National Institute For Health Research Research Articles

Clinical utility of C-reactive protein-based triage for presumptive pulmonary tuberculosis in South African adults

BackgroundIdentification of an accurate, low-cost triage test for pulmonary TB among people presenting to healthcare facilities is an urgent global research priority. We assessed the diagnostic accuracy and clinical utility of C-reactive protein (CRP) for TB triage among symptomatic adult outpatients, irrespective of HIV status. MethodsWe prospectively enrolled adults reporting at least one (for people with HIV) or two (for people without HIV) symptoms of cough, fever, night sweats, or weight loss at two TB clinics in Cape Town, South Africa. Participants provided sputum for culture and Xpert MTB/RIF Ultra. We evaluated the diagnostic accuracy of CRP (measured using a laboratory-based assay) against a TB-culture reference standard as the area under the receiver operating characteristic curve (AUROC), and sensitivity and specificity at pre-specified thresholds. We assessed clinical utility using decision curve analysis and benchmarked against WHO recommendations. ResultsOf 932 included individuals, 255 (27%) had culture-confirmed pulmonary TB and 389 (42%) were living with HIV. CRP demonstrated an AUROC of 0·80 (95% confidence interval 0·77–0·83), with sensitivity 93% (89–95%) and specificity 54% (50–58%) using a primary cut-off of ≥10 mg/L. Performance was similar among people with HIV to those without. In decision curve analysis, CRP-based triage offered greater clinical utility than confirmatory testing for all up to a number willing to test threshold of 20 confirmatory tests per true positive pulmonary TB case diagnosed (threshold probability 5%). If it is possible to perform more confirmatory tests than this, a ‘confirmatory test for all’ strategy performed better. ConclusionsCRP achieved the WHO-defined sensitivity, but not specificity, targets for a triage test for pulmonary TB and showed evidence of clinical utility among symptomatic outpatients, irrespective of HIV status. FundingSouth African Medical Research Council, EDCTP2, Royal Society Newton Advanced Fellowship, Wellcome Trust, National Institute of Health Research, Royal College of Physicians.

Rituximab versus intravenous cyclophosphamide in patients with connective tissue disease-associated interstitial lung disease in the UK (RECITAL): a double-blind, double-dummy, randomised, controlled, phase 2b trial

Rituximab is often used as rescue therapy in interstitial lung disease (ILD) associated with connective tissue disease (CTD), but has not been studied in clinical trials. This study aimed to assess whether rituximab is superior to cyclophosphamide as a treatment for severe or progressive CTD associated ILD. We conducted a randomised, double-blind, double-dummy, phase 2b trial to assess the superiority of rituximab compared with cyclophosphamide. Patients aged 18-80 years with severe or progressive ILD related to scleroderma, idiopathic inflammatory myositis, or mixed CTD, recruited across 11 specialist ILD or rheumatology centres in the UK, were randomly assigned (1:1) to receive rituximab (1000 mg at weeks 0 and 2 intravenously) or cyclophosphamide (600 mg/m2 body surface area every 4 weeks intravenously for six doses). The primary endpoint was rate of change in forced vital capacity (FVC) at 24 weeks compared with baseline, analysed using a mixed-effects model with random intercepts, adjusted for baseline FVC and CTD type. Prespecified secondary endpoints reported in this Article were change in FVC at 48 weeks versus baseline; changes from baseline in 6 min walk distance, diffusing capacity of the lung for carbon monoxide (DLCO), physician-assessed global disease activity (GDA) score, and quality-of-life scores on the St George's Respiratory Questionnaire (SGRQ), King's Brief Interstitial Lung Disease (KBILD) questionnaire, and European Quality of Life Five-Dimension (EQ-5D) questionnaire at 24 and 48 weeks; overall survival, progression-free survival, and time to treatment failure; and corticosteroid use. All endpoints were analysed in the modified intention-to-treat population, which comprised all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT01862926). Between Dec 1, 2014, and March 31, 2020, we screened 145 participants, of whom 101 participants were randomly allocated: 50 (50%) to receive cyclophosphamide and 51 (50%) to receive rituximab. 48 (96%) participants in the cyclophosphamide group and 49 (96%) in the rituximab group received at least one dose of treatment and were included in analyses; 43 (86%) participants in the cyclophosphamide group and 42 (82%) participants in the rituximab group completed 24 weeks of treatment and follow-up. At 24 weeks, FVC was improved from baseline in both the cyclophosphamide group (unadjusted mean increase 99 mL [SD 329]) and the rituximab group (97 mL [234]); in the adjusted mixed-effects model, the difference in the primary endpoint at 24 weeks was -40 mL (95% CI -153 to 74; p=0·49) between the rituximab group and the cyclophosphamide group. KBILD quality-of-life scores were improved at 24 weeks by a mean 9·4 points (SD 20·8) in the cyclophosphamide group and 8·8 points (17·0) in the rituximab group. No significant differences in secondary endpoints were identified between the treatment groups, with the exception of change in GDA score at week 48, which favoured cyclophosphamide (difference 0·90 [95% CI 0·11 to 1·68]). Improvements in lung function and respiratory-related quality-of-life measures were observed in both treatment groups. Lower corticosteroid exposure over 48 weeks of follow-up was recorded in the rituximab group. Two (4%) of 48 participants who received cyclophosphamide and three (6%) of 49 who received rituximab died during the study, all due to complications of CTD or ILD. Overall survival, progression-free survival, and time to treatment failure did not significantly differ between the two groups. All participants reported at least one adverse event during the study. Numerically fewer adverse events were reported by participants receiving rituximab (445 events) than those receiving cyclophosphamide (646 events). Gastrointestinal and respiratory disorders were the most commonly reported adverse events in both groups. There were 62 serious adverse events of which 33 occurred in the cyclophosphamide group and 29 in the rituximab group. Rituximab was not superior to cyclophosphamide to treat patients with CTD-ILD, although participants in both treatment groups had increased FVC at 24 weeks, in addition to clinically important improvements in patient-reported quality of life. Rituximab was associated with fewer adverse events. Rituximab should be considered as a therapeutic alternative to cyclophosphamide in individuals with CTD-ILD requiring intravenous therapy. Efficacy and Mechanism Evaluation Programme (Medical Research Council and National Institute for Health Research, UK).

