Respiratory Syncytial Virus Hospital Admission Rates and Patients' Characteristics Before the Age of 2 Years in England, 2015-2019.

BACKGROUND: A granular understanding of respiratory syncytial virus (RSV) burden in England is needed to prepare for new RSV prevention strategies. We estimated the rates of RSV hospital admissions before the age of 2 years in England and described baseline characteristics. METHODS: A birth cohort of all infants born between March 1, 2015, and February 28, 2017 (n = 449,591) was established using Clinical Practice Research Datalink-Hospital Episode Statistics. Case cohorts included infants with admission for (1) RSV, (2) bronchiolitis, (3) any respiratory tract infection (RTI) <24 months and (4) RSV predicted by an algorithm <12 months. Baseline characteristics were described in the case and comparative cohorts (infants without corresponding admission). Cumulative incidence and admission rates were calculated. Multiple linear regression was used to estimate the proportion of RTI healthcare visits attributable to RSV. RESULTS: The RSV-coded/RSV-predicted case cohorts were composed of 4813/12,694 infants (cumulative incidence: 1.1%/2.8%). Case cohort infants were more likely to have low birth weight, comorbidities and to be born during RSV season than comparative cohort infants, yet >77% were term-healthy infants and >54% were born before the RSV season. During the first year of life, 11.6 RSV-coded and 34.4 RSV-predicted hospitalizations occurred per 1000 person-years. Overall, >25% of unspecified lower RTI admissions were estimated to be due to RSV. CONCLUSIONS: In England, 1 in 91 infants had an RSV-coded admission, likely underestimated by ~3-fold. Most infants were term-healthy infants born before the RSV season. To decrease the total burden of RSV at the population level, immunization programs need to protect all infants.

Impact of European Union Label Changes for Fluoroquinolone-Containing Medicinal Products for Systemic and Inhalation Use: Post-Referral Prescribing Trends.

INTRODUCTION: Concerns of the persistence and severity of the adverse effects of fluoroquinolones, mainly involving the nervous system, muscles and joints, resulted in the 2018 referral procedure led by the European Medicines Agency (EMA). They advised to stop prescribing fluoroquinolones for infections of mild severity or of a presumed self-limiting course and for prevention of infections, plus to restrict prescriptions in cases of milder infections where other treatment options are available, and restrict in at-risk populations. We aimed to examine whether the impact of EMA regulatory interventions implemented throughout 2018-2019 had an impact on fluoroquinolone prescribing rates. METHODS: A retrospective population-based cohort study was conducted using electronic health care records from six European countries between 2016 and 2021. We analysed monthly incident fluoroquinolone use rates overall and for each fluoroquinolone active substance through flexible modelling via segmented regression to detect time points of trend changes, in monthly percentage change (MPC). RESULTS: The incidence of fluoroquinolone use ranged from 0.7 to 8.0/1000 persons per month over all calendar years. While changes in fluoroquinolone prescriptions were observed over time across countries, these were inconsistent and did not seem to be temporally related to EMA interventions (e.g., Belgium: February/May 2018, MPC - 33.3%, 95% confidence interval [CI] - 35.9 to - 30.7; Germany: February/May 2019, MPC - 12.6%, 95% CI - 13.7 to - 11.6]; UK: January/April 2016, MPC - 4.9%, 95% CI - 6.2 to - 3.6). CONCLUSION: The regulatory action associated with the 2018 referral did not seem to have relevant effects on fluoroquinolone prescribing in primary care.

Cost-effectiveness of outpatient versus inpatient non-invasive ventilation setup in obesity hypoventilation syndrome: the OPIP trial.

