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Background: No randomised controlled trials have yet reported on the effectiveness of molnupiravir on longer term outcomes for COVID-19. The PANORAMIC trial found molnupiravir reduced time to recovery in acute COVID-19 over 28 days. We aimed to report the effect of molnupiravir treatment for COVID-19 on wellbeing, severe and persistent symptoms, new infections, health care and social service use, medication use, and time off work at 3 months and 6 months post-randomisation., Methods: This study is a follow-up to the main analysis, which was based on the first 28 days of follow-up and has been previously reported. For this multicentre, primary care, open-label, multi-arm, prospective randomised controlled trial conducted in the UK, participants were eligible if aged at least 50 years, or at least 18 years with a comorbidity, and unwell 5 days or less with confirmed COVID-19 in the community. Participants were randomly assigned to the usual care group or molnupiravir group plus usual care (800 mg twice a day for 5 days), which was stratified by age (<50 years or ≥50 years) and vaccination status (at least one dose: yes or no). The primary outcome was hospitalisation or death (or both) at 28 days; all longer term outcomes were considered to be secondary outcomes and included self-reported ratings of wellness (on a scale of 0-10), experiencing any symptom (fever, cough, shortness of breath, fatigue, muscle ache, nausea and vomiting, diarrhoea, loss of smell or taste, headache, dizziness, abdominal pain, and generally feeling unwell) rated as severe (moderately bad or major problem) or persistent, any health and social care use, health-related quality of life (measured by the EQ-5D-5L), time off work or school, new infections, and hospitalisation., Findings: Between Dec 8, 2021, and April 27, 2022, 25 783 participants were randomly assigned to the molnupiravir plus usual care group (n=12 821) or usual care group (n=12 962). Long-term follow-up data were available for 23 008 (89·2%) of 25 784 participants with 11 778 (91·9%) of 12 821 participants in the molnupiravir plus usual care group and 11 230 (86·6%) of 12 963 in the usual care group. 22 806 (99·1%) of 23 008 had at least one previous dose of a SARS-CoV-2 vaccine. Any severe (3 months: adjusted risk difference -1·6% [-2·6% to -0·6%]; probability superiority [p(sup)]>0·99; number needed to treat [NNT] 62·5; 6 months: -1·9% [-2·9% to -0·9%]; p(sup)>0·99, NNT 52·6) or persistent symptoms (3 months: adjusted risk difference -2·1% [-2·9% to -1·5%]; p(sup)>0·99; NNT 47·6; 6 months: -2·5% [-3·3% to -1·6%]; p(sup)>0·99; NNT 40) were reduced in severity, and health-related quality of life (measured by the EQ-5D-5L) improved in the molnupiravir plus usual care group at 3 months and 6 months (3 months: adjusted mean difference 1·08 [0·65 to 1·53]; p(sup)>0·99; 6 months: 1·09 [0·63 to 1·55]; p(sup)>0·99). Ratings of wellness (3 months: adjusted mean difference 0·15 (0·11 to 0·19); p(sup)>0·99; 6 months: 0·12 (0·07 to 0·16); p(sup)>0·99), experiencing any more severe symptom (3 months; adjusted risk difference -1·6% [-2·6% to -0·6%]; p(sup)=0·99; 6 months: -1·9% [-2·9% to -0·9%]; p(sup)>0·99), and health-care use (3 months: adjusted risk difference -1·4% [-2·3% to -0·4%]; p(sup)>0·99; NNT 71·4; 6 months: -0·5% [-1·5% to 0·4%]; p(sup)>0·99; NNT 200) had high probabilities of superiority with molnupiravir treatment. There were significant differences in persistence of any symptom (910 [8·9%] of 10 190 vs 1027 [11%] of 9332, NNT 67) at 6 months, and reported time off work at 3 months (2017 [17·9%] of 11 274 vs 2385 [22·4%] of 10 628) and 6 months (460 [4·4%] of 10 562 vs 527 [5·4%] of 9846; NNT 100). There were no differences in hospitalisations at long-term follow-up., Interpretation: In a vaccinated population, people treated with molnupiravir for acute COVID-19 felt better, experienced fewer and less severe COVID-19 associated symptoms, accessed health care less often, and took less time off work at 6 months. However, the absolute differences in this open-label design are small with high numbers needed to treat., Funding: UK Research and Innovation and National Institute for Health and Care Research., Competing Interests: Declaration of interests JSN-V-T was seconded to the Department of Health and Social Care, England from Oct 1, 2017, to March 31, 2022. On June 15, 2023, JSN-V-T completed one 3-h paid consultancy assignment for Merck Sharp & Dohme on a subject unrelated to COVID-19, and has given two paid lectures for Gilead who have manufactured COVID-19 treatments in 2022–23, and one paid lecture for AstraZeneca in 2022, who manufacture COVID-19 vaccines. JSN-V-T has consulted occasionally for Moderna (May 1, 2023 onwards) who manufacture COVID-19 vaccines. DML has received personal fees from Gilead for an educational video and from Merck for a roundtable discussion, speaker fees from Biotest, Takeda, and Astra Zeneca, and support to attend a conference from Octapharma. DML holds research grants from GlaxoSmithKline and Bristol Myers Squibb, has received consultancy fees from GlaxoSmithKline paid to his institution, all outside the current work, and reports giving lectures for Biotest, Takeda, and AstraZeneca. JFS has participated in a Data and Safety Monitoring Committee for the sotrovimab paediatric programme for GlaxoSmithKline (fee paid to the institution). JB reports being the Principle Investigator on The Medicines and Healthcare products Regulatory Agency commissioned study with GlaxoSmithKline to look at the evolution of variants in sotrovimab treated patients, and consulting fees from GlaxoSmithKline, hVIVO, Moderna, and Symbios (donated to UCL). SK has been a speaker for Pfizer and ViiV Healthcare. KH reports a grant to Cardiff University (via University of Oxford), and was on the National Institute for Health and Care Research (NIHR) Health Technology Assessment General Committee and Health Technology Assessment Funding Strategy Group until November, 2022, and is currently Deputy Chair of the Research Professors panel. BRS reports consulting fees were paid to his former employer (Berry Consultants) for tiral design and implementation. NPBT reports being on a single advisory board in July, 2021, with Merck & Co. OvH reports consulting fees from MindGap. AU reports honoria from Merck & Co, Gilead Sciences, Pfizer, and Astra Zeneca in relation to this disease area and manuscript. All other authors declare no competing interests., (Copyright © 2025 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Blood pressure (BP) control following stroke is important but currently sub-optimal. This trial aimed to determine whether self-monitoring of hypertension with telemonitoring and a treatment escalation protocol, results in lower BP than usual care in people with previous stroke or transient ischaemic attack (TIA)., Methods: Unblinded randomised controlled trial, comparing a BP telemonitoring-based intervention with control (usual care) for hypertension management in 12 primary care practices in England. People with previous stroke or TIA with clinic systolic BP 130-180 mmHg, taking ≤ 3 antihypertensive medications and on stable treatment for at least four weeks were randomised 1:1 using secure online system to intervention or control. The BP:Together intervention comprised self-monitoring of blood pressure with a digital behavioural intervention which supported telemonitoring of self-monitored BP with feedback to clinicians and patients regarding medication titration. The planned primary outcome was difference in clinic measured systolic BP 12 months from randomisation but was not available following early study termination due to withdrawal of funding during the COVID-19 pandemic. Instead, in addition to pre-randomised data, routinely recorded BP was extracted from electronic patient records both pre- and post-randomisation and presented descriptively only. An intention to treat approach was taken., Results: From 650 postal invitations, 129 (20%) responded, of whom 95 people had been screened for eligibility prior to the pandemic (November 2019-March 2020) and 55 (58%) were randomised. Pre-randomisation routinely recorded mean BP was 145/78 mmHg in the control (n = 26) and 145/79 mmHg in the self-monitoring (n = 21) groups. Post-randomisation mean BP was 134/73 mmHg in the control (n = 19) and 130/75 mmHg in the self-monitoring (n = 25) groups. Participants randomised to self-monitoring used the intervention for ≥ 7 months in 25/27 (93%) of cases., Conclusions: Recruitment of people with stroke/TIA to a trial comparing a BP self-monitoring and digital behavioural intervention to usual care was feasible prior to the COVID-19 pandemic and the vast majority of those randomised to intervention used it while the trial was running. Routinely recorded blood pressure control improved in both groups. Digital interventions including self-monitoring are feasible for people with stroke/TIA and should be definitively evaluated in future trials., Trial Registration: ISRCTN57946500 06/09/2019 Prospective., Competing Interests: Declarations. Ethics approvals and consent to participate: Ethical approval was granted by North West - Greater Manchester East Research Ethics Committee Reference 19/NW/0409.Written informed consent was obtained before eligibility confirmation. Consent for publication: Not applicable. Competing interests: RM has received BP monitors for research from Omron (which were recycled for use in the current study) and Oxford University has received fees and consultancy from Omron for his work. FDRH has received occasional fees or expenses for speaking or consultancy from AZ, BI, Bayer, BMS/Pfizer, and Novartis. BM has received consultancy fees from the Scottish Government for advice on remote monitoring of hypertension. CRo has received consultancy fees from Sensyne Health for work on telemonitoring products. The other authors declare no further conflicts of interest., (© 2024. The Author(s).)

