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Background and ObjectivesIllicit prescription painkiller use among university students is a growing concern, influenced by a range of demographic, mental and physical health, academic, and co-substance use factors contributing to the elevated risk. However, Canadian evidence specific to university students remains limited. This study examined correlates of self-reported illicit prescription painkiller use among Canadian university students.MethodA secondary analysis of data from the American College Health Association National College Health Assessment II Canadian university edition was conducted. The dependent variable was past-year illicit prescription painkiller use, defined as a yes or no response to self-reported use of prescription painkillers without a prescription from a healthcare provider in the past 12 months. Descriptive statistics and binary logistic regression were used to examine associated demographic, academic, physical health, mental health, and co-substance use factors.ResultsAmong the analytical sample of 44,508, 5.8% (n = 2,585) reported illicit prescription painkiller use in the past 12 months. Significant predictors included race, sex, sexual identity, international student status, mental health factors, chronic illness, academic factors, and co-substance use. Higher odds of use were observed among West Asian and Black students, international students, students with chronic illness, students reporting hopelessness, feeling overwhelmed, depression with functional impairment, or suicidal ideation, and students reporting tobacco, alcohol, e-cigarette, or cocaine use.ConclusionsIllicit prescription painkiller use among Canadian university students was associated with demographic, mental health, physical health, academic, and co-substance use factors. Findings support campus-based prevention and support strategies that integrate substance use education, mental health services, and equitable access to care. Understanding Prescription Painkiller Use Without a Prescription Among Canadian University Students: The Role of Mental Health, Student Characteristics, Physical Health, Academics, and Substance UsePlain Language SummaryPrescription painkiller use such as opioids is an important concern among university students. This study used Canadian data from the American College Health Association National College Health Assessment II to examine which student characteristics were associated with this behaviour.Among the analytic sample, 5.8% reported using prescription painkillers without a prescription in the past 12 months. Higher odds of use were seen among students with mental health concerns, chronic illness, international student status, and use of other substances such as tobacco, alcohol, e-cigarettes, and cocaine. Differences were also observed by race, sex, sexual identity, academic year, and grade point average.These findings suggest that prescription painkiller use without a prescription is linked to broader health, social, and academic factors. Universities may benefit from prevention strategies that combine substance use education, mental health support, and improved access to care. La consommation illicite d’analgésiques sur ordonnance chez les étudiants universitaires est un sujet de préoccupation croissante. Elle est influencée par un éventail de facteurs démographiques, liés à la santé mentale et physique, scolaires et liés à la consommation concomitante d’autres substances psychoactives qui contribuent à l’accroissement du risque. Cependant, les données canadiennes propres aux étudiants universitaires demeurent limitées. Cette étude a examiné les facteurs associés à la consommation illicite autodéclarée d’analgésiques sur ordonnance chez les étudiants universitaires canadiens. Nous avons réalisé une analyse secondaire des données tirées de l’édition canadienne de l’enquête de l’American College Health Association National College Health Assessment II. La variable dépendante était la consommation illicite d’analgésiques sur ordonnance au cours de la dernière année, définie comme une réponse affirmative ou négative à la question portant sur la consommation autodéclarée d’analgésiques sur ordonnance sans détenir une ordonnance d’un professionnel de la santé au cours des 12 derniers mois. Les facteurs démographiques, scolaires, liés à la santé physique et mentale et liés à la consommation concomitante d’autres substances psychoactives ont été évalués à l’aide de statistiques descriptives et d’une régression logistique binaire. Dans l’échantillon d’analyse de 44 508 personnes, 5,8 % (n = 2 585) d’entre elles ont déclaré avoir consommé de manière illicite des analgésiques sur ordonnance au cours des 12 derniers mois. Les facteurs prédictifs importants comprenaient l’origine ethnique, le sexe, l’identité sexuelle, le statut d’étudiant étranger, les facteurs liés à la santé mentale, la maladie chronique, les facteurs scolaires et la consommation concomitante de substances psychoactives. Un risque plus élevé de consommation a été observé chez les étudiants originaires de l’Asie de l’Ouest et de race noire, les étudiants étrangers, les étudiants atteints d’une maladie chronique, les étudiants ayant déclaré éprouver un sentiment de désespoir ou de surmenage, ceux atteints de dépression s’accompagnant d’altération fonctionnelle ou d’idées suicidaires, et les étudiants qui consomment du tabac, de l’alcool, des cigarettes électroniques ou de la cocaïne. La consommation illicite d’analgésiques sur ordonnance chez les étudiants canadiens a été associée à des facteurs démographiques, liés à la santé mentale et physique, scolaires et liés à la consommation concomitante d’autres substances psychoactives. Les résultats plaident en faveur des stratégies de prévention et de soutien mises en œuvre sur les campus, qui associent l’éducation sur la consommation de substances psychoactives, les services de santé mentale et l’accès équitable aux soins.

