BACKGROUND:There is insufficient data to inform the management of dolutegravir failure, with the WHO and various countries adopting different approaches, underscoring the need for an evidence-based management approach. METHODS:The Ndovu study is a large multi-country cohort, with a nested randomised controlled trial (RCT), enrolling 6,600 people living with HIV (PLWH) with viral load (VL) of ≥1000 copies/ml after at least 6 months of dolutegravir. Participants aged ≥ 1 year, including pregnant women, will be followed up for 12 months with enhanced adherence counselling (EAC) provided monthly. Viral load (VL) testing will be conducted every 3 months and drug resistance testing conducted if VL ≥ 200 copies/ml. Three hundred and sixty-two participants aged ≥15 years and 30 participants aged 3-14 years with major dolutegravir-associated drug resistant mutations (DRMs) will be enrolled into the RCT and randomised to switch to ritonavir boosted darunavir (DRV/r) or continue with dolutegravir with follow-up for 12 months. VL will be measured at 1, 3, 6 and 12 months and tenofovir levels assessed on dried blood spots at month 1 and month 6. The primary outcome of the cohort is the proportion of participants achieving viral load <200 copies/ml by month 12 and the primary endpoint of the RCT is viral load <200copies/ml at 6 months using a modified FDA snap shot algorithm. Secondary endpoints are DRM patterns associated with non-suppression, level of adherence associated with suppression as well as participant and provider experiences of staying on DTG versus switching to DRV/r. The RCT primary efficacy analysis will be conducted on the Intent-to-Treat Exposed (ITT-E) population and will compare the difference in the proportion of participants with viral load <200 copies/ml 6 months after randomisation between the treatment arms stratified by the randomisation stratification factors. This study is registered at ClinicalTrials.gov, NCT06762054 (cohort) and NCT06747507 (RCT) and enrollment into the cohort started in March 2025. CONCLUSION:The Ndovu study will address critical gaps in the management of DTG failure including the emergence, determinants and implications of DTG resistance. Further, it will evaluate the optimal ART regimens to use in the setting of DTG resistance in adults and children.

To end the tuberculosis (TB) epidemic, the WHO recommends implementing active case-finding to increase TB detection, as well as the provision of TB preventive treatment (TPT) in contacts of people with TB. However, the scale-up of both strategies remains limited in high TB-burden countries such as Thailand. Despite the country’s highly decentralised healthcare system, significant inequalities remain in access to care, particularly in vulnerable populations. We designed an intervention study investigating the effectiveness and feasibility of a novel strategy combining active case-finding and the implementation of short-course TPT in households of newly diagnosed adults with TB in Thailand. This is a pragmatic phase IV stepped-wedge cluster-randomised trial conducted in 20 provincial hospitals (clusters). The study population comprises household members who were exposed within the last 3 months to adults with newly detected bacteriologically confirmed TB. The intervention combines an educational video to the index TB case, provision of an invitation card to household contacts for free TB screening at the facility, with a transport voucher, and support from village or urban health volunteers. Household contacts without active TB are offered TPT regimens according to age: 1-month rifapentine-isoniazid (1HP), 3-month rifapentine-isoniazid (3HP) or 3-month rifampicin-isoniazid (3HR). In the control phase, TB staff implement the current standard of care, including verbal information to persons newly diagnosed with TB on the need to screen their household contacts and provision of standard TPT. Hospitals shift from the control to the intervention phase every 3 months in four randomised sequences until all clusters apply the intervention. Generalised linear mixed models will be used to compare the intervention outcomes versus the standard of care, controlling for clustering and confounding by time. Active case-finding and systematic TPT in at-risk populations is currently limited in Thailand. This protocol incorporates pragmatic design features with a participant-centred approach to assess the effectiveness, feasibility and acceptability of a combined strategy including systematic screening of household contacts, active case-finding and TPT provision. If successful, this strategy will likely contribute to TB elimination in Thailand and beyond. The study is registered at ClinicalTrials.gov NCT05581212 on April 3rd, 2024, and is currently recruiting.

