Whole-school interventions promoting student commitment to school to prevent substance use and violence, and improve educational attainment: a systematic review.

Background: Whole-school interventions modify the school environment to promote health. A subset of these interventions promotes student commitment to school to prevent substance (tobacco, alcohol, other drugs) use and/or violence. A previous review identified the theory of human functioning and school organisation as a comprehensive theory of such interventions, and found evidence that these interventions reduce substance use and/or violence. Objectives: The objectives were to search for, appraise and synthesise evidence to address the following questions: (1) What whole-school interventions promoting student commitment to school to prevent substance use and/or violence have been evaluated, what intervention subtypes are apparent and how closely do these align with the theory of human functioning and school organisation? (2) What factors relating to setting, population and intervention affect implementation? (3) What are the effects on student substance use, violence and educational attainment? (4) What is the cost-effectiveness of such interventions? (5) Are intervention effects mediated by student commitment to school or moderated by setting or population? Data sources: A total of 56 information sources were searched (in January 2020), then an updated search of 48 of these was carried out (in May 2021). Reference lists were also searched and experts were contacted. Review methods: Eligible studies were process/outcome evaluations of whole-school interventions to reduce student violence or substance use among students aged 5-18 years attending schools, via actions aligning with the theory of human functioning and school organisation: modifying teaching to increase engagement, enhancing student-staff relationships, revising school policies, encouraging volunteering or increasing parental involvement. Data extraction and quality assessments used existing tools. Theory and process reports were synthesised qualitatively. Outcome and economic data were synthesised narratively; outcome data were meta-analysed. Results: Searches retrieved 63 eligible reports on 27 studies of 22 interventions. We identified four intervention subtypes focused on student participation in school-wide decisions, improving staff-student relationships, increasing engagement in learning and involving parents. The theories of change of most intervention subtypes aligned closely with the theory of human functioning and school organisation, and informed refinement of an intervention theory of change. Theories of change for interventions increasing learning engagement did not align with this theory, aiming instead to increase school commitment primarily via social skills curricula. Factors influencing the implementation included whether or not interventions were tailorable, workable and well explained. Interventions with action groups comprising staff/students, etc. and providing local data were well implemented. Implementation was also affected by whether or not schools accepted the need for change and staff had the resources for delivery. Meta-analyses suggest small, but significant, intervention effects in preventing violence victimisation and perpetration, and substance use. There was sparse and inconsistent evidence of moderation and some evidence of mediation by student commitment to school. Two economic evaluations suggested that there is the potential for the interventions to be cost-effective. Limitations: The quality of the studies was variable and the economic synthesis was limited to two studies. Conclusions: Whole-school interventions aiming to promote student commitment to school share similar theories of change and factors affecting implementation. They have the potential to contribute to preventing violence and substance use among young people. Future trials should aim to optimise intervention effectiveness by better theorisation, and assess implementation and effect moderators and mediators. Study registration: This study is registered as PROSPERO CRD42019154334. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme (NIHR award ref: 17/151/05) and is published in full in Public Health Research; Vol. 12, No. 2. See the NIHR Funding and Awards website for further award information.

Whole-school health interventions aim to modify how schools are run, to promote students' health. Some aim to promote student commitment to school to prevent the important interlinked outcomes of substance (tobacco, alcohol, other drugs) use and violence. We searched for all evaluations of such interventions. We summarised what this research said about the sorts of interventions used, how they are meant to work, what factors affect delivery, whether or not they reduce violence and substance use and whether or not they are worth the money. We found 63 reports on 27 studies of 22 interventions. We identified four subtypes of interventions. These aimed to involve students in school decisions, improve staff­student relationships, increase engagement in learning or involve parents. Most of these interventions were intended to work by making sure schools focused on student needs, or by improving relationships between staff and students, between different areas of learning or between schools and communities. This aimed to make students feel committed to school and therefore avoid violence or substance use. A few aimed to work mostly by teaching students how to avoid violence and substance use. We found that interventions were well implemented if they were tailored for each school and had good materials and support. Interventions were well delivered if they were led by action groups (comprising staff, students, etc.) or provided schools with information on students' needs. Implementation was affected by whether or not schools accepted the need for change and whether or not staff had the necessary time and money to do the work. These interventions appear to have small, but significant, intervention impacts in preventing violence and substance use among young people. There was not consistent evidence of different effects for different students. A small number of studies suggest that such interventions might show economic benefit, but this would need further research. Future research should focus on interventions that are refined to make sure that they can be well delivered.

Implementation preferences for the management of sexually transmitted infections in the South African health system: a discrete choice experiment.

OBJECTIVES: Despite strengthening HIV prevention with the introduction of pre-exposure prophylaxis (PrEP), STI services have remained relatively unchanged and the standard of care remains syndromic management. We used a discrete choice experiment to investigate service users' preferences for the diagnosis and treatment of STIs in South Africa. METHODS: Between 1 March 2021 and 20 April 2021, a cross-sectional online questionnaire hosted on REDCap was administered through access links sent to WhatsApp support groups for HIV PrEP users and attendees of two primary healthcare clinics and two mobile facilities in the Eastern Cape and Gauteng provinces aged between 18 and 49 years. Participants either self-completed the questionnaire or received support from a research assistant. We used a conditional logit model for the initial analysis and latent class model (LCM) to establish class memberships, with results displayed as ORs and probabilities. RESULTS: We enrolled 496 individuals; the majority were female (69%) and <30 years (74%). The LCM showed two distinct groups. The first group, comprising 68% of the participants, showed a strong preference for self-sampling compared with no sampling (OR 2.16, 95% CI 1.62 to 2.88). A clinic follow-up appointment for treatment was less preferable to same-day treatment (OR 0.78, 95% CI 0.63 to 0.95). Contact slip from index patient (OR 0.86, 95% CI 0.76 to 0.96) and healthcare professional (HCP)-initiated partner notification (OR 0.63, 95% CI 0.55 to 0.73) were both less preferable than expedited partner treatment (EPT). The second group included 32% of participants with a lower preference for self-sampling compared with no sampling (OR 0.65, 95% CI 0.41 to 1.04). There was no treatment option that was significantly different from the others; however, there was a strong preference for HCP-initiated partner notification to EPT (OR 1.53, 95% CI 1.10 to 2.12). CONCLUSIONS: Our results suggest that service users preferred STI testing prior to treatment, with the majority preferring self-taken samples and receiving aetiology-based treatment on the same day.