To systematically review evidence of the clinical effectiveness of psychosocial interventions for adults with substance use disorder that have a co-occurring common mental health disorder or borderline personality disorder. To identify papers that estimate the cost-effectiveness of interventions for patients with substance use disorder and common mental health disorder or borderline personality disorder. An umbrella review (a systematic review of systematic reviews) for clinical effectiveness was conducted. Systematic database searches [MEDLINE, EMBASE, PsycInfo® (American Psychological Association, Washington, DC, USA), Cochrane Database of Systematic Reviews, and Web of Science] were carried out in February 2024. Inclusion criteria: Adults with substance use disorder and common mental health disorder or borderline personality disorder; psychosocial interventions (with or without pharmacological therapies); comparators psychosocial treatments, treatment as usual, waitlist/no treatment; systematic reviews of randomised controlled trials. Data, including critical appraisal, were extracted into a standardised form by one reviewer, and checked by another. Data were discussed in a narrative review. A literature review of MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, and EconLit were undertaken to identify cost-effectiveness papers. An illustrative model was constructed to show how cost-effectiveness could be calculated if data were available. Of 5420 unique records, 30 systematic reviews were included in the clinical review. The methodological quality of the reviews was generally good. Most of the interventions and many of the active comparators studied resulted in some improvement for patients. Most reviews focused on depression, anxiety or post-traumatic stress disorder; there were some looking at mixed common mental health disorder or borderline personality disorder. There was much heterogeneity both between reviews, and between the randomised controlled trials within the reviews. The results suggested integrated treatment for co-occurring diagnosis patients may be better for common mental health disorder outcomes than treatment as usual of parallel uncoordinated services. One study was identified that met the cost-effectiveness criteria. However, this reported results alongside a clinical study and was not a modelling paper. The illustrative model should aid future researchers. Heterogeneity made it difficult to reach an overall conclusion about which therapies were best. Most reviews stated the results were not generalisable across all populations or settings. There were few reviews of borderline personality disorder; or of common mental health disorder other than anxiety/depression/post-traumatic stress disorder. Future research comparing integrated with parallel or sequential treatment, with follow-up of 6 months or longer, and sample size large enough to encompass dropout, may be beneficial. No implications for current practice could be recommended due to heterogeneity of reviews/randomised controlled trials within reviews. This study is registered as PROSPERO CRD42024515813. This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: NIHR166951) and is published in full in Health Technology Assessment; Vol. 30, No. 49. See the NIHR Funding and Awards website for further award information. People with substance use disorders (alcohol or drug) can have a co-occurring (comorbid) mental health disorder. The National Institute for Health and Care Excellence has produced guidance on treating people with co-occurring substance use and serious mental health disorder; however, this does not cover people with less severe mental health difficulties. This project aimed to identify evidence on the effectiveness (how well treatments worked) of psychosocial interventions (talking therapies or services designed to reduce substance use and lessen the symptoms of mental health disorders) for adults with substance use disorders and co-occurring common mental health disorders or borderline personality disorder. Therapies or services relevant to UK practice were investigated. Systematic literature reviews of randomised controlled trials (studies comparing two or more treatments allocated randomly) were sought. This project included 30 reviews of clinical effectiveness. Most reviews investigated depression, anxiety or post-traumatic stress disorder. Most therapies studied improved mental health and reduced substance use; as did some of the comparators (treatment as usual). The trials included in the reviews differed in the people treated, therapies, and the way outcomes of substance use, or mental health, were assessed. This made it difficult to draw conclusions about which therapies were best. Treating both substance use and mental health using a co-ordinated approach to co-occurring disorders (integrated treatment) was usually better than treating one condition alone, and sometimes better than two separate (parallel) treatments at the same time. There was limited evidence looking at treating one condition then the other (sequential), but evidence suggested it was similarly effective to integrated treatment. There was not much research on whether these treatments are cost-effective (good value for money). However, an example was developed to show how the cost-effectiveness of a promising therapy could be estimated.

Post-acute sequelae of COVID-19 or post-COVID-19 condition (also known as long COVID) affects 1-5% of adults globally, most commonly with fatigue, and no evidence-based therapies are available. We aimed to evaluate the efficacy of repurposed medications in fatigue management in adults with long COVID. We did a phase 3, four-group, randomised, controlled, adaptive platform, open-label drug trial nested within a pragmatic, multicentre, cluster-randomised trial of an integrated care pathway (ICP) for long COVID across 12 UK National Health Service (NHS) specialist long COVID care clinics in the UK. Participants had to be adults (>18 years) with long COVID who had not been hospitalised with COVID-19. In addition to NHS specialist-led long COVID care (hereafter, usual care), participants in the ICP trial could receive multiorgan MRI and clinical decision support and/or app-based rehabilitation. Initially, participants in the ICP trial were invited to enrol in the drug trial, but slow recruitment to the drug trial led to establishment of additional drug-only trial sites. Participants enrolled at either ICP trial sites or drug-only trial sites were randomly assigned (1:1:1:1) to receive colchicine 500 μg twice daily, rivaroxaban 10 mg once daily, famotidine 40 mg with loratadine 10 mg once daily, or no drug for 12 weeks. All participants received usual care. Randomisation was done electronically in blocks (various block sizes) and stratified by site, birth sex, ICP trial group allocation, and being a new or previous patient of a drug-only site. The primary endpoint was 12-week fatigue, assessed with the Fatigue Assessment Scale (FAS; with scores ranging from 10 [no fatigue] to 50 [debilitating fatigue], and a >10% change considered clinically meaningful) among randomly assigned individuals who had available baseline and 12-week data, adjusting for baseline fatigue and clinically relevant covariates. Secondary endpoints included 24-week FAS. The nested drug trial is registered, ISRCTN10665760. The trial is complete. Of 6035 eligible participants, 778 (383 co-enrolled in the ICP trial and 395 directly enrolled in the drug trial) were randomly assigned between Aug 22, 2022, and Aug 7, 2024 to colchicine (n=192), famotidine-loratadine (n=193), rivaroxaban (n=197), or no drug (usual long COVID care only; n=196). The mean age of participants was 46 years (SD 12·4), 495 (64%) of 778 were female, and 91 (12%) were from a non-White ethnic group. Across all trial groups, there was severe baseline fatigue (mean FAS score 36·8 [SD 7·49]) and a clinically relevant mean FAS reduction of 4·3 points to 32·5 (SD 9·13) at 12 weeks. Adjusted analyses showed small, statistically significant FAS reductions in the colchicine (-1·49 points [95% CI -2·92 to -0·06], p=0·041) and famotidine-loratadine (-1·48 points [-2·88 to -0·08], p=0·038) groups, but not in the rivaroxaban group (-1·06 points [-2·47 to 0·35, p=0·139), compared with no study drug at 12 weeks. However, 24-week FAS scores, 12 weeks after drug cessation, were not significantly different between groups. Treatment was well tolerated, with ten serious adverse events (requiring hospitalisation but unrelated to trial drugs) reported in eight (1·0%) of the 778 participants, five of which were in three participants in the rivaroxaban group. In participants with long COVID, severe fatigue reduced in all study groups-including the no drug group-over 12 weeks, with small additional reductions in the colchicine and famotidine-loratadine groups compared with the no drug group. Modest effects on FAS were not sustained after drug withdrawal. Long-term long COVID symptom benefit is unlikely with these drugs alone. Future trials could investigate the use of these or other repurposed drugs in specific subgroups of patients with long COVID, combination therapies, and how care is delivered. UK National Institute for Health and Care Research.