Background:Community-wide screening is a crucial strategy to end tuberculosis (TB), but a common concern is potential harm from overtreatment following false positive diagnoses. However, current reference standards determining test performance have limitations, with implications for prevalence thresholds and treatment decisions for community-wide screening. Methods:We estimated coverage of community-wide screening at a prevalence threshold of 0.5% (current global standard), 0.25%, and 0.1% for adult pulmonary TB. We considered test performance for Xpert Ultra against different reference standards (sputum culture, plus clinical evaluation, plus disease progression within two years). Potential harm was estimated through disability adjusted life years (DALYs) incurred or averted by treatment. We report net specificity, positive predictive value (PPV), the ratio of false positives to true positives, and DALYs averted for (non-)treatment based on different reference standards. Results:A lower threshold would increase screening coverage from the current 42% to 84% (0.25% threshold) and 89% (0.1% threshold) of the global TB burden. In a population of 100,000 with 0.5% prevalence, specificity was 99.5% for community screening, but increased to 99.7% using disease progression as reference standard, with PPV increasing from 45 to 66%. In addition, estimated harm of withholding appropriate treatment was approximately 1,200 times higher compared to providing inappropriate treatment, with treatment initiation after a positive Xpert Ultra increasing overall DALYs averted (median 5,977 versus 3,750). Discussion:The benefit of TB treatment following a positive molecular test in community-wide screening likely outweighs the harm associated with possible overtreatment, supporting expanding coverage of simplified community-wide screening. Brief summary:A concern with community-wide tuberculosis screening is the potential for overtreatment. We evaluated diagnostic reference standards and relative health costs of (non-)treatment, finding that after a positive molecular test, the benefit of initiating tuberculosis treatment likely outweighs its harm.

Long-acting (LA) injectable therapy as treatment for HIV-1 infection offers reduced dosing frequency, increased discretion and provides an alternative to two or three-drug daily oral combinations. A parenteral LA formulation of cabotegravir (CAB) and rilpivirine (RPV) given by intramuscular (IM) injection every 2 months (CAB LA + RPV LA Q2M) has shown safety and efficacy in phase 3/3b trials and could increase treatment satisfaction and improve adherence in sub-Saharan Africa. IMPALA (IMProving HIV-1 Control in Africa using Long-Acting Antiretrovirals) is a randomized, controlled, open-label, multicentre, interventional study in Uganda, Kenya, and South Africa of 540 virologically suppressed adults living with HIV-1 infection with a history of sub-optimal adherence to daily oral ART . IMPALA seeks to demonstrate the non-inferior antiviral effectiveness of switching to CAB LA + RPV LA Q2M, compared to the continuation of first-line daily oral ART containing 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) plus dolutegravir (DTG). After providing informed consent, participants are screened for eligibility. Those who are viraemic (HIV RNA ≥200 copies/mL) at screening will be suppressed (<200 copies/mL for ≥3 months) on oral ART prior to randomization. On Day 1, individuals will be randomized 1:1 to either continue daily oral ART, or switch to CAB LA + RPV LA Q2M, (intervention arm) with or without a 1-month oral lead consisting of once daily oral CAB + RPV. The total follow-up period is 24 months. The primary endpoint is HIV-1 RNA <50 copies/ml at 12 months by FDA snapshot. Initial: TMC278LAHTX3005 Version Amendment 1, 30 September 2022 Superseded by: TMC278LAHTX3005 Version Amendment 2, 3 June 2024 This clinical trial was registered on Clinical Trials.gov on 19 September 2022 (NCT05546242), available from https://clinicaltrials.gov/ct2/show/NCT05546242. The study was also registered on Pan African Clinical Trials Registry on 23 January 2023 (PACT202301600757432TMC278LAHTX3005), available from https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=24291.

Background:Epstein-Barr virus (EBV) central nervous system (CNS) infection in immunocompromised hosts and among meningitis cohorts is well recognized. The clinical significance of EBV CNS infection, however, is poorly understood. Methods:Data were collected as part of the Botswana National Meningitis Survey and the Harare Meningitis Aetiology Study. The prevalence of EBV CNS infection (EBV DNA detected in cerebrospinal fluid [CSF] by means of quantitative polymerase chain reaction) was determined, alongside associations with baseline covariates and the in-hospital mortality rate. Results:A total of 581 participants with suspected meningitis were recruited. Of these, 54% were male, the median age (interquartile range) was 38 (29-46) years, and 76% were persons living with human immunodeficiency virus (HIV). Cryptococcal meningitis was the most common microbiologically confirmed infectious meningitis (12.0%), and 6.4% of participants had definite tuberculous meningitis. EBV CNS infection was common (26% [152 of 581]) and was associated with older age, being HIV positive, and CSF pleocytosis (P < .001). It was also associated with increased in-hospital mortality rate (odds ratio, 1.64, [95% confidence interval, 1.10-2.43]; P = .01), but after adjustment for sex, age, and HIV status, there was no longer evidence of an association (adjusted odds ratio, 1.29 [.84-1.98]; P = .25). In subgroup analyses, there was an indication that the association between EBV CNS infection and mortality rate may differ by meningitis subgroup. Conclusions:EBV CNS infection was common among our cohort, and it was strongly associated with CSF pleocytosis. Following multivariable analyses, EBV CNS infection overall was not associated with in-hospital mortality rate. EBV CNS infection in the context of meningitis is most likely a "bystander" virus that reflects heightened CSF inflammation.

