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Background Knowledge of the window of SARS-CoV-2 infectiousness is crucial in developing policies to curb transmission. Mathematical modelling based on scarce empirical evidence and key assumptions has driven isolation and testing policy, but real-world data are needed. We aimed to characterise infectiousness across the full course of infection in a real-world community setting. Methods The Assessment of Transmission and Contagiousness of COVID-19 in Contacts (ATACCC) study was a UK prospective, longitudinal, community cohort of contacts of newly diagnosed, PCR-confirmed SARS-CoV-2 index cases. Household and non-household exposed contacts aged 5 years or older were eligible for recruitment if they could provide informed consent and agree to self-swabbing of the upper respiratory tract. The primary objective was to define the window of SARS-CoV-2 infectiousness and its temporal correlation with symptom onset. We quantified viral RNA load by RT-PCR and infectious viral shedding by enumerating cultivable virus daily across the course of infection. Participants completed a daily diary to track the emergence of symptoms. Outcomes were assessed with empirical data and a phenomenological Bayesian hierarchical model. Findings Between Sept 13, 2020, and March 31, 2021, we enrolled 393 contacts from 327 households (the SARS-CoV-2 pre-alpha and alpha variant waves); and between May 24, 2021, and Oct 28, 2021, we enrolled 345 contacts from 215 households (the delta variant wave). 173 of these 738 contacts were PCR positive for more than one timepoint, 57 of which were at the start of infection and comprised the final study population. The onset and end of infectious viral shedding were captured in 42 cases and the median duration of infectiousness was 5 (IQR 3–7) days. Although 24 (63%) of 38 cases had PCR-detectable virus before symptom onset, only seven (20%) of 35 shed infectious virus presymptomatically. Symptom onset was a median of 3 days before both peak viral RNA and peak infectious viral load (viral RNA IQR 3–5 days, n=38; plaque-forming units IQR 3–6 days, n=35). Notably, 22 (65%) of 34 cases and eight (24%) of 34 cases continued to shed infectious virus 5 days and 7 days post-symptom onset, respectively (survival probabilities 67% and 35%). Correlation of lateral flow device (LFD) results with infectious viral shedding was poor during the viral growth phase (sensitivity 67% [95% CI 59–75]), but high during the decline phase (92% [86–96]). Infectious virus kinetic modelling suggested that the initial rate of viral replication determines the course of infection and infectiousness. Interpretation Less than a quarter of COVID-19 cases shed infectious virus before symptom onset; under a crude 5-day self-isolation period from symptom onset, two-thirds of cases released into the community would still be infectious, but with reduced infectious viral shedding. Our findings support a role for LFDs to safely accelerate deisolation but not for early diagnosis, unless used daily. These high-resolution, community-based data provide evidence to inform infection control guidance. Funding National Institute for Health and Care Research.

Background No effective pharmacological or non-pharmacological interventions exist for patients with long COVID. We aimed to describe recovery 1 year after hospital discharge for COVID-19, identify factors associated with patient-perceived recovery, and identify potential therapeutic targets by describing the underlying inflammatory profiles of the previously described recovery clusters at 5 months after hospital discharge. Methods The Post-hospitalisation COVID-19 study (PHOSP-COVID) is a prospective, longitudinal cohort study recruiting adults (aged ≥18 years) discharged from hospital with COVID-19 across the UK. Recovery was assessed using patient-reported outcome measures, physical performance, and organ function at 5 months and 1 year after hospital discharge, and stratified by both patient-perceived recovery and recovery cluster. Hierarchical logistic regression modelling was performed for patient-perceived recovery at 1 year. Cluster analysis was done using the clustering large applications k-medoids approach using clinical outcomes at 5 months. Inflammatory protein profiling was analysed from plasma at the 5-month visit. This study is registered on the ISRCTN Registry, ISRCTN10980107, and recruitment is ongoing. Findings 2320 participants discharged from hospital between March 7, 2020, and April 18, 2021, were assessed at 5 months after discharge and 807 (32·7%) participants completed both the 5-month and 1-year visits. 279 (35·6%) of these 807 patients were women and 505 (64·4%) were men, with a mean age of 58·7 (SD 12·5) years, and 224 (27·8%) had received invasive mechanical ventilation (WHO class 7–9). The proportion of patients reporting full recovery was unchanged between 5 months (501 [25·5%] of 1965) and 1 year (232 [28·9%] of 804). Factors associated with being less likely to report full recovery at 1 year were female sex (odds ratio 0·68 [95% CI 0·46–0·99]), obesity (0·50 [0·34–0·74]) and invasive mechanical ventilation (0·42 [0·23–0·76]). Cluster analysis (n=1636) corroborated the previously reported four clusters: very severe, severe, moderate with cognitive impairment, and mild, relating to the severity of physical health, mental health, and cognitive impairment at 5 months. We found increased inflammatory mediators of tissue damage and repair in both the very severe and the moderate with cognitive impairment clusters compared with the mild cluster, including IL-6 concentration, which was increased in both comparisons (n=626 participants). We found a substantial deficit in median EQ-5D-5L utility index from before COVID-19 (retrospective assessment; 0·88 [IQR 0·74–1·00]), at 5 months (0·74 [0·64–0·88]) to 1 year (0·75 [0·62–0·88]), with minimal improvements across all outcome measures at 1 year after discharge in the whole cohort and within each of the four clusters. Interpretation The sequelae of a hospital admission with COVID-19 were substantial 1 year after discharge across a range of health domains, with the minority in our cohort feeling fully recovered. Patient-perceived health-related quality of life was reduced at 1 year compared with before hospital admission. Systematic inflammation and obesity are potential treatable traits that warrant further investigation in clinical trials. Funding UK Research and Innovation and National Institute for Health Research.

ObjectivesOur study aimed to systematically review the literature and synthesise findings on potential associations of built environment characteristics with type 2 diabetes (T2D) in Asia.DesignSystematic review of the literature.Data sourcesOnline databases Medline, Embase and Global Health were used to identify peer-reviewed journal articles published from inception to 23 January 2023.Eligibility criteriaEligible studies included cohort, cross-sectional and case–control studies that explored associations of built environment characteristics with T2D among adults 18 years and older in Asia.Data extraction and synthesisCovidence online was used to remove duplicates and perform title, abstract and full-text screening. Data extraction was carried out by two independent reviewers using the OVID database and data were imported into MS Excel. Out of 5208 identified studies, 28 studies were included in this systematic review. Due to heterogeneity in study design, built environment and outcome definitions, a semiqualitative analysis was conducted, which synthesised results using weighted z-scores.ResultsFive broad categories of built environment characteristics were associated with T2D in Asia. These included urban green space, walkability, food environment, availability and accessibility of services such as recreational and healthcare facilities and air pollution. We found very strong evidence of a positive association of particulate matter (PM2.5, PM10), nitrogen dioxide and sulfur dioxide (pConclusionSeveral built environment attributes were significantly related to T2D in Asia. When compared with Western countries, very few studies have been conducted in Asia. Further research is, therefore, warranted to establish the importance of the built environment on T2D. Such evidence is essential for public health and planning policies to (re)design neighbourhoods and help improve public health across Asian countries.PROSPERO registration numberCRD42020214852.

ObjectivesEconomic evaluations of interventions for people with mental–physical multimorbidity, including a depressive disorder, are sparse. This study examines whether such interventions in adults are cost-effective.DesignA systematic review.Data sourcesMEDLINE, CINAHL Plus, PsycINFO, Cochrane CENTRAL, Scopus, Web of Science and NHS EED databases were searched until 5 March 2022.Eligibility criteriaWe included studies involving people aged ≥18 with two or more chronic conditions (one being a depressive disorder). Economic evaluation studies that compared costs and outcomes of interventions were included, and those that assessed only costs or effects were excluded.Data extraction and synthesisTwo authors independently assessed risk of bias in included studies using recommended checklists. A narrative analysis of the characteristics and results by type of intervention and levels of healthcare provision was conducted.ResultsA total of 19 studies, all undertaken in high-income countries, met inclusion criteria. Four intervention types were reported: collaborative care, self-management, telephone-based and antidepressant treatment. Most (14 of 19) interventions were implemented at the organisational level and were potentially cost-effective, particularly, the collaborative care for people with depressive disorder and diabetes, comorbid major depression and cancer and depression and multiple long-term conditions. Cost-effectiveness ranged from £206 per quality-adjusted life year (QALY) for collaborative care programmes for older adults with diabetes and depression at primary care clinics (USA) to £79 723 per QALY for combining collaborative care with improved opportunistic screening for adults with depressive disorder and diabetes (England). Conclusions on cost-effectiveness were constrained by methodological aspects of the included studies: choice of perspectives, time horizon and costing methods.ConclusionsEconomic evaluations of interventions to manage multimorbidity with a depressive disorder are non-existent in low-income and middle-income countries. The design and reporting of future economic evaluations must improve to provide robust conclusions.PROSPERO registration numberCRD42022302036.

ObjectivesTo determine how current psychometric testing approaches used in selection of postgraduate training in UK Public Health are associated with socioeconomic and sociocultural background of applicants (including ethnicity).DesignObservational study using contemporaneous data collected during recruitment and psychometric test scores.SettingAssessment centre of UK national Public Health recruitment for postgraduate Public Health training. The assessment centre element of selection comprises three psychometric assessments: Rust Advanced Numerical Reasoning, Watson-Glaser Critical Thinking Assessment II and Public Health situational judgement test.Participants629 applicants completed the assessment centre in 2021. 219 (34.8%) were UK medical graduates, 73 (116%) were international medical graduates and 337 (53.6%) were from backgrounds other than medicine.Main outcome measureMultivariable-adjusted progression statistics in the form of adjusted OR (aOR), accounting for age, sex, ethnicity, professional background and surrogate measures of familial socioeconomic and sociocultural status.Results357 (56.8%) candidates passed all three psychometric tests. Candidate characteristics negatively associated with progression were black ethnicity (aOR 0.19, 0.08 to 0.44), Asian ethnicity (aOR 0.35, 0.16 to 0.71) and coming from a non-UK medical graduate background (aOR 0.05, 0.03 to 0.12); similar differential attainment was observed in each of the psychometric tests. Even within the UK-trained medical cohort, candidates from white British backgrounds were more likely to progress than those from ethnic minorities (89.2% vs 75.0%, p=0.003).ConclusionAlthough perceived to mitigate the risks of conscious and unconscious bias in selection to medical postgraduate training, these psychometric tests demonstrate unexplained variation that suggests differential attainment. Other specialties should enhance their data collection to evaluate the impact of differential attainment on current selection processes and take forward opportunities to mitigate differential attainment where possible.

