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Objectives Informing research participants of the results of studies in which they took part is viewed as an ethical imperative. However, there is little guidance in the literature about how to do this. The Fluoxetine Or Control Under Supervision trial randomised 3127 patients with a recent acute stroke to 6 months of fluoxetine or placebo and was published in the Lancet on 5 December 2018. The trial team decided to inform the participants of the results at exactly the same time as the Lancet publication, and also whether they had been allocated fluoxetine or placebo. In this report, we describe how we informed participants of the results.Design In the 6-month and 12-month follow-up questionnaires, we invited participants to provide an email address if they wished to be informed of the results of the trial. We re-opened our trial telephone helpline between 5 December 2018 and 31 March 2019.Setting UK stroke services.Participants 3127 participants were randomised. 2847 returned 6-month follow-up forms and 2703 returned 12-month follow-up forms; the remaining participants had died (380), withdrawn consent or did not respond.Results Of those returning follow-up questionnaires, a total of 1845 email addresses were provided and a further 50 people requested results to be sent by post. Results were sent to all email and postal addresses provided; 309 emails were returned unrecognised. Seventeen people replied, of whom three called the helpline and the rest responded by email.Conclusion It is feasible to disseminate results of large trials to research participants, though only around 60% of those randomised wanted to receive the results. The system we developed was efficient and required very little resource, and could be replicated by trialists in the future.Trial registration number ISRCTN83290762; Post-results.

We performed a literature review to identify articles regarding the state of urological cancers in low-to-middle-income countries (LMICs). The challenges that LMICs face are multifactorial and can include poor health education, inadequate screening, as well as limited access to treatment options and trained urologists. Many of the gold standard treatments in high-income countries (HICs) are scarce in LMICs due to their poor socioeconomic status, leading to an advanced stage of disease at diagnosis and, ultimately, a higher mortality rate. These standards of care are vital components of oncological disease management; however, the current and sparse literature available from LMICs indicates that there are many obstacles delaying early diagnosis and management options in LMICs. In the era of evolving medical diagnosis and treatments, sufficient data must be gathered and understood in order to provide appropriate diagnostic and treatment options to curtail rising mortality rates and, therefore, help to alleviate the burden in LMICs.

Abstract Aims The objective of this study was to examine associations between elevated depressive symptoms and increased risk of adverse clinical events patients with heart failure and reduced ejection fraction (HFrEF), as well as the potential contribution of health behaviours. Methods and results One hundred forty‐two men and women with HFrEF were enrolled through heart failure (HF) clinics and followed over time. At baseline and 6 months, depressive symptoms were assessed by the Beck Depression Inventory‐II (BDI‐II) and HFrEF disease activity by B‐type natriuretic peptide (BNP). The Self‐Care of Heart Failure Index (SCHFI) was used to assess HF self‐care behaviours. Proportional hazards regression models assessed the contribution of depressive symptoms and HFrEF disease biomarkers on death or cardiovascular hospitalization. Over a median follow‐up period of 4 years, 42 patients (30%) died, and 84 (60%) had cardiovascular hospitalizations. A 10‐point higher baseline BDI‐II score was associated with a 35% greater risk of death or cardiovascular hospitalization. Higher baseline BDI‐II scores were associated with poorer HF self‐care maintenance behaviours (R = −0.30, P

Background: Cardiovascular disease is the leading cause of death among women in the United States. Past research has highlighted the importance of the relationship between female-specific demographics and traditional risk factors. The present analysis aimed to identify the prevalence of modifiable risk factors in women attending a community cardiovascular health screening. Methods: Data collected between 2011 and 2019 were obtained from the Houston HeartReach Registry. Participants were classified as having or not having each of 4 traditional cardiometabolic risk factors: hypertension, diabetes, body mass index indicating overweight or obesity, and dyslipidemia. Differences in prevalence were compared using the Pearson χ2 test. Results: Most participants had hypertension, overweight or obesity, and dyslipidemia. Older women (≥65 years) had the highest prevalence of all cardiometabolic risk factors. Black participants had a higher prevalence of hypertension (P = .006) and a lower prevalence of dyslipidemia (P = .009) than non-Black participants. Hispanic participants had a lower prevalence of hypertension (P < .001) and a higher prevalence of overweight or obesity (P = .03) than non-Hispanic participants. Participants in the lowest household income bracket (

