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Abstract Infection with SARS-CoV-2 is associated with an increased risk of arterial and venous thrombotic events, but the implications of vaccination for this increased risk are uncertain. With the approval of NHS England, we quantified associations between COVID-19 diagnosis and cardiovascular diseases in different vaccination and variant eras using linked electronic health records for ~40% of the English population. We defined a ‘pre-vaccination’ cohort (18,210,937 people) in the wild-type/Alpha variant eras (January 2020-June 2021), and ‘vaccinated’ and ‘unvaccinated’ cohorts (13,572,399 and 3,161,485 people respectively) in the Delta variant era (June-December 2021). We showed that the incidence of each arterial thrombotic, venous thrombotic and other cardiovascular outcomes was substantially elevated during weeks 1-4 after COVID-19, compared with before or without COVID-19, but less markedly elevated in time periods beyond week 4. Hazard ratios were higher after hospitalised than non-hospitalised COVID-19 and higher in the pre-vaccination and unvaccinated cohorts than the vaccinated cohort. COVID-19 vaccination reduces the risk of cardiovascular events after COVID-19 infection. People who had COVID-19 before or without being vaccinated are at higher risk of cardiovascular events for at least two years.

Objectives Long-term sickness absence from employment has negative consequences for the economy and can lead to widened health inequalities. Sick notes (also called ‘fit notes’) are issued by general practitioners when a person cannot work for health reasons for more than 7 days. We quantified the sick note rate in people with evidence of COVID-19 in 2020, 2021 and 2022, as an indication of the burden for people recovering from COVID-19.Design Cohort study.Setting With National Health Service (NHS) England approval, we used routine clinical data (primary care, hospital and COVID-19 testing records) within the OpenSAFELY-TPP database.Participants People 18–64 years with a recorded positive test or diagnosis of COVID-19 in 2020 (n=365 421), 2021 (n=1 206 555) or 2022 (n=1 321 313); general population matched in age, sex and region in 2019 (n=3 140 326), 2020 (n=3 439 534), 2021 (n=4 571 469) and 2022 (n=4 818 870); people hospitalised with pneumonia in 2019 (n=29 673).Primary outcome measure Receipt of a sick note in primary care.Results Among people with a positive SARS-CoV-2 test or COVID-19 diagnosis, the sick note rate was 4.88 per 100 person-months (95% CI 4.83 to 4.93) in 2020, 2.66 (95% CI 2.64 to 2.67) in 2021 and 1.73 (95% CI 1.72 to 1.73) in 2022. Compared with the age, sex and region-matched general population, the adjusted HR for receipt of a sick note over the entire follow-up period (up to 10 months) was 4.07 (95% CI 4.02 to 4.12) in 2020 decreasing to 1.57 (95% CI 1.56 to 1.58) in 2022. The HR was highest in the first 30 days postdiagnosis in all years. Among people hospitalised with COVID-19, after adjustment, the sick note rate was lower than in people hospitalised with pneumonia.Conclusions Given the under-recording of postacute COVID-19-related symptoms, these findings contribute a valuable perspective on the long-term effects of COVID-19. Despite likely underestimation of the sick note rate, sick notes were issued more frequently to people with COVID-19 compared with those without, even in an era when most people are vaccinated. Most sick notes occurred in the first 30 days postdiagnosis, but the increased risk several months postdiagnosis may provide further evidence of the long-term impact.

Introduction As nearly two-thirds of women presenting at their first antenatal visit are either overweight or obese in urban South Africa, the preconception period is an opportunity to optimise health and offset transgenerational risk of both obesity and non-communicable diseases. This protocol describes the planned economic evaluation of an individually randomised controlled trial of a complex continuum of care intervention targeting women and children in Soweto, South Africa (Bukhali trial).Methods and analysis The economic evaluation of the Bukhali trial will be conducted as a within-trial analysis from both provider and societal perspectives. Incremental costs and health outcomes of the continuum of care intervention will be compared with standard care. The economic impact on implementing agencies (programme costs), healthcare providers, participants and their households will be estimated. Incremental cost-effectiveness ratios (ICERs) will be calculated in terms of cost per case of child adiposity at age years averted. Additionally, ICERs will also be reported in terms of cost per quality-adjusted life year gained. If Bukhali demonstrates effectiveness, we will employ a decision analytical model to examine the cost-effectiveness of the intervention over a child’s lifetime. A Markov model will be used to estimate long-term health benefits, healthcare costs and cost-effectiveness. Probabilistic sensitivity analyses will be conducted to explore uncertainty and ensure robust results. An analysis will be conducted to assess the equity impact of the intervention, by comparing intervention impact within quintiles of socioeconomic status.Ethics and dissemination The Bukhali trial economic evaluation has ethical approval from the Human Ethics Research Committee of the University of the Witwatersrand, Johannesburg, South Africa (M240162). The results of the economic evaluation will be disseminated in a peer-reviewed journal and presented at a relevant international conference.Trial registration number Pan African Clinical Trials Registry (PACTR201903750173871; https://pactr.samrc.ac.za).

Introduction Approximately 250 million children under 5 years of age are at risk of poor development in low-income and middle-income countries. However, existing early childhood development (ECD) interventions can be expensive, labour intensive and challenging to deliver at scale. Mass media may offer an alternative approach to ECD intervention. This protocol describes the planned economic evaluation of a cluster-randomised controlled trial of a radio campaign promoting responsive caregiving and opportunities for early learning during the first 3 years of life in rural Burkina Faso (SUNRISE trial).Methods and analysis The economic evaluation of the SUNRISE trial will be conducted as a within-trial analysis from the provider’s perspective. Incremental costs and health outcomes of the radio campaign will be compared with standard broadcasting (ie, ‘do nothing’ comparator). All costs associated with creating and broadcasting the radio campaign during intervention start-up and implementation will be captured. The cost per child under 3 years old reached by the intervention will be calculated. Incremental cost-effectiveness ratios will be calculated for the trial’s primary outcome (ie, incremental cost per SD of cognitive gain). A cost-consequence analysis will also be presented, whereby all relevant costs and outcomes are tabulated. Finally, an analysis will be conducted to assess the equity impact of the intervention.Ethics and dissemination The SUNRISE trial has ethical approval from the ethics committees of the Ministry of Health, Burkina Faso, University College London and the London School of Hygiene and Tropical Medicine. The results of the economic evaluation will be disseminated in a peer-reviewed journal and presented at a relevant international conference.Trial registration number The SUNRISE trial was registered with ClinicalTrials.gov on 19 April 2019 (identifier: NCT05335395).

