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1.
BMJ Open ; 11(12): e047354, 2021 12 16.
Article in English | MEDLINE | ID: covidwho-1583120

ABSTRACT

OBJECTIVES: To compare in UK medical students the predictive validity of attained A-level grades and teacher-predicted A levels for undergraduate and postgraduate outcomes. Teacher-predicted A-level grades are a plausible proxy for the teacher-estimated grades that replaced UK examinations in 2020 as a result of the COVID-19 pandemic. The study also models the likely future consequences for UK medical schools of replacing public A-level examination grades with teacher-predicted grades. DESIGN: Longitudinal observational study using UK Medical Education Database data. SETTING: UK medical education and training. PARTICIPANTS: Dataset 1: 81 202 medical school applicants in 2010-2018 with predicted and attained A-level grades. Dataset 2: 22 150 18-year-old medical school applicants in 2010-2014 with predicted and attained A-level grades, of whom 12 600 had medical school assessment outcomes and 1340 had postgraduate outcomes available. OUTCOME MEASURES: Undergraduate and postgraduate medical examination results in relation to attained and teacher-predicted A-level results. RESULTS: Dataset 1: teacher-predicted grades were accurate for 48.8% of A levels, overpredicted in 44.7% of cases and underpredicted in 6.5% of cases. Dataset 2: undergraduate and postgraduate outcomes correlated significantly better with attained than with teacher-predicted A-level grades. Modelling suggests that using teacher-estimated grades instead of attained grades will mean that 2020 entrants are more likely to underattain compared with previous years, 13% more gaining the equivalent of the lowest performance decile and 16% fewer reaching the equivalent of the current top decile, with knock-on effects for postgraduate training. CONCLUSIONS: The replacement of attained A-level examination grades with teacher-estimated grades as a result of the COVID-19 pandemic may result in 2020 medical school entrants having somewhat lower academic performance compared with previous years. Medical schools may need to consider additional teaching for entrants who are struggling or who might need extra support for missed aspects of A-level teaching.


Subject(s)
COVID-19 , Education, Medical, Undergraduate , Students, Medical , Humans , Pandemics , Retrospective Studies , SARS-CoV-2 , School Admission Criteria , Schools, Medical , United Kingdom
2.
Int J Environ Res Public Health ; 18(23)2021 Dec 02.
Article in English | MEDLINE | ID: covidwho-1561320

ABSTRACT

Psychological resilience is the ability to use personal qualities to withstand pressure, consisting of the interaction between the individual and the environment over time. It is essential when operating in extreme environments which are typically characterised by a complex combination of stressors with increased elements of risk and adversity. Psychological resilience has never been investigated "live" (e.g., in the moment) throughout the duration of an extreme endurance challenge, despite anecdotal accounts of the need for resilience to successfully function in such environments. The aim of the study was to explore psychological resilience with challenge team members (n = 4, mean age = 46.0 years) involved in a 25-day extreme endurance challenge. The object of the challenge was to 'TAB' (Tactical Advance to Battle, fast marching with weighted packs) 100 peaks in the UK in 25 days and complete long-distance bike rides between base camps. A mixed-methods approach with a focus on qualitative methods was utilised. Specifically, individual reflective video diaries (n = 47) and focus groups (n = 4) were completed and analysed using interpretative phenomenological analysis (IPA). At the same time, the 10-item Connor Davidson Resilience Scale was employed to measure resilience, which highlighted the individualised and dynamic nature of resilience. Two superordinate themes were identified from the video diaries and focus groups, namely, the identification of the stressors within extreme environments and strategies to maintain functioning. Stressors were split into subordinate themes of significant and every day, and collectively, they created a cluster effect which contributed to pressure associated with operating in these environments. Challenge team members employed various strategies to maintain functioning, including using a challenge mindset to positively appraise pressure as a challenging learning experience. Further research should continue to develop an understanding of how participants completing challenges within extreme environments utilise and develop personal qualities to maintain functioning.

4.
Am J Respir Cell Mol Biol ; 2021 Oct 28.
Article in English | MEDLINE | ID: covidwho-1495786

ABSTRACT

Immunopathology occurs in the lung and spleen in fatal COVID-19, involving monocytes/macrophages and plasma cells. Anti-inflammatory therapy reduces mortality but additional therapeutic targets are required. We aimed to gain mechanistic insight into COVID-19 immunopathology by targeted proteomic analysis of pulmonary and splenic tissues. Lung parenchymal and splenic tissue was obtained from 13 post-mortem examinations of patients with fatal COVID-19. Control tissue was obtained from cancer resection samples (lung) and deceased organ donors (spleen). Protein was extracted from tissue by phenol extraction. Olink® multiplex immunoassay panels were used for protein detection and quantification. Proteins with increased abundance in the lung included MCP-3, antiviral TRIM21 and pro-thrombotic TYMP. OSM and EN-RAGE/S100A12 abundance was correlated, and associated with inflammation severity. Unsupervised clustering identified 'early viral' and 'late inflammatory' clusters with distinct protein abundance profiles, and differences in illness duration prior to death and presence of viral RNA. In the spleen, lymphocyte chemotactic factors and CD8A were decreased in abundance, and pro-apoptotic factors were increased. B-cell receptor signalling pathway components and macrophage colony stimulating factor (CSF-1) were also increased. Additional evidence for a sub-set of host factors (including DDX58, OSM, TYMP, IL-18, MCP-3 and CSF-1) was provided by overlap between (i) differential abundance in spleen and lung tissue, (ii) meta-analysis of existing datasets, and (iii) plasma proteomic data. This proteomic analysis of lung parenchymal and splenic tissue from fatal COVID-19 provides mechanistic insight into tissue anti-viral responses, inflammation and disease stages, macrophage involvement, pulmonary thrombosis, splenic B-cell activation and lymphocyte depletion. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).