The effect of combination prevention strategies on HIV incidence among gay and bisexual men who have sex with men in the UK: a model-based analysis.

BACKGROUND: In the UK, the number of new HIV diagnoses among gay and bisexual men who have sex with men (GBMSM) has decreased substantially. We aimed to understand the contribution of different interventions in reducing HIV incidence so far; to estimate future HIV incidence with continuation of current policies and with further scaling up of current interventions; and to estimate the maximum additional annual cost that should be spent towards these interventions for them to offer value for money. METHODS: We calibrated a dynamic, individual-based, stochastic simulation model, the HIV Synthesis Model, to multiple sources of data on HIV among GBMSM aged 15 years or older in the UK. Primarily these were routine HIV surveillance data collected by the UK Health Security Agency. We compared HIV incidence in 2022 with the counterfactual incidence: if HIV testing rates stopped increasing in 2012 and the policy of antiretroviral therapy (ART) at diagnosis was not introduced in mid-2015; if pre-exposure prophylaxis (PrEP) was not introduced; if condom use was low from 2012 in all GBMSM, at levels similar to those observed in 1980; and in the first and second scenario combined. We also projected future outcomes under the assumption of continuation of current policies and considering increases in PrEP and HIV testing uptake and a decrease in condomless sex. FINDINGS: Our model estimated a 77% (90% uncertainty interval [UI] 61-88) decline in HIV incidence since around 2014, with an estimated 597 infections ([90% UI 312-956]; 1·1 per 1000 person-years [90% UI 0·6-1·8]) in men aged 15-64 years in 2022. Both PrEP introduction and increased HIV testing with ART initiation at diagnosis each had a substantial effect on HIV incidence. Without PrEP introduction, we estimate there would have been 2·16 times the number of infections that actually occurred (90% UI 1·06-3·75) between 2012 and 2022; without increased HIV testing and ART initiation at diagnosis there would have been 2·18 times the number of infections that actually occurred (1·18-3·60), and if condomless sex was at the levels before the HIV epidemic, there would have been 2·27 times the number of infections that actually occurred (0·9-5·4). If rates of testing, ART use, and PrEP use remain as they are currently, there is a predicted decline in incidence to 388 HIV infections in 2025 (90% UI 226-650) and to 263 (137-433) in 2030. Increases in HIV testing and PrEP use were predicted to accelerate the decline in HIV incidence. Given the quality-adjusted life-year (QALY) benefit and a cost-effectiveness threshold of £30 000 per QALY gained, in order to be cost-effective an additional £1·62 million could be spent per year to increase testing levels by 34% (90% UI 25-46) and PrEP use by 55% (10-107). To achieve that, a 16% reduction in the cost of delivery of testing and PrEP would be required. INTERPRETATION: Combination prevention, including a PrEP strategy, played a major role in the reduction in HIV incidence observed so far in the UK among GBMSM. Continuation of current activities should lead to a continued decline; however, it is unlikely to lead to reaching the target of fewer than 50 HIV infections per year among GBMSM by 2030. It will be important to reduce costs for testing and PrEP for their continued expansion to be cost-effective. FUNDING: National Institute for Health Research under its Programme Grants for Applied Research Programme and Medical Research Council-UK Research and Innovation.

Estimating the hospital costs of care for people living with HIV in England using routinely collected data.

BACKGROUND: Understanding the health care activity and associated hospital costs of caring for people living with HIV is an important component of assessing the cost effectiveness of new technologies and for budget planning. METHODS: Data collected between 2010 and 2017 from an English HIV treatment centre were combined with national reference costs to estimate the rate of hospital attendances and costs per quarter year, according to demographic and clinical factors. The final dataset included records for 1763 people living with HIV, which was analysed using negative binomial regression models and general estimating equations. RESULTS: People living with HIV experienced an unadjusted average of 0.028 (standard deviation [SD] 0.20) inpatient episodes per quarter, equivalent to one every 9 years, and 1.85 (SD 2.30) outpatient visits per quarter. The unadjusted mean quarterly cost per person with HIV (excluding antiretroviral drug costs) was £439 (SD 604). Outpatient appointments and inpatient episodes accounted for 88% and 6% of total costs, respectively. In adjusted models, low CD4 count was the strongest predictor of inpatient stays and outpatient visits. Low CD4 count and new patient status (having a first visit at the Trust in the last 6 months) were the factors that most increased estimated costs. Associations were weaker or less consistent for demographic factors (age, sex/sexual orientation/ethnicity). Sensitivity analyses suggest that the findings were generally robust to alternative parameter and modelling assumptions. CONCLUSION: A number of factors predicted hospital activity and costs, but CD4 cell count and new patient status were the strongest. The study results can be incorporated into future economic evaluations and budget impact assessments of HIV-related technologies.

The Evolving Nature of Health Technology Assessment: A Critical Appraisal of NICE's New Methods Manual.