Background: Alzheimer’s disease (AD) is the most commonly occurring form of dementia. It is predominantly a disease of later life, affecting 5% of those over 65 in the UK. Objectives: Review and update guidance to the NHS in England and Wales on the clinical effectiveness and cost-effectiveness of donepezil, galantamine, rivastigmine [acetylcholinesterase inhibitors (AChEIs)] and memantine within their licensed indications for the treatment of AD, which was issued in November 2006 (amended September 2007 and August 2009). Data sources: Electronic databases were searched for systematic reviews and/or meta-analyses, randomised controlled trials (RCTs) and ongoing research in November 2009 and updated in March 2010; this updated search revealed no new includable studies. The databases searched included The Cochrane Library (2009 Issue 4, Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials), MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, PsycINFO, EconLit, ISI Web of Science Databases – Science Citation Index, Conference Proceedings Citation Index, and BIOSIS; the Centre for Reviews and Dissemination (CRD) databases – NHS Economic Evaluation Database, Health Technology Assessment, and Database of Abstracts of Reviews of Effects. Review methods: The clinical effectiveness systematic review was undertaken following the principles published by the NHS CRD. We included RCTs whose population was people with AD. The intervention and comparators depended on disease severity, measured by the Mini Mental State Examination (MMSE). Interventions: mild AD (MMSE 21–26) – donepezil, galantamine and rivastigmine; moderate AD (MMSE 10–20) – donepezil, galantamine, rivastigmine and memantine; severe AD (MMSE 99% probability that the AChEIs are more cost-effective than BSC. These analyses assume that the AChEIs have no effect on survival. For the AChEIs, in people with mild to moderate AD, the probabilistic sensitivity analyses suggested that donepezil is the most cost-effective, with a 28% probability of being the most cost-effective option at a WTP of £30,000 per QALY (27% at a WTP of £20,000 per QALY). In the deterministic results, donepezil dominates the other drugs and BSC, which, along with rivastigmine patches, are associated with greater costs and fewer QALYs. Thus, although galantamine has a slightly cheaper total cost than donepezil (£69,592 vs £69,624), the slightly greater QALY gains from donepezil (1.616 vs 1.617) are enough for donepezil to dominate galantamine.The probability that memantine is cost-effective in a moderate to severe cohort compared with BSC at a WTP of £30,000 per QALY is 38% (and 28% at a WTP of £20,000 per QALY). The deterministic ICER for memantine is £32,100 per/QALY and the probabilistic ICER is £36,700 per/QALY. Limitations: Trials were of 6 months maximum follow-up, lacked reporting of key outcomes, provided no subgroup analyses and used insensitive measures. Searches were limited to English language, The model does not include behavioural symptoms and there is uncertainty about the model structure and parameters. Conclusions: The additional clinical effectiveness evidence identified continues to suggest clinical benefit from the AChEIs in alleviating AD symptoms, although there is debate about the magnitude of the effect. Although there is also new evidence on the effectiveness of memantine, it remains less supportive of this drug’s use than the evidence for AChEIs. The conclusions concerning cost-effectiveness are quite different from the previous assessment. This is because both the changes in effectiveness and costs between drug use and non-drug use underlying the ICERs are very small. This leads to highly uncertain results, which are very sensitive to change. Research priorities: RCTs to include mortality, time to institutionalisation and quality of life, powered for subgroup analysis. Funding: The National Institute for Health Research Health Technology Assessment programme.