Background: Maternal mental illness (MMI) affects almost a quarter of mothers and may impact a child's development and physical health. It remains unclear whether MMI is associated with altered utilization of vaccination services. Understanding this association could help to identify families in need of additional support. Methods: Using primary care data from England, we conducted a historical cohort study of 397,519 children born in England between 2006 and 2014 with linked maternal records. Associations between different types of MMI (common mental disorders, severe mental illness and alcohol and substance use disorder) with childhood immunisation were explored using logistic regression for differences in coverage and accelerated failure time models for differences in timeliness before the child's fifth birthday. Results: While there were no differences in vaccination coverage at the age of one, children of mothers with common mental disorders had lower odds of being vaccinated at the ages of two (OR 0.95, 95 %CI: 0.93-0.98) and five (OR 0.86, 95 % CI 0.84-0.89) in comparison to children of mothers with no record of MMI. Vaccination coverage was even lower for children of mothers with comorbid substance disorder and common mental disorder (OR 0.70, 95 % CI: 0.62-0.78 at the age of five). There were no significant differences in timeliness of vaccine receipt by MMI. Conclusions: Inequalities in vaccination coverage associated with MMI grow with increasing age of the child. Extending support services for women with MMI beyond the child's first year of life could offer potential to improve vaccination uptake and reduce childhood infections.

BACKGROUND:Invasive pneumococcal disease (IPD) is associated with increased long-term mortality, but it is unclear if this is explained by pre-existing comorbidities. We aimed to estimate the long-term survival following IPD in comparison with the general population, adjusting for potential confounders such as underlying comorbidities. METHODS:We conducted a matched cohort study comparing long-term survival (>120 days after infection) in individuals with IPD and comparators without IPD. Cases were individuals aged 65 years or older with laboratory-confirmed IPD (2012-19) identified through enhanced national surveillance. Comparators matched on age, sex, and calendar date of laboratory-confirmed diagnosis were drawn from primary care electronic health records in Clinical Practice Research Datalink GOLD. We used Cox regression, stratified by matched set, to compare mortality in people with and without IPD, adjusting for relevant comorbidities, socioeconomic deprivation, and ethnicity. FINDINGS:We included 13 401 IPD cases and 67 005 comparators without IPD. There were 5038 (53·5%) female and 4380 (46·5%) male IPD cases and 19 927 (53·5%) female and 17 351 (46·5%) male comparators without IPD. After adjusting for comorbidities, socioeconomic deprivation, and ethnicity, we found increased all-cause mortality in IPD cases compared with comparators without IPD (hazard ratio 3·74 [95% CI 3·50-3·99]). The predicted median survival was 4·7 years (IQR 2·9-7·4) for IPD cases and more than 11·9 years (IQR 8·7 to >11·9) for comparators without IPD. This increased mortality was consistent across subgroups defined by age, vaccination history, and comorbidity status (including diabetes, chronic respiratory disease, and chronic heart disease). INTERPRETATION:IPD was associated with increased mortality at least 5 years after infection. These findings emphasise the value of IPD prevention and the need for more research into the clinical management of people who have had IPD. Long-term mortality should be incorporated in cost-effectiveness analyses for pneumococcal vaccines. FUNDING:National Institute for Health and Care Research (NIHR) Health Protection Research Unit in Vaccines and Immunisation (NIHR200929).