Impact of the COVID-19 Pandemic on National Institutes of Health-Funded Researchers and Their Projects: The Role of Age, Sex, Experience, and Team Size.

The COVID-19 pandemic has disrupted the social life, work environment, and well-being of millions of people. We examined COVID-19's impact on National Institutes of Health (NIH)-funded extramural principal investigators (PIs) affiliated with public health and preventive medicine departments across the country and their projects; assessed PIs' confidence in achieving project goals; and investigated the role of age, sex, experience, and team size on PIs' confidence in achieving project goals during the pandemic. We sent an anonymous online survey in January 2021 to 1076 extramural PIs affiliated with public health and preventive medicine departments at US institutions; 133 (12.4%) responded. We examined the impact of COVID-19 on the PIs, their project team operations, and their confidence that project objectives would be met, using Likert scales based on age, sex, team size, and PI experience. Of 126 PIs, 94 (74.6%) felt that their day-to-day professional life was impacted a lot or a great deal by COVID-19. More female PIs than male PIs reported that their level of stress changed because of the COVID-19 pandemic. Of 125 PIs, 67 (53.6%) made major adjustments to research operations, 46 (36.8%) made minor adjustments, 5 (4.0%) halted research, and 7 (5.6%) reported not being affected. Of 123 PIs, 89 (72.4%) reported not using NIH COVID-19 accommodations. PIs who led projects 4 or 5 times felt more confident about meeting their research objectives than PIs who led projects 2 or 3 times. Future studies should investigate how to develop more engaging support and communication strategies to assist NIH researchers in mitigating the effects of pandemics or large-scale emergencies.

Effectiveness and cost effectiveness of digital hearing aids in patients with tinnitus and hearing loss: a randomised feasibility trial (THE HUSH Trial)

BackgroundEducation and advice is provided for tinnitus management in all UK audiology clinics. Sound therapy, including provision of hearing aids may be offered, but this is often dependent on a clinician’s decision rather than UK policy. This inconsistent management reflects a lack of evidence around the effectiveness of hearing aids for tinnitus. This open-label, two-arm multicentre randomised controlled feasibility trial gathered data around recruitment, acceptability and outcome assessments to determine the feasibility of conducting a large randomised controlled trial investigating the effectiveness of hearing aids for tinnitus management.MethodsAdults referred to audiology for tinnitus, with an aidable hearing loss were recruited at five UK audiology clinics. They were randomised 1:1 to either education and advice (treatment as usual (TAU), n = 41) or TAU plus hearing aids (n = 42). Outcomes were collected by questionnaires 12 weeks after randomisation. After participation, interviews were conducted with a subset of both participants and clinicians from each trial centre.ResultsEighty three participants from five sites were randomised. Non-aidable hearing loss was the main reason for ineligibility to participate in the trial reported by the sites. Seventy three percent of participants returned the 12-week questionnaires, with return rates by site ranging from 61 to 100%. Fifteen out of 33 participants (45%) reported using hearing aids for the clinician-recommended time, or longer, during the day. The Tinnitus Functional Index (TFI) was the outcome measure most responsive to change. The majority of participants also agreed it was relevant to their tinnitus and hearing loss. Qualitative data demonstrated that the trial was acceptable to participants. Feedback from clinicians revealed a potential lack of equipoise. It also highlighted the differences in referral and treatment pathways between departments and differences in audiometric criteria for fitting hearing aids. Health economic measures were well completed for those returned. No change in health-related quality of life was observed. Costs were higher in the intervention arm, but self-reports of healthcare service use indicated participant confusion in treatment pathways.ConclusionsThis feasibility trial is the first step towards obtaining high quality evidence to determine potential clinical effectiveness and cost effectiveness of hearing aids for tinnitus versus usual care. A definitive trial was deemed to be feasible, with some modifications based on feasibility findings and using the TFI as the primary outcome.This trial was funded by the National Institute for Health Research, Research for Patient Benefit Programme (PB-PG-0816–20,014) and registered with ISRCTN (ISRCTN14218416).