Background: Adults classified as immunosuppressed have been disproportionately affected by the COVID-19 pandemic. Compared to the immunocompetent, certain patients are at increased risk of suboptimal vaccine response and adverse health outcomes if infected. However, there has been insufficient work to pinpoint where these risks concentrate within the immunosuppressed spectrum; surveillance efforts typically treat the immunosuppressed as a single entity, leading to wide confidence intervals. A clinically meaningful and computerised medical record (CMR) compatible method to subdivide immunosuppressed COVID-19 data is urgently needed., Methods: We conducted a rapid scoping review into COVID-19 mortality across UK immunosuppressed categories to assess if differential mortality risk was a viable means of subdivision. We converted the risk hierarchy that surfaced into a pilot digital phenotype-a valueset and series of ontological rules ready to extract immunosuppressed patients from CMR data and stratify outcomes of interest in COVID-19 surveillance dataflows., Results: The rapid scoping review returned COVID-19 mortality data for all immunosuppressed subgroups assessed and revealed significant heterogeneity across the spectrum. There was a clear distinction between heightened COVID-19 mortality in haematological malignancy and transplant patients and mortality that approached the immunocompetent baseline amongst cancer therapy recipients, autoimmune patients, and those with HIV. This process, complemented by expert clinical input, informed the curation of the five-part digital phenotype now ready for testing in real-world data; its ontological rules will enable mutually exclusive, hierarchical extraction with nuanced time and treatment conditions. Unique categorisations have been introduced, including 'Bone Marrow Compromised' and those dedicated to differentiating prescriptions related and unrelated to cancer. Codification was supported by existing reference sets of medical codes; absent or redundant codes had to be resolved manually., Discussion: Although this work is in its earliest phases, the development process we report has been highly informative. Systematic review, clinical consensus building, and implementation studies will test the validity of our results and address criticisms of the rapid scoping exercise they are predicated on., Conclusion: Comprehensive testing for COVID-19 has differentiated mortality risks across the immunosuppressed spectrum. This risk hierarchy has been codified into a digital phenotype for differentiated COVID-19 surveillance; this marks a step towards the needs-based management of these patients that is urgently required., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Leston, Kar, Forbes, Jamie, Wimalaratna, Jiwani, Ordóñez-Mena, Stewart, Whitaker, Joy, Lee, Hobbs and de Lusignan.)

Objectives: Despite being prioritized during initial COVID-19 vaccine rollout, vulnerable individuals at high risk of severe COVID-19 (hospitalization, intensive care unit admission, or death) remain underrepresented in vaccine effectiveness (VE) studies. The RAVEN cohort study (NCT05047822) assessed AZD1222 (ChAdOx1 nCov-19) two-dose primary series VE in vulnerable populations., Methods: Using the Oxford-Royal College of General Practitioners Clinical Informatics Digital Hub, linked to secondary care, death registration, and COVID-19 datasets in England, COVID-19 outcomes in 2021 were compared in vaccinated and unvaccinated individuals matched on age, sex, region, and multimorbidity., Results: Over 4.5 million AZD1222 recipients were matched (mean follow-up ∼5 months); 68% were ≥50 years, 57% had high multimorbidity. Overall, high VE against severe COVID-19 was demonstrated, with lower VE observed in vulnerable populations. VE against hospitalization was higher in the lowest multimorbidity quartile (91.1%; 95% CI: 90.1, 92.0) than the highest quartile (80.4%; 79.7, 81.1), and among individuals ≥65 years, higher in the 'fit' (86.2%; 84.5, 87.6) than the frailest (71.8%; 69.3, 74.2). VE against hospitalization was lowest in immunosuppressed individuals (64.6%; 60.7, 68.1)., Conclusions: Based on integrated and comprehensive UK health data, overall population-level VE with AZD1222 was high. VEs were notably lower in vulnerable groups, particularly the immunosuppressed., Competing Interests: Declaration of Competing Interest Oxford University has entered into a partnership with AstraZeneca for the development of COVID-19 vaccines. KS, LC, MO, ST, SV, TM, TNT, and WM are employees of AstraZeneca and may own stock/shares. AJP was a member of the World Health Organization’s Strategic Advisory Group of Experts on Immunization until January 2022 and remains Chair of the UK Department of Health and Social Care's Joint Committee on Vaccination and Immunisation (JCVI) but does not participate in the JCVI COVID-19 committee. AJP also reports providing advice to Shionogi on COVID-19, and funding from the National Institute for Health Research (NIHR), AstraZeneca, the Bill & Melinda Gates Foundation, Wellcome, the Medical Research Council, the Serum Institute of India, and the Coalition for Epidemic Preparedness Innovations (CEPI); and being a contributor to the intellectual property licensed by Oxford University Innovation to AstraZeneca. DAC reports consulting fees from Oxford University Consulting, Bristol Myers Squibb, and grants from UK Research and Innovation, Wellcome Trust, NIHR, Hong Kong ITC, AstraZeneca, and Glaxo Smith Kline (GSK); and patents held by Oxford University Innovation. JD is an employee at Momentum data and may own stocks/shares. FDRH acknowledges support as Director of the NIHR Applied Research Collaboration Oxford Thames Valley and Theme Lead of the NIHR Oxford University Hospitals Biomedical Research Centre. He also reports fees or expenses for speaking or consultancy from AstraZeneca, Boehringer Ingelheim, Bayer, Bristol Myers Squibb/Pfizer, and Novartis. GJ reports ownership of GSK stocks/shares and honoraria form AstraZeneca. SdeL reports advisory board membership for AstraZeneca, GSK, Sanofi, and Seqirus (fees paid to University); and receiving university research grants from AstraZeneca, GSK, Sanofi, Seqirus, and Takeda. ST reports ownership of GSK stocks/shares. UH is an employee at Oxford University and reports membership on a Janssen advisory committee, funding from Seqirus for podcasts, and research funding from Seqirus and AstraZeneca. WH resorts partial salary funding from AstraZeneca-sponsored research grants. AD, AF, DK, KST, MF, MJ, RB, RW, SNA, and XF declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: Limited evidence exists for the diagnostic performance of point-of-care tests for SARS-CoV-2 and influenza in community healthcare. We carried out a prospective diagnostic accuracy study of the LumiraDx™ SARS-CoV-2 and influenza A or B assay in primary care., Methods: Total of 913 adults and children with symptoms of current SARS-CoV-2 infection were recruited from 18 UK primary care practices during a period when Omicron was the predominant COVID variant of concern (June 2022 to December 2022). Trained health care staff performed the index test, with diagnostic accuracy parameters estimated for SARS-CoV-2 and influenza against real-time reverse-transcription PCR (rtRT-PCR)., Results: 151/887 participants were SARS-CoV-2 rtRT-PCR positive, 109 positive for Influenza A, 6 for Influenza B. Index test sensitivity for SARS-CoV-2 was 80.8% (122 of the 151, 95% CI, 73.6-86.7%) and specificity 98.9% (728 of the 736, 95% CI, 97.9-99.5%). For influenza A, sensitivity was 61.5% (67 of the 109, 95% CI, 51.7-70.6%) and specificity 99.4% (771 of the 776, 95% CI, 98.5-99.8%). Sensitivity to detect SARS-CoV-2 and influenza dropped sharply at rtRT-PCR cycle thresholds (Ct) > 30., Discussions: The LumiraDx™ SARS-CoV-2 and influenza A/B assay had moderate sensitivity for SARS-CoV-2 in symptomatic patients in primary care, with lower performance with high rtRT-PCR Ct. Negative results in this patient group cannot definitively rule out SARS-CoV-2 or influenza., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Effective disease surveillance, including that for COVID-19, is compromised without a standardised method for categorising the immunosuppressed as a clinical risk group., Methods: We conducted a systematic review and meta-analysis to evaluate whether excess COVID-associated mortality compared to the immunocompetent could meaningfully subdivide the immunosuppressed. Our