OBJECTIVES: The National Institute for Health and Care Excellence (NICE) recently completed a review of its methods for health technology assessment, involving a 2-stage public consultation. We appraise proposed methodological changes and analyze key decisions. METHODS: We categorize all changes proposed in the first consultation as "critical," "moderate" or "limited" updates, considering the importance of the topic and the degree of change or the level of reinforcement. Proposals were followed through the review process, for their inclusion, exclusion, or amendment in the second consultation and the new manual. RESULTS: The end-of-life value modifier was replaced with a new "disease severity" modifier and other potential modifiers were rejected. The usefulness of a comprehensive evidence base was emphasized, clarifying when nonrandomized studies can be used, with further guidance on "real-world" evidence developed separately. A greater degree of uncertainty was accepted in circumstances when evidence generation raised challenges, in particular for children, rare diseases, and innovative technologies. For some topics, such as health inequality, discounting, unrelated healthcare costs, and value of information, significant changes were possibly warranted, but NICE decided not to make any revisions at present. CONCLUSION: Most of the changes to NICE's health technology assessment methods are appropriate and modest in impact. Nevertheless, some decisions were not well justified and further research is needed on several topics, including investigation of societal preferences. Ultimately, NICE's role of protecting National Health Services resources for valuable interventions that can contribute toward improving overall population health must be safeguarded, without accepting weaker evidence.

Health-related quality of life among people who inject drugs in Australia.

PURPOSE: There is limited research on health-related quality of life (HRQoL) among people who inject drugs (PWID). We aimed to evaluate factors associated with HRQoL among a cohort of PWID in Australia. METHODS: Participants were enrolled in an observational cohort study (the LiveRLife Study) between 2014 and 2018 at 15 sites in Australia. They provided fingerstick whole-blood samples for point-of-care HCV RNA testing and underwent transient elastography to assess liver disease. Participants completed the EQ-5D-3L survey at enrolment. Regression models were used to assess the impact of clinical and socioeconomic characteristics on the EQ-5D-3L scores. RESULTS: Among 751 participants (median age, 43 years; 67% male), 63% reported injection drug use in the past month, 43% had current HCV infection, and 68% had no/mild liver fibrosis (F0/F1). The mean EQ-5D-3L and EQ-VAS scores were 0.67 and 62, respectively, for the overall study population. There was no significant difference in the EQ-5D-3L scores among people with and without recent injecting drug use (mean: 0.66 vs. 0.68, median: 0.73 vs. 0.78, P = 0.405), and among people receiving and not receiving opioid agonist therapy (mean: 0.66 vs. 0.68, median: 0.73 vs. 0.76, P = 0.215). Participants who were employed were found to have the highest mean EQ-5D-3L (0.83) and EQ-VAS scores (77). The presence of current HCV infection, liver fibrosis stage, and high-risk alcohol consumption had little impact on HRQoL. CONCLUSIONS: The study findings provide important HRQoL data for economic evaluations, useful for guiding the allocation of resources for HCV elimination strategies and interventions among PWID.

A Comparison of Ordered Categorical versus Discrete Choices within a Stated Preference Survey of Whole-Blood Donors.

HIGHLIGHTS: This article compares the relative preferences from stated preference (SP) questions requiring ordered categorical versus discrete choice responses. The approaches were contrasted for blood donation service characteristics that offer opportunities to donate blood.The estimates of relative preferences for alternative blood donation service characteristics were similar between the 2 forms of SP approach.This study illustrates how SP survey questions can be formulated to provide responses on an ordered categorical scale and to estimate marginal rates of substitution between different attributes, which can be compared with those derived from discrete choice experiment (DCE) choices.The article highlights the potential value of considering alternative choice framings rather than relying solely on DCEs.

Universal testing for hepatitis B and hepatitis C in the emergency department: a cost-effectiveness and budget impact analysis of two urban hospitals in the United Kingdom.

BACKGROUND: Numerous studies have shown the effectiveness of testing for hepatitis B (HBV) and hepatitis C (HCV) in emergency departments (ED), due to the elevated prevalence amongst attendees. The aim of this study was to conduct a cost-effectiveness analysis of universal opt-out HBV and HCV testing in EDs based on 2 long-term studies of the real-world effectiveness of testing in 2 large ED's in the UK. METHODS: A Markov model was used to evaluate ED-based HBV and HCV testing versus no ED testing, in addition to current testing practice. The two EDs had a HBV HBsAg prevalence of 0.5-0.9% and an HCV RNA prevalence of 0.9-1.0%. The analysis was performed from a UK health service perspective, over a lifetime time horizon. Costs are reported in British pounds (GBP), and outcomes as quality adjusted life years (QALYs), with both discounted at 3.5% per year. Incremental cost-effectiveness ratios (ICER) are calculated as costs per QALY gained. A willingness-to-pay threshold of £20,000/QALY was used. The cost-effectiveness was estimated for both infections, in both ED's. RESULTS: HBV and HCV testing were highly cost-effective in both settings, with ICERs ranging from £7,177 to £12,387 per QALY gained. In probabilistic analyses, HBV testing was 89-94% likely to be cost-effective at the threshold, while HCV testing was 94-100% likely to be cost-effective, across both settings. In deterministic sensitivity analyses, testing remained cost-effective in both locations at ≥ 0.25% HBsAg prevalence, and ≥ 0.49% HCV RNA prevalence. This is much lower than the prevalence observed in the two EDs included in this study. CONCLUSIONS: HBV and HCV testing in urban EDs is highly cost-effective in the UK, and can be cost-effective at relatively low prevalence. These results should be reflected in UK and European hepatitis testing guidelines.

Short-term and long-term impacts of COVID-19 on economic vulnerability: a population-based longitudinal study (COVIDENCE UK).