Introduction Evidence suggests that responsive caregiving and early learning activities positively impact developmental outcomes, with positive effects throughout the life course. Early childhood development interventions should align with local values, beliefs and resources but there has been little research of caregiver beliefs and perspectives on development and learning, especially in sub-Saharan Africa. This qualitative study explored norms, beliefs, practices and aspirations around child development of caregivers of young children in rural Burkina Faso.Methods We conducted 32 in-depth interviews with mothers and fathers of young children and 24 focus group discussions with mothers, fathers and grandmothers, which included trying behaviours and reporting on experiences. The research informed the development of Scaling Up Nurturing Care, a Radio Intervention to Stimulate Early Childhood Development (SUNRISE), an early child development radio intervention.Results Caregivers described a process of ‘awakening’, through which children become aware of themselves and the world around them.Perceptions of the timing of awakening varied, but the ability to learn was thought to increase as children became older and more awake. Consequently, talking and playing with babies and younger children were perceived to have little developmental impact. Caregivers said children’s interactions with them, alongside God-given intelligence, was believed to impact later behaviour and development. Caregivers felt their role in helping their children achieve later in life was to pay for education, save money, provide advice and be good role models. Interaction and learning activities were not specifically mentioned. Caregivers who trialled interaction and learning activities reported positive experiences for themselves and their child, but interactions were often caregiver led and directive and play was often physical. Key barriers to carrying out the behaviours were poverty and a lack of time.Conclusions Exploring early childhood beliefs and practices can reveal important sociocultural beliefs which, if incorporated into programme planning and implementation, could help achieve more impactful, acceptable and equitable programmes.Trial registration number NCT05335395.

Abstract Background There has been a growing interest in the association between maternal levels of vitamin D during pregnancy and offspring autism. However, whether any associations reflect causal effects is still inconclusive. Methods We used data from a UK-based pregnancy cohort study (Avon Longitudinal Study of Parents and Children) comprising 7689 births between 1991 and 1992 with maternal blood vitamin D levels recorded during pregnancy and at least one recorded outcome measure, including autism diagnosis and autism-associated traits. The association between each outcome with seasonal and gestational age-adjusted maternal serum 25-hydroxyvitamin D during pregnancy was estimated using confounder-adjusted regression models. Multiple imputation was used to account for missing data, and restricted cubic splines were used to investigate nonlinear associations. Mendelian randomization was used to strengthen causal inference. Results No strong evidence of an association between maternal serum 25-hydroxyvitamin D during pregnancy and any offspring autism-associated outcome was found using multivariable regression analysis (autism diagnosis: adjusted OR = 0.98, 95% CI = 0.90–1.06), including with multiple imputation (autism diagnosis: adjusted OR = 0.99, 95% CI = 0.93–1.06), and no evidence of a causal effect was suggested by Mendelian randomization (autism diagnosis: causal OR = 1.08, 95% CI = 0.46–2.55). Some evidence of increased odds of autism-associated traits at lower levels of maternal serum 25-hydroxyvitamin D was found using spline analysis. Limitations Our study was potentially limited by low power, particularly for diagnosed autism cases as an outcome. The cohort may not have captured the extreme lows of the distribution of serum 25-hydroxyvitamin D, and our analyses may have been biased by residual confounding and missing data. Conclusions The present study found no strong evidence of a causal link between maternal vitamin D levels in pregnancy and offspring diagnosis or traits of autism.

Summary: Background: The COVID-19 pandemic disrupted healthcare and may have impacted ethnic inequalities in healthcare. We aimed to describe the impact of pandemic-related disruption on ethnic differences in clinical monitoring and hospital admissions for non-COVID conditions in England. Methods: In this population-based, observational cohort study we used primary care electronic health record data with linkage to hospital episode statistics data and mortality data within OpenSAFELY, a data analytics platform created, with approval of NHS England, to address urgent COVID-19 research questions. We included adults aged 18 years and over registered with a TPP practice between March 1, 2018, and April 30, 2022. We excluded those with missing age, sex, geographic region, or Index of Multiple Deprivation. We grouped ethnicity (exposure), into five categories: White, Asian, Black, Other, and Mixed. We used interrupted time-series regression to estimate ethnic differences in clinical monitoring frequency (blood pressure and Hba1c measurements, chronic obstructive pulmonary disease and asthma annual reviews) before and after March 23, 2020. We used multivariable Cox regression to quantify ethnic differences in hospitalisations related to diabetes, cardiovascular disease, respiratory disease, and mental health before and after March 23, 2020. Findings: Of 33,510,937 registered with a GP as of 1st January 2020, 19,064,019 were adults, alive and registered for at least 3 months, 3,010,751 met the exclusion criteria and 1,122,912 were missing ethnicity. This resulted in 14,930,356 adults with known ethnicity (92% of sample): 86.6% were White, 7.3% Asian, 2.6% Black, 1.4% Mixed ethnicity, and 2.2% Other ethnicities. Clinical monitoring did not return to pre-pandemic levels for any ethnic group. Ethnic differences were apparent pre-pandemic, except for diabetes monitoring, and remained unchanged, except for blood pressure monitoring in those with mental health conditions where differences narrowed during the pandemic. For those of Black ethnicity, there were seven additional admissions for diabetic ketoacidosis per month during the pandemic, and relative ethnic differences narrowed during the pandemic compared to the White ethnic group (Pre-pandemic hazard ratio (HR): 0.50, 95% confidence interval (CI) 0.41, 0.60, Pandemic HR: 0.75, 95% CI: 0.65, 0.87). There was increased admissions for heart failure during the pandemic for all ethnic groups, though highest in those of White ethnicity (heart failure risk difference: 5.4). Relatively, ethnic differences narrowed for heart failure admission in those of Asian (Pre-pandemic HR 1.56, 95% CI 1.49, 1.64, Pandemic HR 1.24, 95% CI 1.19, 1.29) and Black ethnicity (Pre-pandemic HR 1.41, 95% CI: 1.30, 1.53, Pandemic HR: 1.16, 95% CI 1.09, 1.25) compared with White ethnicity. For other outcomes the pandemic had minimal impact on ethnic differences. Interpretation: Our study suggests that ethnic differences in clinical monitoring and hospitalisations remained largely unchanged during the pandemic for most conditions. Key exceptions were hospitalisations for diabetic ketoacidosis and heart failure, which warrant further investigation to understand the causes. Funding: LSHTM COVID-19 Response Grant (DONAT15912).