study adhered to UK Immunisation against infectious disease (Green Book) criteria for defining and categorising immunosuppression. Using OVID (EMBASE, MEDLINE, Transplant Library, and Global Health), PubMed, and Google Scholar, we examined relevant literature between the entirety of 2020 and 2022. We selected for cohort studies that provided mortality data for immunosuppressed subgroups and immunocompetent comparators. Meta-analyses, grey literature and any original works that failed to provide comparator data or reported all-cause or paediatric outcomes were excluded. Odds Ratios (OR) and 95% confidence intervals (CI) of COVID-19 mortality were meta-analysed by immunosuppressed category and subcategory. Subgroup analyses differentiated estimates by effect measure, country income, study setting, level of adjustment, use of matching and publication year. Study screening, extraction and bias assessment were performed blinded and independently by two researchers; conflicts were resolved with the oversight of a third researcher. PROSPERO registration number is CRD42022360755., Findings: We identified 99 unique studies, incorporating data from 1,542,097 and 56,248,181 unique immunosuppressed and immunocompetent patients with COVID-19 infection, respectively. Compared to immunocompetent people (pooled OR, 95%CI), solid organ transplants (2.12, 1.50-2.99) and malignancy (2.02, 1.69-2.42) patients had a very high risk of COVID-19 mortality. Patients with rheumatological conditions (1.28, 1.13-1.45) and HIV (1.20, 1.05-1.36) had just slightly higher risks than the immunocompetent baseline. Case type, setting income and mortality data matching and adjustment were significant modifiers of excess immunosuppressed mortality for some immunosuppressed subgroups., Interpretation: Excess COVID-associated mortality among the immunosuppressed compared to the immunocompetent was seen to vary significantly across subgroups. This novel means of subdivision has prospective benefit for targeting patient triage, shielding and vaccination policies during periods of high disease transmission., Competing Interests: Declaration of Competing Interest The authors of this manuscript are all either directly employed by or affiliated with the Royal College of General Practitioners’ Research and Surveillance Centre (Oxford-RCGP RSC), the UK primary care sentinel network. This work originated as a direct response to the limitations of existing disease surveillance, both within the RSC and comparable networks, to monitor outcomes within the immunosuppressed with high resolution and fidelity. The findings of this work will now be validated within RSC data flows and amongst RSC collaborator groups. However, none of these stated actors or collaborators had any influence on the approach, analysis, interpretation or write-up of this work., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Viral clearance, antibody response and the mutagenic effect of molnupiravir has not been elucidated in at-risk populations. Non-hospitalised participants within 5 days of SARS-CoV-2 symptoms randomised to receive molnupiravir (n = 253) or Usual Care (n = 324) were recruited to study viral and antibody dynamics and the effect of molnupiravir on viral whole genome sequence from 1437 viral genomes. Molnupiravir accelerates viral load decline, but virus is detectable by Day 5 in most cases. At Day 14 (9 days post-treatment), molnupiravir is associated with significantly higher viral persistence and significantly lower anti-SARS-CoV-2 spike antibody titres compared to Usual Care. Serial sequencing reveals increased mutagenesis with molnupiravir treatment. Persistence of detectable viral RNA at Day 14 in the molnupiravir group is associated with higher transition mutations following treatment cessation. Viral viability at Day 14 is similar in both groups with post-molnupiravir treated samples cultured up to 9 days post cessation of treatment. The current 5-day molnupiravir course is too short. Longer courses should be tested to reduce the risk of potentially transmissible molnupiravir-mutated variants being generated. Trial registration: ISRCTN30448031., (© 2024. The Author(s).)

The emergence of the COVID-19 vaccination has been critical in changing the course of the COVID-19 pandemic. To ensure protection remains high in vulnerable groups booster vaccinations in the UK have been targeted based on age and clinical vulnerabilities. We undertook a national retrospective cohort study using data from the 2021 Census linked to electronic health records. We fitted cause-specific Cox models to examine the association between health conditions and the risk of COVID-19 death and all-other-cause death for adults aged 50-100-years in England vaccinated with a booster in autumn 2022. Here we show, having learning disabilities or Down Syndrome (hazard ratio=5.07;95% confidence interval=3.69-6.98), pulmonary hypertension or fibrosis (2.88;2.43-3.40), motor neuron disease, multiple sclerosis, myasthenia or Huntington's disease (2.94, 1.82-4.74), cancer of blood and bone marrow (3.11;2.72-3.56), Parkinson's disease (2.74;2.34-3.20), lung or oral cancer (2.57;2.04 to 3.24), dementia (2.64;2.46 to 2.83) or liver cirrhosis (2.65;1.95 to 3.59) was associated with an increased risk of COVID-19 death. Individuals with cancer of the blood or bone marrow, chronic kidney disease, cystic fibrosis, pulmonary hypotension or fibrosis, or rheumatoid arthritis or systemic lupus erythematosus had a significantly higher risk of COVID-19 death relative to other causes of death compared with individuals who did not have diagnoses. Policy makers should continue to priorities vulnerable groups for subsequent COVID-19 booster doses to minimise the risk of COVID-19 death., (© 2024. Crown.)

Background: COVID-19 vaccines have been shown to be highly effective against hospitalisation and death following COVID-19 infection. COVID-19 vaccine effectiveness estimates against severe endpoints among individuals with clinical conditions that place them at increased risk of critical disease are limited., Methods: We used English primary care medical record data from the Oxford-Royal College of General Practitioners Research and Surveillance Centre sentinel network (N > 18 million). Data were linked to the National Immunisation Management Service database, Second Generation Surveillance System for virology test data, Hospital Episode Statistics, and death registry data. We estimated adjusted vaccine effectiveness (aVE) against COVID-19 infection followed by hospitalisation and death among individuals in specific clinical risk groups using a cohort design during the delta-dominant period. We also report mortality statistics and results from our antibody surveillance in this population., Findings: aVE against severe endpoints was high, 14-69d following a third dose aVE was 96.4% (95.1%-97.4%) and 97.9% (97.2%-98.4%) for clinically vulnerable people given a Vaxzevria and Comirnaty primary course respectively. Lower aVE was observed in the immunosuppressed group: 88.6% (79.1%-93.8%) and 91.9% (85.9%-95.4%) for Vaxzevria and Comirnaty respectively. Antibody levels were significantly lower among the immunosuppressed group than those not in this risk group across all vaccination types and doses. The standardised case fatality rate within 28 days of a positive test was 3.9/1000 in people not in risk groups, compared to 12.8/1000 in clinical risk groups. Waning aVE with time since 2nd dose was also demonstrated, for example, Comirnaty aVE against hospitalisation reduced from 96.0% (95.1-96.7%) 14-69days post-dose 2-82.9% (81.4-84.2%) 182days+ post-dose 2., Interpretation: In all clinical risk groups high levels of vaccine effectiveness against severe endpoints were seen. Reduced vaccine effectiveness was noted among the immunosuppressed group., Competing Interests: Declaration of Competing Interest Simon de Lusignan is the Director of the Oxford-RCGP RSC and has received funding through his University for studies from Astra-Zeneca, Eli Lilly, Sanofi, GSK, MSD. Seqirus and Takeda; and been member of advisory boards for Astra-Zeneca, Seqirus and Sanofi. Ezra Linley reports that the UKHSA Vaccine Evaluation Unit performs contract research on behalf of GSK, Sanofi and Pfizer which is outside the submitted work. FDRH is part funded by the NIHR ARC OTV and has received occasional research and consultancy funding from AZ and Pfizer but not related to vaccines., (Crown Copyright © 2023. Published by Elsevier Ltd. All rights reserved.)