Organised competitive sport represents a unique socio-cultural environment in which performance demands, social influences within sport and anti-doping frameworks shape athletes' substance use behaviours. In 2021, the World Anti-Doping Agency introduced a 'Substances of Abuse' category to address athletes' drug use outside the context of sport. Athletes may use psychoactive drugs, for example, to manage sports related pressure, stress and mental health challenges rather than to enhance performance. While doping in sport remains a widely studied phenomenon, less attention has been given to psychoactive drug use behaviours among athletes involved in organised sports that are driven by motives other than performance enhancement. This scoping review explored psychosocial motivations and associated risk factors for psychoactive drug use across varied athletic populations including young, professional, elite and retired athletes. A scoping review was conducted using a systematic search strategy in the Scopus, Web of Science and PsycINFO databases. The review followed JBI guidelines and the PRISMA-ScR framework. It focused on peer reviewed studies published between 2014 and 2024. Covidence software was utilised for researchers' independent screening processes and the Sport Drug Control Model guided the review's thematic analysis. 38 studies were included. Most studies were conducted in a North American context and were primarily focused on young athletes (55.3%). Cannabis was the most examined drug (68.4%). Athletes' motives for psychoactive drug use were related to benefit appraisal, especially perceived benefits for mood enhancement (for example, relaxation after a game or coping with injuries). Risk factors included young age, male gender, low perceived competence, mood disorders, peer use, contact sports, injuries and career transitions. The findings highlight the importance of ensuring that drug use prevention and harm reduction interventions reach at-risk athletic populations, particularly adolescent athletes, while also addressing sport specific risk factors.

Use of the US Food and Drug Administration's Accelerated Approval pathway assumes that patients are willing to accept uncertainty about clinical benefit in exchange for faster access to new cancer drugs. However, little is known about how patients view this trade-off or the circumstances under which they consider it acceptable. To explore patients' views on the trade-off between faster approval and evidentiary certainty regarding the clinical benefit of new cancer drugs in the US. This qualitative study used semistructured interviews conducted online between January 27 and April 1, 2025, with patients aged 18 years or older diagnosed with breast cancer. Purposive sampling was used to achieve maximum variation in cancer stage, treatment status, age, and sociodemographic background. The primary outcome was patients' views on the trade-off between faster drug approval and evidentiary certainty. Interview transcripts were thematically analyzed to identify key patterns in understanding, experiences of uncertainty, attitudes toward waiting, treatment priorities, and views on regulatory decision-making. A total of 125 individuals registered their interest and met eligibility criteria to participate. After purposive sampling, 30 participated in this study (10 aged 20-39 years [33.3%], 12 aged 40-59 years [40.0%], and 8 aged >60 years [26.7%]; all female), representing 17 US states (9 Northeast, 12 Midwest, 4 South, 5 West). A total of 13 participants (43.3%) had metastatic disease, 21 (70.0%) were receiving active treatment, and 27 (90.0%) had received at least 1 systemic therapy. Faster approval at the expense of certainty about the clinical benefit of new cancer drugs was considered most acceptable when no alternative treatments existed or when the anticipated benefits were transformative. When clinical benefit was uncertain, participants emphasized the importance of survival and quality of life as priority treatment outcomes, the added risks of adverse effects, and the burden of intensive treatment. Many viewed broader access to clinical trials, rather than faster regulatory approval, as an effective way to address unmet needs while facilitating evidence generation for approval. In this qualitative study of patients diagnosed with breast cancer, there was a mismatch between when patients considered trading evidentiary certainty for faster approval as acceptable and the conditions under which many new cancer drugs are approved by the Food and Drug Administration. To better align regulatory approvals with patient values, use of accelerated approval may be most appropriate for drugs that are likely to address genuine treatment gaps or offer meaningful improvements in clinical outcomes over existing alternatives.