ObjectivesTo describe prevalence of chronic kidney disease (CKD), demographic and clinical characteristics, treatment patterns and rates of cardiovascular and renal complications for patients with type 2 diabetes (T2D) treated in routine clinical care.DesignRepeat cross-sectional study (6 monthly cross-sections) and cohort study from 1 January 2017 to 31 December 2019.SettingPrimary care data from English practices contributing to the UK Clinical Practice Research Datalink linked to Hospital Episode Statistics and Office for National Statistics mortality data.ParticipantsPatients with T2D aged >18 years, at least one year of registration data.Primary and secondary outcomesPrimary outcome was prevalence of CKD defined as chronic kidney disease epidemiology collaboration (CKD-EPI) estimated glomerular filtration rate 2, and/or urinary albumin creatinine ratio ≥3 mg/mmol in the past 24 months. Secondary outcomes were prescriptions of medications of interest and clinical and demographic characteristics in the past 3 months.In the cohort study rates of renal and cardiovascular complications, all-cause mortality and hospitalisations over the study period were compared among those with and without CKD.ResultsThere were 574 190 eligible patients with T2D as of 1 January 2017 and 664 296 as of 31 December 2019. Estimated prevalence of CKD across the study period was stable at approximately 30%. Medication use was stable over time in people with CKD and T2D, with low use of steroidal mineralocorticoid receptor antagonists (approximately 4.5% across all time points) and a low use but steady increase in use of sodium-glucose co-transporter-2 inhibitors (from 2.6% to 6.2%). Rates of all complications were higher in those with CKD at the start of the study period, with increasing rates, with increased severity of CKD, heart failure and albuminuria.ConclusionsThe burden of CKD in patients with T2D is high and associated with substantially increased rates of complications particularly in those with comorbid heart failure.

OBJECTIVE: To explore whether kidney Yang deficiency (KYD) is prone to metabolic disorders may be linked to impaired mitochondrial function in thermogenesis and metabolic tissues. METHODS: A rat model of KYD was used, which was established using Sprague Dawley rat dams with warm preference subjected to herbal treatment that can improve kidney Yang. The human relevance was confirmed by reduced serum corticosterone levels, and increased preference for warm location. RESULTS: KYD Rats were underdeveloped. Adenosine-triphosphate (ATP) production was reduced in the brown fat, but increased in the muscle. However, oxidative phosphorylated complexes to generate ATP and mitochondrial biogenesis marker were reduced in both tissues. When the second insult of high-fat diet (HFD) was introduced, KYD rats gained less weight yet developed more severe lipid and glucose metabolic disorders. This may be driven by disregulated liver gluconeogenesis marker forkhead box protein O1 and lipid metabolic regulator cholesterol 7 alpha-hydroxylase. CONCLUSIONS: KYD rats exhibited reduced mito-chondrial function in the brown fat, but were partially compensated by skeletal muscle, associated with the phenotype of warm preference and metabolic disorder, which was further exacerbated by additional HFD consumption. Future studies can focus on treatment targetting mitochondria function to reverse this phenotype.

Introduction Hospital-acquired thrombosis (HAT) is defined as any venous thromboembolism (VTE)-related event during a hospital admission or occurring up to 90 days post discharge, and is associated with significant morbidity, mortality and healthcare-associated costs. Although surgery is an established risk factor for VTE, operations with a short hospital stay (, National Institute for Health Research (NIHR) NIHR133776

ObjectiveTo identify what dimensions of socioeconomic position (SEP) are most closely associated with childhood obesity in Finland, leveraging population-wide data among the whole child population aged 2–17 years in Finland.DesignRegistry-based study.SettingData from several administrative registries linked on individual level covering the whole of Finland were used. Data on height and weight measurements in 2018 were obtained from the Register of Primary Health Care visits and data on sociodemographic and socioeconomic indicators (2014–2018) from Statistics Finland.ParticipantsChildren aged 2–17 years with valid height and weight measurements performed at the child health clinic or school healthcare in 2018 (final n=194 423).Main outcome measuresObesity was defined according to WHO Growth Reference curves. Sociodemographic and socioeconomic indicators were linked on individual level for adults (both parents) who lived in the same household (42 predictors). Boosted regression model was used to analyse the contribution of SEP to obesity.ResultsFrom socioeconomic indicators, annual household income (12.6%) and mother and father’s educational level (12.6% and 8.1%, respectively) had the highest relative influence on obesity risk. The relative influence of a child’s sex was 7.7%.ConclusionsThe parents’ SEP was inversely associated with obesity among the offspring. A remarkable number of objective SEP indicators were analysed with parents’ education and household income finally being the indicators most strongly associated with obesity among children. In future research, more attention should be paid to reliable and objective ways of measuring educational status and income rather than on developing new SEP indicators. Administrative registries with information on both healthcare and socioeconomic indicators can in future provide better opportunities to assess the influence of SEP on various health risks.

Summary Background Prevention, control, and treatment of respiratory tract cancers are important steps towards achieving target 3.4 of the UN Sustainable Development Goals (SDGs)—a one-third reduction in premature mortality due to non-communicable diseases by 2030. We aimed to provide global, regional, and national estimates of the burden of tracheal, bronchus, and lung cancer and larynx cancer and their attributable risks from 1990 to 2019. Methods Based on the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 methodology, we evaluated the incidence, mortality, years lived with disability, years of life lost, and disability-adjusted life-years (DALYs) of respiratory tract cancers (ie, tracheal, bronchus, and lung cancer and larynx cancer). Deaths from tracheal, bronchus, and lung cancer and larynx cancer attributable to each risk factor were estimated on the basis of risk exposure, relative risks, and the theoretical minimum risk exposure level input from 204 countries and territories, stratified by sex and Socio-demographic Index (SDI). Trends were estimated from 1990 to 2019, with an emphasis on the 2010–19 period. Findings Globally, there were 2·26 million (95% uncertainty interval 2·07 to 2·45) new cases of tracheal, bronchus, and lung cancer, and 2·04 million (1·88 to 2·19) deaths and 45·9 million (42·3 to 49·3) DALYs due to tracheal, bronchus, and lung cancer in 2019. There were 209 000 (194 000 to 225 000) new cases of larynx cancer, and 123 000 (115 000 to 133 000) deaths and 3·26 million (3·03 to 3·51) DALYs due to larynx cancer globally in 2019. From 2010 to 2019, the number of new tracheal, bronchus, and lung cancer cases increased by 23·3% (12·9 to 33·6) globally and the number of larynx cancer cases increased by 24·7% (16·0 to 34·1) globally. Global age-standardised incidence rates of tracheal, bronchus, and lung cancer decreased by 7·4% (−16·8 to 1·6) and age-standardised incidence rates of larynx cancer decreased by 3·0% (−10·5 to 5·0) in males over the past decade; however, during the same period, age-standardised incidence rates in females increased by 0·9% (−8·2 to 10·2) for tracheal, bronchus, and lung cancer and decreased by 0·5% (−8·4 to 8·1) for larynx cancer. Furthermore, although age-standardised incidence and death rates declined in both sexes combined from 2010 to 2019 at the global level for tracheal, bronchus, lung and larynx cancers, some locations had rising rates, particularly those on the lower end of the SDI range. Smoking contributed to an estimated 64·2% (61·9–66·4) of all deaths from tracheal, bronchus, and lung cancer and 63·4% (56·3–69·3) of all deaths from larynx cancer in 2019. For males and for both sexes combined, smoking was the leading specific risk factor for age-standardised deaths from tracheal, bronchus, and lung cancer per 100 000 in all SDI quintiles and GBD regions in 2019. However, among females, household air pollution from solid fuels was the leading specific risk factor in the low SDI quintile and in three GBD regions (central, eastern, and western sub-Saharan Africa) in 2019. Interpretation The numbers of incident cases and deaths from tracheal, bronchus, and lung cancer and larynx cancer increased globally during the past decade. Even more concerning, age-standardised incidence and death rates due to tracheal, bronchus, lung cancer and larynx cancer increased in some populations—namely, in the lower SDI quintiles and among females. Preventive measures such as smoking control interventions, air quality management programmes focused on major air pollution sources, and widespread access to clean energy should be prioritised in these settings. Funding Bill & Melinda Gates Foundation.

Introduction Peripheral arterial disease (PAD) is a key risk factor for cardiovascular disease, foot ulceration and lower limb amputation in people with diabetes. Early diagnosis of PAD can enable optimisation of therapies to manage these risks. Its diagnosis is fundamental, though challenging in the context of diabetes. Although a variety of diagnostic bedside tests are available, there is no agreement as to which is the most accurate in routine clinical practice. The aim of this study is to determine the diagnostic performance of a variety of tests (audible waveform assessment, visual waveform assessment, ankle brachial pressure index (ABPI), exercise ABPI and toe brachial pressure index (TBPI)) for the diagnosis of PAD in people with diabetes as determined by a reference test (CT angiography (CTA) or magnetic resonance angiography (MRA)). In selected centres, we also aim to evaluate the performance of a new point-of- care duplex ultrasound scan (PAD-scan). Methods and analysis A prospective multicentre diagnostic accuracy study ( ClinicalTrials. gov Identifier NCT05009602). We aim to recruit 730 people with diabetes from 18 centres across the UK, covering primary and secondary healthcare. Consenting participants will undergo the tests under investigation. Reference tests (CTA or MRA) will be performed within 6 weeks of the index tests. Imaging will be reported by blinded consultant radiologists at a core imaging lab, using a validated scoring system, which will also be used to categorise PAD severity. The presence of one or more arterial lesions of ≥50% stenosis, or tandem lesions with a combined value of ≥50%, will be used as the threshold for the diagnosis of PAD. The primary outcome measure of diagnostic performance will be test sensitivity. Ethics and dissemination The study has received approval from the National Research Ethics Service (NRES) (REC reference 21/PR/1221). Results will be disseminated through research presentations and papers., National Institute for Health Research (NIHR) NIHR131855, NIHR Clinical Lectureship NIHR Imperial Biomedical Research Centre (BRC)