Background and Objective: Point-of-care lateral flow device antigen testing has been used extensively to identify individuals with active SARS-CoV-2 infection in the community. This study aimed to evaluate the diagnostic accuracy of two point-of-care tests (POCTs) for SARS-CoV-2 in routine community care., Methods: Adults and children with symptoms consistent with suspected current COVID-19 infection were prospectively recruited from 19 UK general practices and two COVID-19 testing centres between October 2020 and October 2021. Participants were tested by trained healthcare workers using at least one of two index POCTs (Roche-branded SD Biosensor Standard™ Q SARS-CoV-2 Rapid Antigen Test and/or BD Veritor™ System for Rapid Detection of SARS-CoV-2). The reference standard was laboratory triplex reverse transcription quantitative PCR (RT-PCR) using a combined nasal/oropharyngeal swab. Diagnostic accuracy parameters were estimated, with 95% confidence intervals (CIs), overall, in relation to RT-PCR cycle threshold and in pre-specified subgroups., Results: Of 663 participants included in the primary analysis, 39.2% (260/663, 95% CI 35.5% to 43.0%) had a positive RT-PCR result. The SD Biosensor POCT had sensitivity 84.0% (178/212, 78.3% to 88.6%) and specificity 98.5% (328/333, 96.5% to 99.5%), and the BD Veritor POCT had sensitivity 76.5% (127/166, 69.3% to 82.7%) and specificity 98.8% (249/252, 96.6% to 99.8%) compared with RT-PCR. Sensitivity of both devices dropped substantially at cycle thresholds ≥30 and in participants more than 7 days after onset of symptoms., Conclusions: Both POCTs assessed exceed the Medicines and Healthcare products Regulatory Agency target product profile's minimum acceptable specificity of 95%. Confidence intervals for both tests include the minimum acceptable sensitivity of 80%. In symptomatic patients, negative results on these two POCTs do not preclude the possibility of infection. Tests should not be expected to reliably detect disease more than a week after symptom onset, when viral load may be reduced., Registration: ISRCTN142269., Competing Interests: We have read the journal’s policy and the authors of this manuscript have the following competing interests: The authorship declares funding support for this study from the University of Oxford Medical Sciences Division Benefactors Urgent COVID-19 Fund, the National Institute for Health and Care (NIHR) School of Primary Care Research, and Urgent Public Health funding for the CONDOR Platform from the NIHR and Asthma+Lung UK. The RAPTOR-C19 study team received analysers and assays free of charge from Becton Dickinson for evaluation in this study. GNH declares funding from the National Institute for Health and Care Research (NIHR) paid to the University of Oxford. KD declares grant funding from Alere Inc and Cepheid Inc paid to her institution for unrelated research. TRF declares NIHR support from the NIHR Community Healthcare MIC for diagnostic evaluation research. AJW declares grant funding received by the University of Oxford through a Wellcome Trust Enriching Engagement grant which has supported unrelated patient participation work carried out by the Royal College of General Practitioners Research Surveillance Centre (based at the University of Oxford) for surveillance work. GE declares funding support from the NIHR Community Healthcare MIC recieved by the University of Oxford. AM declares the support of a Wellcome Trust Doctoral Research Fellowship and an NIHR In-practice Fellowship unrelated to this research. PJT declares support from the NIHR Community Healthcare MIC for diagnostic evaluation research. PJT has provided expert support to the Longitude Prize AMR competition administration which is unrelated to this project and for which the University of Oxford received an honorarium. RB declares grant funding for this project from the NIHR and Asthma+Lung UK, with additional funding from the Department of Health and Social Care paid to his host institution. RB declares grants from Siemens Healthineers, Abbott Point-of-Care and Ancon, all paid to his institution for unrelated research. He declares consulting fees received by his institution from Roche, Siemens, Aptamer Group, LumiraDx, Beckman Coulter and Radiometer, with personal fees received from Psyros Diagnostics. RB has received support for attending meetings / travel from Roche and EMCREG International. RB has participated on data safety monitoring boards or advisory boards for the unrelated FORCE Trial, REWIRE Trial, TARGET-CTA, and Magnetocardiography study (MAGNETIC - sponsored by Creavo). RB is the Deputy National Specialty Lead for Trauma & Emergency Care, National Institute for Health and Care Research Clinical Research Network. RB declares receipt of donated reagents for research not detailed in this paper from Roche, LumiraDx, BD, iXensor, Abbott Point-of-Care, Randox, Avacta, Menarini, loan of analysers from Randox and Menarini, and assays run free of charge for research purposes by Chronomics, My110, and Ancon. JJL declares funding from an NIHR Doctoral Research Fellowship which is unrelated to this research. LM declares support from the NIHR Community Healthcare MIC and other NIHR grants to the University of Oxford in support of this work. EL declares unrelated project funding received by the UKHSA Vaccine Evaluation Unit for contract research from GSK, Pfizer and Sanofi. MZ declares her unpaid activities as the Chair of the charitable organisation ISIRV and her membership of the UK SAGE, NERVTAG and JCVI groups. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Nicholson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Aim: To explore the implications for dentists and family doctors of the association between periodontal and systemic diseases and the role of dentists and family doctors in managing non-communicable diseases (NCDs) and promoting healthy lifestyles., Materials and Methods: The consensus reports of the previous Focused Workshops on the associations between periodontitis and diabetes (2017) and periodontitis and cardiovascular diseases (2019) formed the technical reviews to underpin discussions on both topics. For the association with respiratory diseases, a systematic review was specifically commissioned for the Workshop discussions. Working groups prepared proposals independently, and then the proposals were discussed and approved at plenary meetings., Results: Periodontitis is independently associated with cardiovascular diseases, diabetes, chronic obstructive pulmonary disease (COPD), obstructive sleep apnea and COVID-19 complications. Dentists and family doctors should collaborate in managing NCDs, implementing strategies for early detection of periodontitis in primary care centres and of cardiovascular diseases or diabetes in dental settings. Family doctors should be informed about periodontal diseases and their consequences, and oral health professionals (OHPs) should be informed about the relevance of NCDs and the associated risk factors., Conclusions: Closer collaboration between OHPs and family doctors is important in the early detection and management of NCDs and in promoting healthy lifestyles. Pathways for early case detection of periodontitis in family medicine practices and of NCDs in dental practices should be developed and evaluated., (© 2023 The Authors. Journal of Clinical Periodontology published by John Wiley & Sons Ltd.)