Background. Tuberculous meningitis (TBM) disproportionately impacts high-HIV prevalence, resource-limited settings where diagnosis is challenging. The GeneXpert platform has utility in TBM diagnosis, but uptake remains limited. In Botswana, before the introduction of GeneXpert, tuberculosis (TB) testing was only available through mycobacterial culture at the National TB Reference Laboratory. Data describing routine use of Xpert MTB/RIF for cerebrospinal fluid (CSF) testing in resource-limited settings are scarce. Methods. Electronic records for patients with CSF tested in government facilities in Botswana between 2016 and 2022 were obtained from a central online repository as part of ongoing national meningitis surveillance. Samples were excluded from 1 site where Xpert MTB/RIF is performed universally. The proportion receiving TB-specific investigation on CSF and the number positive for Mycobacterium tuberculosis following increased Xpert MTB/RIF capacity were determined. Results. The proportion of CSF samples receiving TB-specific investigation increased from 4.5% (58/1288) in 2016 to 29.0% (201/693) in 2022, primarily due to increased analysis with Xpert MTB/RIF from 0.9% (11/1288) to 23.2% (161/693). There was an overall decline in the annual number of CSF samples analyzed, but the proportion with microbiologically confirmed TBM increased from 0.4% to 1.2%. The proportion of samples tested for TB that were collected from health care facilities >100 km from the National TB Reference Laboratory increased with Xpert MTB/RIF rollout from 65.9% (87/132) to 78.0% (494/633). Conclusions. In Botswana, access to TB culture is challenging in remote populations; more accessible near-patient testing using Xpert MTB/RIF increased the number of patients receiving TB-specific testing on CSF and the number of confirmed TBM cases.

Background Cryptococcal meningitis (CM) causes substantial mortality in African countries with a high prevalence of human immunodeficiency virus (HIV), despite advances in disease management and increasing antiretroviral therapy (ART) coverage. Reliable diagnosis of CM is cheap and more accessible than other indicators of advanced HIV disease burden such as CD4 testing or investigation for disseminated tuberculosis; therefore, monitoring CM incidence has the potential to serve as a valuable metric of HIV programmatic success.Methods Botswana national meningitis surveillance data from 2015 to 2022 were obtained from electronic health records. All electronic laboratory records from cerebrospinal fluid samples analyzed within government healthcare facilities in Botswana were extracted from a central online repository. Adjustments for missing data were made through triangulation with prospective cohort study datasets. CM case frequency was enumerated using a case definition and incidence calculated using national census data.Results A total of 1744 episodes of CM were identified; incidence declined from 15.0 (95% confidence interval [CI], 13.4-16.7) cases/100 000 person-years in 2015 to 7.4 (95% CI, 6.4-8.6) cases/100 000 person-years in 2022. However, the rate of decline slowed following the introduction of universal treatment in 2016. The highest incidence was observed in men and individuals aged 40-44 years. The proportion of cases diagnosed through cryptococcal antigen testing increased from 35.5% to 86.3%.Conclusions CM incidence has decreased in Botswana following expansion of ART coverage but persists at a stubbornly high incidence. Most cases are now diagnosed through the cheap and easy-to-use cryptococcal antigen test, highlighting the potential of using CM as key metric of program success in the Treat All era. Cryptococcal meningitis remains a leading cause of mortality in high-HIV-prevalence settings. In Botswana, cryptococcal meningitis incidence declined with expanded antiretroviral coverage. Rapid cryptococcal antigen test was increasingly used, highlighting cryptococcal meningitis surveillance as an important metric of HIV programmatic success.

Background:The role of computed tomography (CT) before lumbar puncture (LP) is unclear, with limited evidence for a causal link between LP and cerebral herniation or for the ability of CT to identify individuals at risk of herniation. The risks of LP delay or deferral are potentially greater in high-HIV prevalence, resource-limited settings; we analyzed data from such a setting to determine the impact of CT on time to LP and treatment, as well as mortality. Methods:Adults with suspected central nervous system (CNS) infection were enrolled prospectively into the Botswana National Meningitis Survey between 2016 and 2019. Inpatient mortality and clinical data including time of treatment initiation and CT were captured from medical records. Associations between preceding CT and outcomes were assessed using logistic regression. Results:LPs were performed in 711 patients with suspected CNS infection; 27% had a CT before LP, and 73% were HIV positive. Time from admission to LP and time from admission to appropriate treatment were significantly longer in patients who had a CT before LP compared with those who did not (2.8 hours and 13.2 hours, respectively). There was some evidence for treatment delays being associated with increased mortality; however, there was no significant difference in mortality between those who had or did not have CT. Conclusions:Patients who had a CT had delays to diagnostic LP and initiation of appropriate treatment; although treatment delays were associated with increased mortality, our observational study could not demonstrate a causal association between delays in diagnosis and treatment introduced by CT and mortality.