BACKGROUND: Current guidelines recommend that patients with obesity hypoventilation syndrome (OHS) are electively admitted for inpatient initiation of home non-invasive ventilation (NIV). We hypothesised that outpatient NIV setup would be more cost-effective. METHODS: Patients with stable OHS referred to six participating European centres for home NIV setup were recruited to an open-labelled clinical trial. Patients were randomised via web-based system using stratification to inpatient setup, with standard fixed level NIV and titrated during an attended overnight respiratory study or outpatient setup using an autotitrating NIV device and a set protocol, including home oximetry. The primary outcome was cost-effectiveness at 3 months with daytime carbon dioxide (PaCO2) as a non-inferiority safety outcome; non-inferiority margin 0.5 kPa. Data were analysed on an intention-to-treat basis. Health-related quality of life (HRQL) was measured using EQ-5D-5L (5 level EQ-5D tool) and costs were converted using purchasing power parities to £(GBP). RESULTS: Between May 2015 and March 2018, 82 patients were randomised. Age 59±14 years, body mass index 47±10 kg/m2 and PaCO2 6.8±0.6 kPa. Safety analysis demonstrated no difference in ∆PaCO2 (difference -0.27 kPa, 95% CI -0.70 to 0.17 kPa). Efficacy analysis showed similar total per-patient costs (inpatient £2962±£580, outpatient £3169±£525; difference £188.20, 95% CI -£61.61 to £438.01) and similar improvement in HRQL (EQ-5D-5L difference -0.006, 95% CI -0.05 to 0.04). There were no differences in secondary outcomes. DISCUSSION: There was no difference in medium-term cost-effectiveness, with similar clinical effectiveness, between outpatient and inpatient NIV setup. The home NIV setup strategy can be led by local resource demand and patient and clinician preference. TRIAL REGISTRATION NUMBERS: NCT02342899 and ISRCTN51420481.

Prognosis and oncogenomic profiling of patients with tropomyosin receptor kinase fusion cancer in the 100,000 genomes project.

INTRODUCTION: Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are oncogenic drivers in various tumor types. Limited data exist on the overall survival (OS) of patients with tumors with NTRK gene fusions and on the co-occurrence of NTRK fusions with other oncogenic drivers. MATERIALS AND METHODS: This retrospective study included patients enrolled in the Genomics England 100,000 Genomes Project who had linked clinical data from UK databases. Patients who had undergone tumor whole genome sequencing between March 2016 and July 2019 were included. Patients with and without NTRK fusions were matched. OS was analyzed along with oncogenic alterations in ALK, BRAF, EGFR, ERBB2, KRAS, and ROS1, and tumor mutation burden (TMB) and microsatellite instability (MSI). RESULTS: Of 15,223 patients analyzed, 38 (0.25%) had NTRK gene fusions in 11 tumor types, the most common were breast cancer, colorectal cancer (CRC), and sarcoma. Median OS was not reached in both the NTRK gene fusion-positive and -negative groups (hazard ratio 1.47, 95% CI 0.39-5.57, P = 0.572). A KRAS mutation was identified in two (5%) patients with NTRK gene fusions, and both had hepatobiliary cancer. High TMB and MSI were both more common in patients with NTRK gene fusions, due to the CRC subset. While there was a higher risk of death in patients with NTRK gene fusions compared to those without, the difference was not statistically significant. CONCLUSION: This study supports the hypothesis that NTRK gene fusions are primary oncogenic drivers and the co-occurrence of NTRK gene fusions with other oncogenic alterations is rare.

Extended follow-up of children in a phase2b trial of the GMZ2 malaria vaccine.

BACKGROUND: The GMZ2/alum candidate malaria vaccine had an efficacy of 14% (95% confidence interval [CI]: 3.6%, 23%) against clinical malaria over 6 months of follow-up in a phase2b multicentre trial in children 1-5 years of age. Here we report the extended follow up of safety and efficacy over 2 years. METHODS: A total of 1849 (GMZ2 = 926, rabies = 923) children aged 12-60 months were randomized to receive intramuscularly, either 3 doses of 100 µg GMZ2/alum or 3 doses of rabies vaccine as control 28 days apart. The children were followed-up for 24 months for clinical malaria episodes and adverse events. The primary endpoint was documented fever with parasitaemia of at least 5000/µL. RESULTS: There were 2,062 malaria episodes in the GMZ2/alum group and 2,115 in the rabies vaccine group in the intention-to-treat analysis, vaccine efficacy (VE) of 6.5% (95%: CI -1.6%, 14.0%). In children aged 1-2 years at enrolment, VE was 3.6% (95 %CI: -9.1%, 14.8%) in the first year and -4.1% (95 %CI: -18.7%, 87%) in the second year. In children aged 3-5 years at enrolment VE was 19.9% (95 %CI: 7.7%, 30.4%) in the first year and 6.3% (95 %CI: -10.2%, 20.3%) in the second year (interaction by year, P = 0.025, and by age group, P = 0.085). A total of 187 (GMZ2 = 91, rabies = 96) serious adverse events were recorded in 167 individuals over the entire period of the study. There were no GMZ2 vaccine related serious adverse events. CONCLUSIONS: GMZ2/alum was well tolerated. Follow-up over 2 years confirmed a low level of vaccine efficacy with slightly higher efficacy in older children, which suggests GMZ2 may act in concert with naturally acquired immunity.