5.
Nat Med ; 2021 Oct 25.
Article in English | MEDLINE | ID: covidwho-1483142

ABSTRACT

Emerging reports of rare neurological complications associated with COVID-19 infection and vaccinations are leading to regulatory, clinical and public health concerns. We undertook a self-controlled case series study to investigate hospital admissions from neurological complications in the 28 days after a first dose of ChAdOx1nCoV-19 (n = 20,417,752) or BNT162b2 (n = 12,134,782), and after a SARS-CoV-2-positive test (n = 2,005,280). There was an increased risk of Guillain-Barré syndrome (incidence rate ratio (IRR), 2.90; 95% confidence interval (CI): 2.15-3.92 at 15-21 days after vaccination) and Bell's palsy (IRR, 1.29; 95% CI: 1.08-1.56 at 15-21 days) with ChAdOx1nCoV-19. There was an increased risk of hemorrhagic stroke (IRR, 1.38; 95% CI: 1.12-1.71 at 15-21 days) with BNT162b2. An independent Scottish cohort provided further support for the association between ChAdOx1nCoV and Guillain-Barré syndrome (IRR, 2.32; 95% CI: 1.08-5.02 at 1-28 days). There was a substantially higher risk of all neurological outcomes in the 28 days after a positive SARS-CoV-2 test including Guillain-Barré syndrome (IRR, 5.25; 95% CI: 3.00-9.18). Overall, we estimated 38 excess cases of Guillain-Barré syndrome per 10 million people receiving ChAdOx1nCoV-19 and 145 excess cases per 10 million people after a positive SARS-CoV-2 test. In summary, although we find an increased risk of neurological complications in those who received COVID-19 vaccines, the risk of these complications is greater following a positive SARS-CoV-2 test.

6.
Journal of Applied Psychology ; 106(9):1267, 2021.
Article in English | ProQuest Central | ID: covidwho-1454724

ABSTRACT

The COVID-19 pandemic introduced unprecedented challenges for individuals in organizations to maintain their interpersonal connections, which are critical for resource exchange. Because prior research has focused on how networks gradually evolve over time, there is little insight into how an exogenous shock, such as the pandemic, would reshape informal ties among colleagues that comprise their social networks. Drawing upon the optimal matching theory of social support, we develop a psychological perspective on how individuals recalibrate their social ties to enable coping with the uncertainty and anxiety introduced by the pandemic shock. We test our theory using a three-wave network data set from a sample of colocated, full-time MBA students before and after the onset of the pandemic. Following the onset of the pandemic, we found there was an overall reduction in the maintenance of advice ties. We also found that emotional exhaustion exacerbated this effect, and when emotional exhaustion was high, racially homophilous advice ties were just as likely to be dropped as heterophilous advice ties. We also found, unexpectedly, that COVID-19 reduced the maintenance of friendship ties, perhaps because social distancing reduced emotional support opportunities. Thoughts of anticipated inclusion mitigated this negative effect, particularly for racially heterophilous friendships. Individuals in organizations have psychological agency for reordering their social networks to respond to demands created by existential crises.

7.
JAMA ; 326(11): 1013-1023, 2021 09 21.
Article in English | MEDLINE | ID: covidwho-1441906

ABSTRACT

Importance: In patients who require mechanical ventilation for acute hypoxemic respiratory failure, further reduction in tidal volumes, compared with conventional low tidal volume ventilation, may improve outcomes. Objective: To determine whether lower tidal volume mechanical ventilation using extracorporeal carbon dioxide removal improves outcomes in patients with acute hypoxemic respiratory failure. Design, Setting, and Participants: This multicenter, randomized, allocation-concealed, open-label, pragmatic clinical trial enrolled 412 adult patients receiving mechanical ventilation for acute hypoxemic respiratory failure, of a planned sample size of 1120, between May 2016 and December 2019 from 51 intensive care units in the UK. Follow-up ended on March 11, 2020. Interventions: Participants were randomized to receive lower tidal volume ventilation facilitated by extracorporeal carbon dioxide removal for at least 48 hours (n = 202) or standard care with conventional low tidal volume ventilation (n = 210). Main Outcomes and Measures: The primary outcome was all-cause mortality 90 days after randomization. Prespecified secondary outcomes included ventilator-free days at day 28 and adverse event rates. Results: Among 412 patients who were randomized (mean age, 59 years; 143 [35%] women), 405 (98%) completed the trial. The trial was stopped early because of futility and feasibility following recommendations from the data monitoring and ethics committee. The 90-day mortality rate was 41.5% in the lower tidal volume ventilation with extracorporeal carbon dioxide removal group vs 39.5% in the standard care group (risk ratio, 1.05 [95% CI, 0.83-1.33]; difference, 2.0% [95% CI, -7.6% to 11.5%]; P = .68). There were significantly fewer mean ventilator-free days in the extracorporeal carbon dioxide removal group compared with the standard care group (7.1 [95% CI, 5.9-8.3] vs 9.2 [95% CI, 7.9-10.4] days; mean difference, -2.1 [95% CI, -3.8 to -0.3]; P = .02). Serious adverse events were reported for 62 patients (31%) in the extracorporeal carbon dioxide removal group and 18 (9%) in the standard care group, including intracranial hemorrhage in 9 patients (4.5%) vs 0 (0%) and bleeding at other sites in 6 (3.0%) vs 1 (0.5%) in the extracorporeal carbon dioxide removal group vs the control group. Overall, 21 patients experienced 22 serious adverse events related to the study device. Conclusions and Relevance: Among patients with acute hypoxemic respiratory failure, the use of extracorporeal carbon dioxide removal to facilitate lower tidal volume mechanical ventilation, compared with conventional low tidal volume mechanical ventilation, did not significantly reduce 90-day mortality. However, due to early termination, the study may have been underpowered to detect a clinically important difference. Trial Registration: ClinicalTrials.gov Identifier: NCT02654327.