High rates of drug-resistant tuberculosis (DR-TB) continue to threaten public health, especially in Eastern Europe. Costs for treating DR-TB are substantially higher than treating drug-susceptible TB, and higher yet if DR-TB services are delivered in hospital. The WHO recommends that multidrug-resistant (MDR) TB be treated using mainly ambulatory care, shown to have non-inferior health outcomes, however, there has been a delay to transition away from hospital-focused MDR-TB care in certain Eastern European countries. Allocative efficiency analyses were conducted for three countries in Eastern Europe, Belarus, the Republic of Moldova, and Romania, to minimise a combination of TB incidence, prevalence, and mortality by 2035. A primary focus of these studies was to determine the health benefits and financial savings that could be realised if DR-TB service delivery shifted from hospital-focused to ambulatory care. Here we provide a comprehensive assessment of findings from these studies to demonstrate the collective benefit of transitioning from hospital-focused to ambulatory TB care, and to address common regional considerations. We highlight that transitioning from hospital-focused to ambulatory TB care could reduce treatment costs by 20% in Romania, 24% in Moldova, and by as much as 40% in Belarus or almost 35 million US dollars across these three countries by 2035 without affecting quality of care. Improved TB outcomes could be achieved, however, without additional spending by reinvesting these savings in higher-impact TB diagnosis and more efficacious DR-TB treatment regimens. We found commonalities in the large portion of TB cases treated in hospital across these three regional countries, and similar obstacles to transitioning to ambulatory care. National governments in the Eastern European region should examine barriers delaying adoption of ambulatory DR-TB care and consider lost opportunities caused by delays in switching to more efficient treatment modes.

An estimated 2.4 million newborn infants died in 2020, 80% of them in sub-Saharan Africa and South Asia. To achieve the Sustainable Development Target for neonatal mortality reduction, countries with high mortality need to implement evidence-based, cost-effective interventions at scale. Our study aimed to estimate the cost, cost-effectiveness, and benefit-cost ratio of a participatory women's groups intervention scaled up by the public health system in Jharkhand, eastern India. The intervention was evaluated through a pragmatic cluster non-randomised controlled trial in six districts. We estimated the cost of the intervention at scale from a provider perspective, with a 42-month time horizon for 20 districts. We estimated costs using a combination of top-down and bottom-up approaches. All costs were adjusted for inflation, discounted at 3% per year, and converted to 2020 International Dollars (INT$). Incremental cost-effectiveness ratios (ICERs) were estimated using extrapolated effect sizes for the impact of the intervention in 20 districts, in terms of cost per neonatal deaths averted and cost per life year saved. We assessed the impact of uncertainty on results through one-way and probabilistic sensitivity analyses. We also estimated benefit-cost ratio using a benefit transfer approach. Total intervention costs for 20 districts were INT$ 15,017,396. The intervention covered an estimated 1.6 million livebirths across 20 districts, translating to INT$ 9.4 per livebirth covered. ICERs were estimated at INT$ 1,272 per neonatal death averted or INT$ 41 per life year saved. Net benefit estimates ranged from INT$ 1,046 million to INT$ 3,254 million, and benefit-cost ratios from 71 to 218. Our study suggests that participatory women's groups scaled up by the Indian public health system were highly cost-effective in improving neonatal survival and had a very favourable return on investment. The intervention can be scaled up in similar settings within India and other countries.

BackgroundSepsis is characterised by dysregulated, life-threatening immune responses, which are thought to be driven by cytokines such as interleukin 6 (IL-6). Genetic variants in IL6R known to down-regulate IL-6 signalling are associated with improved Coronavirus Disease 2019 (COVID-19) outcomes, a finding later confirmed in randomised trials of IL-6 receptor antagonists (IL6RAs). We hypothesised that blockade of IL6R could also improve outcomes in sepsis.Methods and findingsWe performed a Mendelian randomisation (MR) analysis using single nucleotide polymorphisms (SNPs) in and near IL6R to evaluate the likely causal effects of IL6R blockade on sepsis (primary outcome), sepsis severity, other infections, and COVID-19 (secondary outcomes). We weighted SNPs by their effect on CRP and combined results across them in inverse variance weighted meta-analysis, proxying the effect of IL6RA. Our outcomes were measured in UK Biobank, FinnGen, the COVID-19 Host Genetics Initiative (HGI), and the GenOSept and GainS consortium. We performed several sensitivity analyses to test assumptions of our methods, including utilising variants around CRP and gp130 in a similar analysis. In the UK Biobank cohort (N = 486,484, including 11,643 with sepsis), IL6R blockade was associated with a decreased risk of our primary outcome, sepsis (odds ratio (OR) = 0.80; 95% confidence interval (CI) 0.66 to 0.96, per unit of natural log-transformed CRP decrease). The size of this effect increased with severity, with larger effects on 28-day sepsis mortality (OR = 0.74; 95% CI 0.47 to 1.15); critical care admission with sepsis (OR = 0.48, 95% CI 0.30 to 0.78) and critical care death with sepsis (OR = 0.37, 95% CI 0.14 to 0.98). Similar associations were seen with severe respiratory infection: OR for pneumonia in critical care 0.69 (95% CI 0.49 to 0.97) and for sepsis survival in critical care (OR = 0.22; 95% CI 0.04 to 1.31) in the GainS and GenOSept consortium, although this result had a large degree of imprecision. We also confirm the previously reported protective effect of IL6R blockade on severe COVID-19 (OR = 0.69, 95% CI 0.57 to 0.84) in the COVID-19 HGI, which was of similar magnitude to that seen in sepsis. Sensitivity analyses did not alter our primary results. These results are subject to the limitations and assumptions of MR, which in this case reflects interpretation of these SNP effects as causally acting through blockade of IL6R, and reflect lifetime exposure to IL6R blockade, rather than the effect of therapeutic IL6R blockade.ConclusionsIL6R blockade is causally associated with reduced incidence of sepsis. Similar but imprecisely estimated results supported a causal effect also on sepsis related mortality and critical care admission with sepsis. These effects are comparable in size to the effect seen in severe COVID-19, where IL-6 receptor antagonists were shown to improve survival. These data suggest that a randomised trial of IL-6 receptor antagonists in sepsis should be considered.