Ex vivo delivery of Mirococept: A dose-finding study in pig kidney after showing a low dose is insufficient to reduce delayed graft function in human kidney.

The complement system plays a pivotal role in the pathogenesis of ischemia-reperfusion injury in solid organ transplantation. Mirococept is a potent membrane-localizing complement inhibitor that can be administered ex vivo to the donor kidney prior to transplantation. To evaluate the efficacy of Mirococept in reducing delayed graft function (DGF) in deceased donor renal transplantation, we undertook the efficacy of mirococept (APT070) for preventing ischaemia-reperfusion injury in the kidney allograft (EMPIRIKAL) trial (ISRCTN49958194). A dose range of 5-25 mg would be tested, starting with 10 mg in cohort 1. No significant difference between Mirococept at 10 mg and control was detected; hence the study was stopped to enable a further dose saturation study in a porcine kidney model. The optimal dose of Mirococept in pig kidney was 80 mg. This dose did not induce any additional histological damage compared to controls or after a subsequent 3 hours of normothermic machine perfusion. The amount of unbound Mirococept postperfusion was found to be within the systemic dose range considered safe in the Phase I trial. The ex vivo administration of Mirococept is a safe and feasible approach to treat DGF in deceased donor kidney transplantation. The porcine kidney study identified an optimal dose of 80 mg (equivalent to 120 mg in human kidney) that provides a basis for further clinical development.

Hypoperfusion warm ischaemia time in renal transplants from donors after circulatory death.

BACKGROUND: The donor hypoperfusion phase before asystole in renal transplants from donors after circulatory death (DCD) has been considered responsible for worse outcomes than those from donors after brain death (DBD). METHODS: We included 10 309 adult renal transplants (7128 DBD and 3181 DCD; 1 January 2010-31 December 2016) from the UK Transplant Registry. We divided DCD renal transplants into groups according to hypoperfusion warm ischaemia time (HWIT). We compared delayed graft function (DGF) rates, primary non-function (PNF) rates and graft survival among them using DBD renal transplants as a reference. RESULTS: The DGF rate was 21.7% for DBD cases, but ∼40% for DCD cases with HWIT ≤30 min (0-10 min: 42.1%, 11-20 min: 43%, 21-30 min: 38.4%) and 60% for DCD cases with HWIT >30 min (P < 0.001). All DCD groups showed higher DGF risk than DBD renal transplants in multivariable analysis {0-10 min: odds ratio [OR] 2.686 [95% confidence interval (CI) 2.352-3.068]; 11-20 min: OR 2.531 [95% CI 2.003-3.198]; 21-30 min: OR 1.764 [95% CI 1.017-3.059]; >30 min: OR 5.814 [95% CI 2.798-12.081]}. The highest risk for DGF in DCD renal transplants with HWIT >30 min was confirmed by multivariable analysis [versus DBD: OR 5.814 (95% CI 2.798-12.081) versus DCD: 0-10 min: OR 2.165 (95% CI 1.038-4.505); 11-20 min: OR 2.299 (95% CI 1.075-4.902); 21-30 min: OR 3.3 (95% CI 1.33-8.197)]. No significant differences were detected regarding PNF rates (P = 0.713) or graft survival (P = 0.757), which was confirmed by multivariable analysis. CONCLUSIONS: HWIT >30 min increases the risk for DGF greatly, but without affecting PNF or graft survival.

Can we prevent poststroke cognitive impairment? An umbrella review of risk factors and treatments.