Subject(s)
Carbon Dioxide/blood , Extracorporeal Circulation , Respiration, Artificial/methods , Respiratory Insufficiency/therapy , Aged , Early Termination of Clinical Trials , Extracorporeal Circulation/adverse effects , Female , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Respiration, Artificial/adverse effects , Respiratory Distress Syndrome/therapy , Respiratory Insufficiency/mortality , Tidal Volume
8.
Contemp Clin Trials ; 108: 106482, 2021 09.
Article in English | MEDLINE | ID: covidwho-1427719

ABSTRACT

BACKGROUND: 20-60% of patients with initially locally advanced Renal Cell Carcinoma (RCC) develop metastatic disease despite optimal surgical excision. Adjuvant strategies have been tested in RCC including cytokines, radiotherapy, hormones and oral tyrosine-kinase inhibitors (TKIs), with limited success. The predominant global standard-of-care after nephrectomy remains active monitoring. Immune checkpoint inhibitors (ICIs) are effective in the treatment of metastatic RCC; RAMPART will investigate these agents in the adjuvant setting. METHODS/DESIGN: RAMPART is an international, UK-led trial investigating the addition of ICIs after nephrectomy in patients with resected locally advanced RCC. RAMPART is a multi-arm multi-stage (MAMS) platform trial, upon which additional research questions may be addressed over time. The target population is patients with histologically proven resected locally advanced RCC (clear cell and non-clear cell histological subtypes), with no residual macroscopic disease, who are at high or intermediate risk of relapse (Leibovich score 3-11). Patients with fully resected synchronous ipsilateral adrenal metastases are included. Participants are randomly assigned (3,2:2) to Arm A - active monitoring (no placebo) for one year, Arm B - durvalumab (PD-L1 inhibitor) 4-weekly for one year; or Arm C - combination therapy with durvalumab 4-weekly for one year plus two doses of tremelimumab (CTLA-4 inhibitor) at day 1 of the first two 4-weekly cycles. The co-primary outcomes are disease-free-survival (DFS) and overall survival (OS). Secondary outcomes include safety, metastasis-free survival, RCC specific survival, quality of life, and patient and clinician preferences. Tumour tissue, plasma and urine are collected for molecular analysis (TransRAMPART). TRIAL REGISTRATION: ISRCTN #: ISRCTN53348826, NCT #: NCT03288532, EUDRACT #: 2017-002329-39, CTA #: 20363/0380/001-0001, MREC #: 17/LO/1875, ClinicalTrials.gov Identifier: NCT03288532, RAMPART grant number: MC_UU_12023/25, TransRAMPART grant number: A28690 Cancer Research UK, RAMPART Protocol version 5.0.


Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Carcinoma, Renal Cell/surgery , Chronic Disease , Humans , Kidney Neoplasms/surgery , Quality of Life , Recurrence
9.
Lancet Respir Med ; 9(8): 909-923, 2021 08.
Article in English | MEDLINE | ID: covidwho-1411740

ABSTRACT

BACKGROUND: Previous studies suggested that the prevalence of chronic respiratory disease in patients hospitalised with COVID-19 was lower than its prevalence in the general population. The aim of this study was to assess whether chronic lung disease or use of inhaled corticosteroids (ICS) affects the risk of contracting severe COVID-19. METHODS: In this population cohort study, records from 1205 general practices in England that contribute to the QResearch database were linked to Public Health England's database of SARS-CoV-2 testing and English hospital admissions, intensive care unit (ICU) admissions, and deaths for COVID-19. All patients aged 20 years and older who were registered with one of the 1205 general practices on Jan 24, 2020, were included in this study. With Cox regression, we examined the risks of COVID-19-related hospitalisation, admission to ICU, and death in relation to respiratory disease and use of ICS, adjusting for demographic and socioeconomic status and comorbidities associated with severe COVID-19. FINDINGS: Between Jan 24 and April 30, 2020, 8 256 161 people were included in the cohort and observed, of whom 14 479 (0·2%) were admitted to hospital with COVID-19, 1542 (<0·1%) were admitted to ICU, and 5956 (0·1%) died. People with some respiratory diseases were at an increased risk of hospitalisation (chronic obstructive pulmonary disease [COPD] hazard ratio [HR] 1·54 [95% CI 1·45-1·63], asthma 1·18 [1·13-1·24], severe asthma 1·29 [1·22-1·37; people on three or more current asthma medications], bronchiectasis 1·34 [1·20-1·50], sarcoidosis 1·36 [1·10-1·68], extrinsic allergic alveolitis 1·35 [0·82-2·21], idiopathic pulmonary fibrosis 1·59 [1·30-1·95], other interstitial lung disease 1·66 [1·30-2·12], and lung cancer 2·24 [1·89-2·65]) and death (COPD 1·54 [1·42-1·67], asthma 0·99 [0·91-1·07], severe asthma 1·08 [0·98-1·19], bronchiectasis 1·12 [0·94-1·33], sarcoidosis 1·41 [0·99-1·99), extrinsic allergic alveolitis 1·56 [0·78-3·13], idiopathic pulmonary fibrosis 1·47 [1·12-1·92], other interstitial lung disease 2·05 [1·49-2·81], and lung cancer 1·77 [1·37-2·29]) due to COVID-19 compared with those without these diseases. Admission to ICU was rare, but the HR for people with asthma was 1·08 (0·93-1·25) and severe asthma was 1·30 (1·08-1·58). In a post-hoc analysis, relative risks of severe COVID-19 in people with respiratory disease were similar before and after shielding was introduced on March 23, 2020. In another post-hoc analysis, people with two or more prescriptions for ICS in the 150 days before study start were at a slightly higher risk of severe COVID-19 compared with all other individuals (ie, no or one ICS prescription): HR 1·13 (1·03-1·23) for hospitalisation, 1·63 (1·18-2·24) for ICU admission, and 1·15 (1·01-1·31) for death. INTERPRETATION: The risk of severe COVID-19 in people with asthma is relatively small. People with COPD and interstitial lung disease appear to have a modestly increased risk of severe disease, but their risk of death from COVID-19 at the height of the epidemic was mostly far lower than the ordinary risk of death from any cause. Use of inhaled steroids might be associated with a modestly increased risk of severe COVID-19. FUNDING: National Institute for Health Research Oxford Biomedical Research Centre and the Wellcome Trust.