Molecular subtypes of leiomyosarcoma: Moving toward a consensus

Molecular subtypes of leiomyosarcoma: Moving toward a consensus

The longitudinal effect of social media use on adolescent mental health in the UK: findings from the UK Longitudinal Household Study

BackgroundCross-sectional studies have suggested an association between the use of social media and depression and anxiety in young people. We examined the longitudinal relationship between social media use and young people's mental health, and the role of self-esteem and social connectedness as potential mediators. MethodsAdolescents (aged 10–15 years) from the UK Longitudinal Household Study (2009–19) were included. Mental health was measured by the Strengths and Difficulties Questionnaire Total Difficulties score. The number of hours spent on social media was measured on a 5-point scale, from zero to ≥7 h. Self-esteem and social connectedness were measured at ages 13–14 years. Covariates included demographic and household variables. Unadjusted and adjusted multilevel linear regression models explored whether social media use at ages 12–13 years predicted mental health at ages 14–15 years (expressed as beta values and 95% CIs). Path analysis with structural equation modelling was used to investigate the mediation pathways. FindingsWe included 3228 adolescents (1659 [51·4%] girls and 1569 [48·6%] boys) for whom social media and mental health data at ages 12–13 years and 14–15 years were available. In adjusted analysis, no association between time spent on social media and poorer mental health was identified (n=2603; b=0·21 [95% CI –0·43 to 0·84]; p=0·52). In adjusted path analysis, there was no mediation of self-esteem (indirect effect; n=2316; b=0·24 [95% CI –0·12 to 0·66]; p=0·22) or social connectedness (indirect effect; –0·03 [–0·20 to 0·12]; p=0·74), but in unadjusted analysis, 68% of the effect of social media use on mental health was mediated by self-esteem (indirect effect; n=2569; 0·70 [0·15 to 1·30]; p=0.016) but not by social connectedness. Similar results were found when the analysis was re-run on a multiply imputed dataset that filled in missing values using multiple imputation. InterpretationOur data show the importance of longitudinal evidence. We found there was little evidence to suggest a causal relationship between the use of social media and mental health issues 2 years later. Interventions that address social media use alone might not improve young people's mental health, and considering factors such as self-esteem might be more effective. FundingUK National Institute for Health Research School for Public Health Research (grant reference PD-SPH-2015). The views expressed are those of the authors and not necessarily those of the National Institute for Health Research or the UK Department of Health and Social Care.

Catastrophic expenditure and treatment attrition in patients seeking comprehensive colorectal cancer treatment in India: A prospective multicentre study.

Although colorectal cancer is increasing in India, the cost of comprehensive treatment and its consequences for patients and households are unknown. This study aimed to describe catastrophic expenditure and treatment attrition in patients with a treatment plan for colorectal cancer. A prospective, multicentre, cohort study was conducted in five tertiary hospitals in India from December 2020 to March 2022. Consecutive patients with a new treatment plan for colorectal cancer were followed-up for six months. The total cost of treatment was reported, including out-of-pocket payments (OOPP, paid by patients at the time-of-service use) and covered by third parties (insurance, public funds). The primary outcome was catastrophic expenditure, defined as OOPPs greater than 25% of patient's annual household income and the secondary outcome was treatment attrition, defined as unplanned interruption of the treatment course not recommended by the clinical team. Of 226 patients included, 20 died within six months of being offered a treatment plan and four were lost to follow-up. The median total cost of colorectal cancer treatment was 407,508 Indian Rupees (INR/5340 USD), to which the biggest contributor was the patient's OOPP (median 330,277 INR/4328 USD). Surgery and anaesthesia costs (median 85,944 INR/1126 USD) were higher than radiotherapy (median 55,525 INR/728 USD) and chemotherapy (median 14,780 INR/194 USD). The overall catastrophic expenditure rate was 90.1% (182/202) and the treatment attrition rate was 9.4% (19/202). Patients with treatment attrition made lower OOPPs than those who completed treatment (median 205,926 vs 349,398 INR, p<0.01) but had a similar risk of catastrophic expenditure (OR 0.23, 95%CI 0.03-2.28, p = 0.186). Most treatment costs for colorectal cancer were paid out-of-pocket by patients and catastrophic expenditure was common. Treatment attrition rates at tertiary centres were low, suggesting greater attrition at previous stages of care. Better financial protection may allow more patients to receive comprehensive cancer treatment while avoiding household financial catastrophe. This research was funded by the National Institute for Health Research (NIHR) (NIHR 16.136.79) using UK aid from the UK Government to support global health research, by the India Institute of the University of Birmingham and by the Global Challenges program of the University of Birmingham. The views expressed in this publication are those of the author(s) and not necessarily those of the NIHR or the UK government.