OBJECTIVES: Cognitive impairment poststroke is progressive. We aimed to synthesise the existing evidence evaluating risk factors and the effects of treatments to prevent/improve cognitive function in patients who had a stroke with cognitive impairment. DESIGN: Umbrella review. DATA SOURCE: Medline, PsycINFO, EMBASE, Cochrane and PROSPERO were searched from inception until 11 June 2019. ELIGIBILITY CRITERIA: Published systematic review (SR) that incorporated randomised controlled trials to investigate an intervention to improve poststroke cognitive impairment, or SR of longitudinal observational studies that evaluated the risk factors of this condition. No restrictions were applied. DATA EXTRACTION AND SYNTHESIS: From each eligible study, details were recorded by one reviewer in a validated form. Grading of Recommendations, Assessment, Development and Evaluations criteria were used to assess our certainty level of each outcome, and A Measurement Tool to Assess Systematic Reviews 2 to assess quality. RESULTS: Altogether, 3464 abstracts were retrieved, 135 full texts were evaluated and 22 SRs were included in the final analysis. From four SRs of observational studies, we found 19 significant associations with postulated risk factors, and those which we determined to be confident about were: atrial fibrillation (3 SRs, 25 original studies); relative risk 3.01 (1.96-4.61), ORs 2.4 (1.7-3.5) and 2.0 (1.4-2.8), leukoaraiosis, multiple and recurrent strokes, ORs 2.5 (1.9-3.4), 2.5 (1.9-3.1) and 2.3 (1.5-3.5), respectively. From 18 SRs of interventional trials, we found that interventions including physical activity or cognitive rehabilitation were enhancing cognitive function, while the certainty of the other interventions was rated low, due to limited methodological quality. CONCLUSIONS: This review represents common risk factors related to poststroke cognitive impairment, in particular atrial fibrillation, and points to different interventions that warrant attention in the development of treatment strategies. Physical activity and cognitive rehabilitation interventions showed evidence of enhancing cognitive function; however, we could not recommend a change in practice yet, due to lack of strong evidence. PROSPERO REGISTRATION NUMBER: CRD42018096667.

Risk and Secondary Prevention of Stroke Recurrence: A Population-Base Cohort Study.

BACKGROUND AND PURPOSE: With recent advances in secondary prevention management, stroke recurrence rates may have changed substantially. We aim to estimate risks and trends of stroke recurrence over the past 2 decades in a population-based cohort of patients with stroke. METHODS: Patients with a first-ever stroke between 1995 and 2018 in South London, United Kingdom (n=6052) were collected and analyzed. Rates of recurrent stroke with 95% CIs were stratified by 5-year period of index stroke and etiologic TOAST (Trial of ORG 10172 in Acute Stroke Treatment) subtype. Cumulative incidences were estimated and multivariate Cox models applied to examine associations of recurrence and recurrence-free survival. RESULTS: The rate of stroke recurrence at 5 years reduced from 18% (95% CI, 15%-21%) in those who had their stroke in 1995 to 1999 to 12% (10%-15%) in 2000 to 2005, and no improvement since. Recurrence-free survival has improved (35%, 1995-1999; 67%, 2010-2015). Risk of recurrence or death is lowest for small-vessel occlusion strokes and other ischemic causes (36% and 27% at 5 years, respectively). For cardioembolic and hemorrhagic index strokes around half of first recurrences are of the same type (54% and 51%, respectively). Over the whole study period a 54% increased risk of recurrence was observed among those who had atrial fibrillation before the index stroke (hazard ratio, 1.54 [1.09-2.17]). CONCLUSIONS: The rate of recurrence reduced until mid-2000s but has not changed over the last decade. The majority of cardioembolic or hemorrhagic strokes that have a recurrence are stroke of the same type indicating that the implementation of effective preventive strategies is still suboptimal in these stroke subtypes.

Long-Term Outcomes in Stroke Patients with Cognitive Impairment: A Population-Based Study.

This study assesses five year outcomes of patients with cognitive deficits within the first three months after stroke. Population-based data from the South London Stroke Register between 1995 and 2018 were studied. Cognitive function was assessed using the Abbreviated-Mental-Test or Mini-Mental-State-Examination. Multivariable Poisson regression models with robust standard errors were constructed, to evaluate relative risks (RRs) and associations between post-stroke deterioration in cognitive function during the first three months on dependency, mortality, depression and institutionalisation. A total of 6504 patients with first-ever strokes were registered with a mean age of 73 (SD: 13.2). During the first three months post-stoke, approximately one-third of these stroke survivors either cognitively improved (37%), deteriorated (30%) or remained unchanged (33%). Post-stroke cognitive impairment was associated with increases, in five years, of the risks of mortality, dependency, depression and being institutionalised by RRs 30% (95% confidence interval: 1.1-1.5), 90% (1.3-2.6), 60% (1.1-2.4) and 50% (1.1-2.3), respectively. Deterioration in cognitive function by 10% or more between seven days and three months was associated with an approximate two-fold increased risk in mortality, dependency, and being institutionalised after one year, compared to stable cognitive function; RRs 80% (1.1-3.0), 70% (1.2-2.4) and two-fold (1.3-3.2), respectively. Monitoring further change to maintain cognitive abilities should be a focus to improve outcomes.