Peer reviewed: True, Acknowledgements: The authors are grateful for support from the National Institute for Health Research (NIHR) School for Public Health Research (SPHR) and the NIHR Applied Research Collaboration Northwest London (ARC NWL). This paper is independent research supported by the NIHR ARC NWL. The authors thank their steering committee for their input and guidance and Esta Orchard for facilitating the children’s workshop and stakeholder meeting. The authors thank all the participants who took part in the study including Molly Adkin, Teatske Altenburg, Thomas Beaney, CÃ-ntia Botton, Anna Chalkley, Paul Chapman, Lotte de Vries, Stuart Fairclough, Lawrence Foweather, Chris Gale, Charan Gill, Muhamet Halilaj, Deirdre Harrington, Frances Hillier-Brown, Josie Hopkins, Daniel Katon, Michelle Kelly-Irving, Amy King, Edward Maile, Natalie McConnon, Catherine McKay, Colin Moran, Francesca Neale, Dasha Nicholls, Nikita Punjabi, Anelise Reis Gaya, Mairead Ryan, Tajvir Singh, Jorien Slot-Heijs, Rodrigo Sudatti Delevatti, Cathryn Taylor, Shannon Tessier, Daniel Umpierre, Esther van Sluijs, Tishya Venkatraman, Julian Winn, Kathryn Woods-Townsend, Callum Wright, Maddie Yang. We would also like to thank the children, the PE specialist teacher (Mr Alex Wilke) and the head teacher (Mr Raphael Moss) at Elsley Primary School. The authors thank The Daily Mile Foundation for funding and support., OBJECTIVES: To develop a core outcome set (COS) for physical activity interventions in primary schools. DESIGN: Modified-Delphi study. SETTING: The UK and international. PARTICIPANTS: 104 participants from four stakeholder groups (educators, public health professionals, health researchers, parents); 16 children (aged 8-9 years) from 1 London primary school. INTERVENTIONS: Physical activity interventions. METHODS: Four-stage process: (1) outcomes extracted from relevant studies identified from an umbrella review and a focus group; (2) list of outcomes produced and domains established; (3) stakeholders completed a two-round Delphi survey by rating (Round 1) and re-rating (Round 2) each outcome on a nine-point Likert Scale from 'not important' to 'critical': a>70% participant threshold identified the outcomes rated 'critical' to measure, and outcomes important to children were identified through a workshop; and (4) a stakeholder meeting to achieve consensus of the outcomes to include in the COS. RESULTS: In total, 74 studies were extracted from 53 reviews. A list of 50 outcomes was produced and three domains were established: 'physical activity and health' (16 outcomes), 'social and emotional health' (22 outcomes) and 'educational performance' (12 outcomes). 104 participants completed survey Round 1; 65 participants completed both rounds. In total, 13 outcomes met the threshold; children identified 8 outcomes. Fourteen outcomes achieved consensus to produce the COS: five outcomes for physical activity and health (diet (varied and balanced), energy, fitness, intensity of physical activity, sleep (number of hours)); seven outcomes for social and emotional health (anxiety, depression, enjoyment, happiness, self-esteem, stress, well-being); and two outcomes for educational performance (concentration, focus). CONCLUSIONS: We have developed the first COS for physical activity interventions in primary schools in consultation with those interested in the development and application of an agreed standardised set of outcomes. Future studies including these outcomes will reduce heterogeneity across studies. TRIAL REGISTRATION NUMBER: Core Outcome Measures in Effectiveness Trials Initiative registration number 1322; Results.

Background Priming COVID-19 vaccine schedules have been deployed at variable intervals globally, which might influence immune persistence and the relative importance of third-dose booster programmes. Here, we report exploratory analyses from the Com-COV trial, assessing the effect of 4-week versus 12-week priming intervals on reactogenicity and the persistence of immune response up to 6 months after homologous and heterologous priming schedules using the vaccines BNT162b2 (tozinameran, Pfizer/BioNTech) and ChAdOx1 nCoV-19 (AstraZeneca). Methods Com-COV was a participant-masked, randomised immunogenicity trial. For these exploratory analyses, we used the trial's general cohort, in which adults aged 50 years or older were randomly assigned to four homologous and four heterologous vaccine schedules using BNT162b2 and ChAdOx1 nCoV-19 with 4-week or 12-week priming intervals (eight groups in total). Immunogenicity analyses were done on the intention-to-treat (ITT) population, comprising participants with no evidence of SARS-CoV-2 infection at baseline or for the trial duration, to assess the effect of priming interval on humoral and cellular immune response 28 days and 6 months post-second dose, in addition to the effects on reactogenicity and safety. The Com-COV trial is registered with the ISRCTN registry, 69254139 (EudraCT 2020–005085–33). Findings Between Feb 11 and 26, 2021, 730 participants were randomly assigned in the general cohort, with 77–89 per group in the ITT analysis. At 28 days and 6 months post-second dose, the geometric mean concentration of anti-SARS-CoV-2 spike IgG was significantly higher in the 12-week interval groups than in the 4-week groups for homologous schedules. In heterologous schedule groups, we observed a significant difference between intervals only for the BNT162b2–ChAdOx1 nCoV-19 group at 28 days. Pseudotyped virus neutralisation titres were significantly higher in all 12-week interval groups versus 4-week groups, 28 days post-second dose, with geometric mean ratios of 1·4 (95% CI 1·1–1·8) for homologous BNT162b2, 1·5 (1·2–1·9) for ChAdOx1 nCoV-19–BNT162b2, 1·6 (1·3–2·1) for BNT162b2–ChAdOx1 nCoV-19, and 2·4 (1·7–3·2) for homologous ChAdOx1 nCoV-19. At 6 months post-second dose, anti-spike IgG geometric mean concentrations fell to 0·17–0·24 of the 28-day post-second dose value across all eight study groups, with only homologous BNT162b2 showing a slightly slower decay for the 12-week versus 4-week interval in the adjusted analysis. The rank order of schedules by humoral response was unaffected by interval, with homologous BNT162b2 remaining the most immunogenic by antibody response. T-cell responses were reduced in all 12-week priming intervals compared with their 4-week counterparts. 12-week schedules for homologous BNT162b2 and ChAdOx1 nCoV-19–BNT162b2 were up to 80% less reactogenic than 4-week schedules. Interpretation These data support flexibility in priming interval in all studied COVID-19 vaccine schedules. Longer priming intervals might result in lower reactogenicity in schedules with BNT162b2 as a second dose and higher humoral immunogenicity in homologous schedules, but overall lower T-cell responses across all schedules. Future vaccines using these novel platforms might benefit from schedules with long intervals. Funding UK Vaccine Taskforce and National Institute for Health and Care Research.

ObjectivesThis study aimed to examine the differences in multimorbidity between Aboriginal and Torres Strait Islander people and non-Indigenous Australians, and the effect of multimorbidity on health service use and work productivity.SettingCross-sectional sample of the Household, Income and Labour Dynamics in Australia wave 17.ParticipantsA nationally representative sample of 16 749 respondents aged 18 years and above.Outcome measuresMultimorbidity prevalence and pattern, self-reported health, health service use and employment productivity by Indigenous status.ResultsAboriginal respondents reported a higher prevalence of multimorbidity (24.2%) compared with non-Indigenous Australians (20.7%), and the prevalence of mental–physical multimorbidity was almost twice as high (16.1% vs 8.1%). Multimorbidity pattern varies significantly among the Aboriginal and non-Indigenous Australians. Multimorbidity was associated with higher health service use (any overnight admission: adjusted OR=1.52, 95% CI=1.46 to 1.58), reduced employment productivity (days of sick leave: coefficient=0.25, 95% CI=0.19 to 0.31) and lower perceived health status (SF6D score: coefficient=−0.04, 95% CI=−0.05 to −0.04). These associations were found to be comparable in both Aboriginal and non-Indigenous populations.ConclusionsMultimorbidity prevalence was significantly greater among Aboriginal and Torres Strait Islanders compared with the non-Indigenous population, especially mental–physical multimorbidity. Strategies are required for better prevention and management of multimorbidity for the aboriginal population to reduce health inequalities in Australia.

ObjectivesArm weakness is common after stroke; repetitive activity is critical for recovery but people struggle with knowing what to do, volume, and monitoring progress. We studied the feasibility and acceptability of OnTrack, a digital intervention supporting arm and hand rehabilitation in acute and home settings.DesignA mixed-method, single-arm study evaluating the feasibility of OnTrack for hospital and home use. An independent process evaluation assessed the intervention’s fidelity, dose and reach. Amendments to the protocol were necessary after COVID-19.SettingAcute stroke services and home settings in North West London.Participants12 adults with a stroke diagnosis Intervention12 weeks using the OnTrack system comprising arm tracking and coaching support for self-management.Primary and secondary outcome measuresRecruitment, retention and completion rates; compliance and adherence to the intervention; reasons for study decline/withdrawal.Intervention fidelity and acceptability, evaluated through an independent process evaluation.Patient measures including activity baseline, healthcare activation, arm function and impairment collected at baseline, week 7 and week 14 of participation to assess suitability for a randomised controlled trial (RCT).Results181 individuals screened, 37 met eligibility criteria, 24 recruited (65%); of these, 15 (63%) were recruited before COVID-19, and 9 (37%) during. 12 completed the intervention (50%). Despite COVID-19 disruptions, recruitment, retention and completion were in line with prestudy expectations and acceptable for a definitive trial. Participants felt the study requirements were acceptable and the intervention usable. Fidelity of delivery was acceptable according to predetermined fidelity markers. Outcome measures collected helped determine sample size estimates and primary outcomes for an RCT.ConclusionsThe intervention was found to be usable and acceptable by participants; study feasibility objectives were met and demonstrated that a definitive RCT would be viable and acceptable.Trial registration numberNCT03944486.

Introduction. Methodologically robust clinical trials are required to improve neonatal care and reduce unwanted variations in practice. Previous neonatal research prioritisation processes have identified important research themes rather than specific research questions amenable to clinical trials. Practice-changing trials require well defined research questions, commonly organised using the Population, Intervention, Comparison, Outcome (PICO) structure. By narrowing the scope of research priorities to those which can be answered in clinical trials and by involving a wide range of different stakeholders, we aim to provide a robust and transparent process to identify and prioritise research questions answerable within the NHS to inform future practice-changing clinical trials. Methods and Analysis. A steering group comprising parents, doctors, nurses, allied health professionals, researchers, and representatives from key organisations (Neonatal Society (NS), British Association of Perinatal Medicine (BAPM), Neonatal Nurses Association (NNA) and Royal College of Paediatrics and Child Health (RCPCH)) was identified to oversee this project. We will invite submissions of research questions formatted using the PICO structure from the following stakeholder groups using an online questionnaire: parents, patients, healthcare professionals and academic researchers. Unanswered, non-duplicate research questions will be entered into a three round eDelphi survey of all stakeholder groups. Research questions will be ranked by mean aggregate scores. Ethics and Dissemination. The final list of prioritised research questions will be disseminated through traditional academic channels, directly to key stakeholder groups through representative organisations and on social media. The outcome of the project will be shared with key research organisations such as the National Institute for Health Research (NIHR). Research ethics committee approval is not required. Registration Details. Not registered.