Background: Several SARS-CoV-2 vaccines have been shown to provide protection against COVID-19 hospitalization and death. However, some evidence suggests that notable waning in effectiveness against these outcomes occurs within months of vaccination. We undertook a pooled analysis across the four nations of the UK to investigate waning in vaccine effectiveness (VE) and relative vaccine effectiveness (rVE) against severe COVID-19 outcomes., Methods: We carried out a target trial design for first/second doses of ChAdOx1(Oxford-AstraZeneca) and BNT162b2 (Pfizer-BioNTech) with a composite outcome of COVID-19 hospitalization or death over the period 8 December 2020 to 30 June 2021. Exposure groups were matched by age, local authority area and propensity for vaccination. We pooled event counts across the four UK nations., Results: For Doses 1 and 2 of ChAdOx1 and Dose 1 of BNT162b2, VE/rVE reached zero by approximately Days 60-80 and then went negative. By Day 70, VE/rVE was -25% (95% CI: -80 to 14) and 10% (95% CI: -32 to 39) for Doses 1 and 2 of ChAdOx1, respectively, and 42% (95% CI: 9 to 64) and 53% (95% CI: 26 to 70) for Doses 1 and 2 of BNT162b2, respectively. rVE for Dose 2 of BNT162b2 remained above zero throughout and reached 46% (95% CI: 13 to 67) after 98 days of follow-up., Conclusions: We found strong evidence of waning in VE/rVE for Doses 1 and 2 of ChAdOx1, as well as Dose 1 of BNT162b2. This evidence may be used to inform policies on timings of additional doses of vaccine., (© The Author(s) 2022. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: The safety, effectiveness, and cost-effectiveness of molnupiravir, an oral antiviral medication for SARS-CoV-2, has not been established in vaccinated patients in the community at increased risk of morbidity and mortality from COVID-19. We aimed to establish whether the addition of molnupiravir to usual care reduced hospital admissions and deaths associated with COVID-19 in this population., Methods: PANORAMIC was a UK-based, national, multicentre, open-label, multigroup, prospective, platform adaptive randomised controlled trial. Eligible participants were aged 50 years or older-or aged 18 years or older with relevant comorbidities-and had been unwell with confirmed COVID-19 for 5 days or fewer in the community. Participants were randomly assigned (1:1) to receive 800 mg molnupiravir twice daily for 5 days plus usual care or usual care only. A secure, web-based system (Spinnaker) was used for randomisation, which was stratified by age (<50 years vs ≥50 years) and vaccination status (yes vs no). COVID-19 outcomes were tracked via a self-completed online daily diary for 28 days after randomisation. The primary outcome was all-cause hospitalisation or death within 28 days of randomisation, which was analysed using Bayesian models in all eligible participants who were randomly assigned. This trial is registered with ISRCTN, number 30448031., Findings: Between Dec 8, 2021, and April 27, 2022, 26 411 participants were randomly assigned, 12 821 to molnupiravir plus usual care, 12 962 to usual care alone, and 628 to other treatment groups (which will be reported separately). 12 529 participants from the molnupiravir plus usual care group, and 12 525 from the usual care group were included in the primary analysis population. The mean age of the population was 56·6 years (SD 12·6), and 24 290 (94%) of 25 708 participants had had at least three doses of a SARS-CoV-2 vaccine. Hospitalisations or deaths were recorded in 105 (1%) of 12 529 participants in the molnupiravir plus usual care group versus 98 (1%) of 12 525 in the usual care group (adjusted odds ratio 1·06 [95% Bayesian credible interval 0·81-1·41]; probability of superiority 0·33). There was no evidence of treatment interaction between subgroups. Serious adverse events were recorded for 50 (0·4%) of 12 774 participants in the molnupiravir plus usual care group and for 45 (0·3%) of 12 934 in the usual care group. None of these events were judged to be related to molnupiravir., Interpretation: Molnupiravir did not reduce the frequency of COVID-19-associated hospitalisations or death among high-risk vaccinated adults in the community., Funding: UK National Institute for Health and Care Research., Competing Interests: Declaration of interests JSN-V-T was seconded to the Department of Health and Social Care, England from October, 2017, to March, 2022, and reports lecture fees from Gilead and fees for participation on an advisory board for F Hoffmann-La Roche. KH is a member of the Health Technology Assessment General Committee and Funding Strategy Group, and Research Professors Funding Committee at the UK National Institute for Health and Care Research (NIHR), received a grant from AstraZeneca (paid to their institution) to support a trial of Evusheld for the prevention of COVID-19 in high-risk individuals, and is an independent member of the independent data monitoring committee for the OCTAVE-DUO trial of vaccines in individuals at high risk of COVID-19. DML has received grants or contracts from LifeArc, the UK Medical Research Council, Bristol Myers Squibb, GlaxoSmithKline, the British Society for Antimicrobial Chemotherapy, and Blood Cancer UK, personal fees or honoraria from Biotest UK, Gilead, and Merck, consulting fees from GlaxoSmithKline (paid to their institution), and conference support from Octapharma. DBR has received consulting fees from OMASS Therapeutics and has a leadership and fiduciary role in the Heal-COVID trial TMG. BRS, JM, MAD, CTS, NSB, and MF report grant money paid to their employer from the University of Oxford for the statistical design and analyses of the PANORAMIC trial. JM has also participated on data and safety monitoring boards as part of his employment with Berry Consultants. ML is a member of the data monitoring and ethics committee of RAPIS-TEST (NIHR efficacy and mechanism evaluation). SK reports grants from GlaxoSmithKline, ViiV, Ridgeback Biotherapeutics, Vir, Merck, the UK Medical Research Council, and the Wellcome Trust (all paid to his institution), speaker's honoraria from ViiV, and donations of drugs for clinical studies from ViiV Healthcare, Toyama, and GlaxoSmithKline. JFS has participated on a data safety monitoring board for GlaxoSmithKline. MA has received grants from the Blood and Transplant Research Unit, Janssen, Pfizer, Prenetics, Dunhill Medical Trust, the BMA Trust (Kathleen Harper Fund), and Antibiotic Research UK (all of which were paid to their institution), and consultancy fees from Prenetics and OxDx. MA reports a planned patent for Ramanomics, has participated on data safety monitoring boards or advisory boards for Prenetics, and has an unpaid leadership or fiduciary role in the E3 Initiative. NPBT has received payment for participation on an advisory board from MSD (before any knowledge or planning of this trial). OvH has received consulting fees from MindGap (fees paid to Oxford University lnnovation), has participated on data safety monitoring boards or advisory boards for the CHICO trial, and has an unpaid leadership or fiduciary role in the British Society of Antimicrobial Chemotherapy. AU has received consulting fees and payment or honoraria from MSD, GlaxoSmithKline, and Gilead. NF has received consulting fees from Abbott Diagnostics and GlaxoSmithKline, is a member of the PRINCIPLE trial data safety monitoring board and the NIHR Health Technology Assessment General Funding Committee, and has stocks in Synairgen. JB has received consulting fees from GlaxoSmithKline (paid to her institution). All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: The Oxford-Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) is one of Europe's oldest sentinel systems, working with the UK Health Security Agency (UKHSA) and its predecessor bodies for 55 years. Its surveillance report now runs twice weekly, supplemented by online observatories. In addition to conducting sentinel surveillance from a nationally representative group of practices, the RSC is now also providing data for syndromic surveillance., Objective: The aim of this study was to describe the cohort profile at the start of the 2021-2022 surveillance season and recent changes to our surveillance practice., Methods: The RSC's pseudonymized primary care data, linked to hospital and other data, are held in the Oxford-RCGP Clinical Informatics Digital Hub, a Trusted Research Environment. We describe the RSC's cohort profile as of September 2021, divided into a Primary Care Sentinel Cohort (PCSC)-collecting virological and serological specimens-and a larger group of syndromic surveillance general practices (SSGPs). We report changes to our sampling strategy that brings the RSC into alignment with European Centre for Disease Control guidance and then compare our cohort's sociodemographic characteristics with Office for National Statistics data. We further describe influenza and COVID-19 vaccine coverage for the 2020-2021 season (week 40 of 2020 to week 39 of 2021), with the latter differentiated by vaccine brand. Finally, we report COVID-19-related outcomes in terms of hospitalization, intensive care unit (ICU) admission, and death., Results: As a response to COVID-19, the RSC grew from just over 500 PCSC practices in 2019 to 1879 practices in 2021 (PCSC, n=938; SSGP, n=1203). This represents 28.6% of English general practices and 30.59% (17,299,780/56,550,136) of the population. In the reporting period, the PCSC collected >8000 virology and >23,000 serology samples. The RSC population was broadly representative of the national population in terms of age, gender, ethnicity, National Health Service Region, socioeconomic status, obesity, and smoking habit. The RSC captured vaccine coverage data for influenza (n=5.4 million) and COVID-19, reporting dose one (n=11.9 million), two (n=11 million), and three (n=0.4 million) for the latter as well as brand-specific uptake data (AstraZeneca vaccine, n=11.6 million; Pfizer, n=10.8 million; and Moderna, n=0.7 million). The median (IQR) number of COVID-19 hospitalizations and ICU admissions was 1181 (559-1559) and 115 (50-174) per week, respectively., Conclusions: The RSC is broadly representative of the national population; its PCSC is geographically representative and its SSGPs are newly supporting UKHSA syndromic surveillance efforts. The network captures vaccine coverage and has expanded from reporting primary care attendances to providing data on onward hospital outcomes and deaths. The challenge remains to increase virological and serological sampling to monitor the effectiveness and waning of all vaccines available in a timely manner., (©Meredith Leston, William H Elson, Conall Watson, Anissa Lakhani, Carole Aspden, Clare R Bankhead, Ray Borrow, Elizabeth Button, Rachel Byford, Alex J Elliot, Xuejuan Fan, Uy Hoang, Ezra Linley, Jack Macartney, Brian D Nicholson, Cecilia Okusi, Mary Ramsay, Gillian Smith, Sue Smith, Mark Thomas, Dan Todkill, Ruby SM Tsang, William Victor, Alice J Williams, John Williams, Maria Zambon, Gary Howsam, Gayatri Amirthalingam, Jamie Lopez-Bernal, F D Richard Hobbs, Simon de Lusignan. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 19.12.2022.)