UK renal transplant outcomes in low and high BMI recipients: the need for a national policy.

INTRODUCTION: We assessed the effect of recipient body mass index (BMI) on the outcomes of renal transplantation and the management of obese patients with end-stage renal disease across the UK. METHODS: We analyzed data of 25539 adult renal transplants (2007-2016) from the UK Transplant Registry. Patients were divided in BMI groups [underweight: < 18.5, normal: 18.5-24.9 (reference group), overweight: 25-29.9, class I obese: 30-34.9, class II/III obese: ≥ 35]. We also conducted a national survey of all UK renal transplant centers on the influence of BMI on decisions regarding management of renal transplant candidates. RESULTS: BMI ≥ 25 was an independent risk factor for delayed graft function and primary non-function (p ≤ 0.001). Underweight (p = 0.001), class I obese (p = 0.017) and class II/III obese recipients (p < 0.001) had poorer graft survival, however, 5- and 10-year graft survival rates were good. Patient survival was shorter for underweight recipients (p < 0.001) and longer for overweight (p = 0.028) and class I obese recipients (p = 0.013). The national survey revealed significant variability among transplant centers in BMI threshold for listing patients on transplant waiting list and limited support with conservative or surgical procedures for weight control. CONCLUSIONS: Obesity alone should not be a barrier for renal transplantation. A national strategy is required to give all patients equal chances in transplantation.

The Impact of Pre- and Post-Stroke Statin Use on Stroke Severity and Long-Term Outcomes: A Population-Based Cohort Study.

BACKGROUND: The benefit of statins on stroke incidence is well known. However, data on the relationship between pre- and post-stroke statin use, recurrence, and survival outcomes are limited. We aim to investigate the short- and long-term relationships between statin prescription, stroke recurrence, and survival in patients with first-ever ischemic stroke. METHODS: Data were collected from the population-based South London Stroke Register for the years 1995-2015. Patients were assessed at the time of first ever stroke, 3 months, and annually thereafter. Data on vascular risk factors, treatments prescribed, sociodemographic characteristics, stroke subtype, survival, and stroke recurrence were collected. Cox proportional hazard analyses were used to assess the relationship of statin prescriptions pre- and post-stroke on stroke severity, long-term recurrence and survival. RESULTS: Patients prescribed statins both pre- and post-stroke showed a 24% reduction in mortality (adjusted Hazard Ratio [aHR] 0.76, 0.60-0.97), those who were prescribed statins pre-stroke and then stopped post-stroke showed greater risk of mortality (aHR 1.85, 1.10-3.12) and stroke recurrence (aHR 3.25, 1.35-7.84) compared to those that were not prescribed statins at any time. No associations were observed between pre-stroke statin and severity of the initial stroke overall, though a protective effect against moderate/severe stroke (Glasgow Coma Scale ≤12) was observed in those aged 75+ years (aOR 0.70, 0.52-0.95). CONCLUSIONS: Statins play a significant role in improving the survival rates after a stroke. Adherence to the National Guidelines that promote statin treatment, primary and secondary prevention of stroke should be monitored and a focus for quality improvement programs.

PROFIT, a PROspective, randomised placebo controlled feasibility trial of Faecal mIcrobiota Transplantation in cirrhosis: study protocol for a single-blinded trial.

INTRODUCTION: Patients with advanced cirrhosis have enteric bacterial dysbiosis and translocation of bacteria and their products across the gut epithelial barrier. This culminates in systemic inflammation and endotoxaemia, inducing innate immune dysfunction which predisposes to infection, and development of complications such as bleeding, sepsis and hepatic encephalopathy. This feasibility study aims to assess the safety of administering faecal microbiota transplantion to patients with cirrhosis and explore the effect of the intervention on their prognosis by achieving restoration of a healthy gut microbiome. METHODS AND ANALYSIS: A PROspective, randomised placebo controlled feasibility trial of Faecal mIcrobiota Transplantation is a single-centre, randomised, single-blinded, placebo-controlled study evaluating faecal microbiota transplantation (FMT) against placebo. Patients with advanced but stable cirrhosis with a Model for End-Stage Liver Disease score between 10 and 16 will be recruited. Twenty-four patients will be randomised to FMT plus standard of care (as per our institutional practice) and eight patients to placebo in a ratio of 3:1. Patients will be evaluated at baseline before the study intervention is administered and at 7, 30 and 90 days post-intervention to assess safety and adverse events. FMT/placebo will be administered into the jejunum within 7 days of baseline. The primary outcome measure will be safety and feasibility as assessed by recruitment rates, tolerability and safety of FMT treatment. Results will be disseminated via peer-reviewed journals and international conferences. The recruitment of the first patient occurred on 23 May 2018. ETHICS AND DISSEMINATION: Research Ethics approval was given by the London South East Research Ethics committee (ref 17/LO/2081). TRIAL REGISTRATION NUMBER: NCT02862249 and EudraCT 2017-003629-13.