Quantifying the contribution of poverty and family adversity to adverse child outcomes in the UK: evidence from the UK Millennium Cohort Study

BackgroundAdolescent health is poor in the UK, with higher prevalence of adverse outcomes in adolescents exposed to family adversities that cluster with poverty from early life. However, little evidence exists to quantify the contribution of these exposures to poor child health in the UK to inform policy. The aim of this study was to estimate the proportion of child physical, mental, cognitive, and behavioural outcomes that could be prevented if exposure to poverty and family adversity during childhood were eliminated. MethodsWe used nationally representative birth cohort data from the UK Millennium Cohort Study to calculate population attributable fractions. Exposure trajectories were characterised using previously developed group-based multi-trajectory models of childhood adversities up to age 14 years, including low poverty and family adversity, persistent poverty, persistent parental alcohol use, persistent domestic violence and abuse, and persistent poverty and poor parental mental health trajectory; and we assessed the effect of these trajectories on adolescent outcomes using regression models. These models were used to calculate population attributable fractions by contrasting a hypothetical scenario in which all children were in a low poverty and family adversity trajectory with the real-world scenario. FindingsThe identified exposure trajectories contributed substantially to the burden of childhood developmental problems. Compared with the low poverty and family adversity trajectory, the overall percentage of socioemotional behavioural problems at age 14 years attributable to persistent poverty and family adversity trajectories was 54% (95% CI 45–60). A percentage of 36·1% (95% CI 21·8–46·2) was reported for drug experimentation, 32·6% (18·8–40·7) for cognitive disability, and 27·4% (12·9–34·9) for obesity (appendix). InterpretationPoverty and family adversity contribute to a substantial burden of adverse child health and developmental outcomes in the UK population. FundingThe National Institute for Health Research (NIHR) Policy Research Programme, NIHR Applied Research Collaboration South London at King's College Hospital NHS Foundation Trust, and the UK Medical Research Council.

The relationship between academic influence, NIH funding, and industry payments among academic shoulder and elbow surgeons.

The effect of academic influence, or the volume and quality of a surgeon's publications, on industry payments and National Institutes of Health (NIH) funding has recently been studied in some academic orthopedic subspecialities. The purpose of this study is to evaluate the relationship between academic influence, industry payments, and NIH funding among American Shoulder and Elbow Surgeons accredited shoulder and elbow fellowship faculty. Shoulder and elbow fellowships and affiliated faculty members were identified from the American Shoulder and Elbow Surgeons website. Academic influence, measured by the Hirsch (h)-index, and the number of articles published were determined for faculty members using the Scopus Database Author Identifier tool. Industry payments were derived from the Centers for Medicare and Medicaid Services Open Payments database. NIH funding was determined using the NIH's Research Portfolio Online Reporting tool. Statistical analysis used Spearman correlations and the Mann-Whitney U-test with an alpha value of 0.05 (P<.05). A total of 146 faculty members were included. Twenty-two percent (42 of 146) received nonresearch payments, whereas 78% (114 of 146) received industry research funding averaging $6364 (standard deviation=$21,213). NIH funding averaged $272,589 (standard deviation=$224,635), and 5% received NIH funding (7 of 146). Faculty members who received NIH funding had a higher average h-index than those who did not (38±22 vs. 22.64±22.7, P=.02), whereas those receiving industry research payments had a greater number of publications than those who did not (127.97±127.2 vs. 100.3±122.3, P=.03). Industry nonresearch payments did not impact the number of publications or the h-index. This study demonstrated that academic influence among academic shoulder and elbow surgeons is not greater in those who receive nonresearch industry funding. However, surgeons with industry research funding did produce more publications, whereas NIH funding is associated with greater academic influence.

Elective surgery system strengthening: development, measurement, and validation of the surgical preparedness index across 1632 hospitals in 119 countries

The 2015 Lancet Commission on global surgery identified surgery and anaesthesia as indispensable parts of holistic health-care systems. However, COVID-19 exposed the fragility of planned surgical services around the world, which have also been neglected in pandemic recovery planning. This study aimed to develop and validate a novel index to support local elective surgical system strengthening and address growing backlogs. First, we performed an international consultation through a four-stage consensus process to develop a multidomain index for hospital-level assessment (surgical preparedness index; SPI). Second, we measured surgical preparedness across a global network of hospitals in high-income countries (HICs), middle-income countries (MICs), and low-income countries (LICs) to explore the distribution of the SPI at national, subnational, and hospital levels. Finally, using COVID-19 as an example of an external system shock, we compared hospitals' SPI to their planned surgical volume ratio (SVR; ie, operations for which the decision for surgery was made before hospital admission), calculated as the ratio of the observed surgical volume over a 1-month assessment period between June 6 and Aug 5, 2021, against the expected surgical volume based on hospital administrative data from the same period in 2019 (ie, a pre-pandemic baseline). A linear mixed-effects regression model was used to determine the effect of increasing SPI score. In the first phase, from a longlist of 103 candidate indicators, 23 were prioritised as core indicators of elective surgical system preparedness by 69 clinicians (23 [33%] women; 46 [67%] men; 41 from HICs, 22 from MICs, and six from LICs) from 32 countries. The multidomain SPI included 11 indicators on facilities and consumables, two on staffing, two on prioritisation, and eight on systems. Hospitals were scored from 23 (least prepared) to 115 points (most prepared). In the second phase, surgical preparedness was measured in 1632 hospitals by 4714 clinicians from 119 countries. 745 (45·6%) of 1632 hospitals were in MICs or LICs. The mean SPI score was 84·5 (95% CI 84·1-84·9), which varied between HIC (88·5 [89·0-88·0]), MIC (81·8 [82·5-81·1]), and LIC (66·8 [64·9-68·7]) settings. In the third phase, 1217 (74·6%) hospitals did not maintain their expected SVR during the COVID-19 pandemic, of which 625 (51·4%) were from HIC, 538 (44·2%) from MIC, and 54 (4·4%) from LIC settings. In the mixed-effects model, a 10-point increase in SPI corresponded to a 3·6% (95% CI 3·0-4·1; p<0·0001) increase in SVR. This was consistent in HIC (4·8% [4·1-5·5]; p<0·0001), MIC (2·8 [2·0-3·7]; p<0·0001), and LIC (3·8 [1·3-6·7%]; p<0·0001) settings. The SPI contains 23 indicators that are globally applicable, relevant across different system stressors, vary at a subnational level, and are collectable by front-line teams. In the case study of COVID-19, a higher SPI was associated with an increased planned surgical volume ratio independent of country income status, COVID-19 burden, and hospital type. Hospitals should perform annual self-assessment of their surgical preparedness to identify areas that can be improved, create resilience in local surgical systems, and upscale capacity to address elective surgery backlogs. National Institute for Health Research (NIHR) Global Health Research Unit on Global Surgery, NIHR Academy, Association of Coloproctology of Great Britain and Ireland, Bowel Research UK, British Association of Surgical Oncology, British Gynaecological Cancer Society, and Medtronic.