There is a need for better understanding of the risk of thrombocytopenic, haemorrhagic, thromboembolic disorders following first, second and booster vaccination doses and testing positive for SARS-CoV-2. Self-controlled cases series analysis of 2.1 million linked patient records in Wales between 7th December 2020 and 31st December 2021. Outcomes were the first diagnosis of thrombocytopenic, haemorrhagic and thromboembolic events in primary or secondary care datasets, exposure was defined as 0-28 days post-vaccination or a positive reverse transcription polymerase chain reaction test for SARS-CoV-2. 36,136 individuals experienced either a thrombocytopenic, haemorrhagic or thromboembolic event during the study period. Relative to baseline, our observations show greater risk of outcomes in the periods post-first dose of BNT162b2 for haemorrhagic (IRR 1.47, 95%CI: 1.04-2.08) and idiopathic thrombocytopenic purpura (IRR 2.80, 95%CI: 1.21-6.49) events; post-second dose of ChAdOx1 for arterial thrombosis (IRR 1.14, 95%CI: 1.01-1.29); post-booster greater risk of venous thromboembolic (VTE) (IRR-Moderna 3.62, 95%CI: 0.99-13.17) (IRR-BNT162b2 1.39, 95%CI: 1.04-1.87) and arterial thrombosis (IRR-Moderna 3.14, 95%CI: 1.14-8.64) (IRR-BNT162b2 1.34, 95%CI: 1.15-1.58). Similarly, post SARS-CoV-2 infection the risk was increased for haemorrhagic (IRR 1.49, 95%CI: 1.15-1.92), VTE (IRR 5.63, 95%CI: 4.91, 6.4), arterial thrombosis (IRR 2.46, 95%CI: 2.22-2.71). We found that there was a measurable risk of thrombocytopenic, haemorrhagic, thromboembolic events after COVID-19 vaccination and infection., (© 2022. The Author(s).)

We investigated thrombocytopenic, thromboembolic and hemorrhagic events following a second dose of ChAdOx1 and BNT162b2 using a self-controlled case series analysis. We used a national prospective cohort with 2.0 million(m) adults vaccinated with two doses of ChAdOx or 1.6 m with BNT162b2. The incidence rate ratio (IRR) for idiopathic thrombocytopenic purpura (ITP) 14-20 days post-ChAdOx1 second dose was 2.14, 95% confidence interval (CI) 0.90-5.08. The incidence of ITP post-second dose ChAdOx1 was 0.59 (0.37-0.89) per 100,000 doses. No evidence of an increased risk of CVST was found for the 0-27 day risk period (IRR 0.83, 95% CI 0.16 to 4.26). However, few (≤5) events arose within this risk period. It is perhaps noteworthy that these events all clustered in the 7-13 day period (IRR 4.06, 95% CI 0.94 to 17.51). No other associations were found for second dose ChAdOx1, or any association for second dose BNT162b2 vaccination. Second dose ChAdOx1 vaccination was associated with increased borderline risks of ITP and CVST events. However, these events were rare thus providing reassurance about the safety of these vaccines. Further analyses including more cases are required to determine more precisely the risk profile for ITP and CVST after a second dose of ChAdOx1 vaccine., (© 2022. The Author(s).)

Background: COVID-19 is associated with inflammation and an increased risk of thromboembolic complications. Prophylactic doses of low-molecular-weight heparin have been used in hospitalised and non-critically ill patients with COVID-19. We aimed to evaluate the efficacy and safety of prophylactic low-molecular-weight heparin (enoxaparin) versus standard of care (no enoxaparin) in at-risk outpatients with COVID-19., Methods: This open-label, multicentre, randomised, controlled, phase 3b trial (ETHIC) was done at 15 centres in six countries (Belgium, Brazil, India, South Africa, Spain, and the UK). We consecutively enrolled participants aged at least 30 years who had not received a COVID-19 vaccine and had symptomatic, confirmed COVID-19 in the outpatient setting plus at least one risk factor for severe disease. Within 9 days of symptom onset and by use of a web-based random block design (block size either 2 or 4), eligible participants were randomly assigned (1:1) to receive either subcutaneous enoxaparin for 21 days (40 mg once daily if they weighed <100 kg and 40 mg twice daily if they weighed ≥100 kg) or standard of care (without enoxaparin). The primary efficacy endpoint was the composite of all-cause hospitalisation and all-cause mortality at 21 days after randomisation and, in our main analysis, was analysed in the intention-to-treat population, which comprised all patients who were randomly assigned. Safety was also analysed in the intention-to-treat population for our main analysis. This trial is registered with ClinicalTrials.gov, NCT04492254, and is complete., Findings: Following the advice of the Data and Safety Monitoring Board, this study was terminated early due to slow enrolment and a lower-than-expected event rate. Between Oct 27, 2020, and Nov 8, 2021, 230 patients with COVID-19 were assessed for eligibility, of whom 219 were enrolled and randomly assigned to receive standard of care (n=114) or enoxaparin (n=105). 96 (44%) patients were women, 122 (56%) were men, and one patient had missing sex data. 141 (65%) of 218 participants with data on race and ethnicity were White, 60 (28%) were Asian, and 16 (7%) were Black, mixed race, or Arab or Middle Eastern. Median follow-up in both groups was 21 days (IQR 21-21). There was no difference in the composite of all-cause mortality and hospitalisation at 21 days between the enoxaparin group (12 [11%] of 105 patients) and the standard-of-care group (12 [11%] of 114 patients; unadjusted hazard ratio 1·09 [95% CI 0·49-2·43]; log-rank p=0·83). At 21 days, two (2%) of 105 patients in the enoxaparin group (one minor bleed and one bleed of unknown severity) and one (1%) of 114 patients in the standard-of-care group (major abnormal uterine bleeding) had a bleeding event. 22 (21%) patients in the enoxaparin group and 13 (11%) patients in the standard-of-care group had adverse events. The most common adverse event in both groups was COVID-19-related pneumonia (six [6%] patients in the enoxaparin group and five [4%] patients in the standard-of-care group). One patient in the enoxaparin group died and their cause of death was unknown., Interpretation: The ETHIC trial results suggest that prophylaxis with low-molecular-weight heparin had no benefit for at-risk outpatients with COVID-19. Although the trial was terminated early, our data, combined with data from similar studies, provide further insights to inform international guidelines and influence clinical practice., Funding: The Thrombosis Research Institute and Sanofi UK., Competing Interests: Declaration of interests FC reports speaker fees from Boehringer Ingelheim Pharma, Bayer, Pfizer, and Daiichi-Sankyo Europe, and a modest research grant from Daiichi-Sankyo Europe. JS reports personal fees from Pfizer, AstraZeneca, Novartis, Sanofi, BMS, Dr Reddy's Laboratory, Lupin, and Abbot. RDL reports research grants from Bristol