After inadequate response to first-line biologic or targeted synthetic (b/ts) disease-modifying antirheumatic drug (DMARD) therapy in adults with rheumatoid arthritis, there are numerous alternative DMARD options, and current understanding of their comparative benefits and harms is limited. The aim of this living systematic review and network meta-analysis was to compare the benefits and harms of DMARDs after failure of biologic or targeted synthetic DMARDs in adults with rheumatoid arthritis. We searched CENTRAL, MEDLINE, Embase, and two trial registries (ClinicalTrials.gov and the WHO ICTRP) from inception until 28 November 2025, with no restrictions on language or date of publication. We included randomised controlled trials (RCTs) of adults aged 18 years or older diagnosed with rheumatoid arthritis according to 1958, 1987, or 2010 classification criteria who previously demonstrated inadequate response to a b/ts DMARD. Eligible interventions included conventional synthetic DMARDs (methotrexate, antimalarials, sulfasalazine, leflunomide, ciclosporin, and azathioprine), biologic DMARDs (adalimumab, certolizumab, etanercept, golimumab, infliximab, abatacept, rituximab, tocilizumab, sarilumab, and anakinra), and targeted synthetic DMARDs (tofacitinib, baricitinib, and upadacitinib). Our critical outcomes were American College of Rheumatology 50% (ACR50) response, withdrawals due to adverse events, radiographic progression, Disease Activity Score 28 (DAS28) remission, pain as measured by visual analogue scale, function as measured by the Health Assessment Questionnaire (HAQ), and serious adverse events. Important outcomes included ACR20, ACR70, serious infections, fatigue, and quality of life. We used Cochrane's RoB 1 tool to assess risk of bias in the included studies. We first screened the records using an approach that combined machine learning and crowdsourcing to identify probable RCTs. We then reviewed the records identified as RCTs for eligibility and simultaneously classified them to the appropriate Population, Intervention, Comparator, and Outcome (PICO) question(s). Two review authors then extracted relevant data from the included studies in duplicate and independently, with any disagreements resolved by a third review author. A Bayesian random-effects network meta-analysis was conducted using a semi-informative prior probability distribution. We assessed the certainty of evidence for each outcome using the GRADE approach. We included 19 unique studies (4779 participants) in the review, all of which were parallel-design RCTs. Eleven trials were placebo controlled; two trials had an inactive comparator arm; and six trials had an active comparator arm. The trials were performed in a well-established rheumatoid arthritis population, with the median baseline disease duration ranging from 6.4 to 14 years, median age of participants ranging from 49 to 58 years, and median baseline disease activity (DAS28) ranging from 4.87 to 6.79. ACR50 response We found moderate-/high-certainty evidence that using a tumour necrosis factor (TNF) inhibitor not previously tried, interleukin-6 (IL-6) inhibitors, abatacept, rituximab, and Janus kinase (JAK) inhibitors was more effective than placebo: TNF inhibitor not previously tried (odds ratio (OR) 6.04, 95% credible interval (CrI) 2.49 to 16.3; high-certainty evidence), sarilumab (OR 3.11, 95% CrI 1.25 to 7.76; high-certainty evidence), tocilizumab 4 mg/kg intravenous (OR 5.31, 95% CrI 2.09 to 12.09; high-certainty evidence), tocilizumab 8 mg/kg intravenous (OR 10.03, 95% CrI 3.65 to 31.27; high-certainty evidence), subcutaneous abatacept (OR 4.31, 95% CrI 0.97 to 18.28; moderate-certainty evidence), intravenous abatacept (OR 4.57, 95% CrI 2.21 to 10.18; high-certainty evidence), rituximab (OR 5.50, 95% CrI 2.31 to 13.12; high-certainty evidence), upadacitinib (OR 3.93, 95% CrI 1.53 to 10.32; high-certainty evidence), tofacitinib (OR 3.93, 95% CrI 1.53 to 10.32; high-certainty evidence), baricitinib 2 mg (OR 2.00, 95% CrI 0.77 to 5.23; moderate-certainty evidence), baricitinib 4 mg (OR 2.79, 95% CrI 1.10 to 7.22; high-certainty evidence). With an assumed risk for placebo of 78 out of 1000 patients, the expected effects for the active drugs ranged from 143 (baricitinib 2 mg) to 455 (tocilizumab 8 mg/kg). Withdrawals due to adverse events For most interventions, there were sparse data with low-certainty evidence, except for TNF inhibitor not previously tried (risk ratio (RR) 0.32, 95% CrI 0.07 to 1.1; moderate-certainty evidence), which is probably less harmful than placebo, and sarilumab (RR 1.98, 95% CrI 0.57 to 7.19; moderate-certainty evidence), which is probably more harmful than placebo. Low-certainty evidence suggests that intravenous abatacept (RR 0.92, 95% CrI 0.34 to 2.79), upadacitinib (RR 0.41, 95% CrI 0.08 to 1.83), and baricitinib 2 mg (RR 0.93, 95% CrI 0.22 to 4.01) may be less harmful than placebo. Low-certainty evidence suggests that tocilizumab 4 mg/kg (RR 1.39, 95% CrI 0.39 to 5.28), tocilizumab 8 mg/kg (RR 1.49, 95% CrI 0.51 to 4.81), subcutaneous abatacept (RR 3.11, 95% CrI 0.05 to 249.6), rituximab (RR 2.38, 95% CrI 0.44 to 23.31), tofacitinib (RR 1.37, 95% CrI 0.35 to 5.58), and baricitinib 4 mg (RR 1.43, 95% CrI 0.38 to 5.81) may be more harmful than placebo. Data were insufficient to perform a network meta-analysis for radiographic progression. For DAS28 and the HAQ, there was mostly moderate-/high-certainty evidence of a benefit, with some exceptions for comparisons with indirect evidence only that was of low or very low certainty. For the other efficacy outcomes, data were sparse with wide credible intervals, and the certainty of evidence was typically low. We found high-certainty evidence that nine therapies and moderate-certainty evidence that two therapies provide a clinically important benefit in improving disease activity compared to placebo for people with rheumatoid arthritis after failure of b/ts DMARD therapy. There was significant uncertainty surrounding treatment-related harms, with the evidence having been downgraded for serious or extremely serious imprecision. Pair-wise comparisons showed no significant differences among therapies, although the certainty of evidence was low. The lack of clarity regarding safety and comparative efficacy suggests that treatment decisions should be guided by individual patient characteristics and preferences. This work was supported by grants from the Canadian Institutes for Health Research (CIHR) [Funding Reference Numbers (FRN) 178375 and 180324] and the National Health and Medical Research Council (NHMRC) Cochrane Collaboration. This research was supported by Arthritis Society Canada (Doctoral Studentship TGP-23-0211). This study was outlined in a Cochrane protocol (CD013562; DOI 10.1002/14651858.CD013562).

Current clinical practice guidelines for the primary prevention of cardiovascular disease recommend risk assessment to align the type and intensity of preventive efforts with an individual's risk. The 2025 American Heart Association/American College of Cardiology guideline for the prevention, detection, evaluation, and management of high blood pressure in adults and the 2026 American Heart Association/American College of Cardiology guideline on the management of dyslipidemia incorporate quantitative risk assessment, recommending the PREVENT (Predicting Risk of Cardiovascular Disease Events) equations to guide initiation and intensification of antihypertensive and lipid-lowering therapies, respectively. Given the growing awareness of the clustering of cardiovascular-kidney-metabolic risk factors along with the expanding armamentarium of cardioprotective therapies for obesity, diabetes, and chronic kidney disease, a harmonized approach that comprehensively assesses and addresses risk across these interconnected conditions is needed. The 2026 American Heart Association/American College of Cardiology guideline for the prevention, detection, evaluation, and management of cardiovascular-kidney-metabolic syndrome provides recommendations for the use of the PREVENT equations with outcome-specific risk thresholds for staging, detection of subclinical cardiovascular disease, and decision-making regarding initiation and intensification of cardiovascular-kidney-metabolic therapies. This approach integrates predicted risk (using PREVENT-CVD [cardiovascular disease], PREVENT-ASCVD [atherosclerotic cardiovascular disease], and PREVENT-HF [heart failure]) with the relative risk reduction expected from treatment for each outcome to estimate the expected benefit (ie, absolute risk reduction) from drug therapy. This scientific statement details the rationale for using outcome-specific PREVENT equations, the evidence base for selected risk thresholds, and the potential population-level impact of these recommendations. This scientific statement also offers practical guidance for applying risk assessment as the first step in shared decision-making and for addressing gaps in awareness, risk communication, and optimal implementation of evidence-based preventive therapies to improve outcomes in individuals with or at risk for cardiovascular-kidney-metabolic syndrome.