Subject(s)
Adrenal Cortex Hormones , COVID-19 , Pulmonary Disease, Chronic Obstructive , Administration, Inhalation , Adrenal Cortex Hormones/administration & dosage , Adrenal Cortex Hormones/adverse effects , COVID-19/diagnosis , COVID-19/epidemiology , COVID-19/physiopathology , COVID-19 Testing , Comorbidity , England/epidemiology , Female , Hospitalization/statistics & numerical data , Humans , Intensive Care Units/statistics & numerical data , Male , Middle Aged , Mortality , Pulmonary Disease, Chronic Obstructive/diagnosis , Pulmonary Disease, Chronic Obstructive/drug therapy , Pulmonary Disease, Chronic Obstructive/epidemiology , Risk Assessment , SARS-CoV-2/isolation & purification , Social Class
10.
JMIR Diabetes ; 6(4): e23646, 2021 Nov 02.
Article in English | MEDLINE | ID: covidwho-1403377

ABSTRACT

The COVID-19 pandemic has revolutionized health care for patients and providers alike. Telemedicine has moved from the periphery of our health care system to center stage more rapidly than anyone could have envisioned. Currently, virtual care has quite effectively replicated the traditional health system's care delivery model and reimbursement structure-a patient makes an appointment, then sees a physician (except with video or phone replacing in-office visits) who makes a care plan, and the patient and physician meet again at a later timepoint to assess progress. Replicating this episodic care paradigm virtually has been invaluable for delivering care swiftly during the COVID-19 pandemic; however, we can and should do more with the connectedness and convenience that telemedicine technology enables. Continuous remote care, with a data-driven, proactive outreach to patients, represents a decisive step forward in contrast to the currently available episodic, reactive, patient-initiated care. In the context of continuous remote care, patient biometric and symptom data (patient entered and connected data) are assimilated in real time by artificial intelligence-enabled clinical platforms to bring physicians' and other health care team members' attention to those patients who need intervention, whether this is via medication adjustments, acute care management, or lifestyle coaching. In this paper, we discuss how an innovative continuous remote care approach has improved outcomes in another deadly pandemic-type 2 diabetes mellitus.