Identification of the ideal recruitment situation in pandemic research: learning from the RECOVERY trial in Northern England: a qualitative study

BackgroundIn early 2020, little was known about treatments for COVID-19. The UK responded by initiating a call for research, leading to the formation of the National Institute for Health Research...

Surgical implementation gap: an interrupted time series analysis with interviews examining the impact of surgical trials on surgical practice in England

ObjectivesLandmark studies published near the turn of the 21st century found an implementation gap concerning the effect of evidenced-based findings on clinical practice. The current study examines the uptake of...

Intrapulmonary shunting is a key contributor to hypoxia in COVID-19: An update on the pathophysiology.

BackgroundThe pathophysiology of COVID-19 remains poorly understood. We aimed to estimate the contribution of intrapulmonary shunting and ventilation-to-perfusion (VA/Q) mismatch using a mathematical model to construct oxygen-haemoglobin dissociation curves (ODCs).MethodsODCs were constructed using transcutaneous pulse oximetry at two different fractions of inspired oxygen (FiO2). 199 patients were included from two large district general hospitals in the South East of England from 1st to 14th January 2021. The study was supported by the National Institute of Health Research (NIHR) Clinical Research Network.ResultsOverall mortality was 29%. Mean age was 68.2 years (SEM 1·2) with 46% female. Median shunt on admission was 17% (IQR 8–24.5); VA/Q was 0.61 (IQR 0.52–0.73). Shunt was 37.5% higher in deaths (median 22%, IQR 9–29) compared to survivors (16%, 8–21; p = 0.0088) and was a predictor of mortality (OR 1.04; 95% CI 1.01–1.07). Admission oxygen saturations were more strongly predictive of mortality (OR 0.91, 95% CI 0.87–0.96). There was no difference in VA/Q mismatch between deaths (0.60; IQR 0.50–0.73) and survivors (0.61; IQR 0.52–0.73; p = 0.63) and it was not predictive of mortality (OR 0.68; 95% CI 0.18–2.52; p = 0.55). Shunt negatively correlated with admission oxygen saturation (R -0.533; p<0.0001) whereas VA/Q was not (R 0.1137; p = 0.12).InterpretationShunt, not VA/Q mismatch, was associated with worsening hypoxia, though calculating shunt was not of prognostic value. This study adds to our understanding of the pathophysiology of hypoxaemia in COVID-19. Our inexpensive and reliable technique may provide further insights into the pathophysiology of hypoxia in other respiratory diseases.

Durability of ChAdOx1 nCoV-19 (AZD1222) vaccine and hybrid humoral immunity against variants including omicron BA.1 and BA.4 6 months after vaccination (COV005): a post-hoc analysis of a randomised, phase 1b–2a trial