OBJECTIVE: To determine whether COVID-19 has a significant impact on adequacy of household income to meet basic needs (primary outcome) and work absence due to sickness (secondary outcome), both at the onset of illness (short term) and subsequently (long term). DESIGN: Multilevel mixed regression analysis of self-reported data from monthly online questionnaires, completed 1 May 2020 to 28 October 2021, adjusting for baseline characteristics including age, sex, socioeconomic status and self-rated health. SETTING AND PARTICIPANTS: Participants (n=16 910) were UK residents aged 16 years or over participating in a national longitudinal study of COVID-19 (COVIDENCE UK). RESULTS: Incident COVID-19 was independently associated with increased odds of participants reporting household income as being inadequate to meet their basic needs in the short term (adjusted OR (aOR) 1.39, 95% CI 1.12 to 1.73) though this did not persist in the long term (aOR 1.00, 95% CI 0.86 to 1.16). Exploratory analysis revealed a stronger short-term association among those who reported long COVID, defined as the presence of symptoms lasting more than 4 weeks after disease onset, than those reporting COVID-19 without long COVID (p for trend 0.002). Incident COVID-19 associated with increased odds of reporting sickness absence from work in the long term (aOR 4.73, 95% CI 2.47 to 9.06) but not in the short term (aOR 1.34, 95% CI 0.52 to 3.49). CONCLUSIONS: We demonstrate an independent association between COVID-19 and increased risk of economic vulnerability among COVIDENCE participants, measured by both household income sufficiency and sickness absence from work. Taking these findings together with pre-existing research showing that socioeconomic disadvantage increases the risk of developing COVID-19, this may suggest a 'vicious cycle' of impaired health and poor economic outcomes. TRIAL REGISTRATION NUMBER: NCT04330599.

A cost-effectiveness and value of information analysis to inform future research of tranexamic acid for older adults experiencing mild traumatic brain injury.

BACKGROUND: Tranexamic acid reduces head injury deaths in patients with CT scan evidence of intracranial bleeding after mild traumatic brain injury (TBI). However, the cost-effectiveness of tranexamic acid for people with mild TBI in the pre-hospital setting, prior to CT scanning, is uncertain. A large randomised controlled trial (CRASH-4) is planned to address this issue, but the economic justification for it has not been established. The aim of the analysis was to estimate the likelihood of tranexamic acid being cost-effective given current evidence, the treatment effects required for cost-effectiveness, and the expected value of performing further research. METHODS: An early economic decision model compared usual care for mild TBI with and without tranexamic acid, for adults aged 70 and above. The evaluation was performed from a UK healthcare perspective over a lifetime time horizon, with costs reported in 2020 pounds (GBP) and outcomes reported as quality-adjusted life years (QALYs). All analyses used a £20,000 per QALY cost-effectiveness threshold. RESULTS: In the base case analysis, tranexamic acid was associated with an incremental cost-effectiveness ratio of £4885 per QALY gained, but the likelihood of it being cost-effective was highly dependent on the all-cause mortality treatment effect. The value of perfect information was £22.4 million, and the value of perfect information for parameters that could be collected in a trial was £21.9 million. The all-cause mortality risk ratio for tranexamic acid and the functional outcomes following TBI had the most impact on cost-effectiveness. CONCLUSIONS: There is a high degree of uncertainty in the cost-effectiveness of tranexamic acid for older adults experiencing mild TBI, meaning there is a high value of performing future research in the UK. The value in a global context is likely to be far higher.

Observation versus screening spinal MRI and pre-emptive treatment for spinal cord compression in patients with castration-resistant prostate cancer and spinal metastases in the UK (PROMPTS): an open-label, randomised, controlled, phase 3 trial.

BACKGROUND: Early diagnosis of malignant spinal cord compression (SCC) is crucial because pretreatment neurological status is the major determinant of outcome. In metastatic castration-resistant prostate cancer, SCC is a clinically significant cause of disease-related morbidity and mortality. We investigated whether screening for SCC with spinal MRI, and pre-emptive treatment if radiological SCC (rSCC) was detected, reduced the incidence of clinical SCC (cSCC) in asymptomatic patients with metastatic castration-resistant prostate cancer and spinal metastasis. METHODS: We did a parallel-group, open-label, randomised, controlled, phase 3, superiority trial. Patients with metastatic castration-resistant prostate cancer were recruited from 45 National Health Service hospitals in the UK. Eligible patients were aged at least 18 years, with an Eastern Co-operative Oncology Group performance status of 0-2, asymptomatic spinal metastasis, no previous SCC, and no spinal MRI in the past 12 months. Participants were randomly assigned (1:1), using a minimisation algorithm with a random element (balancing factors were treatment centre, alkaline phosphatase [normal vs raised, with the upper limit of normal being defined at each participating laboratory], number of previous systemic treatments [first-line vs second-line or later], previous spinal treatment, and imaging of thorax and abdomen), to no MRI (control group) or screening spinal MRI (intervention group). Serious adverse events were monitored in the 24 h after screening MRI in the intervention group. Participants with screen-detected rSCC were offered pre-emptive treatment (radiotherapy or surgical decompression was recommended per treating physician's recommendation) and 6-monthly spinal MRI. All patients were followed up every 3 months, and then at month 30 and 36. The primary endpoint was time to and incidence of confirmed cSCC in the intention-to-treat population (defined as all patients randomly assigned), with the primary timepoint of interest being 1 year after randomisation. The study is registered with ISRCTN, ISRCTN74112318, and is now complete. FINDINGS: Between Feb 26, 2013, and April 25, 2017, 420 patients were randomly assigned to the control (n=210) or screening MRI (n=210) groups. Median age was 74 years (IQR 68 to 79), 222 (53%) of 420 patients had normal alkaline phosphatase, and median prostate-specific antigen concentration was 48 ng/mL (IQR 17 to 162). Screening MRI detected rSCC in 61 (31%) of 200 patients with assessable scans in the intervention group. As of data cutoff (April 23, 2020), at a median follow-up of 22 months (IQR 13 to 31), time to cSCC was not significantly improved with screening (hazard ratio 0·64 [95% CI 0·37 to 1·11]; Gray's test p=0·12). 1-year cSCC rates were 6·7% (95% CI 3·8-10·6; 14 of 210 patients) for the control group and 4·3% (2·1-7·7; nine of 210 patients) for the intervention group (difference -2·4% [95% CI -4·2 to 0·1]). Median time to cSCC was not reached in either group. No serious adverse events were reported within 24 h of screening. INTERPRETATION: Despite the substantial incidence of rSCC detected in the intervention group, the rate of cSCC in both groups was low at a median of 22 months of follow-up. Routine use of screening MRI and pre-emptive treatment to prevent cSCC is not warranted in patients with asymptomatic castration-resistant prostate cancer with spinal metastasis. FUNDING: Cancer Research UK.

