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PubMed2026

Adjuvant alectinib versus chemotherapy in resected ALK-positive non-small-cell lung cancer (ALINA): health-related quality-of-life and safety outcomes from a randomised, open-label, phase 3 trial.

BACKGROUND: For patients with resected, ALK-positive non-small-cell lung cancer (NSCLC), adjuvant alectinib significantly improved disease-free survival versus platinum-based chemotherapy in the global, phase 3, open-label, randomised ALINA trial. We report safety and health-related quality-of-life (HRQoL) outcomes from the ALINA trial. METHODS: Eligible patients aged 18 years or older with resected, ALK-positive, stage IB (≥4 cm)-IIIA NSCLC (per the American Joint Committee on Cancer and the Union for International Cancer Control Cancer Staging Manual 7th edition) and an Eastern Cooperative Oncology Group performance status of 0-1 were randomly assigned (1:1) via a block-stratified randomisation method to receive oral alectinib (600 mg twice daily) for 24 months or intravenous platinum-based chemotherapy for four 3-week cycles. Randomisation was stratified according to disease stage and race. The primary endpoint, previously reported, was disease-free survival. Safety was a secondary endpoint and HRQoL was an exploratory endpoint. Safety was assessed by the investigator as per the National Cancer Institute Common Terminology Criteria for Adverse Events version 5·0 until 28 days after the last alectinib dose or chemotherapy cycle. HRQoL was assessed via the Short-Form 36-item health survey version 2 (SF-36v2) questionnaire at baseline, every 3 weeks to week 12, then every 12 weeks until disease recurrence, consent withdrawal, death, or week 96. Norm-based scoring was applied; clinically meaningful changes were defined using the SF-36v2 manual. Safety was assessed in the safety-evaluable population and HRQoL in the intention-to-treat population. This study is registered with ClinicalTrials.gov (NCT03456076) and is ongoing. FINDINGS: Between Aug 16, 2018, and Dec 8, 2021, 257 patients were assigned to receive alectinib (n=130) or chemotherapy (n=127). 123 (48%) patients were male and 134 (52%) were female; 143 (56%) were Asian. The safety-evaluable population comprised 128 patients who received alectinib and 120 patients who received chemotherapy; median duration of safety follow-up was 24·8 months (IQR 22·0-24·9) in the alectinib group and 3·7 months (IQR 3·7-3·8) in the chemotherapy group. The safety of adjuvant alectinib was generally consistent with its known profile. The most common grade 3-4 adverse events were blood creatine phosphokinase increased (eight [6%] of 128), alanine aminotransferase increased (two [2%] of 128), and blood bilirubin increased (two [2%] of 128) in the alectinib group, and neutrophil count decreased (12 [10%] of 120), neutropenia (ten [8%] of 120), and nausea (five [4%] of 120) in the chemotherapy group. Serious treatment-related adverse events occurred in two (2%; one each with appendicitis and pneumonitis) of 128 patients in the alectinib group and eight (7%) of 120 patients in the chemotherapy group ( most common were gastrointestinal disorders in three [3%] patients). No deaths due to adverse events were reported in either group. There were fewer discontinuations due to adverse events with alectinib (seven [5%]) versus chemotherapy (15 [13%]). A clinically meaningful difference in improvement from baseline was seen at week 12 for bodily pain, role physical, mental health, social functioning, and vitality SF-36v2 domains with alectinib; improvements in physical and mental HRQoL were maintained over 2 years of active treatment (at week 96, mean Mental Component Summary score: 49·9 [SD 10·4]; mean Physical Component Summary score: 48·8 [SD 7·2]) and reached levels similar to the general population (population norm: 50). INTERPRETATION: For patients with resected ALK-positive NSCLC, adjuvant alectinib had a manageable safety profile; HRQoL improved and was maintained over 2 years of active treatment. Together with the disease-free survival benefit seen in ALINA, these data support adjuvant alectinib as an important new standard-of-care for patients with resected ALK-positive NSCLC. FUNDING: F Hoffmann-La Roche.

Adult↗

PubMed2026

Open Dialogue versus treatment as usual for adults presenting in crisis to mental health services in England (the ODDESSI Trial): a multisite cluster-randomised trial.