Fatigue is common in many long-term medical conditions. Interventions to date have largely been in single conditions. To conduct a mixed-methods evidence synthesis of the clinical and cost-effectiveness and acceptability of non-pharmacological interventions for fatigue in adults with long-term medical conditions. Randomised controlled trials, cost-effectiveness studies, or qualitative studies of non-pharmacological interventions for fatigue in long-term medical conditions where fatigue was either a criterion for inclusion, the primary target of the intervention, or the primary or coprimary outcome. Studies of post-infectious, post-traumatic, cancer-related or idiopathic fatigue were excluded. Searches used the MEDical Literature Analysis and Retrieval System, Excerpta Medica dataBASE, Cumulative Index to Nursing and Allied Health Literature, and American Psychological Association PsycInfo® (American Psychological Association, Washington, DC, USA) databases. We used systematic CLUSTER searching for qualitative studies and Epistemonikos for systematic reviews. We held three rounds of five focus groups involving people with fatigue in long-term conditions to ensure that assumptions in, and reporting of, the research had validity with the patient population. Risk-of-bias assessment of all studies included in the network meta-analysis was undertaken using an adapted version 2 of the Cochrane risk-of-bias tool for randomised controlled trials. Clinical effectiveness evaluation used random effects network meta-analyses at three time points. The cost-effectiveness analysis involved a de novo analysis of interventions identified as clinically effective. The qualitative synthesis involved a thematic synthesis of primary studies of interventions and a mega-synthesis of reviews of patient experience of fatigue across different conditions. Focus groups were analysed by thematic analysis, and findings from all work packages were integrated in a final synthesis by the research team. The clinical effectiveness review included 88 randomised controlled trials, involving 27 interventions, with 6636 participants included at end of treatment, 1849 in the short term and 2322 in the long term. Compared to usual care at long-term follow-up, cognitive-behavioural therapy-based interventions and physical activity promotion showed statistically significant reductions in fatigue (standardised mean difference -0.4, 95% credible interval -0.63 to -0.21, 9 studies; and -0.52, -0.86 to -0.18, 2 studies), respectively. Effective interventions provided positive net monetary benefit versus usual care, particularly when delivered in a group format, when valuing a quality-adjusted life-year at £20,000. Individuals vary in their experience of fatigue in ways that are not simply due to their medical condition, indicating that interventions need to be adaptable to individuals' experiences and capabilities. The evidence base is relatively small, heterogeneous and includes studies at moderate to high risk of bias. More than half of the included trials were in multiple sclerosis. Interventions for fatigue that support people to increase physical activity or are based on cognitive-behavioural therapy are acceptable and effective in reducing fatigue in people with different long-term medical conditions, with the potential to be cost-effective. Based on the qualitative synthesis, we propose a three-stage component model for interventions. Future trials should focus on the feasibility and effectiveness of transdiagnostic fatigue services, fatigue interventions in multimorbidity, and investigations of emerging non-invasive stimulation interventions. This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number NIHR154660. We looked for research studies of non-drug treatments for fatigue in people with long-term medical conditions. We brought together the best evidence from studies of clinical effectiveness, cost-effectiveness, people’s experience of these treatments and people’s experience of fatigue in different conditions. We ran focus groups with people with fatigue and long-term medical conditions. This meant we could match the research findings with the experience of people in the United Kingdom. Treatments for fatigue which support people to increase physical activity or deliver cognitive–behavioural therapy-reduced fatigue. The effect was moderate but enough to make a difference for most people and across different conditions. Some treatments were not effective. We also found reports of new treatments that might work but need more testing. Providing effective treatments costs the health services but produces measurable improvements. Group interventions cost less to deliver and may have other advantages. There is no one-size-fits-all treatment – treatments should match the person and their situation. People’s experience of fatigue can differ, even compared to others with the same condition. Fatigue is often an invisible problem. The people in our focus groups told us they would like their professionals to tell them more about fatigue and about the non-drug treatments that may work. We now know more about non-drug interventions that work and do not work for fatigue in long-term medical conditions and that there is variation between people with the same condition. Health professionals need to recognise and respect this. Our research has shown some promising options, and we want more people to access these.

Left ventricular (LV) systolic dysfunction, defined here as reduced LV ejection fraction ≤40% or left wall motion abnormality, is commonly found in patients with ischemic stroke. Although there is an increased risk of incident and recurrent embolic stroke among patients with LV dysfunction without thrombus detected, the data supporting anticoagulation in these patients are limited. In this scientific statement, we summarize the latest evidence regarding the risk of incident and recurrent stroke in patients with LV dysfunction as well as best practice recommendations regarding the management of this population after stroke. We provide a narrative summary and meta-analysis of secondary analyses of randomized clinical trials that evaluated outcomes following anticoagulation versus nonanticoagulation strategies. Whereas anticoagulation is associated with a lower risk of incident stroke in patients with LV dysfunction without thrombus, there remains no net benefit of this strategy over a nonanticoagulant strategy for primary stroke prevention. For patients with stroke and LV dysfunction, anticoagulation may be associated with a lower risk of recurrent stroke and a net benefit when compared with antiplatelet therapy. Anticoagulation treatment decisions in these patients may involve individualized consideration, shared decision-making between patients and healthcare professionals upon discussing risks and benefits, and multidisciplinary collaboration between cardiology and neurology clinicians to optimize cardiac and brain health. As a key modifiable stroke risk factor and therapeutic target, LV dysfunction represents a target for future research.