Association between health-related quality of life and menopausal status and symptoms in women living with HIV aged 45-60 years in England: An analysis of the PRIME study.

OBJECTIVES: The aim of this study was to compare the health-related quality of life between mid-life women with HIV and the general population and to investigate the association between health-related quality of life and menopausal (1) status and (2) symptoms among women with HIV. METHODS: Cross-sectional data of women with HIV aged 45-60 years from the Positive Transitions Through the Menopause Study. Health-related quality of life was assessed using the Euroqol questionnaire with utility scores categorizing health as perfect (score = 1.00), sub-optimal (0.75-0.99) or poor (< 0.75). Scores were compared between Positive Transitions Through the Menopause study participants and women (aged 45-59 years) from the Health Survey for England. Associations between health-related quality of life and menopausal status/symptoms in Positive Transitions Through the Menopause participants were assessed using a multivariable two-part regression model, the results of which are combined to produce a single marginal effect. RESULTS: In total, 813 women from the Positive Transitions Through the Menopause study were included (median age 49 (interquartile range: 47-53) years); the majority were of Black African ethnicity (72.2%). Overall, 20.9%, 43.7% and 35.3% of women were pre-, peri- and post-menopausal, respectively, and 69.7% experienced mild/moderate/severe menopausal symptoms. Approximately, 40% reported perfect health, 22.1% sub-optimal health and 39.0% poor health, similar to women from the Health Survey for England (perfect health: 36.9%, sub-optimal health: 25.2%, poor health: 37.9%). In multivariable models, we found an association between health-related quality of life and peri-menopausal status (marginal effect: 0.07 (0.02, 0.12)); however, the association with post-menopausal status was attenuated (marginal effect: 0.01 (-0.05, 0.06)). There remained a strong association between lower utility scores and moderate (marginal effect: 0.16 (0.11, 0.20)) and severe (marginal effect: 0.32 (0.27, 0.39)) menopausal symptoms. CONCLUSION: There were no differences in health-related quality of life between women with HIV (Positive Transitions Through the Menopause participants) and women from the Health Survey for England dataset. Among Positive Transitions Through the Menopause participants, health-related quality of life was reduced in peri-menopausal women and those with increasingly severe menopausal symptoms. Our findings highlight the importance of proactive assessment of menopausal status and symptoms to optimize health-related quality of life in women living with HIV as they reach mid-life and beyond.

Risk factors for developing COVID-19: a population-based longitudinal study (COVIDENCE UK).

BACKGROUND: Risk factors for severe COVID-19 include older age, male sex, obesity, black or Asian ethnicity and underlying medical conditions. Whether these factors also influence susceptibility to developing COVID-19 is uncertain. METHODS: We undertook a prospective, population-based cohort study (COVIDENCE UK) from 1 May 2020 to 5 February 2021. Baseline information on potential risk factors was captured by an online questionnaire. Monthly follow-up questionnaires captured incident COVID-19. We used logistic regression models to estimate multivariable-adjusted ORs (aORs) for associations between potential risk factors and odds of COVID-19. RESULTS: We recorded 446 incident cases of COVID-19 in 15 227 participants (2.9%). Increased odds of developing COVID-19 were independently associated with Asian/Asian British versus white ethnicity (aOR 2.28, 95% CI 1.33 to 3.91), household overcrowding (aOR per additional 0.5 people/bedroom 1.26, 1.11 to 1.43), any versus no visits to/from other households in previous week (aOR 1.31, 1.06 to 1.62), number of visits to indoor public places (aOR per extra visit per week 1.05, 1.02 to 1.09), frontline occupation excluding health/social care versus no frontline occupation (aOR 1.49, 1.12 to 1.98) and raised body mass index (BMI) (aOR 1.50 (1.19 to 1.89) for BMI 25.0-30.0 kg/m2 and 1.39 (1.06 to 1.84) for BMI >30.0 kg/m2 versus BMI <25.0 kg/m2). Atopic disease was independently associated with decreased odds (aOR 0.75, 0.59 to 0.97). No independent associations were seen for age, sex, other medical conditions, diet or micronutrient supplement use. CONCLUSIONS: After rigorous adjustment for factors influencing exposure to SARS-CoV-2, Asian/Asian British ethnicity and raised BMI were associated with increased odds of developing COVID-19, while atopic disease was associated with decreased odds. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT04330599).

A high-dose 24-hour tranexamic acid infusion for the treatment of significant gastrointestinal bleeding: HALT-IT RCT.