11.
BMJ ; 374: n1931, 2021 08 26.
Article in English | MEDLINE | ID: covidwho-1376469

ABSTRACT

OBJECTIVE: To assess the association between covid-19 vaccines and risk of thrombocytopenia and thromboembolic events in England among adults. DESIGN: Self-controlled case series study using national data on covid-19 vaccination and hospital admissions. SETTING: Patient level data were obtained for approximately 30 million people vaccinated in England between 1 December 2020 and 24 April 2021. Electronic health records were linked with death data from the Office for National Statistics, SARS-CoV-2 positive test data, and hospital admission data from the United Kingdom's health service (NHS). PARTICIPANTS: 29 121 633 people were vaccinated with first doses (19 608 008 with Oxford-AstraZeneca (ChAdOx1 nCoV-19) and 9 513 625 with Pfizer-BioNTech (BNT162b2 mRNA)) and 1 758 095 people had a positive SARS-CoV-2 test. People aged ≥16 years who had first doses of the ChAdOx1 nCoV-19 or BNT162b2 mRNA vaccines and any outcome of interest were included in the study. MAIN OUTCOME MEASURES: The primary outcomes were hospital admission or death associated with thrombocytopenia, venous thromboembolism, and arterial thromboembolism within 28 days of three exposures: first dose of the ChAdOx1 nCoV-19 vaccine; first dose of the BNT162b2 mRNA vaccine; and a SARS-CoV-2 positive test. Secondary outcomes were subsets of the primary outcomes: cerebral venous sinus thrombosis (CVST), ischaemic stroke, myocardial infarction, and other rare arterial thrombotic events. RESULTS: The study found increased risk of thrombocytopenia after ChAdOx1 nCoV-19 vaccination (incidence rate ratio 1.33, 95% confidence interval 1.19 to 1.47 at 8-14 days) and after a positive SARS-CoV-2 test (5.27, 4.34 to 6.40 at 8-14 days); increased risk of venous thromboembolism after ChAdOx1 nCoV-19 vaccination (1.10, 1.02 to 1.18 at 8-14 days) and after SARS-CoV-2 infection (13.86, 12.76 to 15.05 at 8-14 days); and increased risk of arterial thromboembolism after BNT162b2 mRNA vaccination (1.06, 1.01 to 1.10 at 15-21 days) and after SARS-CoV-2 infection (2.02, 1.82 to 2.24 at 15-21 days). Secondary analyses found increased risk of CVST after ChAdOx1 nCoV-19 vaccination (4.01, 2.08 to 7.71 at 8-14 days), after BNT162b2 mRNA vaccination (3.58, 1.39 to 9.27 at 15-21 days), and after a positive SARS-CoV-2 test; increased risk of ischaemic stroke after BNT162b2 mRNA vaccination (1.12, 1.04 to 1.20 at 15-21 days) and after a positive SARS-CoV-2 test; and increased risk of other rare arterial thrombotic events after ChAdOx1 nCoV-19 vaccination (1.21, 1.02 to 1.43 at 8-14 days) and after a positive SARS-CoV-2 test. CONCLUSION: Increased risks of haematological and vascular events that led to hospital admission or death were observed for short time intervals after first doses of the ChAdOx1 nCoV-19 and BNT162b2 mRNA vaccines. The risks of most of these events were substantially higher and more prolonged after SARS-CoV-2 infection than after vaccination in the same population.


Subject(s)
COVID-19 Vaccines/adverse effects , COVID-19/prevention & control , Thrombocytopenia/epidemiology , Thromboembolism/epidemiology , Vaccination/statistics & numerical data , Adolescent , Adult , Aged , Aged, 80 and over , COVID-19/diagnosis , COVID-19/epidemiology , COVID-19 Vaccines/administration & dosage , England/epidemiology , Female , Humans , Male , Middle Aged , Pandemics , Risk Assessment , SARS-CoV-2 , Young Adult
12.
Lancet ; 397(10286): 1711-1724, 2021 05 08.
Article in English | MEDLINE | ID: covidwho-1301056

ABSTRACT

BACKGROUND: COVID-19 has disproportionately affected minority ethnic populations in the UK. Our aim was to quantify ethnic differences in SARS-CoV-2 infection and COVID-19 outcomes during the first and second waves of the COVID-19 pandemic in England. METHODS: We conducted an observational cohort study of adults (aged ≥18 years) registered with primary care practices in England for whom electronic health records were available through the OpenSAFELY platform, and who had at least 1 year of continuous registration at the start of each study period (Feb 1 to Aug 3, 2020 [wave 1], and Sept 1 to Dec 31, 2020 [wave 2]). Individual-level primary care data were linked to data from other sources on the outcomes of interest: SARS-CoV-2 testing and positive test results and COVID-19-related hospital admissions, intensive care unit (ICU) admissions, and death. The exposure was self-reported ethnicity as captured on the primary care record, grouped into five high-level census categories (White, South Asian, Black, other, and mixed) and 16 subcategories across these five categories, as well as an unknown ethnicity category. We used multivariable Cox regression to examine ethnic differences in the outcomes of interest. Models were adjusted for age, sex, deprivation, clinical factors and comorbidities, and household size, with stratification by geographical region. FINDINGS: Of 17 288 532 adults included in the study (excluding care home residents), 10 877 978 (62·9%) were White, 1 025 319 (5·9%) were South Asian, 340 912 (2·0%) were Black, 170 484 (1·0%) were of mixed ethnicity, 320 788 (1·9%) were of other ethnicity, and 4 553 051 (26·3%) were of unknown ethnicity. In wave 1, the likelihood of being tested for SARS-CoV-2 infection was slightly higher in the South Asian group (adjusted hazard ratio 1·08 [95% CI 1·07-1·09]), Black group (1·08 [1·06-1·09]), and mixed ethnicity group (1·04 [1·02-1·05]) and was decreased in the other ethnicity group (0·77 [0·76-0·78]) relative to the White group. The risk of testing positive for SARS-CoV-2 infection was higher in the South Asian group (1·99 [1·94-2·04]), Black group (1·69 [1·62-1·77]), mixed ethnicity group (1·49 [1·39-1·59]), and other ethnicity group (1·20 [1·14-1·28]). Compared with the White group, the four remaining high-level ethnic groups had an increased risk of COVID-19-related hospitalisation (South Asian group 1·48 [1·41-1·55], Black group 1·78 [1·67-1·90], mixed ethnicity group 1·63 [1·45-1·83], other ethnicity group 1·54 [1·41-1·69]), COVID-19-related ICU admission (2·18 [1·92-2·48], 3·12 [2·65-3·67], 2·96 [2·26-3·87], 3·18 [2·58-3·93]), and death (1·26 [1·15-1·37], 1·51 [1·31-1·71], 1·41 [1·11-1·81], 1·22 [1·00-1·48]). In wave 2, the risks of hospitalisation, ICU admission, and death relative to the White group were increased in the South Asian group but attenuated for the Black group compared with these risks in wave 1. Disaggregation into 16 ethnicity groups showed important heterogeneity within the five broader categories. INTERPRETATION: Some minority ethnic populations in England have excess risks of testing positive for SARS-CoV-2 and of adverse COVID-19 outcomes compared with the White population, even after accounting for differences in sociodemographic, clinical, and household characteristics. Causes are likely to be multifactorial, and delineating the exact mechanisms is crucial. Tackling ethnic inequalities will require action across many fronts, including reducing structural inequalities, addressing barriers to equitable care, and improving uptake of testing and vaccination. FUNDING: Medical Research Council.