BACKGROUND: Shorter but effective tuberculosis treatment regimens would be of value to the tuberculosis treatment community. High-dose rifampicin has been associated with more rapid and secure lung sterilization and may enable shorter tuberculosis treatment regimens. METHODS: We randomly assigned adults who were given a diagnosis of rifampicin-susceptible pulmonary tuberculosis to a 6-month control regimen, a similar 4-month regimen of rifampicin at 1200 mg/d (study regimen 1 [SR1]), or a 4-month regimen of rifampicin at 1800 mg/d (study regimen 2 [SR2]). Sputum specimens were collected at regular intervals. The primary end point was a composite of treatment failure and relapse in participants who were sputum smear positive at baseline. The noninferiority margin was 8 percentage points. Using a sequence of ordered hypotheses, noninferiority of SR2 was tested first. RESULTS: Between January 2017 and December 2020, 672 patients were enrolled in six countries, including 191 in the control group, 192 in the SR1 group, and 195 in the SR2 group. Noninferiority was not shown. Favorable responses rates were 93, 90, and 87% in the control, SR1, and SR2 groups, respectively, for a country-adjusted absolute risk difference of 6.3 percentage points (90% confidence interval, 1.1 to 11.5) comparing SR2 with the control group. The proportions of participants experiencing a grade 3 or 4 adverse event were 4.0, 4.5, and 4.4% in the control, SR1, and SR2 groups, respectively. CONCLUSIONS: Four-month high-dose rifampicin regimens did not have dose-limiting toxicities or side effects but failed to meet noninferiority criteria compared with the standard 6-month control regimen for treatment of pulmonary tuberculosis. (Funded by the MRC/Wellcome Trust/DFID Joint Global Health Trials Scheme; ClinicalTrials.gov number, NCT02581527.)

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

Abstract Background The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) alpha variant (B.1.1.7) is associated with higher transmissibility than wild-type virus, becoming the dominant variant in England by January 2021. We aimed to describe the severity of the alpha variant in terms of the pathway of disease from testing positive to hospital admission and death. Methods With the approval of NHS England, we linked individual-level data from primary care with SARS-CoV-2 community testing, hospital admission, and Office for National Statistics all-cause death data. We used testing data with S-gene target failure as a proxy for distinguishing alpha and wild-type cases, and stratified Cox proportional hazards regression to compare the relative severity of alpha cases with wild-type diagnosed from 16 November 2020 to 11 January 2021. Results Using data from 185 234 people who tested positive for SARS-CoV-2 in the community (alpha = 93 153; wild-type = 92 081), in fully adjusted analysis accounting for individual-level demographics and comorbidities as well as regional variation in infection incidence, we found alpha associated with 73% higher hazards of all-cause death (adjusted hazard ratio [aHR]: 1.73; 95% confidence interval [CI]: 1.41–2.13; P < .0001) and 62% higher hazards of hospital admission (1.62; 1.48–1.78; P < .0001) compared with wild-type virus. Among patients already admitted to the intensive care unit, the association between alpha and increased all-cause mortality was smaller and the CI included the null (aHR: 1.20; 95% CI: .74–1.95; P = .45). Conclusions The SARS-CoV-2 alpha variant is associated with an increased risk of both hospitalization and mortality than wild-type virus.