BACKGROUND: Tranexamic acid reduces blood loss in surgery and the risk of death in trauma patients. Meta-analyses of small trials suggest that tranexamic acid decreases the number of deaths from gastrointestinal bleeding, but these meta-analyses are prone to selection bias. OBJECTIVE: The trial provides reliable evidence of the effect of tranexamic acid on mortality, rebleeding and complications in significant acute gastrointestinal bleeding. DESIGN: A multicentre, randomised, placebo-controlled trial and economic analysis. Patients were assigned by selecting one treatment pack from a box of eight, which were identical apart from the pack number. Patients, caregivers and outcome assessors were masked to allocation. The main analyses were by intention to treat. SETTING: The setting was 164 hospitals in 15 countries, co-ordinated from the London School of Hygiene & Tropical Medicine. PARTICIPANTS: Adults with significant upper or lower gastrointestinal bleeding (n = 12,009) were eligible if the responsible clinician was substantially uncertain about whether or not to use tranexamic acid. The clinical diagnosis of significant bleeding implied a risk of bleeding to death, including hypotension, tachycardia or signs of shock, or urgent transfusion, endoscopy or surgery. INTERVENTION: Tranexamic acid (a 1-g loading dose over 10 minutes, then a 3-g maintenance dose over 24 hours) or matching placebo. MAIN OUTCOME MEASURES: The primary outcome was death due to bleeding within 5 days of randomisation. Secondary outcomes were all-cause and cause-specific mortality; rebleeding; need for endoscopy, surgery or radiological intervention; blood product transfusion; complications; disability; and days spent in intensive care or a high-dependency unit. RESULTS: A total of 12,009 patients were allocated to receive tranexamic acid (n = 5994, 49.9%) or the matching placebo (n = 6015, 50.1%), of whom 11,952 (99.5%) received the first dose. Death due to bleeding within 5 days of randomisation occurred in 222 (3.7%) patients in the tranexamic acid group and in 226 (3.8%) patients in the placebo group (risk ratio 0.99, 95% confidence interval 0.82 to 1.18). Thromboembolic events occurred in 86 (1.4%) patients in the tranexamic acid group and 72 (1.2%) patients in the placebo group (risk ratio 1.20, 95% confidence interval 0.88 to 1.64). The risk of arterial thromboembolic events (myocardial infarction or stroke) was similar in both groups (0.7% in the tranexamic acid group vs. 0.8% in the placebo group; risk ratio 0.92, 95% confidence interval 0.60 to 1.39), but the risk of venous thromboembolic events (deep-vein thrombosis or pulmonary embolism) was higher in tranexamic acid-treated patients than in placebo-treated patients (0.8% vs. 0.4%; risk ratio 1.85, 95% confidence interval 1.15 to 2.98). Seizures occurred in 38 patients who received tranexamic acid and in 22 patients who received placebo (0.6% vs. 0.4%, respectively; risk ratio 1.73, 95% confidence interval 1.03 to 2.93). In the base-case economic analysis, tranexamic acid was not cost-effective and resulted in slightly poorer health outcomes than no tranexamic acid. CONCLUSIONS: Tranexamic acid did not reduce death from gastrointestinal bleeding and, although inexpensive, it is not cost-effective in adults with acute gastrointestinal bleeding. FUTURE WORK: These results caution against a uniform approach to the management of patients with major haemorrhage and highlight the need for randomised trials targeted at specific pathophysiological processes. LIMITATIONS: Although this is one of the largest randomised trials in gastrointestinal bleeding, we cannot rule out a modest increase or decrease in death due to bleeding with tranexamic acid. TRIAL REGISTRATION: Current Controlled Trials ISRCTN11225767, ClinicalTrials.gov NCT01658124 and EudraCT 2012-003192-19. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 58. See the NIHR Journals Library website for further project information.

Acute gastrointestinal bleeding (bleeding from the gut) is a common emergency and an important cause of death and illness worldwide. In the UK, more than 65,000 people each year are admitted to hospital because of acute gastrointestinal bleeding; approximately 10% of them die within 30 days. Gastrointestinal bleeding is also common in low- and middle-income countries. The care of patients with gastrointestinal bleeding has improved in recent decades, but death rates remain high. Gastrointestinal bleeding is often caused by stomach ulcers, but also by liver damage owing to alcohol or hepatitis C infection. An effective and affordable treatment for gastrointestinal bleeding could save many lives and may reduce the need for blood transfusions, which is important because blood is a scarce resource in some health-care settings. Tranexamic acid, also known as TXA, is a cheap drug that reduces bleeding in other conditions. It helps blood to clot, thereby decreasing bleeding. A trial in bleeding accident victims found that tranexamic acid reduced the chances of bleeding to death, without any increase in side effects. We wanted to find out if tranexamic acid safely improves outcomes in patients with gastrointestinal bleeding, particularly to prevent deaths. To investigate this, the HALT-IT (Haemorrhage ALleviation with Tranexamic acid ­ Intestinal system) trial studied 12,009 patients with significant gastrointestinal bleeding in 164 hospitals across 15 countries. Half of the patients received tranexamic acid and the other half received a dummy drug, called a placebo. The treatments were assigned randomly and given in addition to all other treatments needed. Neither the patient nor the doctor knew which treatment a patient received. The trial showed that tranexamic acid did not reduce deaths from gastrointestinal bleeding. Instead, tranexamic acid was linked to an increased risk of complications, including unwanted blood clots (such as deep-vein thrombosis) and seizures. The economic analysis indicated that giving tranexamic acid to patients with gastrointestinal bleeding does not represent value for money for the NHS.

Peer advocacy and access to healthcare for people who are homeless in London, UK: a mixed method impact, economic and process evaluation protocol.

INTRODUCTION: People who are homeless experience higher morbidity and mortality than the general population. These outcomes are exacerbated by inequitable access to healthcare. Emerging evidence suggests a role for peer advocates-that is, trained volunteers with lived experience-to support people who are homeless to access healthcare. METHODS AND ANALYSIS: We plan to conduct a mixed methods evaluation to assess the effects (qualitative, cohort and economic studies); processes and contexts (qualitative study); fidelity; and acceptability and reach (process study) of Peer Advocacy on people who are homeless and on peers themselves in London, UK. People with lived experience of homelessness are partners in the design, execution, analysis and dissemination of the evaluation. ETHICS AND DISSEMINATION: Ethics approval for all study designs has been granted by the National Health Service London-Dulwich Research Ethics Committee (UK) and the London School of Hygiene and Tropical Medicine's Ethics Committee (UK). We plan to disseminate study progress and outputs via a website, conference presentations, community meetings and peer-reviewed journal articles.