Summary: Background: The direct effects of general adiposity (body mass index (BMI)) and central adiposity (waist-to-hip-ratio (WHR)) on circulating lipoproteins, lipids, and metabolites are unknown. Methods: We used new metabolic data from UK Biobank (N=109,532, a five-fold higher N over previous studies). EDTA-plasma was used to quantify 249 traits with nuclear-magnetic-resonance spectroscopy including subclass-specific lipoprotein concentrations and lipid content, plus pre-glycemic and inflammatory metabolites. We used univariable and multivariable two-stage least-squares regression models with genetic risk scores for BMI and WHR as instruments to estimate total (unadjusted) and direct (mutually-adjusted) effects of BMI and WHR on metabolic traits; plus effects on statin use and interaction by sex, statin use, and age (proxy for medication use). Findings: Higher BMI decreased apolipoprotein B and low-density lipoprotein cholesterol (LDL-C) before and after WHR-adjustment, whilst BMI increased triglycerides only before WHR-adjustment. These effects of WHR were larger and BMI-independent. Direct effects differed markedly by sex, e.g., triglycerides increased only with BMI among men, and only with WHR among women. Adiposity measures increased statin use and showed metabolic effects which differed by statin use and age. Among the youngest (38-53y, statins-5%), BMI and WHR (per-SD) increased LDL-C (total effects: 0.04-SD, 95%CI=-0.01,0.08 and 0.10-SD, 95%CI=0.02,0.17 respectively), but only WHR directly. Among the oldest (63-73y, statins-29%), BMI and WHR directly lowered LDL-C (-0.19-SD, 95%CI=-0.27,-0.11 and -0.05-SD, 95%CI=-0.16,0.06 respectively). Interpretation: Excess adiposity likely raises atherogenic lipid and metabolite levels exclusively via adiposity stored centrally, particularly among women. Apparent effects of adiposity on lowering LDL-C are likely explained by an effect of adiposity on statin use. Funding: UK Medical Research Council; British Heart Foundation; Novo Nordisk; National Institute for Health Research; Wellcome Trust; Cancer Research UK

Objectives We report the results of a mixed-methods process evaluation that aimed to provide insight on the Afya conditional cash transfer (CCT) intervention fidelity and acceptability.Intervention, setting and participants The Afya CCT intervention aimed to retain women in the continuum of maternal healthcare including antenatal care (ANC), delivery at facility and postnatal care (PNC) in Siaya County, Kenya. The cash transfers were delivered using an electronic card reader system at health facilities. It was evaluated in a trial that randomised 48 health facilities to intervention or control, and which found modest increases in attendance for ANC and immunisation appointments, but little effect on delivery at facility and PNC visits.Design A mixed-methods process evaluation was conducted. We used the Afya electronic portal with recorded visits and payments, and reports on use of the electronic card reader system from each healthcare facility to assess fidelity. Focus group interviews with participants (N=5) and one-on-one interviews with participants (N=10) and healthcare staff (N=15) were conducted to assess the acceptability of the intervention. Data analyses were conducted using descriptive statistics and qualitative content analysis, as appropriate.Results Delivery of the Afya CCT intervention was negatively affected by problems with the electronic card reader system and a decrease in adherence to its use over the intervention period by healthcare staff, resulting in low implementation fidelity. Acceptability of cash transfers in the form of mobile transfers was high for participants. Initially, the intervention was acceptable to healthcare staff, especially with respect to improvements in attaining facility targets for ANC visits. However, acceptability was negatively affected by significant delays linked to the card reader system.Conclusions The findings highlight operational challenges in delivering the Afya CCT intervention using the Afya electronic card reader system, and the need for greater technology readiness before further scale-up.Trial registration number NCT03021070.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

HIV/AIDS remains a leading global cause of disease burden, especially in low- and middle-income countries (LMICs). In 2020, more than 80% of all people living with HIV (PLHIV) lived in LMICs. While progress has been made in extending coverage of HIV/AIDS services, only 66% of all PLHIV were virally suppressed at the end of 2020. In addition to more resources, the efficiency of spending is key to accelerating progress towards global 2030 targets for HIV/AIDs, including viral load suppression. This study aims to estimate the efficiency of HIV/AIDS spending across 78 countries. We employed a data envelopment analysis (DEA) and a truncated regression to estimate the technical efficiency of 78 countries, mostly low- and middle-income, in delivering HIV/AIDS services from 2010 to 2018. Publicly available data informed the model. We considered national HIV/AIDS spending as the DEA input, and prevention of mother to child transmission (PMTCT) and antiretroviral treatment (ART) as outputs. The model was adjusted by independent variables to account for country characteristics and investigate associations with technical efficiency. On average, there has been substantial improvement in technical efficiency over time. Spending was converted into outputs almost twice as efficiently in 2018 (81.8%; 95% CI = 77.64, 85.99) compared with 2010 (47.5%; 95% CI = 43.4, 51.6). Average technical efficiency was 66.9% between 2010 and 2018, in other words 33.1% more outputs could have been produced relative to existing levels for the same amount of spending. There is also some variation between WHO/UNAIDS regions. European and Eastern and Southern Africa regions converted spending into outputs most efficiently between 2010 and 2018. Rule of Law, Gross National Income, Human Development Index, HIV prevalence and out-of-pocket expenditures were all significantly associated with efficiency scores. The technical efficiency of HIV investments has improved over time. However, there remains scope to substantially increase HIV/AIDS spending efficiency and improve progress towards 2030 global targets for HIV/AIDS. Given that many of the most efficient countries did not meet 2020 global HIV targets, our study supports the WHO call for additional investment in HIV/AIDS prevention and control to meet the 2030 HIV/AIDS and eradication of the AIDS epidemic.