The SARS-CoV-2 Omicron variant is increasing in prevalence around the world. Accurate estimation of disease severity associated with Omicron is critical for pandemic planning. We found lower risk of accident and emergency (AE) attendance following SARS-CoV-2 infection with Omicron compared to Delta (HR: 0.39 (95% CI: 0.30 – 0.51; P<.0001). For AE attendances that lead to hospital admission, Omicron was associated with an 85% lower hazard compared with Delta (HR: 0.14 (95% CI: 0.09 – 0.24; P<.0001)).Conflicts of Interests Nothing to declare.Funding statement This work was supported by the Medical Research Council MR/V015737/1. TPP provided technical expertise and infrastructure within their data centre pro bono in the context of a national emergency. Rosalind Eggo is funded by HDR UK (grant: MR/S003975/1), MRC (grant: MC_PC 19065), NIHR (grant: NIHR200908).### Competing Interest StatementThe authors have declared no competing interest.### Funding StatementThis work was supported by the Medical Research Council MR/V015737/1. TPP provided technical expertise and infrastructure within their data centre pro bono in the context of a national emergency. Rosalind Eggo is funded by HDR UK (grant: MR/S003975/1), MRC (grant: MC_PC 19065), NIHR (grant: NIHR200908).### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:This study was approved by the Health Research Authority (REC reference 20/LO/0651) and by the LSHTM Ethics Board (reference 21863).I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesDetailed pseudonymised patient data is potentially re-identifiable and therefore not shared.

BACKGROUND:Residents in care homes have been severely impacted by COVID-19. We describe trends in the mortality risk among residents of care homes compared to private homes.METHODS:On behalf of NHS England we used OpenSAFELY-TPP to calculate monthly age-standardised risks of death due to all causes and COVID-19 among adults aged >=65 years between 1/2/2019 and 31/03/2021. Care home residents were identified using linkage to Care and Quality Commission data.FINDINGS:We included 4,340,648 people aged 65 years or older on the 1st of February 2019, 2.2% of whom were classified as residing in a care or nursing home. Age-standardised mortality risks were approximately 10 times higher among care home residents compared to those in private housing in February 2019: comparative mortality figure (CMF) = 10.59 (95%CI = 9.51, 11.81) among women, and 10.87 (9.93, 11.90) among men. By April 2020 these relative differences had increased to more than 17 times with CMFs of 17.57 (16.43, 18.79) among women and 18.17 (17.22, 19.17) among men. CMFs did not increase during the second wave, despite a rise in the absolute age-standardised COVID-19 mortality risks.INTERPRETATION:COVID-19 has had a disproportionate impact on the mortality of care home residents in England compared to older residents of private homes, but only in the first wave. This may be explained by a degree of acquired immunity, improved protective measures or changes in the underlying frailty of the populations. The care home population should be prioritised for measures aimed at controlling COVID-19.FUNDING:Medical Research Council MR/V015737/1.

OBJECTIVE To compare the effectiveness of the BNT162b2 mRNA (Pfizer-BioNTech) and the ChAdOx1 (Oxford-AstraZeneca) covid-19 vaccines against infection and covid-19 disease in health and social care workers. DESIGN Cohort study, emulating a comparative effectiveness trial, on behalf of NHS England. SETTING Linked primary care, hospital, and covid-19 surveillance records available within the OpenSAFELY-TPP research platform, covering a period when the SARS-CoV-2 Alpha variant was dominant. PARTICIPANTS 317 341 health and social care workers vaccinated between 4 January and 28 February 2021, registered with a general practice using the TPP SystmOne clinical information system in England, and not clinically extremely vulnerable. INTERVENTIONS Vaccination with either BNT162b2 or ChAdOx1 administered as part of the national covid-19 vaccine roll-out. Main outcome measures Recorded SARS-CoV-2 positive test, or covid-19 related attendance at an accident and emergency (A&E) department or hospital admission occurring within 20 weeks of receipt of the first vaccine dose. Results Over the duration of 118 771 person-years of follow-up there were 6962 positive SARS-CoV-2 tests, 282 covid-19 related A&E attendances, and 166 covid-19 related hospital admissions. The cumulative incidence of each outcome was similar for both vaccines during the first 20 weeks after vaccination. The cumulative incidence of recorded SARS-CoV-2 infection 20 weeks after first-dose vaccination with BNT162b2 was 21.7 per 1000 people (95% confidence interval 20.9 to 22.4) and with ChAdOx1 was 23.7 (21.8 to 25.6), representing a difference of 2.04 per 1000 people (0.04 to 4.04). The difference in the cumulative incidence per 1000 people of covid-19 related A&E attendance at 20 weeks was 0.06 per 1000 people (95% CI -0.31 to 0.43). For covid-19 related hospital admission, this difference was 0.11 per 1000 people (-0.22 to 0.44). Conclusions In this cohort of healthcare workers where we would not anticipate vaccine type to be related to health status, we found no substantial differences in the incidence of SARS-CoV-2 infection or covid-19 disease up to 20 weeks after vaccination. Incidence dropped sharply at 3-4 weeks after vaccination, and there were few covid-19 related hospital attendance and admission events after this period. This is in line with expected onset of vaccine induced immunity and suggests strong protection against Alpha variant covid-19 disease for both vaccines in this relatively young and healthy population of healthcare workers.