Myers Squibb, Pfizer, Amgen, GlaxoSmithKline, Medtronic, and Sanofi Aventis, and personal fees from Bristol Myers Squibb, Pfizer, Boehringer Ingelheim, and Bayer, outside the submitted work. BJ reports personal fees from Bayer HealthCare and Sanofi-Aventis. JIA reports speaker fees from Sanofi, Rovi, Bayer, and Aspen. FDRH acknowledges part support as Director of the National Institute for Health and Care Research (NIHR) Applied Research Collaboration Oxford Thames Valley and Theme Lead of the NIHR Oxford University Hospital Biomedical Research Centre, and has also received occasional fees or expenses for speaking or consultancy from AstraZeneca, Boehringer Ingelheim, Bayer, BMS/Pfizer, and Novartis. HG reports personal fees from Pfizer, Bayer, and Boehringer Ingelheim. PM reports honoraria from Bayer Pharma and Portolo. SS reports speaker fees from Bayer Pharma, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Sanofi Aventis, and Pfizer, and consultancy fees from Bayer Pharma, Boehringer Ingelheim, Daiichi Sankyo, Sanofi Aventis, Aspen, and Pfizer. SH reports personal fees from Bayer, Bristol Myers Squibb, Daiichi Sankyo, Portola, and Sanofi, outside the submitted work. AGGT reports grants from Bayer Healthcare and personal fees from Bayer Healthcare, Bristol Myers Squibb/Pfizer, Daiichi Sankyo, and Boehringer Ingelheim, outside the submitted work. WA reports honoraria from Bayer Pharma, Bristol Myers Squibb, Pfizer, Daiichi Sankyo, Portola, Aspen, Sanofi, Leo Pharma, Norgine, and Werfen. ATR reports consultancy fees from Bayer Pharma, Daiichi Sankyo, Sanofi, Aspen, and Pfizer. KP reports a consultancy fee from Johnson & Johnson. AKK reports research grants from Anthos, Bayer, and Sanofi and personal fees from Anthos Therapeutics, Bayer, and Sanofi. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objectives: To describe rates and variation in uptake of pneumococcal and measles, mumps and rubella (MMR) vaccines in children and associated change in vaccine-preventable diseases (VPDs) across the first and second waves of the COVID-19 pandemic., Methods: Retrospective database study of all children aged <19 registered with a general practice in the Oxford Royal College of General Practitioners Research and Surveillance Centre English national sentinel surveillance network between 2 November 2015 and 18 July 2021., Results: Coverage of booster dose of pneumococcal vaccine decreased from 94.5% (95% CI 94.3% to 94.7%) at its height on International Organization for Standardization (ISO) week 47 (2020) to 93.6% (95% CI 93.4% to 93.8%) by the end of the study. Coverage of second dose of MMR decreased from 85.0% (95% CI 84.7% to 85.3%) at its height on ISO week 37 (2020) to 84.1% (95% CI 83.8% to 84.4%) by the end of the study. The break point in trends for MMR was at ISO week 34 (2020) (95% CI weeks 32-37 (2020)), while for pneumococcal vaccine the break point was later at ISO week 3 (2021) (95% CI week 53 (2020) to week 8 (2021)). Vaccination coverage for children of white ethnicity was less likely to decrease than other ethnicities. Rates of consultation for VPDs fell and remained low since August 2020., Conclusion: Childhood vaccination rates started to fall ahead of the onset of the second wave; this fall is accentuating ethnic, socioeconomic and geographical disparities in vaccine uptake and risks widening health disparities. Social distancing and school closures may have contributed to lower rates of associated VPDs, but there may be increased risk as these measures are removed., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To monitor changes in seroprevalence of SARS-CoV-2 antibodies in populations over time and between different demographic groups., Methods: A subset of practices in the Oxford-Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) sentinel network provided serum samples, collected when volunteer patients had routine blood tests. We tested these samples for SARS-CoV-2 antibodies using Abbott (Chicago, USA), Roche (Basel, Switzerland) and/or Euroimmun (Luebeck, Germany) assays, and linked the results to the patients' primary care computerised medical records. We report seropositivity by region and age group, and additionally examined the effects of gender, ethnicity, deprivation, rurality, shielding recommendation and smoking status., Results: We estimated seropositivity from patients aged 18-100 years old, which ranged from 4.1% (95% CI 3.1-5.3%) to 8.9% (95% CI 7.8-10.2%) across the different assays and time periods. We found higher Euroimmun seropositivity in younger age groups, people of Black and Asian ethnicity (compared to white), major conurbations, and non-smokers. We did not observe any significant effect by region, gender, deprivation, or shielding recommendation., Conclusions: Our results suggest that prior to the vaccination programme, most of the population remained unexposed to SARS-CoV-2., Competing Interests: Declaration of Competing Interest EL, ST, RB report the Public Health England Vaccine Evaluation Unit performs contract research on behalf of GSK, Sanofi and Pfizer which is outside the submitted work. Prof Lusignan reports and through his University he has had grants not directly relating to this work from AstraZeneca, GSK, Pfizer, Sanofi, Seqirus and Takeda for vaccine related research and membership of advisory boards for AstraZeneca, Sanofi and Seqirus., (Copyright © 2022. Published by Elsevier Ltd.)

Background: It remains unclear to what extent reductions in urgent referrals for suspected cancer during the COVID-19 pandemic were the result of fewer patients attending primary care compared to GPs referring fewer patients., Methods: Cohort study including electronic health records data from 8,192,069 patients from 663 English practices. Weekly consultation rates, cumulative consultations and referrals were calculated for 28 clinical features from the NICE suspected cancer guidelines. Clinical feature consultation rate ratios (CRR) and urgent referral rate ratios (RRR) compared time periods in 2020 with 2019., Findings: Consultations for cancer clinical features decreased by 24.19% (95% CI: 24.04-24.34%) between 2019 and 2020, particularly in the 6-12 weeks following the first national lockdown. Urgent referrals for clinical features decreased by 10.47% (95% CI: 9.82-11.12%) between 2019 and 2020. Overall, once patients consulted with primary care, GPs urgently referred a similar or greater proportion of patients compared to previous years., Conclusion: Due to the significant fall in patients consulting with clinical features of cancer there was a lower than expected number of urgent referrals in 2020. Sustained efforts should be made throughout the pandemic to encourage the public to consult their GP with cancer clinical features., (© 2021. The Author(s).)

