened levels of self-reported impulsivity may reflect the experience of anxiety in both OCD and ED populations whereas a lack of inhibitory control may represent a specific behavioral deficit in OCD.

Microvascular endothelial cells of the bovine corpus luteum: a comparative examination of the estrous cycle and pregnancy.

Endothelial cells derived from the corpus luteum (CLENDOs) exhibit diverse characteristics presumably serving their wide-ranging roles in luteal function and fate. Here, several attributes of CLENDOs derived from cows at midcycle (days 9-12 of the estrous cycle) were compared with CLENDOs from early pregnancy (day 60 of pregnancy). Flow cytometric analysis of cells fluorescently-tagged with the lectins Bandeiraea simplicifolia (BS-1) and Concanavalin A (ConA) indicated that CLENDOs of midcycle CL do not differ from those of pregnancy. Mean fluorescence intensity for BS-1 was 15 +/- 1 and 23 +/- 7 fluorescent units for midcycle CLENDOs and CLENDOs of pregnancy, respectively (P>0.05). For ConA, mean fluorescence was 25 +/- 2 and 26 +/- 1 fluorescent units, respectively (P>0.05). The CLENDOs were also exposed to cytokines to assess differences in activation of nuclear factor kappa B signaling (NF-kappaB), induction of the transcription factor interferon regulatory factor 1 (IRF1), cytokine production, and cytokine-induced cell death. In response to TNF, for instance, both types of CLENDOs exhibited a rapid, 5-fold decrease in NF-kappaB inhibitor alpha (NFKBIA) protein expression (P<0.05), and a 4-fold increase in IRF1 expression (P<0.05), that did not differ with phenotype (P>0.05). Similarly, both types of CLENDOs produced tumor necrosis factor alpha and chemokine ligand 2 in response to IFNG stimulation (P<0.05) that did not differ with phenotype (P>0.05). Lastly, extended exposure of CLENDOs of midcycle CL to cytokines induced cell death (~50% cell death vs. control) similar to the incidence of cell death seen previously in CLENDOs of early pregnancy. The results indicate that several physical and functional characteristics of CLENDOs of midcycle CL are retained through early pregnancy, including lectin-binding properties, sensitivity to cytokines, and the activation of cytokine-initiated intracellular signals.

Health policy and systems research in Africa, Asia and Latin America

Part No. 3: Health Policy and Systems Research (HPSR) in Latin America and the Caribbean: The Context of HPSR in Latin America and the Caribbean, Socio-economic context and health in LAC, Health systems in LAC,Overview of current HPSR in the LAC region, Research agenda, Capacity for shared learning, Relevance and utilisation of research results,Implications for the proposed Alliance for HPSR.