Initial global-level estimates reported in June 2020 by the World Health Organization suggested that levels of disruption to TB service delivery could be as high as 25%-50% and result in an additional 6·3 million cases of tuberculosis (TB) and an additional 1·4 million TB-related deaths attributable to COVID-19 between 2020 and 2025. Quarterly epidemiological estimates and programmatic TB data capturing disruption levels to each TB service were collected by National TB Programmes in Indonesia, Kyrgyzstan, Malawi, Mozambique, and Peru. Data from 2019, for a pre-COVID-19 baseline, and throughout 2020, together with the NTP's COVID-19 response plans, were used within Optima TB models to project TB incidence and deaths over five years because of COVID-19-related disruptions, and the extent to which those impacts may be mitigated through proposed catch-up strategies in each country. Countries reported disruptions of up to 64% to demand-driven TB diagnosis. However, TB service availability disruptions were shorter and less severe, with TB treatment experiencing levels of disruption of up to 21%. We predicted that under the worse-case scenario cumulative new latent TB infections, new active TB infections, and TB-related deaths could increase by up to 23%, 11%, and 20%, respectively, by 2024. However, three of the five countries were on track to mitigate these increases to 3% or less by maintaining TB services in 2021 and 2022 and by implementing proposed catch-up strategies. Indonesia was already experiencing the worse-case scenario, which could lead to 270,000 additional active TB infections and 36,000 additional TB-related deaths by the end of 2024. The COVID-19 pandemic is projected to negatively affect progress towards 2035 End TB targets, especially in countries already off-track. Findings highlight both successful TB service delivery adaptions in 2020 and the need to proactively maintain TB service availability despite potential future waves of more transmissible COVID-19 variants.

There is limited evidence on the cost and cost-effectiveness of cash transfer programmes to improve maternal and child health in Kenya and other sub-Saharan African countries. This article presents the economic evaluation results of the Afya trial, assessing the costs, cost-effectiveness and equity impact of a demand-side financing intervention that promotes utilisation of maternal health services in rural Kenya. The cost of implementing the Afya intervention was estimated from a provider perspective. Cost data were collected prospectively from all implementing and non-implementing partners, and from health service providers. Cost-efficiency was analysed using cost-transfer ratios and cost per mother enrolled into the intervention. Cost-effectiveness was assessed as cost per additional eligible antenatal care visit as a result of the intervention, when compared with standard care. The equity impact of the intervention was also assessed using a multidimensional poverty index (MPI). Programme cost per mother enrolled was International (INT)$313 of which INT$ 92 consisted of direct transfer payments, suggesting a cost transfer ratio of 2.4. Direct healthcare utilisation costs reflected a small proportion of total provider costs, amounting to INT$ 21,756. The total provider cost of the Afya intervention was INT$808,942. The provider cost per additional eligible ANC visit was INT$1,035. This is substantially higher than estimated annual health expenditure per capita at the county level of $INT61. MPI estimates suggest around 27.4% of participant households were multidimensionally poor. MPI quintiles did not significantly modify the intervention effect, suggesting the impact of the intervention did not differ by socioeconomic status. Based on the available evidence, it is not possible to conclude whether the Afya intervention was cost-effective. A simple comparison with current health expenditure in Siaya county suggests that the intervention as implemented is likely to be unaffordable. Consideration needs to be given to strengthening the supply-side of the cash transfer intervention before replication or uptake at scale.

Summary: Background: Long-term care facilities (LTCFs) have reported high SARS-CoV-2 infection rates and related mortality, but the proportion of infected people among those who have survived, and duration of the antibody response to natural infection, is unknown. We determined the prevalence and stability of nucleocapsid antibodies (the standard assay for detection of previous infection) in staff and residents in LTCFs in England. Methods: This was a prospective cohort study of residents 65 years or older and of staff 65 years or younger in 201 LTCFs in England between March 1, 2020, and May 7, 2021. Participants were linked to a unique pseudo-identifier based on their UK National Health Service identification number. Serial blood samples were tested for IgG antibodies against SARS-CoV-2 nucleocapsid protein using the Abbott ARCHITECT i-system (Abbott, Maidenhead, UK) immunoassay. Primary endpoints were prevalence and cumulative incidence of antibody positivity, which were weighted to the LTCF population. Incidence rate of loss of antibodies (seroreversion) was estimated from Kaplan-Meier curves. Findings: 9488 samples were included, 8636 (91·0%) of which could be individually linked to 1434 residents and 3288 staff members. The cumulative incidence of nucleocapsid seropositivity was 34·6% (29·6–40·0) in residents and 26·1% (23·0–29·5) in staff over 11 months. 239 (38·6%) residents and 503 women (81·3%) were included in the antibody-waning analysis, and median follow-up was 149 days (IQR 107–169). The incidence rate of seroreversion was 2·1 per 1000 person-days at risk, and median time to reversion was 242·5 days. Interpretation: At least a quarter of staff and a third of surviving residents were infected with SAR-CoV-2 during the first two waves of the pandemic in England. Nucleocapsid-specific antibodies often become undetectable within the first year following infection, which is likely to lead to marked underestimation of the true proportion of people with previous infection. Given that natural infection might act to boost vaccine responses, better assays to identify natural infection should be developed. Funding: UK Government Department of Health and Social Care.