IntroductionCongenital cytomegalovirus (cCMV) is the leading cause of neurodevelopmental and hearing impairment from in-utero infection. Late diagnosis results in limited treatment options and may compromise long-term outcome.MethodsA retrospective audit of infants with cCMV referred to a Tertiary Pediatric Infectious Diseases center from 2012–2021. Data collected included timing of diagnostics, treatment initiation and reasons for delays.Results90 infants with confirmed cCMV were included, 46/90 (51%) were symptomatic at birth. Most common reasons for diagnostics in asymptomatic infants were failed newborn hearing screening (17/44, 39%) and antenatal risk-factors (14/44, 32%). Median age at cCMV diagnosis was 3 (range 0–68) and 7 (0–515) days, with median referral age 10 (1–120) and 22 (2–760) days for symptomatic and asymptomatic infants respectively. There was a significant risk of delay in diagnosis (>21 days) for asymptomatic infants [RR 2.93 (1.15–7.45); p = 0.02]. Of asymptomatic infants who received treatment, 13/24 (54%) commenced it within 28 days of life, a significant delay in treatment compared to 30/36 (83%) symptomatic infants [RR 2.75 (1.18–6.43); p = 0.02]. The commonest reason for delayed treatment initiation was delayed first diagnostic test for both symptomatic 4/6 (67%) and asymptomatic infants 9/11 (82%).ConclusionsDelays in diagnosis and treatment for cCMV are unacceptably frequent and significantly higher in asymptomatic infants. Our study highlights the need for increased awareness among healthcare professionals, reconsideration of age-targets for Newborn Hearing Screening, and research that addresses the barriers to implementation of universal screening, which would ultimately facilitate prompt diagnosis and management of all infants with cCMV.

ObjectivesDuring the COVID-19 pandemic, convolutional neural networks (CNNs) have been used in clinical medicine (eg, X-rays classification). Whether CNNs could inform the epidemiology of COVID-19 classifying street images according to COVID-19 risk is unknown, yet it could pinpoint high-risk places and relevant features of the built environment. In a feasibility study, we trained CNNs to classify the area surrounding bus stops (Lima, Peru) into moderate or extreme COVID-19 risk.DesignCNN analysis based on images from bus stops and the surrounding area. We used transfer learning and updated the output layer of five CNNs: NASNetLarge, InceptionResNetV2, Xception, ResNet152V2 and ResNet101V2. We chose the best performing CNN, which was further tuned. We used GradCam to understand the classification process.SettingBus stops from Lima, Peru. We used five images per bus stop.Primary and secondary outcome measuresBus stop images were classified according to COVID-19 risk into two labels: moderate or extreme.ResultsNASNetLarge outperformed the other CNNs except in the recall metric for the moderate label and in the precision metric for the extreme label; the ResNet152V2 performed better in these two metrics (85% vs 76% and 63% vs 60%, respectively). The NASNetLarge was further tuned. The best recall (75%) and F1 score (65%) for the extreme label were reached with data augmentation techniques. Areas close to buildings or with people were often classified as extreme risk.ConclusionsThis feasibility study showed that CNNs have the potential to classify street images according to levels of COVID-19 risk. In addition to applications in clinical medicine, CNNs and street images could advance the epidemiology of COVID-19 at the population level.

Summary Background The safety and efficacy of 24 weeks of lumacaftor–ivacaftor combination therapy in children aged 6–11 years with cystic fibrosis homozygous for the F508del-CFTR mutation was previously shown in two phase 3 studies. Here, we report long-term safety and efficacy data. Methods In this phase 3, open-label, multicentre, extension study (study 110), we examined the long-term safety, tolerability, and efficacy of lumacaftor–ivacaftor in children pooled from two phase 3 parent studies (open-label study 011B and randomised, placebo-controlled study 109). The study was conducted at 61 clinics in the USA, Australia, Belgium, Canada, Denmark, France, Germany, Sweden, and the UK. Children with cystic fibrosis homozygous for the F508del-CFTR mutation who had received lumacaftor–ivacaftor or placebo in the parent studies were treated with lumacaftor–ivacaftor for up to 96 weeks; those who had received the combination therapy in the parent studies (the treatment-to-treatment group) received up to 120 weeks of treatment in total. Participants aged 6–11 years at the start of the parent study received lumacaftor 200 mg–ivacaftor 250 mg orally once every 12 h; those aged 12 years or older received lumacaftor 400 mg–ivacaftor 250 mg orally once every 12 h. The primary endpoint was safety and tolerability in all children who had received at least one dose of the study drug. Secondary endpoints included change from baseline in lung clearance index 2·5% (LCI2·5), sweat chloride concentration, body-mass index, and Cystic Fibrosis Questionnaire–Revised respiratory domain score. This extension study is registered with ClinicalTrials.gov , NCT02544451 , and has been completed. Findings The extension study ran from Aug 13, 2015, to Aug 17, 2018. Of 239 children who enrolled in the study and received at least one dose of lumacaftor–ivacaftor, 215 (90%) completed 96 weeks of treatment. Most children (236 [99%] of 239 children) had adverse events that were mild (49 [21%] of 239) or moderate (148 [62%] of 239) in severity, and there was a low rate of adverse events leading to treatment discontinuation. The most frequently reported adverse events were common manifestations or complications of cystic fibrosis, such as cough and pulmonary exacerbation, or were consistent with the known safety profile of lumacaftor–ivacaftor in older children and adults. No new safety concerns were identified with extended lumacaftor–ivacaftor treatment. Children in the placebo-to-treatment group had improvements in efficacy endpoints consistent with those observed in the parent studies. Improvements observed in children treated with lumacaftor–ivacaftor in the parent study were generally maintained in the extension study. Interpretation Lumacaftor–ivacaftor therapy in children homozygous for F508del-CFTR who initiated treatment at age 6–11 years was generally safe and well tolerated, and efficacy was sustained for up to 120 weeks. These data support the long-term use of lumacaftor–ivacaftor to treat children aged 6 years and older who are homozygous for the F508del-CFTR mutation. Funding Vertex Pharmaceuticals Incorporated.

BackgroundVirtual reality (VR) is a technology that produces a virtual manifestation of the real world. In recent years, VR has been increasingly used as a tool in medical education. The use of VR in medical education has large potential, as it allows for distance learning and training which may be challenging to deliver in real life. VR encompasses different tools and applications. There is a need to explore how VR has been employed in medical education to date.ObjectiveThe objective of this scoping review is to conceptualise the VR tools available and the applications of VR in undergraduate medical education as reported in the literature. This scoping review will identify any gaps in this field and provide suggestions for future research.Methods and analysisThe relevant studies will be examined using the Joanna Briggs Institute methodological framework for scoping studies. A comprehensive search from a total of six electronic databases and grey literature sources will be performed. The reference list of included studies will be screened for additional studies. The screening and data extraction will be done in parallel and independently by two review authors. Any discrepancies will be resolved through consensus or discussion with a third review author. A data extraction form has been developed using key themes from the research questions. The extracted data will be qualitatively analysed and presented in a diagrammatic or tabular form, alongside a narrative summary, in line with Preferred Reporting Items for Systematic Reviews and Meta-Analysis: extension for Scoping Reviews reporting guidelines.Ethics and disseminationAll data will be collected from published and grey literature. Ethics approval is therefore not a requirement. We will present our findings at relevant conferences and submit them for publications in peer-reviewed journals.

Introduction Some people are so anxious about COVID that it impairs their functioning. However, little is known about the course of severe COVID anxiety or what can be done to help people who experience it. Methods and analysis Cohort study with a nested feasibility trial with follow-up at three and six months. We recruited 306 people who were aged 18 and over, lived in the United Kingdom and had severe COVID anxiety (indicated by a score of nine or more on the Coronavirus Anxiety Scale). To take part in the nested feasibility trial, participants also had to have a score of 20 or more on the Short Health Anxiety Inventory. We excluded people from the trial if they had had COVID-19 within the previous four weeks, if they were currently self-isolating or if they were already receiving psychological treatment. We publicised the study nationally through adverts, social media and posts on chat boards. We also recruited participants via clinicians working in primary and secondary care NHS services in London. All those in the active arm will be offered five to ten sessions of remotely delivered modified Cognitive Behaviour Therapy for Health Anxiety (CBT-HA). We will examine the proportion of participants who remain above threshold on the Coronavirus Anxiety Scale at three and six months and factors that influence levels of COVID anxiety over six months using mixed-effects logistic regression. The key feasibility metrics for the nested trial are the level of uptake of CBT-HA and the rate of follow-up. Ethics and dissemination Approved by Leicester Central Research Ethics Committee (reference: 20/EM/0238). The results of the study will be published in peer-reviewed scientific journals. Trial registration: International Standard Randomised Control Trial Number Register - ISRCTN14973494

BackgroundThe COVID-19 pandemic has disrupted routine childhood vaccinations worldwide with low- and middle-income countries (LMICs) most affected. This study aims to quantify levels of disruption to routine vaccinations in LMICs.MethodsA systematic review (PROSPERO CRD42021286386) was conducted of MEDLINE, Embase, Global Health, CINAHL, Scopus and MedRxiv, on the 11th of February 2022. Primary research studies published from January 2020 onwards were included if they reported levels of routine pediatrics vaccinations before and after March 2020. Study appraisal was performed using NHLBI tool for cross-sectional studies. Levels of disruption were summarized using medians and interquartile ranges.ResultsA total of 39 cross-sectional studies were identified. These showed an overall relative median decline of −10.8% [interquartile range (IQR) −27.6%, −1.4%] across all vaccines. Upper-middle-income countries (upper-MICs) (−14.3%; IQR −24.3%, −2.4%) and lower-MICs (−18.0%; IQR −48.6%, −4.1%) showed greater declines than low-income countries (−3.1%; IQR −12.8%, 2.9%), as did vaccines administered at birth (−11.8%; IQR −27.7%, −3.5%) compared to those given after birth (−8.0%; IQR −28.6%, −0.4%). Declines during the first 3 months of the pandemic (−8.1%; IQR −35.1%, −1.4%) were greater than during the remainder of 2020 (−3.9%; IQR −13.0%, 11.4%) compared to baseline.ConclusionThere has been a decline in routine pediatric vaccination, greatest in MICs and for vaccines administered at birth. Nations must prioritize catch-up programs alongside public health messaging to encourage vaccine uptake.Systematic review registrationIdentifier: CRD42021286386.