High HIV and active tuberculosis prevalence and increased mortality risk in adults with symptoms of TB: a systematic review and meta-analyses.

INTRODUCTION: HIV and tuberculosis (TB) remain leading causes of preventable death in low- and middle-income countries (LMICs). The World Health Organization (WHO) recommends HIV testing for all individuals with TB symptoms, but implementation has been suboptimal. We conducted a systematic literature review and meta-analyses to estimate HIV and TB prevalence, and short-term (two to six months) mortality, among adults with TB symptoms at community- and facility level. METHODS: We searched Embase, Global Health and MEDLINE databases, and reviewed conference abstracts for studies reporting simultaneous HIV and TB screening of adults in LMICs published between January 2003 and December 2017. Meta-analyses were performed to estimate prevalence of HIV, undiagnosed TB and mortality risk at different health system levels. RESULTS: Sixty-two studies including 260,792 symptomatic adults were identified, mostly from Africa and Asia. Median HIV prevalence was 19.2% (IQR: 8.3% to 40.4%) at community level, 55.7% (IQR: 20.9% to 71.2%) at primary care level and 80.7% (IQR: 73.8% to 84.6%) at hospital level. Median TB prevalence was 6.9% (IQR: 3.3% to 8.4%) at community, 20.5% (IQR: 11.7% to 46.4%) at primary care and 36.4% (IQR: 22.9% to 40.9%) at hospital level. Median short-term mortality was 22.6% (IQR: 15.6% to 27.7%) among inpatients, 3.1% (IQR: 1.2% to 4.2%) at primary care and 1.6% (95% CI: 0.45 to 4.13, n = 1 study) at community level. CONCLUSIONS: Adults with TB symptoms have extremely high prevalence of HIV infection, even when identified through community surveys. TB prevalence and mortality increased substantially at primary care and inpatient level respectively. Strategies to expand symptom-based TB screening combined with HIV and TB testing for all symptomatic individuals should be of the highest priority for both disease programmes in LMICs with generalized HIV epidemics. Interventions to reduce short-term mortality are urgently needed.

Rapid urine-based screening for tuberculosis in HIV-positive patients admitted to hospital in Africa (STAMP): a pragmatic, multicentre, parallel-group, double-blind, randomised controlled trial.