Approximately 85% of tuberculosis (TB) related deaths occur in low- and middle-income countries where health resources are scarce. Effective priority setting is required to maximise the impact of limited budgets. The Optima TB tool has been developed to support analytical capacity and inform evidence-based priority setting processes for TB health benefits package design. This paper outlines the Optima TB framework and how it was applied in Belarus, an upper-middle income country in Eastern Europe with a relatively high burden of TB. Optima TB is a population-based disease transmission model, with programmatic cost functions and an optimisation algorithm. Modelled populations include age-differentiated general populations and higher-risk populations such as people living with HIV. Populations and prospective interventions are defined in consultation with local stakeholders. In partnership with the latter, demographic, epidemiological, programmatic, as well as cost and spending data for these populations and interventions are then collated. An optimisation analysis of TB spending was conducted in Belarus, using program objectives and constraints defined in collaboration with local stakeholders, which included experts, decision makers, funders and organisations involved in service delivery, support and technical assistance. These analyses show that it is possible to improve health impact by redistributing current TB spending in Belarus. Specifically, shifting funding from inpatient- to outpatient-focused care models, and from mass screening to active case finding strategies, could reduce TB prevalence and mortality by up to 45% and 50%, respectively, by 2035. In addition, an optimised allocation of TB spending could lead to a reduction in drug-resistant TB infections by 40% over this period. This would support progress towards national TB targets without additional financial resources. The case study in Belarus demonstrates how reallocations of spending across existing and new interventions could have a substantial impact on TB outcomes. This highlights the potential for Optima TB and similar modelling tools to support evidence-based priority setting.

Summary: Background: SARS-CoV-2 infection represents a major challenge for long-term care facilities (LTCFs) and many residents and staff are seropositive following persistent outbreaks. We aimed to investigate the association between the SARS-CoV-2 antibody status at baseline and subsequent infection in this population. Methods: We did a prospective cohort study of SARS-CoV-2 infection in staff (aged 65 years) at 100 LTCFs in England between Oct 1, 2020, and Feb 1, 2021. Blood samples were collected between June and November, 2020, at baseline, and 2 and 4 months thereafter and tested for IgG antibodies to SARS-CoV-2 nucleocapsid and spike proteins. PCR testing for SARS-CoV-2 was done weekly in staff and monthly in residents. Cox regression was used to estimate hazard ratios (HRs) of a PCR-positive test by baseline antibody status, adjusted for age and sex, and stratified by LTCF. Findings: 682 residents from 86 LCTFs and 1429 staff members from 97 LTCFs met study inclusion criteria. At baseline, IgG antibodies to nucleocapsid were detected in 226 (33%) of 682 residents and 408 (29%) of 1429 staff members. 93 (20%) of 456 residents who were antibody-negative at baseline had a PCR-positive test (infection rate 0·054 per month at risk) compared with four (2%) of 226 residents who were antibody-positive at baseline (0·007 per month at risk). 111 (11%) of 1021 staff members who were antibody-negative at baseline had PCR-positive tests (0·042 per month at risk) compared with ten (2%) of 408 staff members who were antibody-positive staff at baseline (0·009 per month at risk). The risk of PCR-positive infection was higher for residents who were antibody-negative at baseline than residents who were antibody-positive at baseline (adjusted HR [aHR] 0·15, 95% CI 0·05–0·44, p=0·0006), and the risk of a PCR-positive infection was also higher for staff who were antibody-negative at baseline compared with staff who were antibody-positive at baseline (aHR 0·39, 0·19–0·82; p=0·012). 12 of 14 reinfected participants had available data on symptoms, and 11 of these participants were symptomatic. Antibody titres to spike and nucleocapsid proteins were comparable in PCR-positive and PCR-negative cases. Interpretation: The presence of IgG antibodies to nucleocapsid protein was associated with substantially reduced risk of reinfection in staff and residents for up to 10 months after primary infection. Funding: UK Government Department of Health and Social Care.

Abstract Background Undernutrition causes around 3.1 million child deaths annually, around 45% of all child deaths. India has one of the highest proportions of maternal and child undernutrition globally. To accelerate reductions in undernutrition, nutrition-specific interventions need to be coupled with nutrition-sensitive programmes that tackle the underlying causes of undernutrition. This paper describes the planned economic evaluation of the UPAVAN trial, a four-arm, cluster randomised controlled trial that tests the nutritional and agricultural impacts of an innovative agriculture extension platform of women’s groups viewing videos on nutrition-sensitive agriculture practices, coupled with a nutrition-specific behaviour-change intervention of videos on nutrition, and a participatory learning and action approach. Methods The economic evaluation of the UPAVAN interventions will be conducted from a societal perspective, taking into account all costs incurred by the implementing agency (programme costs), community and health care providers, and participants and their households, and all measurable outcomes associated with the interventions. All direct and indirect costs, including time costs and donated goods, will be estimated. The economic evaluation will take the form of a cost-consequence analysis, comparing incremental costs and incremental changes in the outcomes of the interventions, compared with the status quo. Robustness of the results will be assessed through a series of sensitivity analyses. In addition, an analysis of the equity impact of the interventions will be conducted. Discussion Evidence on the cost and cost-effectiveness of nutrition-sensitive agriculture interventions is scarce. This limits understanding of the costs of rolling out or scaling up programs. The findings of this economic evaluation will provide useful information for different multisectoral stakeholders involved in the planning and implementation of nutrition-sensitive agriculture programmes. Trial registration ISRCTN65922679. Registered on 21 December 2016