Background: Qualitative data suggest pre-marital sex stigma presents a major obstacle to AGYW's use of HIV prevention methods. Lack of social acceptability therefore is included as a barrier to motivation to use condoms in HIV prevention cascades. Representative survey data on community norms are rare but necessary to test the validity of this assumption and measure their contributions to gaps in prevention cascades. Methods: General-population survey participants in Manicaland (ages≥15,N = 9803) were asked if they agreed/disagreed with statements on social norms. AGYW were asked whether community views are an obstacle to their using condoms. Proportions agreeing/disagreeing with these statements were calculated, variations in community members’ views were investigated in multivariable logistic-regression models, and the association between AGYW's perceiving negative community norms and condom use was measured. Results: 93.5%(95%CI,93%-94%) of respondents agreed that ‘Many young women have sex before marriage these days’. 57%(56%-59%) of men and 70%(69%-71%) of women disagreed that ‘If I have a teenage daughter and she has sex before marriage, I would be ok with this’; and 41%(40%-43%) of men and 57%(56%-59%) of women disagreed that ‘If I have a teenage daughter, I would tell her about condoms’. Fathers but not mothers were more likely to disagree with their daughters having sex before marriage (Figure). Similar proportions of parents and other community members were against telling daughters about condoms. 68%(61%-75%) of sexually-active unmarried AGYW said negative community views were unimportant in decisions to use condoms. Condom use didn't differ between those who agreed/disagreed that negative community views are important (46.9% vs. 50.0%; AOR = 0.88, 95%CI, 0.48–1.62; N = 202). Conclusions: Community resistance to condom promotion based on pre-marital sex stigma may be weakening as a barrier to AGYW's motivation to use condoms in Manicaland. Community-led interventions to accelerate this dynamic in social norms and support AGYW's agency could reduce HIV incidence.

Technical advances in diagnostic techniques have permitted the possibility of multi-disease-based approaches for diagnosis and treatment monitoring of several infectious diseases, including tuberculosis (TB), human immunodeficiency virus (HIV), viral hepatitis and sexually transmitted infections (STI). However, in many countries, diagnosis and monitoring, as well as disease response programs, still operate as vertical systems, potentially causing delay in diagnosis and burden to patients and preventing the optimal use of available resources. With countries facing both human and financial resource constraints, during the COVID-19 pandemic even more than before, it is important that available resources are used as efficiently as possible, potential synergies are leveraged to maximise benefit for patients, continued provision of essential health services is ensured. For the infectious diseases, TB, HIV, hepatitis C (HCV) and STI, sharing devices and integrated services starting with rapid, quality-assured, and complete diagnostic services is beneficial for the continued development of adequate, efficient and effective treatment strategies. Here we explore the current and future potential (as well as some concerns), importance, implications and necessary implementation steps for the use of platforms for multi-disease testing for TB, HIV, HCV, STI and potentially other infectious diseases, including emerging pathogens, using the example of the COVID-19 pandemic. Daniel Simões was the recipient of PhD grant PD/BD/128008/2016 from Fundação para a Ciência e Tecnologia (FCT), co-funded by the “Programa Operacional Capital Humano/Fundo Social Europeu” (POCH/FSE). The funder did not have any role in manuscript preparation, revision or submission. Sí

Objectives: To assess the frequency of reporting of ethnicity (or ‘race’) and socioeconomic status (SES) indicators in high-impact journals. Design: Targeted literature review Data sources: The 10 highest ranked general medical journals using Google scholar h5 index. Eligibility criteria: Inclusion criteria were, human research, reporting participant level data. Exclusion criteria were non-research article, animal/other non-human participant/subject; or no participant characteristics reported. Data extraction and synthesis: Working backwards from 19/04/2021 in each journal, two independent reviewers selected the 10 most recent articles meeting inclusion/exclusion criteria, to create a sample of 100 articles. Data on the frequency of reporting of ethnicity (or ‘race’) and SES indicators were extracted and presented using descriptive statistics. Results: Of one hundred research articles included, 35 reported ethnicity and 13 SES. By contrast, 99 reported age, and 97 reported sex or gender. Among the articles not reporting ethnicity only 3 (5%) highlighted this as a limitation, and only 6 (7%) where SES data were missing. Median number of articles reporting ethnicity per journal was 2.5/10 (range 0 to 9). Only 2 journals explicitly requested reporting of ethnicity (or race), and 1 requested SES. Conclusions: The majority of research published in high-impact medical journals does not include data on the ethnicity and socioeconomic status of participants, and this omission is rarely acknowledged as a limitation. This situation persists despite the well-established importance of this issue and ICMJE recommendations to include relevant demographic variables to ensure representative samples. Standardized explicit minimum standards are required. Strengths and Limitations of this study - This study included recent studies from a range of the highest impact general medical journals. - Different inclusion/exclusion criteria for articles could be justifiably used which may have produced different results. - We identified high-impact journals using the google scholar h5 index, however various other equally valid impact metrics exist, which could change the journals considered. - Our analysis focused on if ethnicity and/or race was reported, but not how they are reported which is an important and related area for discussion and research to that covered in this study.

IntroductionThe lifetime risk of women undergoing surgery for the presence of benign ovarian pathology in the UK is 5%–10%. Despite minimally invasive surgical techniques, evidence suggests a number of healthy ovarian follicles and tissues are resected intraoperatively, resulting in subsequent decline of ovarian reserve. As such, there is an increasing demand for the implementation of fertility preservation surgery (FPS). This study will evaluate the effect on ovarian reserve following two different surgical interventions for the management of benign ovarian cysts.Methods and analysisWe will conduct a two-armed randomised controlled trial comparing laparoscopic ovarian cystectomy, considered gold standard treatment as per the Royal College of Obstetricians and Gynaecologists (RCOG) Green Top guidelines for the management of benign ovarian cysts, with ultrasound-guided laparoscopic ovarian cystectomy (UGLOC), a novel method of FPS. The study commencement date was October 2021, with a completion date aimed for October 2024. The primary outcome will be the difference in anti-Müllerian hormone (AMH) (pmol/L) and antral follicle count (AFC) measured 3 and 6 months postoperatively from the preoperative baseline. Secondary outcomes include assessment of various surgical and histopathological findings, including duration of hospital stay (days), duration of surgery (minutes), presence of intraoperative cyst rupture (yes/no), presence of ovarian tissue within the resected specimen (yes/no) and the grade of follicles excised within the specimen (grade 0–4). We aim to randomise 94 patients over 3 years to achieve power of 80% at an alpha level of 0.05.Ethics and disseminationFindings will be published in peer-reviewed journals and presented at national and international conferences and scientific meetings. The Chelsea NHS Research and Ethics Committee have awarded ethical approval of the study (21/LO/036).Trial registration numberNCT05032846.

ObjectiveElderly patients presenting with falls are known to carry an extremely high risk of future fragility fractures. Current osteoporosis guidelines recommend using fracture risk calculators such as FRAX, QFracture or Garvan to guide management. However, they differ considerably in their inputs and may therefore provide contrasting risk estimations in certain individuals. In this study, we compare these risk calculators in a high-risk cohort of elderly patients admitted to hospital with falls.DesignHospital-based cross-sectional study.SettingSecondary care, London, UK.ParticipantsData from 120 consecutive elderly patients who had falls presenting to a single hospital over 4 months were collected. 10-year major and hip fracture risks were calculated using FRAX, QFracture and Garvan. 1-year major and hip fracture risks from QFracture were assessed against prospective incidence of fracture.ResultsMedian 10-year major fracture risk was: FRAX 19.5%, QFracture 26.0%, Garvan 32.5%. Median 10-year hip fracture risk was: FRAX 9.6%, QFracture 21.1%, Garvan 6.5%. Correlation between FRAX and QFracture was r=0.672 for major, r=0.676 for hip fracture (both pConclusionsAlthough strong correlations between calculators were observed in the study cohort, there were differences of up to 13% between estimated risks. QFracture captured several elderly-specific inputs not considered by other calculators and so projected higher fracture risk than the other calculators. QFracture provided 1-year fracture risks that were comparable with the prospective observed fracture incidence in the cohort. This study has important clinical implications for the use of fracture risk calculators to guide treatment decisions, particularly in the high-risk cohort of elderly patients admitted to hospital following falls.

Background: Rifampicin, an antibiotic, is the principal component of the multidrug regimen used in the treatment of pulmonary tuberculosis. Daily use of rifampicin can lead to severe side effects, however, intermittent use is more associated with the occurrence of disseminated intravascular coagulation (DIC). This case report is the first reported case of rifampicin-induced DIC in the United Kingdom, of which the authors are aware. The report aims to highlight the importance of a rarely documented, and potentially fatal side effect of a commonly used drug, as well as outline the treatment of resultant DIC. Case presentation: We report a case of a 40-year-old man, of South Asian descent, initially presenting with shortness of breath, cough and fever. The patient had a past medical history of tuberculosis, which had not been fully treated. Computed tomography imaging and chest radiography demonstrated numerous pulmonary nodules. Together with the radiological findings, culture evidence led to a diagnosis of miliary tuberculosis. The patient was initiated on Rifater (isoniazid, rifampicin, pyrazinamide) and moxifloxacin. On day three after initiation of treatment, the patient developed thrombocytopenia (7 × 10 9 /L), and prolongation of APTT (40.5 seconds) and PT (22.7 seconds). Blood film analysis showed microangiopathic haemolytic anaemia, consistently bilirubin was elevated (58 μmol/L). Other secondary causes were excluded, which ultimately pointedtowards a diagnosis of DIC. Rifampicin was halted, and the patient was trialled on two other regimens to control his tuberculosis. The DIC continued, until novel administration of intravenous immunoglobulin (IVIg), which restored his coagulation screen to normal levels. Rifampicin is considered to be the most likely inducer of DIC in this case. Conclusion: This report adds to the very limited, but significant literature on rifampicin-induced DIC. A thorough history of previous exposure to rifampicin is recommended before initiating an intermittent schedule of the drug. Future administration of rifampicin can potentially be life-threatening and is contraindicated. The report also highlights a novel approach to administering potentially life-saving treatment in the form of IVIg in the circumstance of a rifampicin-induced DIC.