Subject(s)
COVID-19/ethnology , Hospitalization/statistics & numerical data , Intensive Care Units/statistics & numerical data , Patient Admission/statistics & numerical data , Adult , COVID-19/epidemiology , COVID-19/mortality , Cohort Studies , England , Humans , Observational Studies as Topic , Survival Analysis
13.
Lancet Infect Dis ; 21(11): 1518-1528, 2021 11.
Article in English | MEDLINE | ID: covidwho-1281645

ABSTRACT

BACKGROUND: A more transmissible variant of SARS-CoV-2, the variant of concern 202012/01 or lineage B.1.1.7, has emerged in the UK. We aimed to estimate the risk of critical care admission, mortality in patients who are critically ill, and overall mortality associated with lineage B.1.1.7 compared with non-B.1.1.7. We also compared clinical outcomes between these two groups. METHODS: For this observational cohort study, we linked large primary care (QResearch), national critical care (Intensive Care National Audit & Research Centre Case Mix Programme), and national COVID-19 testing (Public Health England) databases. We used SARS-CoV-2 positive samples with S-gene molecular diagnostic assay failure (SGTF) as a proxy for the presence of lineage B.1.1.7. We extracted two cohorts from the data: the primary care cohort, comprising patients in primary care with a positive community COVID-19 test reported between Nov 1, 2020, and Jan 26, 2021, and known SGTF status; and the critical care cohort, comprising patients admitted for critical care with a positive community COVID-19 test reported between Nov 1, 2020, and Jan 27, 2021, and known SGTF status. We explored the associations between SARS-CoV-2 infection with and without lineage B.1.1.7 and admission to a critical care unit (CCU), 28-day mortality, and 28-day mortality following CCU admission. We used Royston-Parmar models adjusted for age, sex, geographical region, other sociodemographic factors (deprivation index, ethnicity, household housing category, and smoking status for the primary care cohort; and ethnicity, body-mass index, deprivation index, and dependency before admission to acute hospital for the CCU cohort), and comorbidities (asthma, chronic obstructive pulmonary disease, type 1 and 2 diabetes, and hypertension for the primary care cohort; and cardiovascular disease, respiratory disease, metastatic disease, and immunocompromised conditions for the CCU cohort). We reported information on types and duration of organ support for the B.1.1.7 and non-B.1.1.7 groups. FINDINGS: The primary care cohort included 198 420 patients with SARS-CoV-2 infection. Of these, 117 926 (59·4%) had lineage B.1.1.7, 836 (0·4%) were admitted to CCU, and 899 (0·4%) died within 28 days. The critical care cohort included 4272 patients admitted to CCU. Of these, 2685 (62·8%) had lineage B.1.1.7 and 662 (15·5%) died at the end of critical care. In the primary care cohort, we estimated adjusted hazard ratios (HRs) of 2·15 (95% CI 1·75-2·65) for CCU admission and 1·65 (1·36-2·01) for 28-day mortality for patients with lineage B.1.1.7 compared with the non-B.1.1.7 group. The adjusted HR for mortality in critical care, estimated with the critical care cohort, was 0·91 (0·76-1·09) for patients with lineage B.1.1.7 compared with those with non-B.1.1.7 infection. INTERPRETATION: Patients with lineage B.1.1.7 were at increased risk of CCU admission and 28-day mortality compared with patients with non-B.1.1.7 SARS-CoV-2. For patients receiving critical care, mortality appeared to be independent of virus strain. Our findings emphasise the importance of measures to control exposure to and infection with COVID-19. FUNDING: Wellcome Trust, National Institute for Health Research Oxford Biomedical Research Centre, and the Medical Sciences Division of the University of Oxford.


Subject(s)
COVID-19/mortality , Critical Care/statistics & numerical data , Intensive Care Units/statistics & numerical data , SARS-CoV-2/isolation & purification , Adolescent , Adult , Aged , Aged, 80 and over , COVID-19/diagnosis , COVID-19/therapy , COVID-19/virology , COVID-19 Nucleic Acid Testing/statistics & numerical data , England/epidemiology , Female , Hospital Mortality , Humans , Male , Middle Aged , Risk Assessment/statistics & numerical data , Risk Factors , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Severity of Illness Index , Young Adult
15.
BMJ Open ; 11(6): e043906, 2021 06 16.
Article in English | MEDLINE | ID: covidwho-1276955