Background Ghana’s national tuberculosis (TB) prevalence survey conducted in 2013 showed higher than expected TB prevalence indicating that many people with TB were not being identified and treated. Responding to this, we assessed barriers to TB case finding from the perspective, experiences and practices of healthcare workers (HCWs) in rural and urban health facilities in the Volta region, Ghana. Methods We conducted structured clinic observations and in-depth interviews with 12 HCWs (including five trained in TB case detection) in four rural health facilities and a municipal hospital. Interview transcripts and clinic observation data were manually organised, triangulated and analysed into health system-related and HCW-related barriers. Results The key health system barriers identified included lack of TB diagnostic laboratories in rural health facilities and no standard referral system to the municipal hospital for further assessment and TB testing. In addition, missed opportunities for early diagnosis of TB were driven by suboptimal screening practices of HCWs whose application of the national standard operating procedures (SOP) for TB case detection was inconsistent. Further, infection prevention and control measures in health facilities were not implemented as recommended by the SOP. HCW-related barriers were mainly lack of training on case detection guidelines, fear of infection (exacerbated by lack of appropriate personal protective equipment [PPE]) and lack of motivation among HCWs for TB work. Solutions to these barriers suggested by HCWs included provision of at least one diagnostic facility in each sub-municipality, provision of transport subsidies to enable patients’ travel for testing, training of newly-recruited staff on case detection guidelines, and provision of appropriate PPE. Conclusion TB case finding was undermined by few diagnostic facilities; inconsistent referral mechanisms; poor implementation, training and quality control of a screening tool and guidelines; and HCWs fearing infection and not being motivated. We recommend training for and quality monitoring of TB diagnosis and treatment with a focus on patient-centred care, an effective sputum transport system, provision of the TB symptom screening tool and consistent referral pathways from peripheral health facilities.

BACKGROUND:Mortality from COVID-19 shows a strong relationship with age and pre-existing medical conditions, as does mortality from other causes. We aimed to investigate how specific factors are differentially associated with COVID-19 mortality as compared to mortality from causes other than COVID-19. METHODS:Working on behalf of NHS England, we carried out a cohort study within the OpenSAFELY platform. Primary care data from England were linked to national death registrations. We included all adults (aged ≥18 years) in the database on 1st February 2020 and with >1 year of continuous prior registration; the cut-off date for deaths was 9th November 2020. Associations between individual-level characteristics and COVID-19 and non-COVID deaths, classified according to the presence of a COVID-19 code as the underlying cause of death on the death certificate, were estimated by fitting age- and sex-adjusted logistic models for these two outcomes. FINDINGS:17,456,515 individuals were included. 17,063 died from COVID-19 and 134,316 from other causes. Most factors associated with COVID-19 death were similarly associated with non-COVID death, but the magnitudes of association differed. Older age was more strongly associated with COVID-19 death than non-COVID death (e.g. ORs 40.7 [95% CI 37.7-43.8] and 29.6 [28.9-30.3] respectively for ≥80 vs 50-59 years), as was male sex, deprivation, obesity, and some comorbidities. Smoking, history of cancer and chronic liver disease had stronger associations with non-COVID than COVID-19 death. All non-white ethnic groups had higher odds than white of COVID-19 death (OR for Black: 2.20 [1.96-2.47], South Asian: 2.33 [2.16-2.52]), but lower odds than white of non-COVID death (Black: 0.88 [0.83-0.94], South Asian: 0.78 [0.75-0.81]). INTERPRETATION:Similar associations of most individual-level factors with COVID-19 and non-COVID death suggest that COVID-19 largely multiplies existing risks faced by patients, with some notable exceptions. Identifying the unique factors contributing to the excess COVID-19 mortality risk among non-white groups is a priority to inform efforts to reduce deaths from COVID-19. FUNDING:Wellcome, Royal Society, National Institute for Health Research, National Institute for Health Research Oxford Biomedical Research Centre, UK Medical Research Council, Health Data Research UK.