BACKGROUND: Current diagnostics for HIV-associated tuberculosis are suboptimal, with missed diagnoses contributing to high hospital mortality and approximately 374 000 annual HIV-positive deaths globally. Urine-based assays have a good diagnostic yield; therefore, we aimed to assess whether urine-based screening in HIV-positive inpatients for tuberculosis improved outcomes. METHODS: We did a pragmatic, multicentre, double-blind, randomised controlled trial in two hospitals in Malawi and South Africa. We included HIV-positive medical inpatients aged 18 years or more who were not taking tuberculosis treatment. We randomly assigned patients (1:1), using a computer-generated list of random block size stratified by site, to either the standard-of-care or the intervention screening group, irrespective of symptoms or clinical presentation. Attending clinicians made decisions about care; and patients, clinicians, and the study team were masked to the group allocation. In both groups, sputum was tested using the Xpert MTB/RIF assay (Xpert; Cepheid, Sunnyvale, CA, USA). In the standard-of-care group, urine samples were not tested for tuberculosis. In the intervention group, urine was tested with the Alere Determine TB-LAM Ag (TB-LAM; Alere, Waltham, MA, USA), and Xpert assays. The primary outcome was all-cause 56-day mortality. Subgroup analyses for the primary outcome were prespecified based on baseline CD4 count, haemoglobin, clinical suspicion for tuberculosis; and by study site and calendar time. We used an intention-to-treat principle for our analyses. This trial is registered with the ISRCTN registry, number ISRCTN71603869. FINDINGS: Between Oct 26, 2015, and Sept 19, 2017, we screened 4788 HIV-positive adults, of which 2600 (54%) were randomly assigned to the study groups (n=1300 for each group). 13 patients were excluded after randomisation from analysis in each group, leaving 2574 in the final intention-to-treat analysis (n=1287 in each group). At admission, 1861 patients were taking antiretroviral therapy and median CD4 count was 227 cells per µL (IQR 79-436). Mortality at 56 days was reported for 272 (21%) of 1287 patients in the standard-of-care group and 235 (18%) of 1287 in the intervention group (adjusted risk reduction [aRD] -2·8%, 95% CI -5·8 to 0·3; p=0·074). In three of the 12 prespecified, but underpowered subgroups, mortality was lower in the intervention group than in the standard-of-care group for CD4 counts less than 100 cells per µL (aRD -7·1%, 95% CI -13·7 to -0·4; p=0.036), severe anaemia (-9·0%, -16·6 to -1·3; p=0·021), and patients with clinically suspected tuberculosis (-5·7%, -10·9 to -0·5; p=0·033); with no difference by site or calendar period. Adverse events were similar in both groups. INTERPRETATION: Urine-based tuberculosis screening did not reduce overall mortality in all HIV-positive inpatients, but might benefit some high-risk subgroups. Implementation could contribute towards global targets to reduce tuberculosis mortality. FUNDING: Joint Global Health Trials Scheme of the Medical Research Council, the UK Department for International Development, and the Wellcome Trust.

Informed, advance refusals of treatment by people with severe mental illness in a randomised controlled trial of joint crisis plans: demand, content and correlates.

BACKGROUND: In the UK, crisis planning for mental health care should acknowledge the right to make an informed advance treatment refusal under the Mental Capacity Act 2005. Our aims were to estimate the demand for such treatment refusals within a sample of service users who had had a recent hospital admission for psychosis or bipolar disorder, and to examine the relationship between refusals, and service user characteristics. METHODS: To identify refusals we conducted content analysis of Joint Crisis Plans, which are plans formulated by service users and their clinical team with involvement from an external facilitator, and routine care plans in sub-samples from a multi-centre randomised controlled trial of Joint Crisis Plans (plus routine mental health care) versus routine care alone (CRIMSON) in England. Factors hypothesised to be associated with refusals were identified using the trial data collected through baseline interviews of service users and clinicians and collection of routine clinical data. RESULTS: Ninety-nine of 221 (45%) of the Joint Crisis Plans contained a treatment refusal compared to 10 of 424 (2.4%) baseline routine care plans. No Joint Crisis Plans recorded disagreement with refusals on the part of clinicians. Among those with completed Joint Crisis Plans, adjusted analyses indicated a significant association between treatment refusals and perceived coercion at baseline (odds ratio = 1.21, 95% CI 1.02-1.43), but not with baseline working alliance or a past history of involuntary admission. CONCLUSIONS: We demonstrated significant demand for written treatment refusals in line with the Mental Capacity Act 2005, which had not previously been elicited by the process of treatment planning. Future treatment/crisis plans should incorporate the opportunity for service users to record a treatment refusal during the drafting of such plans. TRIAL REGISTRATION: ISRCTN11501328 Registered 13th March 2008.

An evaluation of tuberculosis contact investigations against national standards.

BACKGROUND: Contact tracing is a key element in England's 2015 collaborative TB strategy, although proposed indicators of successful contact tracing remain undescribed. METHODS: We conducted descriptive and multivariable analyses of contact tracing of TB cases in London between 1 July 2012 and 31 December 2015 using cohort review data from London's TB Register, identifying characteristics associated with improved indicators and yield. RESULTS: Of the pulmonary TB cases notified, 60% (2716/4561) had sufficient information for inclusion. Of these, 91% (2481/2716) had at least 1 contact (median: 4/case (IQR: 2-6)) identified, with 86% (10 251/11 981) of these contacts evaluated. 4.1% (177/4328), 1.3% (45/3421) and 0.70% (51/7264) of evaluated contacts of pulmonary smear-positive, pulmonary smear-negative and non-pulmonary cases, respectively, had active disease. Cases who were former prisoners or male were less likely to have at least one contact identified than those never imprisoned or female, respectively. Cases diagnosed at clinics with more directly observed therapy or social workers were more likely to have one or more contacts identified. Contacts screened at a different clinic to their index case or of male index cases were less likely to be evaluated than those screened at the same clinic or of women, respectively; yield of active disease was similar by sex. 10% (490/4850) of evaluated child contacts had latent TB infection. CONCLUSIONS: These are the first London-wide estimates of TB contact tracing indicators which are important for monitoring the strategy's success and informing risk assessment of index cases. Understanding why differences in indicators occur between groups could improve contact tracing outcomes.