BACKGROUND: Open Dialogue is a person-centred, transdiagnostic model of mental health care that emphasises continuity, therapeutic relationships, and collaboration with the service user's social network. Open Dialogue is a service-wide approach to care involving network meetings with the service user, members of their social network, and usually two practitioners who support the network throughout the duration of care. In this cluster-randomised trial, we aimed to evaluate the clinical effectiveness of Open Dialogue versus treatment as usual for adults presenting in crisis to community mental health services in England. METHODS: This multicentre, parallel two-arm, cluster-randomised, controlled superiority trial was conducted in mental health services in five National Health Service trusts in London and the South of England. Clusters were defined at the level of primary care practices within service catchment areas. Participants were adults aged 18 years or older presenting in crisis to mental health services and registered with a practice within trial clusters. Randomisation was done at the cluster level (1:1), stratified by catchment area, and balanced on average general practice (GP) list size and Index of Multiple Deprivation (2015). The chief investigator, senior statistician, and assessors of the primary outcome were masked in the study. Participants either received Open Dialogue or treatment as usual, which refers to the functional team model currently implemented throughout English mental health services. The primary outcome was time (days) to first relapse following initial recovery from the index crisis censored at the end of the 2-year follow-up period. Participant-reported secondary outcomes were EuroQol Visual Analogue Scale, Social Provisions Scale, Lubben Social Network Scale, Questionnaire about the Process of Recovery, and the Client Satisfaction Questionnaire, measured at five timepoints over 2 years, and clinical measures were extracted from electronic health records. People with relevant lived experience were involved in the design and execution of the study. Fidelity to the model of care in Open Dialogue and treatment as usual, and adherence to the delivery of Open Dialogue, were measured prior to each site starting participant recruitment, then every 6 months thereafter until the final participant follow-up in that site. The trial was retrospectively registered (ISRCTN52653325) and is complete. FINDINGS: 185 general practices associated with six mental health Trusts across England were identified for screening. 105 practices were excluded, and 80 were included in cluster formation, forming 32 clusters that were randomly assigned (16 to treatment as usual and 16 to the Open Dialogue intervention). One mental health trust (two clusters) withdrew, resulting in five mental health trusts (30 clusters) participating in the trial. Between June 25, 2019, and Dec 9, 2021, 494 participants (266 [54%] female gender, 221 [45%] male gender, 341 [69%] White British) with a mean age of 38·1 years (SD 13·4) provided consent for study inclusion (223 in the treatment as usual group and 271 in the Open Dialogue group). Of these, 174 (78%) in the treatment as usual group and 225 (83%) in the Open Dialogue group recovered and had data enabling relapse determination; there was no significant difference between groups on the primary outcome of time to relapse following initial recovery (marginal hazard ratio 0·95 [95% CI 0·67-1·32]). For secondary outcomes, Open Dialogue was associated with significantly lower probabilities of psychiatric inpatient admission and re-referral to crisis care or secondary mental health services, and with improvements in self-rated recovery, health-related quality of life, and satisfaction with services. There were no significant differences in social network quality or size. There were 386 serious adverse events (281 in the treatment as usual group and 105 in the Open Dialogue group); 376 (97%) were deemed to be unrelated to the intervention. INTERPRETATION: Open Dialogue did not reduce time to first relapse compared with treatment as usual, the primary outcome, but it reduced acute inpatient bed use, improved service user reported outcomes and experience, and there were no significant safety concerns. Further investigation is required to determine whether Open Dialogue can enhance the effectiveness and acceptability of crisis care and continuing care in community mental health services. FUNDING: National Institute for Health Research.

Humans↗

PubMed2026

Hyper-oncotic albumin administration reduces mortality in acute Respiratory Distress Syndrome compared to crystalloid: a systematic review and meta-analysis.

BACKGROUND: To evaluate the association between albumin administration as volume replacement and mortality in adult ARDS patients, we performed this meta-analysis and trial sequential analysis (TSA). METHODS: We searched databases including PubMed, Science Direct, Scopus, Web of Science databases and Cochrane Central Register of Controlled Trials up to 12 December 2024. We screened trials that included adult ARDS patients and compared albumin with crystalloid. The 28-day mortality served as the primary endpoint, while the oxygenation change, the length of ICU stay and the length of hospital stay were designated as secondary outcomes. To clarify the differing concentrations of albumin, we formed two distinct subgroups: the hyper-oncotic albumin subgroup (≥20%) and the iso-oncotic albumin subgroup (4%∼5%). Statistical synthesis was performed with Cochrane Review Manager 5.4.1, employing random-effects models. To mitigate random errors, TSA was implemented with α = 0.05 and β = 0.20 parameters. RESULTS: The analysis incorporated 5 publications: 3 randomized controlled trials (RCTs) and 2 non-randomized studies (NRSs). Overall mortality was lower in the albumin group (33.2%, 97/292) than in the crystalloid group (44.9%, 133/296) (OR = 0.61, 95%CI 0.43-0.85, p = 0.004). RCTs (n = 204) showed no benefit (OR = 0.83, p = 0.54), but NRSs (n = 384) demonstrated reduced mortality (OR = 0.52, p = 0.002). Hyper-oncotic albumin was associated with lower mortality in NRSs (OR = 0.40, p = 0.02) but not in RCTs (OR = 0.74, p = 0.57). Iso-oncotic albumin showed no benefit (OR = 0.88, p = 0.72). Regarding the impact of albumin on oxygenation, significant improvements in oxygenation were observed only on the first (p = 0.05) and second days (p < 0.0001). The TSA indicated a continued need for high-quality RCTs. CONCLUSIONS: Our analysis suggests that hyper-oncotic albumin may reduce mortality and improve early oxygenation in ARDS patients compared to crystalloids. Larger RCTs are urgently needed to validate these findings and define their potential role in clinical management.