ABSTRACT

RATIONALE: Clinical trials are the gold standard for testing interventions. COVID-19 has further raised their public profile and emphasised the need to deliver better, faster, more efficient trials for patient benefit. Considerable overlap exists between data required for trials and data already collected routinely in electronic healthcare records (EHRs). Opportunities exist to use these in innovative ways to decrease duplication of effort and speed trial recruitment, conduct and follow-up. APPROACH: The National Institute of Health Research (NIHR), Health Data Research UK and Clinical Practice Research Datalink co-organised a national workshop to accelerate the agenda for 'data-enabled clinical trials'. Showcasing successful examples and imagining future possibilities, the plenary talks, panel discussions, group discussions and case studies covered: design/feasibility; recruitment; conduct/follow-up; collecting benefits/harms; and analysis/interpretation. REFLECTION: Some notable studies have successfully accessed and used EHR to identify potential recruits, support randomised trials, deliver interventions and supplement/replace trial-specific follow-up. Some outcome measures are already reliably collected; others, like safety, need detailed work to meet regulatory reporting requirements. There is a clear need for system interoperability and a 'route map' to identify and access the necessary datasets. Researchers running regulatory-facing trials must carefully consider how data quality and integrity would be assessed. An experience-sharing forum could stimulate wider adoption of EHR-based methods in trial design and execution. DISCUSSION: EHR offer opportunities to better plan clinical trials, assess patients and capture data more efficiently, reducing research waste and increasing focus on each trial's specific challenges. The short-term emphasis should be on facilitating patient recruitment and for postmarketing authorisation trials where research-relevant outcome measures are readily collectable. Sharing of case studies is encouraged. The workshop directly informed NIHR's funding call for ambitious data-enabled trials at scale. There is the opportunity for the UK to build upon existing data science capabilities to identify, recruit and monitor patients in trials at scale.


Subject(s)
COVID-19 , Humans , Patient Selection , SARS-CoV-2 , United Kingdom
16.
BMJ Open ; 11(3): e044753, 2021 03 04.
Article in English | MEDLINE | ID: covidwho-1119314

ABSTRACT

OBJECTIVE: Describe the experiences and views of medical applicants from diverse social backgrounds following the closure of schools and universities and the cancellation of public examinations in the UK due to COVID-19. DESIGN: Cross-sectional questionnaire study, part of the longitudinal UK Medical Applicant Cohort Study (UKMACS). SETTING: UK medical school admissions in 2020. PARTICIPANTS: 2887 participants completed an online questionnaire from 8 April to 22 April 2020. Eligible participants had registered to take the University Clinical Admissions Test in 2019 and agreed to be invited to take part, or had completed a previous UKMACS questionnaire, had been seriously considering applying to medicine in the UK for entry in 2020, and were UK residents. MAIN OUTCOME MEASURES: Views on calculated grades, views on medical school admissions and teaching in 2020 and 2021, reported experiences of education during the national lockdown. RESULTS: Respondents were concerned about the calculated grades that replaced A-level examinations: female and Black Asian and Minority Ethnic applicants felt teachers would find it difficult to grade and rank students accurately, and applicants from non-selective state schools and living in deprived areas had concerns about the standardisation process. Calculated grades were generally not considered fair enough to use in selection, but were considered fair enough to use in combination with other measures including interview and aptitude test scores. Respondents from non-selective state (public) schools reported less access to educational resources compared with private/selective school pupils, less online teaching in real time and less time studying during lockdown. CONCLUSIONS: The COVID-19 pandemic has and will have significant and long-term impacts on the selection, education and performance of our medical workforce. It is important that the views and experiences of applicants from diverse backgrounds are considered in decisions affecting their future and the future of the profession.


Subject(s)
COVID-19 , School Admission Criteria , Schools, Medical/standards , Students, Medical/psychology , Attitude , Cohort Studies , Communicable Disease Control , Cross-Sectional Studies , Female , Humans , Male , Pandemics , Surveys and Questionnaires , United Kingdom
17.
Am J Respir Crit Care Med ; 203(2): 192-201, 2021 01 15.
Article in English | MEDLINE | ID: covidwho-1059843

ABSTRACT

Rationale: In life-threatening coronavirus disease (COVID-19), corticosteroids reduce mortality, suggesting that immune responses have a causal role in death. Whether this deleterious inflammation is primarily a direct reaction to the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or an independent immunopathologic process is unknown.Objectives: To determine SARS-CoV-2 organotropism and organ-specific inflammatory responses and the relationships among viral presence, inflammation, and organ injury.Methods: Tissue was acquired from 11 detailed postmortem examinations. SARS-CoV-2 organotropism was mapped by using multiplex PCR and sequencing, with cellular resolution achieved by in situ viral S (spike) protein detection. Histologic evidence of inflammation was quantified from 37 anatomic sites, and the pulmonary immune response was characterized by using multiplex immunofluorescence.Measurements and Main Results: Multiple aberrant immune responses in fatal COVID-19 were found, principally involving the lung and reticuloendothelial system, and these were not clearly topologically associated with the virus. Inflammation and organ dysfunction did not map to the tissue and cellular distribution of SARS-CoV-2 RNA and protein between or within tissues. An arteritis was identified in the lung, which was further characterized as a monocyte/myeloid-rich vasculitis, and occurred together with an influx of macrophage/monocyte-lineage cells into the pulmonary parenchyma. In addition, stereotyped abnormal reticuloendothelial responses, including excessive reactive plasmacytosis and iron-laden macrophages, were present and dissociated from viral presence in lymphoid tissues.Conclusions: Tissue-specific immunopathology occurs in COVID-19, implicating a significant component of the immune-mediated, virus-independent immunopathologic process as a primary mechanism in severe disease. Our data highlight novel immunopathologic mechanisms and validate ongoing and future efforts to therapeutically target aberrant macrophage and plasma-cell responses as well as promote pathogen tolerance in COVID-19.