Effectiveness of Seasonal Malaria Chemoprevention in Children under Ten Years of Age in Senegal: A Stepped-Wedge Cluster-Randomised Trial.

BACKGROUND: Seasonal Malaria Chemoprevention (SMC) with sulfadoxine-pyrimethamine (SP) plus amodiaquine (AQ), given each month during the transmission season, is recommended for children living in areas of the Sahel where malaria transmission is highly seasonal. The recommendation for SMC is currently limited to children under five years of age, but, in many areas of seasonal transmission, the burden in older children may justify extending this age limit. This study was done to determine the effectiveness of SMC in Senegalese children up to ten years of age. METHODS AND FINDINGS: SMC was introduced into three districts over three years in central Senegal using a stepped-wedge cluster-randomised design. A census of the population was undertaken and a surveillance system was established to record all deaths and to record all cases of malaria seen at health facilities. A pharmacovigilance system was put in place to detect adverse drug reactions. Fifty-four health posts were randomised. Nine started implementation of SMC in 2008, 18 in 2009, and a further 18 in 2010, with 9 remaining as controls. In the first year of implementation, SMC was delivered to children aged 3-59 months; the age range was then extended for the latter two years of the study to include children up to 10 years of age. Cluster sample surveys at the end of each transmission season were done to measure coverage of SMC and the prevalence of parasitaemia and anaemia, to monitor molecular markers of drug resistance, and to measure insecticide-treated net (ITN) use. Entomological monitoring and assessment of costs of delivery in each health post and of community attitudes to SMC were also undertaken. About 780,000 treatments were administered over three years. Coverage exceeded 80% each month. Mortality, the primary endpoint, was similar in SMC and control areas (4.6 and 4.5 per 1000 respectively in children under 5 years and 1.3 and 1.2 per 1000 in children 5-9 years of age; the overall mortality rate ratio [SMC: no SMC] was 0.90, 95% CI 0.68-1.2, p = 0.496). A reduction of 60% (95% CI 54%-64%, p < 0.001) in the incidence of malaria cases confirmed by a rapid diagnostic test (RDT) and a reduction of 69% (95% CI 65%-72%, p < 0.001) in the number of treatments for malaria (confirmed and unconfirmed) was observed in children. In areas where SMC was implemented, incidence of confirmed malaria in adults and in children too old to receive SMC was reduced by 26% (95% CI 18%-33%, p < 0.001) and the total number of treatments for malaria (confirmed and unconfirmed) in these older age groups was reduced by 29% (95% CI 21%-35%, p < 0.001). One hundred and twenty-three children were admitted to hospital with a diagnosis of severe malaria, with 64 in control areas and 59 in SMC areas, showing a reduction in the incidence rate of severe disease of 45% (95% CI 5%-68%, p = 0.031). Estimates of the reduction in the prevalence of parasitaemia at the end of the transmission season in SMC areas were 68% (95% CI 35%-85%) p = 0.002 in 2008, 84% (95% CI 58%-94%, p < 0.001) in 2009, and 30% (95% CI -130%-79%, p = 0.56) in 2010. SMC was well tolerated with no serious adverse reactions attributable to SMC drugs. Vomiting was the most commonly reported mild adverse event but was reported in less than 1% of treatments. The average cost of delivery was US$0.50 per child per month, but varied widely depending on the size of the health post. Limitations included the low rate of mortality, which limited our ability to detect an effect on this endpoint. CONCLUSIONS: SMC substantially reduced the incidence of outpatient cases of malaria and of severe malaria in children, but no difference in all-cause mortality was observed. Introduction of SMC was associated with an overall reduction in malaria incidence in untreated age groups. In many areas of Africa with seasonal malaria, there is a substantial burden in older children that could be prevented by SMC. SMC in older children is well tolerated and effective and can contribute to reducing malaria transmission. TRIAL REGISTRATION: ClinicalTrials.gov NCT00712374.