BackgroundDeaths from COVID-19 have exceeded 1.8 million globally (January 2020). We examined trends in markers of neonatal care before and during the pandemic at two tertiary neonatal units in Zimbabwe and Malawi.MethodsWe analysed data collected prospectively via the NeoTree app at Sally Mugabe Central Hospital (SMCH), Zimbabwe, and Kamuzu Central Hospital (KCH), Malawi. Neonates admitted from 1 June 2019 to 25 September 2020 were included. We modelled the impact of the first cases of COVID-19 (Zimbabwe: 20 March 2020; Malawi: 3 April 2020) on number of admissions, gestational age and birth weight, source of admission referrals, prevalence of neonatal encephalopathy, and overall mortality.FindingsThe study included 3,450 neonates at SMCH and 3,350 neonates at KCH. Admission numbers at SMCH did not initially change after the first case of COVID-19 but fell by 48% during a nurses’ strike (Relative risk (RR) 0·52, 95%CI 0·40-0·68, p < 0·002). At KCH, admissions dropped by 42% (RR 0·58; 95%CI 0·48-0·70; p < 0·001) soon after the first case of COVID-19. At KCH, gestational age and birth weight decreased slightly (1 week, 300 grams), outside referrals dropped by 28%, and there was a slight weekly increase in mortality. No changes in these outcomes were found at SMCH.InterpretationThe indirect impacts of COVID-19 are context-specific. While this study provides vital evidence to inform health providers and policy makers, national data are required to ascertain the true impacts of the pandemic on newborn health.FundingInternational Child Health Group, Wellcome Trust.RESEARCH IN CONTEXTEvidence before this studyWe searched PubMed for evidence of the indirect impact of the COVID-19 pandemic on neonatal care in low-income settings using the search terms neonat*ornewborn, andCOVID-19orSARS-CoV 2orcoronavirus, and the Cochrane low and middle income country (LMIC) filters, with no language limits between 01.10.2019 and 21.11.20. While there has been a decrease in global neonatal mortality rates, the smaller improvements seen in low-income settings are threatened by the direct and indirect impact of the COVID-19 pandemic. A modelling study of this threat predicted between 250000-1.1 million extra neonatal deaths as a result of decreased service provision and access in LMICs. A webinar and survey of frontline maternal/newborn healthcare workers in >60 countries reported a decline in both service attendance and in quality of service across the ante-, peri- and post-natal journey. Reporting fear of attending services, and difficulty in access, and a decrease in service quality due to exacerbation of existing service weaknesses, confusion over guidelines and understaffing. Similar findings were reported in a survey of healthcare workers providing childhood and maternal vaccines in LMICs. One study to date has reported data from Nepal describing an increase in stillbirths and neonatal deaths, with institutional deliveries nearly halved during lockdown.Added value of this studyTo our knowledge, this is the first and only study in Sub-Saharan Africa describing the impact of COVID-19 pandemic on health service access and outcomes for newborns in two countries. We analysed data from the digital quality improvement and data collection tool, the NeoTree, to carry out an interrupted time series analysis of newborn admission rates, gestational age, birth weight, diagnosis of hypoxic ischaemic encephalopathy and mortality from two large hospitals in Malawi and Zimbabwe (n∼7000 babies). We found that the indirect impacts of COVID-19 were context-specific. In Sally Mugabe Central Hospital, Zimbabwe, initial resilience was demonstrated in that there was no evidence of change in mortality, birth weight or gestational age. In comparison, at Kamuzu Central Hospital, Malawi, soon after the first case of COVID-19, the data revealed a fall in admissions (by 42%), gestational age (1 week), birth weight (300 grams), and outside referrals (by 28%), and there was a slight weekly increase in mortality (2%). In the Zimbabwean hospital, admission numbers did not initially change after the first case of COVID-19 but fell by 48% during a nurses’ strike, which in itself was in response to challenges exacerbated by the pandemic.Implications of all the available evidenceOur data confirms the reports from frontline healthcare workers of a perceived decline in neonatal service access and provision in LMICs. Digital routine healthcare data capture enabled rapid profiling of indirect impacts of COVID-19 on newborn care and outcomes in two tertiary referral hospitals, Malawi and Zimbabwe. While a decrease in service access was seen in both countries, the impacts on care provided and outcome differed by national context. Health systems strengthening, for example digital data capture, may assist in planning context-specific mitigation efforts.

ObjectiveTo evaluate the association between having concomitant chronic obstructive pulmonary disease (COPD) or asthma, and in-patient mortality and post-discharge management among patients hospitalised for acute heart failure (HF).SettingData were obtained from patients enrolled in the National Heart Failure Audit.Participants217 329 patients hospitalised for HF in England–Wales between March 2012 and 2018.OutcomesIn-hospital mortality, referrals to cardiology follow-up and prescriptions for HF medications were compared between patients with comorbid COPD (COPD-HF) or asthma (asthma-HF) versus HF-alone using mixed-effects logistic regression.ResultsPatients with COPD-HF were more likely to die during hospitalisation, and those with asthma-HF had a reduced likelihood of death, compared with patients who had HF-alone ((adjusted)ORadj, 95% CI: 1.10, 1.06 to 1.14 and ORadj, 95% CI: 0.84, 0.79 to 0.88). In patients who survived to discharge, referral to HF follow-up services differed between groups: patients with COPD-HF had reduced odds of cardiology follow-up (ORadj, 95% CI 0.79, 0.77 to 0.81), while cardiology referral odds for asthma-HF were similar to HF-alone. Overall, proportions of HF medication prescriptions at discharge were low for both COPD-HF and asthma-HF groups, particularly prescriptions for beta-blockers.ConclusionsIn this nationwide analysis, we showed that COPD and asthma significantly impact the clinical course in patients hospitalised for HF. COPD is associated with higher in-patient mortality and lower cardiology referral odds, while COPD and asthma are both associated with lower use of prognostic HF therapies on discharge. These data highlight therapeutic gaps and a need for better integration of cardiopulmonary services to improve healthcare provision for patients with HF and coexisting respiratory disease.

Background Immunosuppressive treatments inhibit vaccine-induced immunity against SARS-CoV-2. We evaluated whether a 2-week interruption of methotrexate treatment immediately after the COVID-19 vaccine booster improved antibody responses against the S1 receptor-binding domain (S1-RBD) of the SARS-CoV-2 spike protein compared with uninterrupted treatment in patients with immune-mediated inflammatory diseases. Methods We did an open-label, prospective, two-arm, parallel-group, multicentre, randomised, controlled, superiority trial in 26 hospitals in the UK. We recruited adults from rheumatology and dermatology clinics who had been diagnosed with an immune-mediated inflammatory disease (eg, rheumatoid arthritis, psoriasis with or without arthritis, axial spondyloarthritis, atopic dermatitis, polymyalgia rheumatica, and systemic lupus erythematosus) and who were taking low-dose weekly methotrexate (≤25 mg per week) for at least 3 months. Participants also had to have received two primary vaccine doses from the UK COVID-19 vaccination programme. We randomly assigned the participants (1:1), using a centralised validated computer randomisation program, to suspend methotrexate treatment for 2 weeks immediately after their COVID-19 booster (suspend methotrexate group) or to continue treatment as usual (continue methotrexate group). Participants, investigators, clinical research staff, and data analysts were unmasked, while researchers doing the laboratory analyses were masked to group assignment. The primary outcome was S1-RBD antibody titres 4 weeks after receiving the COVID-19 booster vaccine dose, assessed in the intention-to-treat population. This trial is registered with ISRCT, ISRCTN11442263; following the pre-planned interim analysis, recruitment was stopped early. Findings Between Sept 30, 2021 and March 3, 2022, we recruited 340 participants, of whom 254 were included in the interim analysis and had been randomly assigned to one of the two groups: 127 in the continue methotrexate group and 127 in the suspend methotrexate group. Their mean age was 59·1 years, 155 (61%) were female, 130 (51%) had rheumatoid arthritis, and 86 (34%) had psoriasis with or without arthritis. After 4 weeks, the geometric mean S1-RBD antibody titre was 22 750 U/mL (95% CI 19 314–26 796) in the suspend methotrexate group and 10 798 U/mL (8970–12 997) in the continue methotrexate group, with a geometric mean ratio (GMR) of 2·19 (95% CI 1·57–3·04; p Interpretation A 2-week interruption of methotrexate treatment for people with immune-mediated inflammatory diseases resulted in enhanced boosting of antibody responses after COVID-19 vaccination. This intervention is simple, low-cost, and easy to implement, and could potentially translate to increased vaccine efficacy and duration of protection for susceptible groups. Funding National Institute for Health and Care Research.

ObjectivesTo identify factors that influenced women who chose to leave academic medicine.Design and main outcome measuresIndependent consultants led a focus group of women in medicine who had left academia after completion of their postgraduate research degree at Imperial College London Faculty of Medicine. Thematic analysis was performed on the transcribed conversations.Participants and settingNine women physicians who completed a postgraduate degree (MD or PhD) at a large London Medical School and Academic Health Sciences Centre, Imperial College London, but did not go on to pursue a career in academic medicine.ResultsInfluences to leave clinical academia were summarised under eight themes—career intentions, supervisor support, institutional human resources support, inclusivity, work–life balance, expectations, mentors and role models, and pregnancy and maternity leave.ConclusionThe women in our focus group reported several factors contributing to their decision to leave clinical academia, which included lack of mentoring tailored to specific needs, low levels of acceptance for flexible working to help meet parental responsibilities and perceived explicit gender biases. We summarise the multiple targeted strategies that Imperial College London has implemented to promote retention of women in academic medicine, although more research needs to be done to ascertain the most effective interventions.

Healthcare-associated infections (HAIs) and antimicrobial-resistant (AMR) infections are leading causes of neonatal morbidity and mortality, contributing to an extended hospital stay and increased healthcare costs. Although the burden and impact of HAI/AMR in resource-limited neonatal units are substantial, there are few HAI/AMR prevention studies in these settings. We reviewed the mechanism of action and evidence supporting HAI/AMR prevention interventions, including care bundles, for hospitalized neonates in low- and middle-income countries (LMIC).

ObjectivesTo assess patient-level and hospital-level predictors of death and variation in death rates following admission for COVID-19 in England’s first two waves after accounting for random variation. To quantify the correlation between hospitals’ first and second wave death rates.DesignObservational study using administrative data.SettingAcute non-specialist hospitals in England.ParticipantsAll patients admitted with a primary diagnosis of COVID-19.Primary and secondary outcomesIn-hospital death.ResultsHospital Episode Statistics (HES) data were extracted for all acute hospitals in England for COVID-19 admissions from March 2020 to March 2021. In wave 1 (March to July 2020), there were 74 484 admissions and 21 883 deaths (crude rate 29.4%); in wave 2 (August 2020 to March 2021), there were 165 642 admissions and 36 040 deaths (21.8%). Wave 2 patients were younger, with more hypertension and obesity but lower rates of other comorbidities. Mortality improved for all ages; in wave 2, it peaked in December 2020 at 24.2% (lower than wave 1’s peak) but halved by March 2021. In multiple multilevel modelling combining HES with hospital-level data from Situational Reports, wave 2 and wave 1 variables significantly associated with death were mostly the same. The median odds ratio for wave 1 was just 1.05 and for wave 2 was 1.07. At 99.8% control limits, 3% of hospitals were high and 7% were low funnel plot outliers in wave 1; these figures were 9% and 12% for wave 2. Four hospitals were (low) outliers in both waves. The correlation between hospitals’ adjusted mortality rates between waves was 0.45 (pConclusionsEngland’s first two COVID-19 waves were similar regarding predictors and moderate interhospital variation. Despite the challenges, variation in death rates and length of stay between hospitals was modest and might be accounted for by unobserved patient factors.