Robotic-arm assisted total knee arthroplasty (RO TKA) has been developed to improve surgical precision and reproducibility compared with conventional techniques. However, the economic implications of adopting robotic technology remain uncertain, particularly within publicly funded healthcare systems. This study aimed to evaluate the in-hospital costs and health-related quality of life outcomes associated with RO TKA compared with conventional TKA (CO TKA) using a cost-utility framework within a UK National Health Service (NHS) institution. A propensity-matched cohort cost-utility analysis was performed including 200 patients undergoing primary TKA for end-stage osteoarthritis at a single high-volume tertiary centre. 100 patients underwent RO TKA and 100 underwent CO TKA, matched 1:1 for age, sex and American Society of Anesthesiologists (ASA)&#xa0;grade. Direct in-hospital costs were obtained using a micro-costing approach. Health-related quality of life was measured using the EQ-5D-3&#xa0;L preoperatively and at one year postoperatively to estimate quality-adjusted life years (QALYs). The primary outcome was the incremental cost-effectiveness ratio (ICER). Deterministic and probabilistic sensitivity analyses were performed to assess uncertainty. Mean total in-hospital costs were higher for RO TKA compared with CO TKA (&#xa3;6,517 vs. &#xa3;6,204), representing an incremental cost of &#xa3;313 per patient. Patients undergoing RO TKA demonstrated a significantly shorter length of stay (2.3 vs. 3.1 days; p&#x2009;=&#x2009;0.008) and lower ward (p&#x2009;=&#x2009;0.029) and drug and pharmacy (p&#x2009;=&#x2009;0.041) costs. One-year postoperative EQ-5D-3&#xa0;L scores were higher in the RO TKA cohort (0.82 vs. 0.75; p&#x2009;<&#x2009;0.001), resulting in a greater mean QALY gain (0.192 vs. 0.140). The incremental QALY gain of 0.052 produced an ICER of &#xa3;6,019 per QALY gained, well below the National Institute for Health and Care Excellence&#xa0;(NICE) willingness-to-pay threshold of &#xa3;20,000-&#xa3;30,000 per QALY. Sensitivity analyses confirmed the robustness of these findings. RO TKA demonstrated improved postoperative health utility and is likely to achieve cost-effectiveness despite modestly higher upfront costs. Within a publicly funded healthcare system, RO TKA is likely to represent a clinically and economically viable innovation in knee arthroplasty, under the costing assumptions applied in this analysis.

Androgen deprivation therapy (ADT) is used as an adjuvant treatment in men with prostate cancer. It is associated with bone loss and increased fracture risk. In this systematic review and meta-analysis, we evaluated the effects of antiresorptives on bone health in men with non-metastatic prostate cancer (nmPCa) on ADT. We searched four databases until October 14th 2024 for randomized controlled trials (RCTs) of antiresorptives in men with non-metastatic prostate cancer on ADT. We included 26 RCTs: Intravenous bisphosphonates (N&#xa0;=&#xa0;17), oral bisphosphonates (N&#xa0;=&#xa0;5) or denosumab (N&#xa0;=&#xa0;2). 2 RCTs included both oral bisphosphonate and denosumab. Oral bisphosphonates had no effect on fracture incidence at 12-months (RR&#xa0;=&#xa0;0.57; 95%CI[0.10, 3.23]; very low certainty). Intravenous bisphosphonates had no effect on the risk of morphometric vertebral fractures at 36-months (RR&#xa0;=&#xa0;1.06; 95%CI[0.57,1.98]; very low certainty). One trial showed that denosumab probably results in a large reduction in new morphometric vertebral fracture risk at 12 (RR&#xa0;=&#xa0;0.15), 24 (RR&#xa0;=&#xa0;0.31) and 36-months (RR&#xa0;=&#xa0;0.38; 95%CI[0.19-0.78]). Treatment with bisphosphonates or denosumab for 12-months increased BMD at the hip (+1.5 to +3.9%) and lumbar spine (+4.0 to +6.8%) and decreased BTMs (-26 to -78%). Data on mortality is scarce. The most common adverse events were gastrointestinal across all antiresorptives. Acute phase reactions were common with Intravenous bisphosphonates, while jaw osteonecrosis occurred more rarely. Denosumab decreases morphometric vertebral fractures risk in men with nmPCa receiving ADT. Anti-resorptive treatment had a protective effect on BMD and decreased BTMs. Well-designed powered RCTs are needed to assess their effect on fracture risk.

Prolonged cold storage (CS) of donor kidneys results in poor outcomes after transplantation. We reported earlier that cold storage (CS) of rat kidneys for 18 h followed by transplantation (CS + Tx) reduces proteasome function, disrupts protein homeostasis, and compromises graft function. The goal of the present study was to define the contribution of specific heat shock proteins (Hsp) to CS-induced disruption of renal graft function and determine the benefit conferred by their pharmacological inhibition. We subjected kidneys isolated from donor Lewis rats to 18-h CS with or without pharmacological inhibition of heat shock protein 72 (Hsp72), a stress-inducible member of the Hsp70 family. Subsequently, the donor kidneys were transplanted into Lewis rats (CS + Tx). Hsp72 was upregulated in kidney grafts after CS + Tx, and this finding was coupled to a reciprocal loss of cognate Hsc70 and profound tubular injury. Knockdown of Hsc70 in renal cells increased Hsp72, compromised proteasome function, and increased mitochondrial oxidative stress. The addition of HS-72, a Hsp72-specific inhibitor, to the CS solution restored proteasome function and improved renal injury/function after transplantation. Our study shows that CS + Tx dysregulates heat shock proteins in the kidney, and targeting a single disrupted protein, Hsp72, can improve graft function.NEW & NOTEWORTHY Our study using a rat renal transplant model shows that cold storage (CS)-induced injury involves dysregulation of heat shock proteins in the kidney and provides proof of concept that targeting a single disrupted protein, heat shock protein 72 (Hsp72), can improve graft function.