Tranexamic acid to reduce head injury death in people with traumatic brain injury: the CRASH-3 international RCT.

BACKGROUND: Tranexamic acid safely reduces mortality in traumatic extracranial bleeding. Intracranial bleeding is common after traumatic brain injury and can cause brain herniation and death. We assessed the effects of tranexamic acid in traumatic brain injury patients. OBJECTIVE: To assess the effects of tranexamic acid on death, disability and vascular occlusive events in traumatic brain injury patients. We also assessed cost-effectiveness. DESIGN: Randomised trial and economic evaluation. Patients were assigned by selecting a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients, caregivers and those assessing outcomes were masked to allocation. All analyses were by intention to treat. We assessed the cost-effectiveness of tranexamic acid versus no treatment from a UK NHS perspective using the trial results and a Markov model. SETTING: 175 hospitals in 29 countries. PARTICIPANTS: Adults with traumatic brain injury within 3 hours of injury with a Glasgow Coma Scale score of ≤ 12 or any intracranial bleeding on computerised tomography scan, and no major extracranial bleeding, were eligible. INTERVENTION: Tranexamic acid (loading dose 1 g over 10 minutes then infusion of 1 g over 8 hours) or matching placebo. MAIN OUTCOME MEASURES: Head injury death in hospital within 28 days of injury in patients treated within 3 hours of injury. Secondary outcomes were early head injury deaths, all-cause and cause-specific mortality, disability, vascular occlusive events, seizures, complications and adverse events. RESULTS: Among patients treated within 3 hours of injury (n = 9127), the risk of head injury death was 18.5% in the tranexamic acid group versus 19.8% in the placebo group (855/4613 vs. 892/4514; risk ratio 0.94, 95% confidence interval 0.86 to 1.02). In a prespecified analysis excluding patients with a Glasgow Coma Scale score of 3 or bilateral unreactive pupils at baseline, the results were 12.5% in the tranexamic acid group versus 14.0% in the placebo group (485/3880 vs. 525/3757; risk ratio 0.89, 95% confidence interval 0.80 to 1.00). There was a reduction in the risk of head injury death with tranexamic acid in those with mild to moderate head injury (166/2846 vs. 207/2769; risk ratio 0.78, 95% confidence interval 0.64 to 0.95), but in those with severe head injury (689/1739 vs. 685/1710; risk ratio 0.99, 95% confidence interval 0.91 to 1.07) there was no apparent reduction (p-value for heterogeneity = 0.030). Early treatment was more effective in mild and moderate head injury (p = 0.005), but there was no obvious impact of time to treatment in cases of severe head injury (p = 0.73). The risk of disability, vascular occlusive events and seizures was similar in both groups. Tranexamic acid is highly cost-effective for mild and moderate traumatic brain injury (base case of £4288 per quality-adjusted life-year gained). CONCLUSION: Early tranexamic acid treatment reduces head injury deaths. Treatment is cost-effective for patients with mild or moderate traumatic brain injury, or those with both pupils reactive. FUTURE WORK: Further trials should examine early tranexamic acid treatment in mild head injury. Research on alternative routes of administration is needed. LIMITATIONS: Time to treatment may have been underestimated. TRIAL REGISTRATION: Current Controlled Trials ISRCTN15088122, ClinicalTrials.gov NCT01402882, EudraCT 2011-003669-14, Pan African Clinical Trial Registry PACTR20121000441277. FUNDING: The project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 26. See the NIHR Journals Library website for further project information. In addition, funding was provided by JP Moulton Charitable Trust, Joint Global Health Trials (Medical Research Council, Department for International Development and the Wellcome Trust). This project was funded by the NIHR Global Health Trials programme.

Traumatic brain injury is a leading cause of death and disability worldwide, with over 60 million new cases each year. When the head is injured there is often bleeding inside the brain, which can continue for some time and worsen after hospital admission. This bleeding increases pressure inside the skull, causing further damage to the brain, which can be fatal or result in serious disability. Tranexamic acid is a cheap drug that reduces bleeding in other conditions. A large trial of accident victims (other than those with head injury) found that it reduced the chances of bleeding to death. We wanted to find out if tranexamic acid would also reduce deaths among patients with head injuries. We studied just under 13,000 patients with traumatic brain injury who did not have other major injuries to their bodies from 175 hospitals across 29 countries. Patients were assigned at random to receive either tranexamic acid or a dummy medicine called a placebo. Neither the clinical team nor the patient knew which medicine the patient received. All patients received the usual treatments given to head-injured patients. Outcomes from 9127 participants were analysed. Among patients treated early, within 3 hours, the rate of head injury death was 18.5% (855/4613) in the tranexamic acid group and 19.8% (892/4514) in the placebo group. We found no evidence of an effect of tranexamic acid overall. However, in patients with mild or moderate traumatic brain injury, there was a 20% reduction in deaths. There were no side effects and no increase in disability in survivors when the drug was used. The economic analysis shows that tranexamic acid represents value for money for patients with mild or moderate traumatic brain injury.

Causes of hospitalisation among a cohort of people with HIV from a London centre followed from 2011 to 2018.