BackgroundCOVID-19 vaccine rollout is lagging in Africa, where there has been a high rate of SARS-CoV-2 infection. We aimed to evaluate the effect of SARS-CoV-2 infection before vaccination with the ChAdOx-nCoV19 (AZD1222) vaccine on antibody responses through to 180 days.MethodsWe did an unmasked post-hoc immunogenicity analysis after the first and second doses of AZD1222 in a randomised, placebo-controlled, phase 1b–2a study done in seven locations in South Africa. AZD1222 recipients who were HIV-uninfected, were stratified into baseline seropositive or seronegative groups using the serum anti-nucleocapsid (anti-N) immunoglobulin G (IgG) electroluminescence immunoassay to establish SARS-CoV-2 infection before the first dose of AZD1222. Binding IgG to spike (anti-S) and receptor binding domain (anti-RBD) were measured before the first dose (day 0), second dose (day 28), day 42, and day 180. Neutralising antibody (NAb) against SARS-CoV-2 variants D614G, beta, delta, gamma, and A.VOI.V2, and omicron BA1 and BA.4 variants, were measured by pseudovirus assay (day 28, day 42, and day 180). This trial is registered with ClinicalTrials.gov, NCT04444674, and the Pan African Clinicals Trials Registry, PACTR202006922165132.FindingsOf 185 individuals who were randomly assigned to AZD1222, we included 91 individuals who were baseline seropositive and 58 who were baseline seronegative, in the final analysis. In the seropositive group, there was little change of anti-S IgG (and anti-RBD IgG) or neutralising antibody (NAb) titres at day 42 compared with at day 28. Anti-S (and anti-RBD) IgG geometric mean concentrations (GMCs) were higher throughout in the seropositive compared with the seronegative group, including at day 180 (GMCs 517·8 [95% CI 411·3–651·9] vs 82·1 [55·2–122·3] BAU/mL). Also D614G NAb geometric mean titres (GMTs) were higher in the seropositive group than the seronegative group, as was the percentage with titres of at least 185 (80% putative risk reduction threshold [PRRT] against wild-type–alpha COVID-19), including at day 180 (92·0% [74·0–99·0] vs 18·2% [2·3–51·8). Similar findings were observed for beta, A.VOI.V2, and gamma. For delta, BA.1, and BA.4, NAb GMTs and the proportion with titres above the PRRT were substantially higher in the seropositive compared with seronegative group at day 28 and day 42, but no longer differed between the groups by day 180.InterpretationA single dose of AZD1222 in the general African population, where COVID-19 vaccine coverage is low and SARS-CoV-2 seropositivity is 90%, could enhance the magnitude and quality of antibody responses to SARS-CoV-2.FundingThe Bill & Melinda Gates Foundation, the South African Medical Research Council, the UK Research and Innovation, the UK National Institute for Health Research, and the South African Medical Research Council.TranslationFor the Zulu translation of the abstract see Supplementary Materials section.

Current Status of National Institutes of Health Research Funding for Women Surgeon-Scientists

Women have made substantial advancements in academic surgery, but research funding disparities continue to hamper their progress, and current literature on the status of National Institutes of Health (NIH) funding awarded to women surgeon-scientists appears to be conflicting. To examine gender-based differences in NIH funding awarded to surgeon-scientists by comparing total grant amounts awarded and the distribution of grants by gender and research type. This cross-sectional study was performed using a previously created database of NIH-funded surgeons from 2010 to 2020. Active physician data from the Association of American Medical Colleges were used to calculate total surgeon populations. This study was performed at the NIH using the NIH internal data platform, iSearch Grants. A total of 715 men and women surgeon-scientists funded by the NIH in 2010 and 1031 funded in 2020 were included in the analysis. The main outcome was the number of women among the total number of surgeons who received NIH grants and the total grant amounts awarded to them. Bivariate χ2 analyses were performed using population totals and substantiated by z tests of population proportions. This study included 715 physicians (n = 579 men [81.0%]) in 2010 and 1031 physicians (n = 769 men [74.6%]) in 2020. In 2020, women comprised 27.4% of the surgical workforce and 25.4% of surgeons with research funding in the US, but they received only 21.7% of total NIH research funding awarded to all surgeons. The number of funded women surgeon-scientists, however, significantly increased from 2010 to 2020 (262 [25.4%] in 2020 vs 136 [19.0%] in 2010; P < .001) as did their funding ($189.7 million [21.7%] in 2020 vs $75.9 million [12.3%] in 2010; P < .001). Furthermore, the proportion of US women surgeons overall with NIH funding significantly increased in 2020 vs 2010 (0.7% vs 0.5%; P < .001). Basic science, clinical outcomes, and clinical trial R01 grants also increased among women surgeon-scientists. Women and men K grant holders had a similar mean (SD) number of R01 application attempts before success (2.7 [3.01] vs 2.3 [3.15]; P = .60) and similar K-to-R award conversion rates (23.5% vs 26.7%; P = .55). This cross-sectional study found an increasing number of women surgeon-scientists receiving NIH funding in 2020 vs 2010 as well as increases in the median grant amounts awarded. Although these results are promising, a discrepancy remains in the proportion of women in the surgical workforce compared with those funded by the NIH and the total grant amounts awarded to them.

Improving cervical cancer survival-A multifaceted strategy to sustain progress for this global problem.

Cervical cancer is associated with profound socioeconomic and racial disparities in incidence, mortality, morbidity, and years of life lost. The last standard-of-care treatment innovation for locally advanced cervical cancer occurred in 1999, when cisplatin chemotherapy was added to pelvic radiation therapy (chemoradiation therapy). Chemoradiation therapy is associated with a 30%-50% failure rate, and there is currently no cure for recurrent or metastatic disease. The enormity of the worldwide clinical problem of cervical cancer morbidity and mortality as well as the egregiously unchanged mortality rate over the last several decades are recognized by the National Institutes of Health as urgent priorities. This is reflected within the Office of Research on Women's Health effort to advance National Institutes of Health research on the health of women, as highlighted in a recent symposium. In the current review, the authors address the state of the science and opportunities to improve cervical cancer survival with an emphasis on improving access, using technology in innovative and widely implementable ways, and improving current understanding of cervical cancer biology. LAY SUMMARY: Cervical cancer is associated with profound socioeconomic and racial disparities in incidence, mortality, morbidity, and years of life lost. In this review, the state of the science and opportunities to improve cervical cancer survival are presented with an emphasis on improving access, using technology in innovative and widely implementable ways, and improving current understanding of cervical cancer biology.