Humans↗

PubMed2026

Incidence of Cirrhosis in Fibrotic Metabolic Dysfunction-Associated Steatohepatitis: A Meta-Analysis of Placebo Arms from Randomized Clinical Trials.

BACKGROUNDS AND AIMS: Metabolic dysfunction-associated steatohepatitis (MASH) with stage F2-F3 fibrosis represents the main target population for emerging pharmacotherapies. However, data on short-term progression to cirrhosis (F4) in this group remain limited. We aimed to evaluate the incidence of cirrhosis in placebo-treated patients with fibrotic MASH in randomized controlled trials (RCTs). METHODS: In this single-arm meta-analysis, we systematically searched PubMed and Cochrane Library from inception to December 13, 2024, for pharmacological Phase ≥ 2 RCTs reporting cirrhosis events (detected in liver biopsy or clinical signs) among patients with fibrotic MASH receiving placebo. Incidence rates were pooled using generalized linear mixed models with Clopper-Pearson confidence intervals (CIs). RESULTS: We identified a total of 11 RCTs, including 586 patients with fibrotic MASH. Total follow-up was 657.23 person-years (PYs), with 83 cirrhosis events reported. The pooled incidence rate was 13.09 per 100 PYs (95% CI 7.81 to 21.12, I2 = 75.6%, τ2 = 0.682). In subgroup analysis, the incidence of cirrhosis was 3.40 per 100 PYs in MASH F2 (95% CI 1.10 to 10.02, I2 = 0%, τ2 = 0) and 17.90 per 100 PYs (95% CI 10.63 to 28.55, I2 = 70.2%, τ2 = 0.561) in MASH F3, with significant differences between stages (p = 0.006). Sensitivity analyses showed consistent estimates. Most RCTs were judged to have a low risk of bias. CONCLUSIONS: This study provides stage-specific data on cirrhosis incidence in fibrotic MASH, highlighting the high short-term risk associated with MASH F3 in trial settings. These data may inform benchmarks to guide event expectations, enrichment strategies, sample size assumptions, and the interpretation of future MASH clinical trials.

Humans↗

PubMed2026

High-dose radiotherapy in patients with high-risk prostate cancers treated with long-term androgen deprivation therapy (GETUG AFU 18): a randomised, phase 3 trial.