Background: The UK COVID-19 vaccination programme has prioritised vaccination of those at the highest risk of COVID-19 mortality and hospitalisation. The programme was rolled out in Scotland during winter 2020-21, when SARS-CoV-2 infection rates were at their highest since the pandemic started, despite social distancing measures being in place. We aimed to estimate the frequency of COVID-19 hospitalisation or death in people who received at least one vaccine dose and characterise these individuals., Methods: We conducted a prospective cohort study using the Early Pandemic Evaluation and Enhanced Surveillance of COVID-19 (EAVE II) national surveillance platform, which contained linked vaccination, primary care, RT-PCR testing, hospitalisation, and mortality records for 5·4 million people (around 99% of the population) in Scotland. Individuals were followed up from receiving their first dose of the BNT162b2 (Pfizer-BioNTech) or ChAdOx1 nCoV-19 (Oxford-AstraZeneca) COVID-19 vaccines until admission to hospital for COVID-19, death, or the end of the study period on April 18, 2021. We used a time-dependent Poisson regression model to estimate rate ratios (RRs) for demographic and clinical factors associated with COVID-19 hospitalisation or death 14 days or more after the first vaccine dose, stratified by vaccine type., Findings: Between Dec 8, 2020, and April 18, 2021, 2 572 008 individuals received their first dose of vaccine-841 090 (32·7%) received BNT162b2 and 1 730 918 (67·3%) received ChAdOx1. 1196 (<0·1%) individuals were admitted to hospital or died due to COVID-19 illness (883 hospitalised, of whom 228 died, and 313 who died due to COVID-19 without hospitalisation) 14 days or more after their first vaccine dose. These severe COVID-19 outcomes were associated with older age (≥80 years vs 18-64 years adjusted RR 4·75, 95% CI 3·85-5·87), comorbidities (five or more risk groups vs less than five risk groups 4·24, 3·34-5·39), hospitalisation in the previous 4 weeks (3·00, 2·47-3·65), high-risk occupations (ten or more previous COVID-19 tests vs less than ten previous COVID-19 tests 2·14, 1·62-2·81), care home residence (1·63, 1·32-2·02), socioeconomic deprivation (most deprived quintile vs least deprived quintile 1·57, 1·30-1·90), being male (1·27, 1·13-1·43), and being an ex-smoker (ex-smoker vs non-smoker 1·18, 1·01-1·38). A history of COVID-19 before vaccination was protective (0·40, 0·29-0·54)., Interpretation: COVID-19 hospitalisations and deaths were uncommon 14 days or more after the first vaccine dose in this national analysis in the context of a high background incidence of SARS-CoV-2 infection and with extensive social distancing measures in place. Sociodemographic and clinical features known to increase the risk of severe disease in unvaccinated populations were also associated with severe outcomes in people receiving their first dose of vaccine and could help inform case management and future vaccine policy formulation., Funding: UK Research and Innovation (Medical Research Council), Research and Innovation Industrial Strategy Challenge Fund, Scottish Government, and Health Data Research UK., Competing Interests: Declaration of interests AS, JM, and CR are members of the Scottish Government Chief Medical Officer's COVID-19 Advisory Group. JM is a member of the New and Emerging Respiratory Virus Threats Advisory Group (NERVTAG) and AS is a member of the NERVTAG Risk Stratification Subgroup and an unfunded member of Astra-Zeneca's COVID-19 Strategic Consultancy Group: Thrombocytopenia Taskforce. JM is a member of the Scientific Advisory Group on Emergencies (SAGE) and chairs the COVID Scottish National Incident Management Team and the Scientific Committee of the European Centre for Disease Prevention and Control/WHO-funded IMOVE-COVID-19 group. CM reports research funding from Medical Research Council (MRC), Health Data Research UK, National Institute for Health Research (NIHR), and Scottish Chief Scientist Office (CSO). SJS reports research funding from Wellcome Trust, MRC, NIHR, and Scottish CSO. CRS declares funding from the MRC, NIHR, Scottish CSO, and the New Zealand Ministry for Business, Innovation and Employment and Health Research Council during the conduct of this study. SVK is co-chair of the Scottish Government's Expert Reference Group on COVID-19 and ethnicity, is a member of the SAGE subgroup on ethnicity, and acknowledges funding from a NHS Research Scotland Senior Clinical Fellowship, MRC, and Scottish CSO. CR is a member of the Scientific Pandemic Influenza Group on Modelling and the Medicines and Healthcare Products Regulatory Agency Vaccine Benefit and Risk Working Group. JLKM is a member of the COVID Scottish National Incident Management Team. SdL has received funding through his University from AstraZeneca. FDRH acknowledges part support from the NIHR Applied Research Collaboration Oxford Thames Valley and the NIHR Oxford University Hospital Biomedical Research Centre. All other authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Introduction: There is an urgent need to idenfy treatments for COVID-19 that reduce illness duration and hospital admission in those at higher risk of a longer illness course and complications., Methods and Analysis: The Platform Randomised trial of INterventions against COVID-19 In older peoPLE trial is an open-label, multiarm, prospective, adaptive platform, randomised clinical trial to evaluate potential treatments for COVID-19 in the community. A master protocol governs the addition of new interventions as they become available, as well as the inclusion and cessation of existing intervention arms via frequent interim analyses. The first three interventions are hydroxychloroquine, azithromycin and doxycycline. Eligible participants must be symptomatic in the community with possible or confirmed COVID-19 that started in the preceding 14 days and either (1) aged 65 years and over or (2) aged 50-64 years with comorbidities. Recruitment is through general practice, health service helplines, COVID-19 'hot hubs' and directly through the trial website. Participants are randomised to receive either usual care or a study drug plus usual care, and outcomes are collected via daily online symptom diary for 28 days from randomisation. The research team contacts participants and/or their study partner following days 7, 14 and 28 if the online diary is not completed. The trial has two coprimary endpoints: time to first self-report of feeling recovered from possible COVID-19 and hospital admission or death from possible COVID-19 infection, both within 28 days from randomisation. Prespecified interim analyses assess efficacy or futility of interventions and to modify randomisation probabilities that allocate more participants to interventions with better outcomes., Ethics and Dissemination: Ethical approval Ref: 20/SC/0158 South Central - Berkshire Research Ethics Committee; IRAS Project ID: 281958; EudraCT Number: 2020-001209-22. Results will be presented to policymakers and at conferences and published in peer-reviewed journals., Trial Registration Number: ISRCTN86534580., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Hypertension has been identified as a risk factor for coronavirus disease 2019 (COVID-19) and associated adverse outcomes. This study examined the association between preinfection blood pressure (BP) control and COVID-19 outcomes using data from 460 general practices in England. Eligible patients were adults with hypertension who were tested or diagnosed with COVID-19. BP control was defined by the most recent BP reading within 24 months of the index date (January 1, 2020). BP was defined as controlled (<130/80 mm Hg), raised (130/80-139/89 mm Hg), stage 1 uncontrolled (140/90-159/99 mm Hg), or stage 2 uncontrolled (≥160/100 mm Hg). The primary outcome was death within 28 days of COVID-19 diagnosis. Secondary outcomes were COVID-19 diagnosis and COVID-19-related hospital admission. Multivariable logistic regression was used to examine the association between BP control and outcomes. Of the 45 418 patients (mean age, 67 years; 44.7% male) included, 11 950 (26.3%) had controlled BP. These patients were older, had more comorbidities, and had been diagnosed with hypertension for longer. A total of 4277 patients (9.4%) were diagnosed with COVID-19 and 877 died within 28 days. Individuals with stage 1 uncontrolled BP had lower odds of COVID-19 death (odds ratio, 0.76 [95% CI, 0.62-0.92]) compared with patients with well-controlled BP. There was no association between BP control and COVID-19 diagnosis or hospitalization. These findings suggest BP control may be associated with worse COVID-19 outcomes, possibly due to these patients having more advanced atherosclerosis and target organ damage. Such patients may need to consider adhering to stricter social distancing, to limit the impact of COVID-19 as future waves of the pandemic occur.

Background: Creating an ontology for COVID-19 surveillance should help ensure transparency and consistency. Ontologies formalize conceptualizations at either the domain or application level. Application ontologies cross domains and are specified through testable use cases. Our use case was an extension of the role of the Oxford Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) to monitor the current pandemic and become an in-pandemic research platform., Objective: This study aimed to develop an application ontology for COVID-19 that can be deployed across the various use-case domains of the RCGP RSC research and surveillance activities., Methods: We described our domain-specific use case. The actor was the RCGP RSC sentinel network, the system was the course of the COVID-19 pandemic, and the outcomes were the spread and effect of mitigation measures. We used our established 3-step method to develop the ontology, separating ontological concept development from code mapping and data extract validation. We developed a coding system-independent COVID-19 case identification algorithm. As there were no gold-standard pandemic surveillance ontologies, we conducted a rapid Delphi consensus exercise through the International Medical Informatics Association Primary Health Care Informatics working group and extended networks., Results: Our use-case domains included primary care, public health, virology, clinical research, and clinical informatics. Our ontology supported (1) case identification, microbiological sampling, and health outcomes at an individual practice and at the national level; (2) feedback through a dashboard; (3) a national observatory; (4) regular updates for Public Health England; and (5) transformation of a sentinel network into a trial platform. We have identified a total of 19,115 people with a definite COVID-19 status, 5226 probable cases, and 74,293 people with possible COVID-19, within the RCGP RSC network (N=5,370,225)., Conclusions: The underpinning structure of our ontological approach has coped with multiple clinical coding challenges. At a time when there is uncertainty about international comparisons, clarity about the basis on which case definitions and outcomes are made from routine data is essential., (©Simon de Lusignan, Harshana Liyanage, Dylan McGagh, Bhautesh Dinesh Jani, Jorgen Bauwens, Rachel Byford, Dai Evans, Tom Fahey, Trisha Greenhalgh, Nicholas Jones, Frances S Mair, Cecilia Okusi, Vaishnavi Parimalanathan, Jill P Pell, Julian Sherlock, Oscar Tamburis, Manasa Tripathy, Filipa Ferreira, John Williams, F D Richard Hobbs. Originally published in JMIR Public Health and Surveillance (http://publichealth.jmir.org), 17.11.2020.)