Current gaps and opportunities in screening, prevention, and treatment of cervical cancer.

In their fiscal year 2021 reports, the US House and Senate Appropriations Committees requested that the National Institutes of Health (NIH) evaluate current research related to women's health and topics that include stagnant cervical cancer survival. In response, the NIH Office of Research on Women's Health, with input from women's health experts; members of the public; representatives from NIH institutes, centers, and offices; and members of the NIH Advisory Committee on Research on Women's Health, reviewed the public health needs and current NIH activities on cervical cancer. The Advancing NIH Research on the Health of Women: A 2021 Conference held in October 2021 reviewed these findings and allowed the identification of opportunities to strengthen research. In this review, the authors summarize public health needs related to cervical cancer and NIH activities in this realm. Cervical cancer has become a rare disease in theUnited States, yet significant portions of the US population remain under screened orunscreened for cervical cancer, human papillomavirus vaccination rates remain low, access to high-quality treatment remains a challenge for many, and large inequities by race and ethnicity persist. Novel, inclusive, and intentional research isneeded to produce improvements in cervical cancer survival within the UnitedStates.

Designing genetic studies for people with intellectual disabilities: Practical lessons from a pilot study

AbstractGenetic variations are overrepresented in people with intellectual disability (PwID), particularly those with physical and mental health co‐morbidities, but remain significantly under‐diagnosed. Lack of suitable research studies, a natural extension of the complexities posed of consenting and recruitment is considered culpable. There is a resultant dearth of evidence on establishing bespoke genetic studies for adult PwID. This report outlines the challenges faced in the implementation and administration of a pilot genetic study for adult PwID hoping to better inform future genetic study designs for PwID. Adult participants with a diagnosis of ID (ICD10 F70‐F73) and epilepsy (ICD10 G40) were recruited to The Peninsula study exploring genomic stratification in intellectual disability and epilepsy via the ethically approved Royal Devon and Exeter Tissue Bank (RDETB) (16/SC/016). Managed within the National Institute for Health Research (NIHR) Exeter Clinical Research Framework, the RDETB was set up to proactively collect and store ‘spare’ tissue from routine clinical procedures such as venepunctures for routine good practice biochemistry monitoring. Participants who satisfied the criteria for the need for routine bloods to monitor their general health were identified to be invited for participation. From October 2017 to March 2020 from a total caseload of 375 PwID and epilepsy, 291 were screened (77.6%), 116 (39.9%) identified as potentially eligible and sent study information and genetic samples obtained from 30 (8%). Analysis showed 75% of PwID had some biochemical abnormalities requiring further medical attention. The recruitment was influenced by the clinical care set up in implementing the sanctioned ethics. However, where bloods were achieved it proved to be beneficial in identifying hitherto undiagnosed medical problems. While the challenges to gain consent, are considerable, the reasonable adjustments needed to facilitate participation and the immediate clinical benefits where engagement was successful are significant.

An international observational study to assess the impact of the Omicron variant emergence on the clinical epidemiology of COVID-19 in hospitalised patients.