BACKGROUND: For patients with high-risk prostate cancer, the role of dose-escalated radiotherapy in combination with long-term androgen deprivation treatment (ADT) is controversial, without any demonstrated benefit on cancer-specific or overall survival. We aimed to evaluate the effect of a 10 Gy dose increase, from 70 Gy to 80 Gy, on progression-free survival in men with high-risk prostate cancer. METHODS: In this multicentre, open-label, randomised, phase 3 trial, we enrolled patients with high-risk prostate cancer, defined as prostate-specific antigen of 20 ng/mL or more, Gleason score of at least 8, or clinical stage T3-T4, from 25 centres in France. Participants were randomly assigned (1:1) by minimisation, stratified by centre and previous pelvic lymph node dissection, to receive prostate-targeted dose-escalated external beam radiotherapy (80 Gy; 2 Gy per fraction for 8 weeks) or standard-dose external beam radiotherapy (70 Gy; 2 Gy per fraction for 7 weeks), combined with long-term ADT. Neither the participants nor the investigators were masked to the allocated treatment. The primary endpoint was 5-year progression-free survival defined as the time from randomisation to first biochemical (defined as prostate-specific antigen >nadir plus 2 ng/mL) or clinical (ie, local, regional, or metastatic) disease progression, analysed in the intention-to-treat population, with 197 events required. 5-year progression-free survival was the prespecified endpoint, and 10-year progression-free survival was additionally reported (post hoc) in view of the low number of events at 5 years. The trial is registered at ClinicalTrials.gov, NCT00967863, and is complete. FINDINGS: Between April 6, 2009, and Jan 24, 2013, 505 patients with high-risk prostate cancer were enrolled; 250 were assigned to receive dose-escalated radiotherapy (80 Gy) and 255 to receive standard dose radiotherapy (70 Gy). All participants were male and ethnicity data were not collected. At a median follow-up of 9·5 years (IQR 8·5-10·3), 5-year progression-free survival was 91·4% (95% CI 87·0-94·4) in the dose-escalation group versus 88·1% (83·2-91·6) in the control group, and 10-year progression-free survival was 83·6% (77·8-88·0) versus 72·2% (65·3-78·0; stratified HR 0·56, 95% CI 0·40-0·78, p<0·0001). Grade 3 or worse adverse events assessed at 6 months (acute toxicity) were observed in 60 (24%) of patients in the dose-escalation group and 62 (25%) in the control group. The most frequent grade 3 or worse adverse events were sexual disorders (28 [11%] in the dose-escalation group vs 20 [8%] in the control group) and bladder or urethra disorders (12 [5%] vs 19 [8%]). Adverse events assessed at 5 years (late toxicity) occurred in 118 (70%) of 168 in the dose-escalation group and 122 (73%) of 168 in the control group; grade 3 or worse late toxicities occurred in 19 (8%) participants in the dose-escalated radiotherapy group versus 17 (7%) participants in the control group. The most common late grade 3 adverse event was bladder or urethra disorders (seven [4%] vs three [2%], respectively). Serious adverse events occurred in nine (4%) patients in the dose escalation group and nine (4%) in the control group; none were considered to be treatment related. There were no treatment-related deaths. INTERPRETATION: For patients with high-risk prostate cancer, radiotherapy at a total dose of 80 Gy, in combination with long-term ADT, improved progression-free survival and could be a potential option in this situation. However, given the low number of events, further research is needed to consolidate and confirm the benefit in dose-escalation in prostate cancer-specific survival and overall survival. FUNDING: French National Cancer Institute and AstraZeneca.

Aged↗

PubMed2026

Comparative efficacy of LDL-C-lowering therapies in first-time vs. recurrent myocardial infarction prevention: a meta-analysis of large-scale randomized controlled trials.

AIMS: Reducing elevated low-density lipoprotein cholesterol (LDL-C) is central to global efforts to prevent myocardial infarction (MI). While many studies have evaluated LDL-C-lowering therapies in first-time and recurrent MI prevention, direct comparisons of their relative efficacy are lacking. Therefore, we conducted a systematic review and meta-analysis to compare the efficacy of LDL-C-lowering therapies in first-time vs. recurrent MI prevention. METHODS AND RESULTS: We searched three databases until 30 November 2024, for randomized controlled trials (RCTs) with at least 1000 patient-years of follow-up. Efficacy was quantified as relative risk (RR) with 95% confidence intervals (CIs). Differences in benefit magnitude were assessed using Cochran's Q test. Data were pooled with a random-effects model, and heterogeneity was measured using the I2 statistic. Additionally, we applied the Cochrane Risk of Bias Tool to evaluate study quality and utilized the GRADE method to assess the certainty of the evidence. This study included 22 large-scale RCTs involving 180 304 participants. In first-time MI prevention, LDL-C-lowering therapies achieved a remarkable 38% reduction in MI risk [12 RCTs; 79 604 participants; RR, 0.62 (95% CI, 0.55-0.69); P < 0.001]. In recurrent MI prevention, these therapies were associated with a more modest but significant 16% risk reduction [11 RCTs; 100 700 participants; RR, 0.84 (95% CI, 0.80-0.88); P < 0.001]. Importantly, the benefit magnitude between the two groups was significantly different (Q = 22.63; P < 0.001), highlighting the greater relative benefit in first-time MI prevention. Furthermore, the robustness of our findings was consistently supported by leave-one-out analyses, the absence of publication bias, high-quality GRADE evidence, and subgroup and sensitivity analyses. CONCLUSION: Our findings suggest that LDL-C-lowering therapies may offer a greater benefit in preventing first-time MI compared with recurrent MI.

Humans↗

PubMed2026

Weight regain following discontinuation of glucagon-like peptide-1 receptor agonists in adults who are overweight or obese: a systematic review and meta-analysis.