SMS text message reminders have been used to promote many health behaviors, such as improving diet and physical activity, managing chronic health conditions, reminding patients about medical appointments, and supporting medication adherence across a range of health conditions. Despite their promise, developing effective reminders tailored to specific patient populations is resource-intensive. AI may facilitate item development, and online research panels may provide an efficient way to test message content with target users prior to implementing large-scale trials. This study aimed to (1) develop a library of antidepressant adherence-promoting SMS text messages that are perceived as helpful, (2) test whether an online panel approach can be used to evaluate them, and (3) identify message characteristics perceived as most helpful by patients with depression taking antidepressant medication. In total, 83 SMS text message reminders were developed based on barriers to adherence and behavior change technique pairings, with approximately half authored by the study team, and half generated by AI. Using an online panel, we recruited 181 American adults with depression currently prescribed an antidepressant medication. Each participant rated a subset of messages on how much they thought each would help them remember to take their medication. Associations between message characteristics and ratings were estimated using generalized linear models in Stata. Survey weights were used in analyses to align the sample with national antidepressant user demographics. The online panel was able to rapidly recruit a sample of participants, who provided 7520 item ratings in total. AI-generated messages were rated as significantly more helpful than those authored by humans (adjusted mean difference 0.24 on a 5-point scale, 95% CI 0.12-0.36; P<.001). Messages addressing delayed symptom benefit were preferred over other adherence barriers, and behavior change techniques emphasizing self-monitoring (P<.001), habit formation (P<.001), and natural consequences (P<.001) received significantly higher ratings than those using external influence or support. No difference was observed between motivational and informational message content. Online panels offer a rapid, scalable approach to evaluating SMS text message reminders for patients currently taking antidepressants. When provided with specific instructions and human-led examples, AI can efficiently generate message content perceived to be helpful in promoting medication adherence. Given that AI-generated content received higher ratings than human-authored messages, future work may consider using this tool to support rapid intervention development. In addition, identifying common barriers to adherence and applying behavior change techniques to address those barriers can inform targeted message development and support adherence. Taken together, these findings demonstrate the utility of combining low-cost methods such as online panel research with AI to accelerate the design and preliminary evaluation of digital health interventions.

Blood pressure (BP)-lowering therapy reduces cardiovascular risk, but whether its proportional benefits increase with longer treatment duration remains unclear. We conducted an individual participant-level data meta-analysis of 51 randomized trials from the Blood Pressure Lowering Treatment Trialists' Collaboration (358,642 participants; median follow-up: 4.2&#x2009;years). Using Cox proportional hazards models, we estimated time-stratified hazard ratios (HRs) for major cardiovascular events (MACE; fatal or non-fatal stroke, ischemic heart disease or heart failure) across annual follow-up intervals up to more than 5&#x2009;years, standardized to a 5-mmHg systolic BP reduction. Network meta-analysis examined whether temporal patterns differed across antihypertensive drug classes. Annual MACE incidence was highest during year 1 (3.0% treatment versus 3.6% control), declined during years 1-5 and then rose at more than 5&#x2009;years (3.1% versus 3.4%). BP lowering reduced MACE risk, with benefits established early and not progressively increasing over time. A 5-mmHg systolic BP reduction was associated with a 12% lower MACE risk in year 1 (HR&#x2009;=&#x2009;0.88, 95% confidence interval (CI): 0.84-0.91), with modest attenuation thereafter: HRs were 0.88 (0.85-0.92) in years 1-2, 0.94 (0.90-0.98) in years 2-3, 0.87 (0.83-0.92) in years 3-4, 0.97 (0.91-1.03) in years 4-5 and 0.94 (0.87-1.01) at more than 5&#x2009;years (P for trend&#x2009;=&#x2009;0.006). Similar patterns occurred across five drug classes. These findings indicate that the relative cardiovascular benefits of BP lowering emerge within months and do not increase over time, suggesting that prioritizing higher-risk individuals for treatment yields greater clinical utility than prolonged treatment in low-risk individuals.

We offer the perspectives of two veterans on the last quarter century of quality improvement efforts in oncology care. We believe that our colleagues deliver high quality care, but challenges remain in demonstrating this assertion to patients, payers, policy makers and to our colleagues. The journey began with the American College of Surgeons (ACOS) establishing minimum standards for cancer surgery in 1919 and evolved through state cancer registries, culminating in the Surveillance, Epidemiology, and End Results (SEER) program. Donabedian's structure-process-outcome framework and Porter's value equation provided conceptual frameworks for action. ASCO developed the Quality Oncology Practice Initiative (QOPI) in 2002. Physician-led self-assessment and chart abstraction could drive improvement. QOPI expanded to include certification programs and safety standards. Integrating quality measurement and improvement with payment incentives has proven challenging. Medicare's successive payment reform attempts-from Resource-Based Relative Value (RBRVS) through the Oncology Care Model (OCM) to the Enhancing Oncology Model-have shown mixed results, with minimal to no improvements in quality measures and limited cost-savings. Private payer initiatives based on clinical pathways largely failed to reduce costs and have been scaled back. Contemporary challenges include vertical integration of health care systems without clear quality benefits, rising drug costs, physician burnout, and erosion of public trust. New tools and iterations offer hope: artificial intelligence (AI)-powered clinical documentation and analysis could dramatically reduce administrative burdens, cross-platform electronic record sharing should enable longitudinal quality analysis, and restoration of patient agency through market forces and social media may better align quality incentives. We posit that better future results require returning to bottom-up, physician-led quality improvement while leveraging AI and data-sharing technologies to make quality measurement a natural component of cancer care rather than an externally imposed burden.