Background: Chronic myeloid leukaemia (CML) is a form of cancer affecting the blood, characterised by excessive proliferation of white blood cells in the bone marrow and circulating blood. In the UK, an estimated 560 new cases of CML are diagnosed each year. Objectives: The purpose of this study was to assess the clinical effectiveness and cost-effectiveness of dasatinib and nilotinib in the treatment of people with imatinib-resistant (ImR) and imatinib-intolerant (ImI) CML. A systematic review of the clinical effectiveness literature, a review of manufacturer submissions and a critique and exploration of manufacturer submissions for accelerated phase and blast crisis CML were carried out and a decision-analytic model was developed to estimate the cost-effectiveness of dasatinib and nilotinib in chronic phase CML. Systematic review methods: Key databases were searched for relevant studies from their inception to June 2009 [MEDLINE (including MEDLINE In-Process & Other Non-Indexed Citations), EMBASE, (ISI Web of Science) Conference Proceedings Citation Index and four others]. One reviewer assessed titles and abstracts of studies identified by the search strategy, with a sample checked by a second reviewer. The full text of relevant papers was obtained and screened against the full inclusion criteria independently by two reviewers. Data from included studies were extracted by one reviewer and checked by a second. Clinical effectiveness studies were synthesised through narrative review. Economic evaluation methods: Cost-effectiveness analyses reported in manufacturer submissions to the National Institute of Health and Clinical Excellence were critically appraised and summarised narratively. In addition, the models for accelerated phase and blast crisis underwent a more detailed critique and exploration. Two separate decision-analytic models were developed for chronic phase CML, one simulating a cohort of individuals who have shown or developed resistance to normal dose imatinib and one representing individuals who have been unable to continue imatinib treatment owing to adverse events. One-way, multiway and probabilistic sensitivity analyses were performed to explore structural and parameter uncertainty. Results: Fifteen studies were included in the systematic review. Chronic phase: effectiveness data were limited but dasatinib and nilotinib appeared efficacious in terms of obtaining cytogenetic response and haematological response in both ImR and ImI populations. In terms of cost-effectiveness, it was extremely difficult to reach any conclusions regarding either agent in the ImR population. All three models (Novartis, PenTAG and Bristol-Myers Squibb) were seriously flawed in one way or another, as a consequence of the paucity of data appropriate to construct robust decision-analytic models. Accelerated and blast crisis: all available data originated from observational single-arm studies and there were considerable and potentially important differences in baseline characteristics which seriously undermined any process for making meaningful comparisons between treatments. Owing to a lack of available clinical data, de novo models of accelerated phase and blast crisis have not been developed. The economic evaluations carried out by the manufacturers of nilotinib and dasatinib were seriously undermined by the absence of evidence on high-dose imatinib in these populations. Limitations: The study has been necessarily constrained by the paucity of available clinical data, the differences in definitions used in the studies and the subsequent impossibility of undertaking a meaningful cost-effectiveness analyses to inform all policy questions. Conclusions: Dasatinib and nilotinib appeared efficacious in terms of obtaining cytogenetic and haematological responses in both ImR and ImI populations. It was difficult to reach any cost-effectiveness conclusions as a consequence of the paucity of the data. Future research should include a three-way, double-blind, randomised clinical trial of dasatinib, nilotinib and high-dose imatinib. Funding: The National Institute of Health Research Healthy Technology Assessment Programme.

Objectives: To investigate the harmful health effects of taking ecstasy (3,4-methylenedioxymethamphetamine, MDMA) for recreational purposes. Data sources: MEDLINE, EMBASE, PsycINFO and Web of Knowledge were searched. Additional information on deaths was collected from the General Mortality Register (GMR) and the Special Mortality Register collated by the National Programme on Substance Abuse Deaths (np-SAD). Review methods: Studies were categorised according to design, with systematic research syntheses (Level I evidence) the most valid and least open to bias. Where Level I evidence was not available, controlled observational studies (Level II evidence) were systematically reviewed. If neither Level I nor Level II evidence was available, uncontrolled case series and case reports (Level III evidence) were systematically surveyed. Data were extracted by one reviewer and a sample checked by a second. The heterogeneity of Level II evidence was addressed by undertaking stratified analyses for current and former ecstasy users and comparing them either with control groups using other illegal drugs but not ecstasy (polydrug controls) or with controls naïve to illegal drugs (drug-naïve controls). Statistical heterogeneity was minimised by using a random-effects model throughout and investigated using study-level regression analysis (metaregression). Results: Five Level I syntheses were identified; for each it was difficult to ascertain the exact methods adopted and evidence included. Small but significant deficits for ecstasy users compared to controls were reported in areas relating to attention, memory, psychomotor speed, executive systems functioning, and self-reported depressive symptoms. Data from Level II studies were directly pooled for seven individual outcomes, suggesting that ecstasy users performed worse than controls on common measures of immediate and delayed verbal recall (RAVLT, RBMT, digit span). No difference was seen in IQ (NART). The 915 outcome measures identified in Level II studies were analysed in broad domains: immediate and delayed verbal and visual memory, working memory, two measures of attention, three measures of executive function, perceptual organisation, self-rated depression, memory and anxiety, and impulsivity measured objectively and subjectively. Ecstasy users performed significantly worse than polydrug controls in 13/16 domains and significantly worse than drug-naïve controls in 7/12 domains for which sufficient data were available. The largest, most consistent exposure effects were seen in meta-analyses of memory (especially verbal and working memory, with less marked effects seen in visual memory). Former ecstasy users frequently showed deficits that matched or exceeded those seen amongst current users. At aggregate level, the effects do not appear to be dose-related, but are variably confounded by other drug use, particularly alcohol. Of Level III evidence, in the 10 years to 2006, the np-SAD and the GMR recorded an average of around 50 drug-related deaths per year involving ecstasy; it was the sole drug implicated in around 10 cases per year. Retrospective case series, based on hospital emergency department records, reported a death rate of 0–2% from emergency admissions related to ecstasy. Two major syndromes are most commonly reported as the immediate cause of death in fatal cases: hyperthermia and hyponatraemia. Conclusions: A broad range of relatively low-quality literature suggests that recreational use of ecstasy is associated with significant deficits in neurocognitive function (particularly immediate and delayed verbal memory) and increased psychopathological symptoms. The clinical significance of the exposure effect in individual cases will be variable but, on average, deficits are likely to be relatively small. Ecstasy is associated with a range of acute harms but appears to be a rare cause of death in isolation.