Subject(s)
COVID-19/immunology , Inflammation/virology , Lung/immunology , Multiple Organ Failure/virology , SARS-CoV-2/immunology , Aged , Aged, 80 and over , Autopsy , Biopsy , COVID-19/pathology , COVID-19/virology , COVID-19 Nucleic Acid Testing , Female , Fluorescent Antibody Technique , Humans , Inflammation/immunology , Inflammation/pathology , Lung/pathology , Lung/virology , Male , Multiple Organ Failure/immunology , Multiple Organ Failure/pathology , SARS-CoV-2/pathogenicity , Severity of Illness Index
18.
Crit Care Med ; 49(1): 102-111, 2021 01 01.
Article in English | MEDLINE | ID: covidwho-1024138

ABSTRACT

OBJECTIVES: To identify characteristics that predict 30-day mortality among patients critically ill with coronavirus disease 2019 in England, Wales, and Northern Ireland. DESIGN: Observational cohort study. SETTING: A total of 258 adult critical care units. PATIENTS: A total of 10,362 patients with confirmed coronavirus disease 2019 with a start of critical care between March 1, 2020, and June 22, 2020, of whom 9,990 were eligible (excluding patients with a duration of critical care less than 24 hr or missing core variables). MEASUREMENTS AND MAIN RESULTS: The main outcome measure was time to death within 30 days of the start of critical care. Of 9,990 eligible patients (median age 60 yr, 70% male), 3,933 died within 30 days of the start of critical care. As of July 22, 2020, 189 patients were still receiving critical care and a further 446 were still in acute hospital. Data were missing for between 0.1% and 7.2% of patients across prognostic factors. We imputed missing data ten-fold, using fully conditional specification and continuous variables were modeled using restricted cubic splines. Associations between the candidate prognostic factors and time to death within 30 days of the start of critical care were determined after adjustment for multiple variables with Cox proportional hazards modeling. Significant associations were identified for age, ethnicity, deprivation, body mass index, prior dependency, immunocompromise, lowest systolic blood pressure, highest heart rate, highest respiratory rate, Pao2/Fio2 ratio (and interaction with mechanical ventilation), highest blood lactate concentration, highest serum urea, and lowest platelet count over the first 24 hours of critical care. Nonsignificant associations were found for sex, sedation, highest temperature, and lowest hemoglobin concentration. CONCLUSIONS: We identified patient characteristics that predict an increased likelihood of death within 30 days of the start of critical care for patients with coronavirus disease 2019. These findings may support development of a prediction model for benchmarking critical care providers.


Subject(s)
COVID-19/mortality , Critical Illness/mortality , Severity of Illness Index , Adult , COVID-19/therapy , Cohort Studies , Critical Illness/therapy , England , Female , Hospital Mortality , Humans , Male , Middle Aged , Northern Ireland , Prognosis , Respiration, Artificial/mortality , Wales
19.
Nature ; 584(7821): 430-436, 2020 08.
Article in English | MEDLINE | ID: covidwho-981546

ABSTRACT

Coronavirus disease 2019 (COVID-19) has rapidly affected mortality worldwide1. There is unprecedented urgency to understand who is most at risk of severe outcomes, and this requires new approaches for the timely analysis of large datasets. Working on behalf of NHS England, we created OpenSAFELY-a secure health analytics platform that covers 40% of all patients in England and holds patient data within the existing data centre of a major vendor of primary care electronic health records. Here we used OpenSAFELY to examine factors associated with COVID-19-related death. Primary care records of 17,278,392 adults were pseudonymously linked to 10,926 COVID-19-related deaths. COVID-19-related death was associated with: being male (hazard ratio (HR) 1.59 (95% confidence interval 1.53-1.65)); greater age and deprivation (both with a strong gradient); diabetes; severe asthma; and various other medical conditions. Compared with people of white ethnicity, Black and South Asian people were at higher risk, even after adjustment for other factors (HR 1.48 (1.29-1.69) and 1.45 (1.32-1.58), respectively). We have quantified a range of clinical factors associated with COVID-19-related death in one of the largest cohort studies on this topic so far. More patient records are rapidly being added to OpenSAFELY, we will update and extend our results regularly.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/mortality , Pneumonia, Viral/mortality , Adolescent , Adult , Age Distribution , Age Factors , Aged , Aged, 80 and over , Aging , Asthma/epidemiology , COVID-19 , Cohort Studies , Coronavirus Infections/prevention & control , Coronavirus Infections/virology , Diabetes Mellitus/epidemiology , Female , Humans , Hypertension/epidemiology , Male , Middle Aged , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Pneumonia, Viral/virology , Proportional Hazards Models , Risk Assessment , SARS-CoV-2 , Sex Characteristics , Smoking/epidemiology , State Medicine , Young Adult
20.
Nature ; 591(7848): 92-98, 2021 03.
Article in English | MEDLINE | ID: covidwho-971937

ABSTRACT

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice.


Subject(s)
COVID-19/genetics , COVID-19/physiopathology , Critical Illness , 2',5'-Oligoadenylate Synthetase/genetics , COVID-19/pathology , Chromosomes, Human, Pair 12/genetics , Chromosomes, Human, Pair 19/genetics , Chromosomes, Human, Pair 21/genetics , Critical Care , Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/genetics , Drug Repositioning , Female , Genome-Wide Association Study , Humans , Inflammation/genetics , Inflammation/pathology , Inflammation/physiopathology , Lung/pathology , Lung/physiopathology , Lung/virology , Male , Multigene Family/genetics , Receptor, Interferon alpha-beta/genetics , Receptors, CCR2/genetics , TYK2 Kinase/genetics , United Kingdom
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