Jobes and Barnett (see record 2024-78987-001) decided to emphasize and recommend only psychological interventions (e.g., dialectical behavior therapy) in the clinical treatment for suicidal risk and behavior. Such interventions have been, in fact, proven effective in research emphasizing randomized controlled trials. Jobes and Barnett, however, decided not to include a section dealing with medications because they concluded that, with some exceptions (e.g., clozapine), the majority of medications have "little to no evidence" in randomized controlled trials. The article by Jobes and Barnett not only appears to be unintentionally biased in favor of only recommending psychological interventions, but it also appears clinically unsound to advise clinicians to de-emphasize medications in the present clinical context. The core message in the article (emphasis on psychological interventions, but not on medications) does not appear in accord with the American Psychological Association RxP Designation Committee with the mission to review and approve programs in prescriptive authority for psychologists nor with the wide range of medications with evidenced clinical benefits derived from randomized controlled trials funded by the National Institutes of Health and approved for marketing by the U.S. Food and Drug Administration. (PsycInfo Database Record (c) 2026 APA, all rights reserved).

At a time when there was no unifying hypothesis and no broadly effective treatments for heart failure with a preserved ejection fraction (HFpEF), it was proposed that HFpEF represented a multitude of different disorders. Accordingly, characterization of phenotypic heterogeneity was envisioned as a means of identifying novel causal pathways that could lead to new treatments while simultaneously discerning patients who would selectively benefit from a specific therapy. However, efforts over the past decade to characterize phenotypic diversity in diverse and complex ways have not achieved these goals. Subgroup analyses of neutral HFpEF trials have failed to reliably identify responders to treatments. Neither proteomics nor unsupervised cluster analysis across multiple phenotypic domains has yielded reproducible results (even in the same dataset), elucidated novel mechanistic pathways for new drug development, or identified patients most likely to benefit from treatment. In marked contrast to these efforts to characterize phenotypic heterogeneity, large-scale trials in HFpEF enrolled patients using broad eligibility criteria, and they established the benefits of sodium-glucose cotransporter 2 inhibitors and mineralocorticoid receptor antagonists without evidence for subgroup effects. However, it is noteworthy that patients enrolled in recent large-scale HFpEF trials were characterized by general uniformity with respect to the presence of excess adiposity, with central obesity being a feature of the vast majority of enrolled participants. Of note, patients with obesity showed particularly large benefits when treated with effective drugs for HFpEF. These observations raise the possibility that, if these trials had permitted the participation of patients with class III obesity or with lower natriuretic peptide levels, the magnitude of the observed treatment effects might have been greater than originally reported. These findings are consistent with a central role for visceral adiposity (and the secretion of an altered suite of adipokines) in the pathogenesis of HFpEF. Therefore, because the field of HFpEF has a unifying hypothesis (applicable to the large majority of patients), enrolled a broad population of patients in large-scale trials without subgroup interactions, and has several broadly applicable effective treatments (as is true for heart failure with a reduced ejection fraction), the motivation to characterize phenotypic heterogeneity in HFpEF in complex ways may no longer be supported or needed.

Mescaline (3,4,5-trimethoxyphenethylamine) is a classic serotonergic psychedelic with a history of indigenous ceremonial use. There is renewed scientific interest in mescaline because of the potential psychiatric benefits of psychedelic-assisted therapy. Mescaline primarily exerts its psychoactive effects through serotonin-2A (5-HT 2A ) receptor agonism. There is a lack of controlled clinical trials evaluating mescaline in patient populations, and most modern safety data are derived from healthy volunteers. Consequently, its safety in individuals with cardiovascular, metabolic, or psychiatric comorbidities remains unclear. Additional uncertainty exists regarding its psychological risks, long duration of action, and long-term safety in therapeutic settings. Randomized, placebo-controlled studies in healthy participants demonstrate that mescaline produces dose-dependent subjective effects with moderate, transient autonomic stimulation and no serious medical complications under controlled conditions. Adverse effects are generally self-limited, and pooled safety analyses and observational data support an overall favorable safety profile in screened human populations. Mescaline shows preliminary safety in healthy humans but remains understudied in clinical populations. Controlled clinical trials are needed to establish its safety and therapeutic potential.

Describe trends in real-world BRCA and homologous recombination deficiency (HRD) testing rates among patients with advanced epithelial ovarian cancer (EOC). In this US-nationwide electronic health record-derived deidentified database study, eligible adult patients diagnosed with OC on/after 1 January 2016&#xa0;had stage III/IV EOC at diagnosis, and initiated 1L platinum-based chemotherapy (1 January 2017-30 June 2023 [index date]). Results were descriptive. Among 2135 patients, 66.0% received BRCA and/or HRD testing before the final 1L chemotherapy dose. BRCA/HRD testing was higher among patients receiving chemotherapy-bevacizumab (78.6%) versus chemotherapy alone (60.6%). BRCA/HRD testing rates increased from 2017 to 2023. BRCA/HRD testing rates were lower among patients who were older (aged&#x2009;&#x2265;75&#x2009;years), had stage IV disease at diagnosis, were Black/African American, had nonserous epithelial histology, had an Eastern Cooperative Oncology Group performance status score of &#x2265;2, and had no evidence of cytoreductive surgery. Real-world BRCA/HRD testing rates increased from 2017 to 2023 among US patients with EOC. Subgroups often underserved in US healthcare settings had lower testing rates, possibly preventing some from receiving optimal treatments. Increasing provider education and support for biomarker testing and improving patient access may help reduce differences and improve treatment outcomes. Why was the study done?Doctors use tests to look for changes in cancer-related genes, such as BRCA, to help choose the best treatments for people with advanced ovarian cancer. Some patients may benefit from targeted medicines based on these results. This study looked at how often these tests are used in real-world practice in the United States.What did the researchers do and find?The study included over 2,000 adults with advanced ovarian cancer treated between 2017 and 2023. It examined when patients received genetic testing and whether testing rates changed over time or differed between groups. Overall, testing increased during this period and more than half of patients were tested before completing their last dose of chemotherapy. However, not all patients were tested equally. Testing was less common in older patients, Black/African American patients, those with more advanced disease, and those with lower income.What do the results mean?Although testing rates are improving, some groups are still less likely to receive these important tests. This means that they may miss the opportunity to receive treatments that could work better for them.What is the objective influence on the wider field?Improving access to testing can help ensure that all patients have the best chance to receive the most appropriate treatment, which may improve outcomes in ovarian cancer.