Whilst timely clinical characterisation of infections caused by novel SARS-CoV-2 variants is necessary for evidence-based policy response, individual-level data on infecting variants are typically only available for a minority of patients and settings. Here, we propose an innovative approach to study changes in COVID-19 hospital presentation and outcomes after the Omicron variant emergence using publicly available population-level data on variant relative frequency to infer SARS-CoV-2 variants likely responsible for clinical cases. We apply this method to data collected by a large international clinical consortium before and after the emergence of the Omicron variant in different countries. Our analysis, that includes more than 100,000 patients from 28 countries, suggests that in many settings patients hospitalised with Omicron variant infection less often presented with commonly reported symptoms compared to patients infected with pre-Omicron variants. Patients with COVID-19 admitted to hospital after Omicron variant emergence had lower mortality compared to patients admitted during the period when Omicron variant was responsible for only a minority of infections (odds ratio in a mixed-effects logistic regression adjusted for likely confounders, 0.67 [95% confidence interval 0.61-0.75]). Qualitatively similar findings were observed in sensitivity analyses with different assumptions on population-level Omicron variant relative frequencies, and in analyses using available individual-level data on infecting variant for a subset of the study population. Although clinical studies with matching viral genomic information should remain a priority, our approach combining publicly available data on variant frequency and a multi-country clinical characterisation dataset with more than 100,000 records allowed analysis of data from a wide range of settings and novel insights on real-world heterogeneity of COVID-19 presentation and clinical outcome. Bronner P. Gonçalves, Peter Horby, Gail Carson, Piero L. Olliaro, Valeria Balan, Barbara Wanjiru Citarella, and research costs were supported by the UK Foreign, Commonwealth and Development Office (FCDO) and Wellcome [215091/Z/18/Z, 222410/Z/21/Z, 225288/Z/22/Z]; and Janice Caoili and Madiha Hashmi were supported by the UK FCDO and Wellcome [222048/Z/20/Z]. Peter Horby, Gail Carson, Piero L. Olliaro, Kalynn Kennon and Joaquin Baruch were supported by the Bill & Melinda Gates Foundation [OPP1209135]; Laura Merson was supported by University of Oxford's COVID-19 Research Response Fund - with thanks to its donors for their philanthropic support. Matthew Hall was supported by a Li Ka Shing Foundation award to Christophe Fraser. Moritz U.G. Kraemer was supported by the Branco Weiss Fellowship, Google.org, the Oxford Martin School, the Rockefeller Foundation, and the European Union Horizon 2020 project MOOD (#874850). The contents of this publication are the sole responsibility of the authors and do not necessarily reflect the views of the European Commission. Contributions from Srinivas Murthy, Asgar Rishu, Rob Fowler, James Joshua Douglas, François Martin Carrier were supported by CIHR Coronavirus Rapid Research Funding Opportunity OV2170359 and coordinated out of Sunnybrook Research Institute. Contributions from Evert-Jan Wils and David S.Y. Ong were supported by a grant from foundation Bevordering Onderzoek Franciscus; and Andrea Angheben by the Italian Ministry of Health "Fondi Ricerca corrente-L1P6" to IRCCS Ospedale Sacro Cuore-Don Calabria. The data contributions of J.Kenneth Baillie, Malcolm G. Semple, and Ewen M. Harrison were supported by grants from the National Institute for Health Research (NIHR; award CO-CIN-01), the Medical Research Council (MRC; grant MC_PC_19059), and by the NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool in partnership with Public Health England (PHE) (award 200907), NIHR HPRU in Respiratory Infections at Imperial College London with PHE (award 200927), Liverpool Experimental Cancer Medicine Centre (grant C18616/A25153), NIHR Biomedical Research Centre at Imperial College London (award IS-BRC-1215-20013), and NIHR Clinical Research Network providing infrastructure support. All funders of the ISARIC Clinical Characterisation Group are listed in the appendix.

Cost-effectiveness of statin therapy in categories of patients in the UK

Abstract Background Cardiovascular disease (CVD) mortality has declined steadily over the last few decades across Europe and North America. Purpose To provide contemporary estimates of long-term effectiveness and cost-effectiveness of statin therapy in different categories of patients in UK. Methods The CTT-UKB micro-simulation model, developed using the Cholesterol Treatment Trialists' Collaboration data (CTT: 118,000 participants; 5 years follow-up), and calibrated in the UK Biobank cohort (UKB: 502,000 participants; 9 years follow-up). The model integrates parametric risk equations for incident myocardial infarction, stroke, coronary revascularization, diabetes, cancer and vascular and nonvascular death, and projects annually these endpoints and survival using patient characteristics at entry. UKB data and linked primary and hospital care data informed healthcare costs in the model (2020 UK£); 2021 UK NHS Drug Tariff informed statin costs (atorvastatin 40mg at £1.22 and 80mg at £1.68 per 28 tablets); and Health Survey for England data informed health-related quality of life in the model. Previous CTT meta-analysis, atorvastatin dose-response randomized trials, and further meta-analyses of statin trials and cohort studies informed effects of 40mg/80mg atorvastatin therapy daily on rates of incident myocardial infarction, stroke, coronary revascularization, vascular death, diabetes, myopathy and rhabdomyolysis. The model was used to project gains in quality-adjusted life years (QALYs) and additional cost per QALY with lifetime use of atorvastatin 40mg or 80mg daily in categories of UKB participants by sex, age at statin initiation (40–49; 50–59 and 60–70 years), and 10-year CVD risk (QRISK3 risk (%): &amp;lt;5; 5–10, 10–15, 15–20, ≥20). Further scenarios explored effects of 5-year delay of statin initiation in people under 45 years of age or stopping statin therapy at 80 years of age. Results Across men and women in categories by age and CVD risk, lifetime use of atorvastatin 40mg daily was associated with increases in survival by 0.44–1.69 years (0.28–1.02 QALYs), and atorvastatin 80mg daily with increases in survival of 0.45–1.87 years (0.32–1.13 QALYs; Figure 1) with gains larger among participants at higher CVD risk. Both atorvastatin 40mg and 80mg doses were in the range of cost-effective treatments with incremental cost per QALY gained with atorvastatin 40mg daily versus no statin therapy below £7200/QALY and with atorvastatin 80mg vs 40mg daily below £16000/QALY (Figure 2) across all patient categories studied. Compared to lifetime statin therapy, stopping therapy at 80 years of age substantially reduced benefits and was not cost-effective in any patient category studied. Similarly, compared to immediate initiation, 5-year delay of statin therapy in 40–45 years old patients was not a cost-effective. Conclusions In the UK, statin therapy remains highly cost-effective across men and women 40–70 years old, including those at 10-year CVD risk &amp;lt;5%. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): UK National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Programme, UK National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Programme, UK Medical Research Council (MRC), British Heart Foundation