BACKGROUND: We describe the spectrum of ICD-10 classified causes for hospitalisations occurring between 2011 and 2018 in a cohort of people living with HIV (PLHIV). METHODS: This sub-study includes 798 PLHIV participating in the Antiretroviral, Sexual Transmission Risk and Attitudes (ASTRA) questionnaire study who were recruited from a large London centre. A medical record review identified the occurrence and causes of hospitalisation from the date of questionnaire completion (February-December 2011) until 1 June 2018. Up to five causes were classified by an HIV clinician using the ICD-10 system. RESULTS: There were 274 hospitalisations in 153 people (rate = 5.8/100 person-years; 95% CI: 5.1, 6.5). Causes were wide-ranging; the most common were circulatory (16.8%), digestive (13.1%), respiratory (11.7%), infectious diseases (11.0%), injury/poisoning (10.6%), genitourinary diseases (9.9%) and neoplasms (9.1%). A tenth (27/274) of hospitalisations were related to at least one AIDS-defining illness. Median duration of hospitalisation was 5 days (IQR 2-9). At the time of hospitalisation, median CD4 count was high (510 cells/µl; IQR: 315-739), while median CD4 nadir was relatively low (113 cells/µl; IQR: 40-239). At admission, half of individuals (51%) had a previous AIDS-defining illness and 21% had viral load > 50 copies/ml. Individuals admitted for infectious diseases were particularly likely to have unfavourable HIV-related clinical characteristics (low CD4, viral non-suppression, not on antiretroviral therapy (ART), previous AIDS). CONCLUSIONS: In the modern combination antiretroviral therapy era, the spectrum of causes of hospitalisation in PLHIV in the UK is wide-ranging, highlighting the importance of holistic care for PLHIV, including prevention, early detection and treatment of comorbidities.

Costs and cost-effectiveness of cervical cancer screening strategies in women living with HIV in Burkina Faso: The HPV in Africa Research Partnership (HARP) study.

INTRODUCTION: This study estimated the costs and incremental cost per case detected of screening strategies for high-grade cervical intraepithelial neoplasia (CIN2+) in women living with HIV (WLHIV) attending HIV clinics in Burkina Faso. METHODS: The direct healthcare provider costs of screening tests (visual inspection with acetic acid (VIA), VIA combined visual inspection with Lugol's iodine (VIA/VILI), cytology and a rapid HPV DNA test (careHPV)) and confirmatory tests (colposcopy, directed biopsy and systematic four-quadrant (4Q) biopsy) were collected alongside the HPV in Africa Research Partnership (HARP) study. A model was developed for a hypothetical cohort of 1000 WLHIV using data on CIN2+ prevalence and the sensitivity of the screening tests. Costs are reported in USD (2019). RESULTS: The study enrolled 554 WLHIV with median age 36 years (inter-quartile range, 31-41) and CIN2+ prevalence of 5.8%. The average cost per screening test ranged from US$3.2 for VIA to US$24.8 for cytology. Compared to VIA alone, the incremental cost per CIN2+ case detected was US$48 for VIA/VILI and US$814 for careHPV. Despite higher costs, careHPV was more sensitive for CIN2+ cases detected compared to VIA/VILI (97% and 56%, respectively). The cost of colposcopy was US$6.6 per person while directed biopsy was US$33.0 and 4Q biopsy was US$48.0. CONCLUSION: Depending on the willingness to pay for the detection of a case of cervical cancer, decision makers in Burkina Faso can consider a variety of cervical cancer screening strategies for WLHIV. While careHPV is more costly, it has the potential to be cost-effective depending on the willingness to pay threshold. Future research should explore the lifetime costs and benefits of cervical cancer screening to enable comparisons with interventions for other diseases.

Prospective association of social circumstance, socioeconomic, lifestyle and mental health factors with subsequent hospitalisation over 6-7 year follow up in people living with HIV.

BACKGROUND: Predictors of hospitalisation in people with HIV (PLHIV) in the contemporary treatment era are not well understood. METHODS: This ASTRA sub-study used clinic data linkage and record review to determine occurrence of hospitalisations among 798 PLHIV from baseline questionnaire (February to December 2011) until 1 June 2018. Associations of baseline social circumstance, socioeconomic, lifestyle, mental health, demographic and clinical factors with repeated all-cause hospitalisation from longitudinal data were investigated using Prentice-Williams-Peterson models. Associations were also assessed in 461 individuals on antiretroviral therapy (ART) with viral load ≤50 copies/ml and CD4 count ≥500 cells/ µl. FINDINGS: Rate of hospitalisation was 5.8/100 person-years (95% CI: 5.1-6.5). Adjusted for age, demographic group and time with diagnosed HIV, the following social circumstance, socioeconomic, lifestyle and mental health factors predicted hospitalisation: no stable partner (adjusted hazard ratio (aHR)=1.59; 95% CI=1.16-2.20 vs living with partner); having children (aHR=1.50; 1.08-2.10); non-employment (aHR=1.56; 1.07-2.27 for unemployment; aHR=2.39; 1.70-3.37 for sick/disabled vs employed); rented housing (aHR=1.72; 1.26-2.37 vs homeowner); not enough money for basic needs (aHR=1.82; 1.19-2.78 vs enough); current smoking (aHR=1.39; 1.02-1.91 vs never); recent injection-drug use (aHR=2.11; 1.30-3.43); anxiety symptoms (aHRs=1.39; 1.01-1.91, 2.06; 1.43-2.95 for mild and moderate vs none/minimal); depressive symptoms (aHRs=1.67; 1.17-2.38, 1.91; 1.30-2.78 for moderate and severe vs none/minimal); treated/untreated depression (aHRs=1.65; 1.03-2.64 for treated depression only, 1.87; 1.39-2.52 for depressive symptoms only; 1.53; 1.05-2.24; for treated depression and depressive symptoms, versus neither). Associations were broadly similar in those with controlled HIV and high CD4. INTERPRETATION: Social circumstance, socioeconomic disadvantage, adverse lifestyle factors and poorer mental health are strong predictors of hospitalisation in PLHIV, highlighting the need for targeted interventions and care. FUNDING: British HIV Association (BHIVA) Research Award (2017); SMR funded by a PhD fellowship from the Royal Free Charity.