Abstract Background Antenatal care (ANC), facility delivery and postnatal care (PNC) are proven to reduce maternal and child mortality and morbidity in high-burden settings. However, few pregnant rural women use these services sufficiently. This study aims to assess the impact, cost-effectiveness and scalability of conditional cash transfers to promote increased contact between pregnant women or women who have recently given birth and the formal healthcare system in Kenya. Methods The intervention tested is a conditional cash transfer to women for ANC health visits, a facility birth and PNC visits until their newborn baby reaches 1 year of age. The study is a cluster randomized controlled trial in Siaya County, Kenya. The trial clusters are 48 randomly selected public primary health facilities, 24 of which are in the intervention arm of the study and 24 in the control arm. The unit of randomization is the health facility. A target sample of 7200 study participants comprises pregnant women identified and recruited at their first ANC visit over a 12-month recruitment period and their subsequent newborns. All pregnant women attending one of the selected trial facilities for their first ANC visit during the recruitment period are eligible for the trial and invited to participate. Enrolled mothers are followed up at all health visits during their pregnancy, at facility delivery and for a number of visits after delivery. They are also contacted at three additional time points after enrolling in the study: 5–10days after enrolment, 6 months after the expected delivery date and 12 27 months after birth. If they have not delivered in a facility, there is an additional follow-up 2 wees after the expected due date. The impact of the conditional cash transfers on maternal healthcare services and utilization will be measured by the trial’s primary outcomes: the proportion of all eligible ANC visits made during pregnancy, delivery at a health facility, the proportion of all eligible PNC visits attended, the proportion of referrals attended during the pregnancy and the postnatal period, and the proportion of eligible child immunization appointments attended. Secondary outcomes include; health screening and infection control, live birth, maternal and child survival 48 h after delivery, exclusive breastfeeding, post-partum contraceptive use and maternal and newborn morbidity. Data sources for the measurement of outcomes include routine health records, an electronic card-reader system and telephone surveys and focus group discussions. A full economic evaluation will be conducted to assess the cost of delivery and cost effectiveness of the intervention and the benefit incidence and equity impact of trial activities and outcomes. Discussion This trial will contribute to evidence on the effectiveness and cost-effectiveness of conditional cash transfers in facilitating health visits and promoting maternal and child health in rural Kenya and in other comparable contexts. Trial registration ClinicalTrials.gov, NCT03021070. Registered on 13 January 2017.

Objectives To investigate how the COVID-19 pandemic affected the number of people aged 50+ years presenting to primary care with features that could potentially indicate cancer, and to explore how reporting differed by patient characteristics and in face-to-face vs remote consultations.Design, setting and participants A retrospective cohort study of general practitioner (GP), nurse and paramedic primary care consultations in 21 practices in South-West England covering 123 947 patients. The models compared potential cancer indicators reported in April–July 2019 with April–July 2020.Main outcome measures Potential indicators of cancer were identified using code lists for symptoms, signs, test results and diagnoses listed in the National Institute for Health and Care Excellence suspected cancer referral guidance (NG12).Results During April–July 2019, 17% of registered patients aged 50+ years reported a potential cancer indicator in a consultation with a GP or nurse. During April–July 2020, this reduced to 11% (incidence rate ratio (IRR) 0.64, 95% CI 0.62 to 0.67, p

Global infection and mortality rates from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) are disproportionately high in certain populations, including amongst older people. Care home residents are frequently exposed to infection due to contact with staff and other residents, and are highly susceptible to infection due to their age and co-morbidity. In England, official statistics suggest that at least 25% of all deaths in care home residents since the start of pandemic are linked to coronavirus disease 2019 (COVID-19), but limited testing for SARS-CoV-2 early in the pandemic means estimates of the true burden of disease are lacking. Additionally, little is known about patterns of transmission between care homes, the community and hospitals, or the relationship between infection and immunity in care home staff and residents. The VIVALDI study plans to address these questions. VIVALDI is a prospective cohort study aiming to recruit 6,500 staff and 5000 residents from 105 care homes across England. Successive rounds of testing for infection will be performed over a period of 12 months. Nasopharyngeal swabs will detect evidence of viral RNA and therefore active infection (accompanied by collection of data on symptoms), whereas blood tests will detect antibodies and evidence of cellular immunity to SARS-CoV-2. Whole genome sequencing of viral isolates to investigate pathways of transmission of infection is planned in collaboration with the COVID-19 Genomics UK Consortium. Qualitative interviews with care home staff will investigate the impact of the pandemic on ways of working and how test results influence infection control practices and behaviours. Data from residents and staff will be linked to national datasets on hospital admissions, antibody and PCR test results, mortality and care home characteristics. Data generated will support national public health efforts to prevent transmission of COVID-19 and protect care home staff and residents from infection. Protocol registration: ISRCTN14447421 05/06/2020

BackgroundPsoriasis is a common inflammatory skin disease that has been reported to be associated with obesity. We aimed to investigate a possible causal relationship between body mass index (BMI) and psoriasis.Methods and findingsFollowing a review of published epidemiological evidence of the association between obesity and psoriasis, mendelian randomization (MR) was used to test for a causal relationship with BMI. We used a genetic instrument comprising 97 single-nucleotide polymorphisms (SNPs) associated with BMI as a proxy for BMI (expected to be much less confounded than measured BMI). One-sample MR was conducted using individual-level data (396,495 individuals) from the UK Biobank and the Nord-Trøndelag Health Study (HUNT), Norway. Two-sample MR was performed with summary-level data (356,926 individuals) from published BMI and psoriasis genome-wide association studies (GWASs). The one-sample and two-sample MR estimates were meta-analysed using a fixed-effect model. To test for a potential reverse causal effect, MR analysis with genetic instruments comprising variants from recent genome-wide analyses for psoriasis were used to test whether genetic risk for this skin disease has a causal effect on BMI. Published observational data showed an association of higher BMI with psoriasis. A mean difference in BMI of 1.26 kg/m2 (95% CI 1.02-1.51) between psoriasis cases and controls was observed in adults, while a 1.55 kg/m2 mean difference (95% CI 1.13-1.98) was observed in children. The observational association was confirmed in UK Biobank and HUNT data sets. Overall, a 1 kg/m2 increase in BMI was associated with 4% higher odds of psoriasis (meta-analysis odds ratio [OR] = 1.04; 95% CI 1.03-1.04; P = 1.73 × 10(-60)). MR analyses provided evidence that higher BMI causally increases the odds of psoriasis (by 9% per 1 unit increase in BMI; OR = 1.09 (1.06-1.12) per 1 kg/m2; P = 4.67 × 10(-9)). In contrast, MR estimates gave little support to a possible causal effect of psoriasis genetic risk on BMI (0.004 kg/m2 change in BMI per doubling odds of psoriasis (-0.003 to 0.011). Limitations of our study include possible misreporting of psoriasis by patients, as well as potential misdiagnosis by clinicians. In addition, there is also limited ethnic variation in the cohorts studied.ConclusionsOur study, using genetic variants as instrumental variables for BMI, provides evidence that higher BMI leads to a higher risk of psoriasis. This supports the prioritization of therapies and lifestyle interventions aimed at controlling weight for the prevention or treatment of this common skin disease. Mechanistic studies are required to improve understanding of this relationship.