ObjectiveTo determine population-based rates of non-fatal complications of rheumatic heart disease (RHD).DesignRetrospective cohort study based on multiple sources of routine clinical and administrative data amalgamated by probabilistic record-linkage.SettingFiji, an upper-middle-income country, where most of the population has access to government-funded healthcare services.ParticipantsNational cohort of 2116 patients with clinically apparent RHD aged 5–69 years during 2008 and 2012.Primary and secondary outcome measuresThe primary outcome was hospitalisation for any of heart failure, atrial fibrillation, ischaemic stroke and infective endocarditis. Secondary outcomes were first hospitalisation for each of the complications individually in the national cohort as well as in hospital (n=1300) and maternity (n=210) subsets. Information on outcomes was obtained from discharge diagnoses coded in the hospital patient information system. Population-based rates were obtained using relative survival methods with census data as the denominator.ResultsAmong 2116 patients in the national cohort (median age, 23.3 years; 57.7% women), 546 (25.8%) were hospitalised for an RHD complication, a substantial proportion of all cardiovascular admissions in the country during this period in those aged 0–40 years (heart failure, 210/454, 46.3%; ischaemic stroke 31/134, 23.1%). Absolute numbers of RHD complications peaked during the third decade of life with higher population-based rates in women compared with men (incidence rate ratio 1.4, 95% CI 1.3 to 1.6, pConclusionsOur study defines the burden of RHD-attributable morbidity in the general population of Fiji, potentially reflecting the situation in low-income and middle-income countries worldwide. Hospitalisation for an RHD complication is associated with markedly increased risk of death, re-emphasising the importance of effective early prevention.

Background: Asthma treatment guidelines recommend increasing corticosteroid dose to control symptoms and reduce exacerbations. This approach is potentially flawed because symptomatic asthma can occur without corticosteroid responsive type-2 (T2)-driven eosinophilic inflammation, and inappropriately high-dose corticosteroid treatment might have little therapeutic benefit with increased risk of side-effects. We compared a biomarker strategy to adjust corticosteroid dose using a composite score of T2 biomarkers (fractional exhaled nitric oxide [FENO], blood eosinophils, and serum periostin) with a standardised symptom–risk-based algorithm (control). Methods: We did a single-blind, parallel group, randomised controlled trial in adults (18–80 years of age) with severe asthma (at treatment steps 4 and 5 of the Global Initiative for Asthma) and FENO of less than 45 parts per billion at12 specialist severe asthma centres across England, Scotland, and Northern Ireland. Patients were randomly assigned (4:1) to either the biomarker strategy group or the control group by an online electronic case-report form, in blocks of ten, stratified by asthma control and use of rescue systemic steroids in the previous year. Patients were masked to study group allocation throughout the entirety of the study. Patients attended clinic every 8 weeks, with treatment adjustment following automated treatment-group-specific algorithms: those in the biomarker strategy group received a default advisory to maintain treatment and those in the control group had their treatment adjusted according to the steps indicated by the trial algorithm. The primary outcome was the proportion of patients with corticosteroid dose reduction at week 48, in the intention-to-treat (ITT) population. Secondary outcomes were inhaled corticosteroid (ICS) dose at the end of the study; cumulative dose of ICS during the study; proportion of patients on maintenance oral corticosteroids (OCS) at study end; rate of protocol-defined severe exacerbations per patient year; time to first severe exacerbation; number of hospital admissions for asthma; changes in lung function, Asthma Control Questionnaire-7 score, Asthma Quality of Life Questionnaire score, and T2 biomarkers from baseline to week 48; and whether patients declined to progress to OCS. A secondary aim of our study was to establish the proportion of patients with severe asthma in whom T2 biomarkers remained low when corticosteroid therapy was decreased to a minimum ICS dose. This study is registered with ClinicalTrials.gov, NCT02717689 and has been completed. Findings: Patients were recruited from Jan 8, 2016, to July 12, 2018. Of 549 patients assessed, 301 patients were included in the ITT population and were randomly assigned to the biomarker strategy group (n=240) or to the control group(n=61). 28·4% of patients in the biomarker strategy group were on a lower corticosteroid dose at week 48 compared with 18·5% of patients in the control group (adjusted odds ratio [aOR] 1·71 [95% CI 0·80–3·63]; p=0·17). In the per-protocol (PP) population (n=121), a significantly greater proportion of patients were on a lower corticosteroid dose at week 48 in the biomarker strategy group (30·7% of patients) compared with the control group (5·0% of patients; aOR 11·48 [95% CI 1·35–97·83]; p=0·026). Patient choice to not follow treatment advice was the principle reason for loss to PP analysis. There was no difference in secondary outcomes between study groups and no loss of asthma control among patients in the biomarker strategy group who reduced their corticosteroid dose. Interpretation: Biomarker-based corticosteroid adjustment did not result in a greater proportion of patients reducing corticosteroid dose versus control. Understanding the reasons for patients not following treatment advice in both treatment strategies is an important area for future research. The prevalence of T2 biomarker-low severe asthma was low.

Summary Background People experiencing homelessness are vulnerable to COVID-19 due to the risk of transmission in shared accommodation and the high prevalence of comorbidities. In England, as in some other countries, preventive policies have been implemented to protect this population. We aimed to estimate the avoided deaths and health-care use among people experiencing homelessness during the so-called first wave of COVID-19 in England—ie, the peak of infections occurring between February and May, 2020—and the potential impact of COVID-19 on this population in the future. Methods We used a discrete-time Markov chain model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection that included compartments for susceptible, exposed, infectious, and removed individuals, to explore the impact of the pandemic on 46 565 individuals experiencing homelessness: 35 817 living in 1065 hostels for homeless people, 3616 sleeping in 143 night shelters, and 7132 sleeping outside. We ran the model under scenarios varying the incidence of infection in the general population and the availability of prevention measures: specialist hotel accommodation, infection control in homeless settings, and mixing with the general population. We divided our scenarios into first wave scenarios (covering Feb 1–May 31, 2020) and future scenarios (covering June 1, 2020–Jan 31, 2021). For each scenario, we ran the model 200 times and reported the median and 95% prediction interval (2·5% and 97·5% quantiles) of the total number of cases, the number of deaths, the number hospital admissions, and the number of intensive care unit (ICU) admissions. Findings Up to May 31, 2020, we calibrated the model to 4% of the homeless population acquiring SARS-CoV-2, and estimated that 24 deaths (95% prediction interval 16–34) occurred. In this first wave of SARS-CoV-2 infections in England, we estimated that the preventive measures imposed might have avoided 21 092 infections (19 777–22 147), 266 deaths (226–301), 1164 hospital admissions (1079–1254), and 338 ICU admissions (305–374) among the homeless population. If preventive measures are continued, we projected a small number of additional cases between June 1, 2020, and Jan 31, 2021, with 1754 infections (1543–1960), 31 deaths (21–45), 122 hospital admissions (100–148), and 35 ICU admissions (23–47) with a second wave in the general population. However, if preventive measures are lifted, outbreaks in homeless settings might lead to larger numbers of infections and deaths, even with low incidence in the general population. In a scenario with no second wave and relaxed measures in homeless settings in England, we projected 12 151 infections (10 718–13 349), 184 deaths (151–217), 733 hospital admissions (635–822), and 213 ICU admissions (178–251) between June 1, 2020, and Jan 31, 2021. Interpretation Outbreaks of SARS-CoV-2 in homeless settings can lead to a high attack rate among people experiencing homelessness, even if incidence remains low in the general population. Avoidance of deaths depends on prevention of transmission within settings such as hostels and night shelters. Funding National Institute for Health Research, Wellcome, and Medical Research Council.

Introduction\udThe World Health Organization recommends full disclosure of HIV-positive status to adolescents who acquired HIV perinatally (APHIV) by age 12. However, even among adolescents (aged 10–19) already on antiretroviral therapy (ART), disclosure rates are low. Caregivers often report the child being too young and fear of disclosure worsening adolescents’ mental health as reasons for non-disclosure. We aimed to identify the predictors of disclosure and the association of disclosure with adherence, viral suppression and mental health outcomes among adolescents in sub-Saharan Africa.\ud\udMethods\udAnalyses included three rounds (2014–2018) of data collected among a closed cohort of adolescents living with HIV in Eastern Cape, South Africa. We used logistic regression with respondent random-effects to identify factors associated with disclosure, and assess differences in ART adherence, viral suppression and mental health symptoms between adolescents by disclosure status. We also explored differences in the change in mental health symptoms and adherence between study rounds and disclosure groups with logistic regression.\ud\udResults\udEight hundred and thirteen APHIV were interviewed at baseline, of whom 769 (94.6%) and 729 (89.7%) were interviewed at the second and third rounds, respectively. The proportion aware of their HIV-positive status increased from 63.1% at the first round to 85.5% by the third round. Older age (adjusted odds ratio [aOR]: 1.27; 1.08–1.48) and living in an urban location (aOR: 2.85; 1.72–4.73) were associated with disclosure between interviews. There was no association between awareness of HIV-positive status and ART adherence, viral suppression or mental health symptoms among all APHIV interviewed. However, among APHIV not aware of their status at baseline, adherence decreased at the second round among those who were disclosed to (N = 131) and increased among those not disclosed to (N = 151) (interaction aOR: 0.39; 0.19–0.80). There was no significant difference in the change in mental health symptoms between study rounds and disclosure groups.\ud\udConclusions\udAwareness of HIV-positive status was not associated with higher rates of mental health symptoms, or lower rates of viral suppression among adolescents. Disclosure was not associated with worse mental health. These findings support the recommendation for timely disclosure to APHIV; however, adherence support post-disclosure is important.

ObjectivesStudies have shown that demand-side interventions, such as conditional cash transfers and vouchers, can increase the proportion of women giving birth in a health facility in low-income and middle-income countries, but there is limited evidence of the effectiveness of supply-side interventions. We evaluated the impact of the Subsidy Reinvestment and Empowerment Programme Maternal and Child Health Project (SURE-P MCH) on rates of institutional delivery and antenatal care.Design, setting and participantsWe used a differences-in-differences study design that compared changes in rates of institutional delivery and antenatal care in areas that had received additional support through the SURE-P MCH programme relative to areas that did not. Data on outcomes were obtained from the 2013 Nigerian Demographic and Health Survey.ResultsWe found that the programme significantly increased the proportion of women giving birth in a health facility by approximately 7 percentage points (p=0.069) or approximately 10% relative to the baseline after 9 months of implementation. The programme, however, did not significantly increase the use of antenatal care.ConclusionThe findings of this study suggest there could be important improvements in institutional delivery rates through greater investment in supply-side interventions.