HIP94235 b, a 120 Myr old sub-Neptune, provides us the unique opportunity to study mass loss at a pivotal stage of the system’s evolution: the end of a 100 Myr old phase of intense XUV irradiation. We present two observations of HIP94235 b using the Hubble Space Telescope’s Space Telescope Imaging Spectrograph in the Ly α wavelength region. We do not observe discernible differences across either the blue and red wings of the Ly α line profile in and out of transit, and report no significant detection of outflowing neutral hydrogen around the planet. We constrain the rate of neutral hydrogen escaping HIP94235 b to an upper limit of 10 ^13 gs ^−1 , which remains consistent with energy-limited model predictions of 10 ^11 gs ^−1 . The Ly α nondetection is likely due to the extremely short photoionization timescale of the neutral hydrogen escaping the planet’s atmosphere. This timescale, approximately 15 minutes, is significantly shorter than that of any other planets with STIS observations. Through energy-limited mass loss models, we anticipate that HIP94235 b will transition into a super-Earth within a timescale of 1 Gyr.

Small, close-in exoplanets are divided into two subpopulations: super-Earths and sub-Neptunes. Most super-Earths are thought to have lost their primordially accreted hydrogen-dominated atmospheres via thermally driven winds. We consider the global chemical equilibrium of super-Earths and the lasting impacts of their fleeting hydrogen atmospheres. We find that hydrogen is efficiently sequestered into the interior, oxidizing iron and endogenously producing ∼0.5%–1.0% water by mass. As the atmospheres of super-Earths are continuously sculpted by mass loss and chemical equilibration, they remain hydrogen-dominated by mole (number) fraction but become steam-dominated by mass, which may be observable with JWST for planets transitioning across the radius valley. One of the main effects of efficient sequestration of hydrogen into the interior is to produce an underdense bulk interior compared to that of Earth. We predict bulk densities of super-Earths to be ∼5.0 g cm ^−3 for a 1 M _⊕ planet, which is consistent with high-precision mass measurements and also population-level inference analyses from atmospheric escape models.

Within the first few hundreds of millions of years, many physical processes sculpt the eventual properties of young planets. NASA’s Transiting Exoplanet Survey Satellite (TESS) mission has surveyed young stellar associations across the entire sky for transiting planets, providing glimpses into the various stages of planetary evolution. Using our own detection pipeline, we search a magnitude-limited sample of 7219 young stars (≲200 Myr) observed in the first 4 yr of TESS for small (2–8 R _⊕ ), short period (1.6–20 days) transiting planets. The completeness of our survey is characterized by a series of injection and recovery simulations. Our analysis of TESS 2 minute cadence and Full Frame Image (FFI) light curves recover all known TESS Objects of Interest (TOIs), as well as four new planet candidates not previously identified as TOIs. We derive an occurrence rate of ${35}_{-10}^{+13} \% $ for mini-Neptunes and ${27}_{-8}^{+10} \% $ for super-Neptunes from the 2 minute cadence data, and ${22}_{-6.8}^{+8.6}$ % for mini-Neptunes and ${13}_{-4.9}^{+3.9}$ % for super-Neptunes from the FFI data. To independently validate our results, we compare our survey yield with the predicted planet yield assuming Kepler planet statistics. We consistently find a mild increase in the occurrence of super-Neptunes and a significant increase in the occurrence of Neptune-sized planets with orbital periods of 6.2–12 days when compared to their mature counterparts. The young planet distribution from our study is most consistent with evolution models describing the early contraction of hydrogen-dominated atmospheres undergoing atmospheric escape and inconsistent with heavier atmosphere models offering only mild radial contraction early on.