BackgroundIt has been suggested that greater maternal adiposity during pregnancy affects lifelong risk of offspring fatness via intrauterine mechanisms. Our aim was to use Mendelian randomisation (MR) to investigate the causal effect of intrauterine exposure to greater maternal body mass index (BMI) on offspring BMI and fat mass from childhood to early adulthood.Methods and findingsWe used maternal genetic variants as instrumental variables (IVs) to test the causal effect of maternal BMI in pregnancy on offspring fatness (BMI and dual-energy X-ray absorptiometry [DXA] determined fat mass index [FMI]) in a MR approach. This was investigated, with repeat measurements, from ages 7 to 18 in the Avon Longitudinal Study of Parents and Children (ALSPAC; n = 2,521 to 3,720 for different ages). We then sought to replicate findings with results for BMI at age 6 in Generation R (n = 2,337 for replication sample; n = 6,057 for total pooled sample). In confounder-adjusted multivariable regression in ALSPAC, a 1 standard deviation (SD, equivalent of 3.7 kg/m2) increase in maternal BMI was associated with a 0.25 SD (95% CI 0.21-0.29) increase in offspring BMI at age 7, with similar results at later ages and when FMI was used as the outcome. A weighted genetic risk score was generated from 32 genetic variants robustly associated with BMI (minimum F-statistic = 45 in ALSPAC). The MR results using this genetic risk score as an IV in ALSPAC were close to the null at all ages (e.g., 0.04 SD (95% CI -0.21-0.30) at age 7 and 0.03 SD (95% CI -0.26-0.32) at age 18 per SD increase in maternal BMI), which was similar when a 97 variant generic risk score was used in ALSPAC. When findings from age 7 in ALSPAC were meta-analysed with those from age 6 in Generation R, the pooled confounder-adjusted multivariable regression association was 0.22 SD (95% CI 0.19-0.25) per SD increase in maternal BMI and the pooled MR effect (pooling the 97 variant score results from ALSPAC with the 32 variant score results from Generation R) was 0.05 SD (95%CI -0.11-0.21) per SD increase in maternal BMI (p-value for difference between the two results = 0.05). A number of sensitivity analyses exploring violation of the MR results supported our main findings. However, power was limited for some of the sensitivity tests and further studies with relevant data on maternal, offspring, and paternal genotype are required to obtain more precise (and unbiased) causal estimates.ConclusionsOur findings provide little evidence to support a strong causal intrauterine effect of incrementally greater maternal BMI resulting in greater offspring adiposity.

Vitamin D deficiency has been associated with several common diseases, including cancer and is being investigated as a possible risk factor for these conditions. We reported the striking prevalence of vitamin D deficiency in Scotland. Previous epidemiological studies have reported an association between low dietary vitamin D and colorectal cancer (CRC). Using a case-control study design, we tested the association between plasma 25-hydroxy-vitamin D (25-OHD) and CRC (2,001 cases, 2,237 controls). To determine whether plasma 25-OHD levels are causally linked to CRC risk, we applied the control function instrumental variable (IV) method of the mendelian randomization (MR) approach using four single nucleotide polymorphisms (rs2282679, rs12785878, rs10741657, rs6013897) previously shown to be associated with plasma 25-OHD. Low plasma 25-OHD levels were associated with CRC risk in the crude model (odds ratio (OR): 0.76, 95% Confidence Interval (CI): 0.71, 0.81, p: 1.4×10(-14)) and after adjusting for age, sex and other confounding factors. Using an allele score that combined all four SNPs as the IV, the estimated causal effect was OR 1.16 (95% CI 0.60, 2.23), whilst it was 0.94 (95% CI 0.46, 1.91) and 0.93 (0.53, 1.63) when using an upstream (rs12785878, rs10741657) and a downstream allele score (rs2282679, rs6013897), respectively. 25-OHD levels were inversely associated with CRC risk, in agreement with recent meta-analyses. The fact that this finding was not replicated when the MR approach was employed might be due to weak instruments, giving low power to demonstrate an effect (

Smokers have a higher prevalence of major depressive episodes and depressive symptoms than the general population, but whether this association is causal, or is due to confounding or reverse causation is uncertain because of the problems inherent in some epidemiological studies. Mendelian randomization, in which a genetic variant is used as a surrogate for measuring exposure, is an approach which may be used to better understand this association. We investigated the rs1051730 single nucleotide polymorphism in the nicotine acetylcholine receptor gene cluster (CHRNA5-CHRNA3-CHRNB4), associated with smoking phenotypes, to determine whether women who continued to smoke were also more likely to report a low mood during pregnancy. We found among women who smoked pre-pregnancy, those with the 1051730 T allele smoked more and were less likely to quit smoking during pregnancy, but were also less likely to report high levels of depressed mood at 18 weeks of pregnancy (per allele OR = 0.84, 95%CI 0.72 to 0.99, p = 0.034). The association between genotype and depressed mood was limited to women who were smokers prior to pregnancy, with weak evidence of an interaction between smoking status and genotype (p = 0.07). Our results do not support a causal role of smoking on depressed mood, but are consistent with a self-medication hypothesis, whereby smoking is used to alleviate symptoms of depression. A replication study using multiple genetic variants which influence smoking via different pathways is required to confirm these findings and provide evidence that the genetic variant is reflecting the effect of quitting smoking on depressed mood, and is not directly affecting mood.

Observational studies suggest that obese men have a lower risk of incident prostate cancer, but an increased risk of advanced and fatal cancers. These observations could be due to confounding, detection bias, or a biological effect of obesity. Genetic studies are less susceptible to confounding than observational epidemiology and can suggest how associations between phenotypes (such as obesity) and diseases arise. To determine whether the associations between obesity and prostate cancer are causal, we conducted a genetic association study of the relationship between a single nucleotide polymorphism known to be associated with obesity (FTO rs9939609) and prostate cancer. Data are from a population-based sample of 1550 screen-detected prostate cancers, 1815 age- and general practice matched controls with unrestricted prostate specific antigen (PSA) values and 1175 low-PSA controls (PSA