IntroductionDespite the potential benefits of advance care planning, uptake in older adults is low. In general, there is a lack of guidance as to how to initiate advance care planning conversations and encourage individuals to take action in planning their future care, including after emergency hospitalisation. Participatory action research methods are harnessed in health services research to design interventions that are relevant to end-users and stakeholders. This study aims to involve older persons, carers and healthcare professionals in co-designing an intervention to increase uptake of advance care planning in later life, which can be used by social contacts and healthcare professionals, particularly in the context of a recent emergency hospitalisation.Methods and analysisThe theory-driven participatory design research method integrates and adapts accelerated experience-based co-design with the behaviour change wheel, in the form of a collaborative multi-stakeholder co-design workshop. In total, 12 participants, comprising 4 lay persons aged 70+, 4 carers and 4 healthcare professionals with experience in elder care, will be recruited to participate in two online half-day sessions, together comprising one online workshop. There will be a maximum of two workshops. First, in the discovery phase, participants will reflect on findings from earlier qualitative research on views and experiences of advance care planning from three workstreams: patients, carers and healthcare professionals. Second, in the co-design phase, participants will explore practical mechanisms in which older persons aged 70+ can be encouraged to adopt advance care planning behaviours based on the behaviour change wheel, in order to co-design a behavioural intervention to increase uptake of advance care planning in older adults after an emergency hospitalisation.Ethics and disseminationEthical approval has been obtained from the Science Engineering Technology Research Ethics Committee at Imperial College London (Reference: 19IC5538). The findings from this study will be disseminated through publications, conferences and meetings.

IntroductionIt is unknown if a temporary break in long-term immune-suppressive treatment after vaccination against COVID-19 improves vaccine response. The objective of this study was to evaluate if a 2-week interruption in low-dose weekly methotrexate treatment after SARS-CoV-2 vaccine boosters enhances the immune response compared with continuing treatment in adults with autoimmune inflammatory conditions.Methods and analysisAn open-label, pragmatic, prospective, parallel group, randomised controlled superiority trial with internal feasibility assessment and nested mechanistic substudy will be conducted in rheumatology and dermatology clinics in approximately 25 UK hospitals. The sample size is 560, randomised 1:1 to intervention and usual care arms. The main outcome measure is anti-spike receptor-binding domain (RBD) antibody level, collected at prebooster (baseline), 4 weeks (primary outcome) and 12 weeks (secondary outcome) post booster vaccination. Other secondary outcome measures are patient global assessments of disease activity, disease flares and their treatment, EuroQol 5- dimention 5-level (EQ-5D-5L), self-reported adherence with advice to interrupt or continue methotrexate, neutralising antibody titre against SARS-CoV-2 (mechanistic substudy) and oral methotrexate biochemical adherence (mechanistic substudy). Analysis of B-cell memory and T-cell responses at baseline and weeks 4 and 12 will be investigated subject to obtaining additional funding. The principal analysis will be performed on the groups as randomised (ie, intention to treat). The difference between the study arms in anti-spike RBD antibody level will be estimated using mixed effects model, allowing for repeated measures clustered within participants. The models will be adjusted for randomisation factors and prior SARS-CoV-2 infection status.Ethics and disseminationThis study was approved by the Leeds West Research Ethics Committee and Health Research Authority (REC reference: 21/HRA/3483, IRAS 303827). Participants will be required to give written informed consent before taking part in the trial. Dissemination will be via peer review publications, newsletters and conferences. Results will be communicated to policymakers.Trial registration numberISRCTN11442263.

ObjectivesWhile smoking tobacco remains a substantial cause of harm in Europe, novel products such as electronic cigarettes or e-cigarettes (ECs) and heated tobacco products (HTPs) have entered the market recently. While debate still persists over the role of these novel products, they are now in widespread use. This study aimed to explore the prevalence and methods of attempts to quit EC and HTP.SettingWe analysed the 2020 Eurobarometer survey, which collected data in 28 European countries.ParticipantsA representative sample of individuals residing in these countries aged ≥15 years.Primary and secondary outcome measuresMultilevel regression analyses were performed to assess differences in quit attempts and cessation methods among tobacco smokers and exclusive EC/HTP users separately.Results51.1% of current tobacco smokers and 27.1% of exclusive EC or HTP users reported having ever made a quit attempt. The majority of former and current smokers (75.8%) who made a quit attempt did so unassisted, with 28.8% reporting at least one attempt using a cessation aid. The most popular cessation aids were nicotine replacement therapy or other medication (13.4%) and ECs (11.3%). 58.8% of exclusive EC or HTP users who had made a quit attempt did so unassisted, with 39.5% reporting the use of a cessation aid.ConclusionMost EC and HTP users in Europe try to quit unassisted, although more of them report the use of a cessation aid compared with tobacco smokers. Cessation support services should take into consideration the increasing numbers of users of EC and HTP who may be trying to quit.

Background: Priming COVID-19 vaccine schedules have been deployed at variable intervals globally, which may influence immune persistence and the relative importance of third-dose ‘booster’ programmes. Here, we report on the impact of 4- versus 12-week priming intervals on reactogenicity and the persistence of immune response up to 6 months following homologous and heterologous priming schedules using BNT162b2 (BNT, tozinameran, Comirnaty, Pfizer/BioNTech) and ChAdOx1 nCoV-19 (ChAd, Vaxzevria, AstraZeneca). Methods: Com-COV is a participant-blinded, randomised immunogenicity trial. Results are reported here for the ‘General’ cohort, in which adults aged over 50 years were randomised to four homologous and heterologous schedules using BNT and ChAd with 4- or 12-week priming intervals. Immunogenicity analyses were on the intention-to-treat population (ITT), without evidence of COVID-19 infection at baseline or for the trial duration, with the purpose of describing the effect of priming interval on humoral and cellular immune response at peak and later timepoints, in addition to the effects on reactogenicity and safety Findings: Between 11th–26th Feb 2021, 730 participants were randomised in the general cohort, with 77-89 per arm in the ITT analysis. At 28-days and 6-months post-second dose, the geometric mean concentration (GMC) of anti-SARS-CoV-2 spike IgG was significantly higher in 12- versus 4-week interval arms for homologous schedules. In heterologous arms, there was only a significant difference between intervals for the BNT/ChAd arm at 28-days. Pseudotyped virus neutralisation titres were significantly higher in all 12-week versus 4-week schedules, 28-days post-second dose, with geometric mean ratios 1.4 (95%CI: 1.1-1.8, BNT/BNT), 1.5 (95%CI: 1.2-1.9, ChAd/BNT), 1.6 (95%CI 1.3-2.1, BNT/ChAd) and2.4 (95%CI: 1.7-3.2, ChAd/ChAd). At 6 months post-second dose, anti-spike IgG GMCs fell to 0.17-0.24 of the 28-day post-second dose value across all eight study arms, with only BNT/BNT displaying a slightly slower decay for the 12-week versus 4-week schedule in the adjusted analysis. The rank order of schedules by humoral response was unaffected by interval with BNT/BNT remaining the most immunogenic by antibody response. T-cell responses were reduced in all 12-week priming intervals versus their 4-week counterparts. 12-week schedules for BNT/BNT and ChAd/BNT schedules were up to 80% less reactogenic than 4-week schedules. Interpretation: These data support flexibility in priming interval in all studied COVID-19 vaccine schedules. Longer priming intervals may result in lower reactogenicity in schedules with BNT as a second-dose and higher humoral immunogenicity in homologous schedules, but overall lower T-cell responses across all schedules. Future vaccines employing these novel platforms may benefit from prolonged-interval schedules. ISRCTN:69254139, EudraCT:2020-005085-33.

Data sharing: Fully anonymised data will be provided upon reasonable request to the corresponding author. Copyright © 2022 The Author(s). Background: There are few evidence-based interventions for long COVID; however, holistic approaches supporting recovery are advocated. We assessed whether an online breathing and wellbeing programme improves health related quality-of-life (HRQoL) in people with persisting breathlessness following COVID-19. Methods: We conducted a parallel-group, single-blind, randomised controlled trial in patients who had been referred from one of 51 UK-based collaborating long COVID clinics. Eligible participants were aged 18 years or older; were recovering from COVID-19 with ongoing breathlessness, with or without anxiety, at least 4 weeks after symptom onset; had internet access with an appropriate device; and were deemed clinically suitable for participation by one of the collaborating COVID-19 clinics. Following clinical assessment, potential participants were given a unique online portal code. Participants were randomly assigned (1:1) to either immediate participation in the English National Opera (ENO) Breathe programme or to usual care. Randomisation was done by the research team using computer-generated block randomisation lists, with block size 10. The researcher responsible for randomisation was masked to responses. Participants in the ENO Breathe group participated in a 6-week online breathing and wellbeing programme, developed for people with long COVID experiencing breathlessness, focusing on breathing retraining using singing techniques. Those in the deferred group received usual care until they exited the trial. The primary outcome, assessed in the intention-to-treat population, was change in HRQoL, assessed using the RAND 36-item short form survey instrument mental health composite (MHC) and physical health composite (PHC) scores. Secondary outcome measures were the chronic obstructive pulmonary disease assessment test score, visual analogue scales (VAS) for breathlessness, and scores on the dyspnoea-12, the generalised anxiety disorder 7-item scale, and the short form-6D. A thematic analysis exploring participant experience was also conducted using qualitative data from focus groups, survey responses, and email correspondence. This trial is registered with ClinicalTrials.gov, NCT04830033. Findings: Between April 22 and May 25, 2021, 158 participants were recruited and randomly assigned. Of these, eight (5%) individuals were excluded and 150 participants were allocated to a treatment group (74 in the ENO Breathe group and 76 in the usual care group). Compared with usual care, ENO Breathe was associated with an improvement in MHC score (regression coefficient 2·42 [95% CI 0·03 to 4·80]; p=0·047), but not PHC score (0·60 [–1·33 to 2·52]; p=0·54). VAS for breathlessness (running) favoured ENO Breathe participation (−10·48 [–17·23 to –3·73]; p=0·0026). No other statistically significant between-group differences in secondary outcomes were observed. One minor self-limiting adverse event was reported by a participant in the ENO Breathe group who felt dizzy using a computer for extended periods. Thematic analysis of ENO Breathe participant experience identified three key themes: (1) improvements in symptoms; (2) feeling that the programme was complementary to standard care; and (3) the particular suitability of singing and music to address their needs. Interpretation: Our findings suggest that an online breathing and wellbeing programme can improve the mental component of HRQoL and elements of breathlessness in people with persisting symptoms after COVID-19. Mind–body and music-based approaches, including practical, enjoyable, symptom-management techniques might have a role supporting recovery. Imperial College London