OBJECTIVE: This study aims to explore the effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on weight changes and the occurrence of adverse reactions in overweight or obese adults after drug withdrawal. METHODS: Computerized searches were conducted in evidence-based databases such as PubMed, Embase, Cochrane Library and Scopus. The search period was from the establishment of the database to December 2025. Collect randomised controlled trials (RCTs) and controlled trials on GLP-1RAs, including tirzepatide, semaglutide, liraglutide, and dulaglutide, for the treatment of overweight or obese adult patients. The risk of bias in the included studies was assessed using the Cochrane Risk of Bias V2.0 tool provided by the Cochrane Collaboration, and meta-analysis was performed using the R programming language. RESULTS: A total of 699 studies were initially retrieved. Eventually, six studies involving 8,993 patients were included in the quantitative analysis, comprising 5,553 patients in the discontinuation group and 3,440 in the continued treatment group. The results of the meta-analysis showed that, compared with the continued treatment group, the weight difference in the discontinuation group was mean difference (MD) = 17.90%, 95% confidence interval (CI) [14.11-21.69], P < 0.0001. It can be seen that there was a significant rebound in weight after drug withdrawal, and there was statistical heterogeneity among the studies (P = 0.0082). Subgroup analysis further revealed that the weight rebound amplitude after discontinuation of tirzepatide was significantly higher than that of semaglutide. This result suggests that the differences in the mechanism of action of different GLP-1RAs may be the reason for the differences in weight changes after discontinuation. In addition, the percentage difference in body weight between after and before drug withdrawal was MD = 9.11%, 95% CI [7.91-10.30], P < 0.0001, further verifying the trend of weight rebound after drug withdrawal. The summary of adverse reaction reports analyzed and studied indicates that after drug withdrawal, the overall adverse reactions of patients decreased, gastrointestinal adverse reactions decreased, and the incidence of cardiovascular events was not affected by drug withdrawal. CONCLUSION: There is a significant weight rebound phenomenon after discontinuation of GLP-1RAs, and the rebound magnitudes vary among different types of drugs. At the same time, there is a risk of adverse reactions during the use of such drugs.

Humans↗

PubMed2026

Venetoclax added to dose-adjusted EPOCH-R for newly diagnosed double-hit lymphomas: phase 2 results from ALLIANCE A051701, an open-label, randomised, controlled, phase 2-3 trial.

BACKGROUND: High-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6, known as double-hit lymphoma, is a highly aggressive malignancy with poor outcomes after standard chemoimmunotherapy. We aimed to study whether the addition of the BCL2-inhibitor venetoclax to chemoimmunotherapy in patients with double-hit lymphoma resulted in superior efficacy compared with chemotherapy alone. METHODS: ALLIANCE A051701 is an open-label, randomised, controlled, phase 2-3 trial in separate cohorts of patients with double-hit lymphoma and patients with double-expressor lymphoma. In this analysis, we report phase 2 results from the double-hit lymphoma cohort. Patients aged 18-80 years with newly diagnosed double-hit lymphoma and Eastern Cooperative Oncology Group (ECOG) performance status 0-2 were recruited from 41 hospitals and outpatient clinics in the USA. Patients were randomly assigned (1:1) to receive DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) either alone (DA-EPOCH-R group) or with venetoclax (DA-EPOCH-R plus venetoclax group) using permuted block randomisation schedule. All patients and investigators were aware of group assignment. DA-EPOCH-R was administered on a 21-day schedule for up to six total cycles. Venetoclax was given as 600 mg by mouth daily on days 4-8 of cycle 1 and on days 1-5 of cycles 2-6. The primary endpoint was progression-free survival in the modified intent-to-treat population inclusive of all eligible patients with centrally confirmed double-hit lymphoma. The safety analysis population consisted of all evaluable patients who received at least one dose of protocol treatment. This trial is registered with ClinicalTrials.gov (NCT03984448) and is closed to enrolment. FINDINGS: 36 patients were randomly assigned to the DA-EPOCH-R group and 37 to the DA-EPOCH-R plus venetoclax group between Oct 22, 2019, and Sept 18, 2020. Median age was 65 years (IQR 56-73) and baseline demographic factors were well balanced between groups, with 30 (45%) female and 36 (55%) male patients. Most patients (59 [89%]) were white, two (3%) were Asian, one (2%) was Black or African American, and four (6%) had unknown or unreported ethnicity. The majority of patients had MYC-BCL2 double-hit lymphoma (59 [89%] patients), advanced stage disease (57 [86%] patients), and high-intermediate/high-risk IPI score (42 [64%] patients). Median follow-up was 34·7 months (IQR 30·1-36·8). Median progression-free survival was 28·4 months (95% CI 5·2-not estimable) in the DA-EPOCH-R group (n=30) and 7·7 months (95% CI 4·7-NE) in the DA-EPOCH-R plus venetoclax group (n=36; hazard ratio [HR] 1·13, 95% CI 0·53-2·37; p=0·75). Deaths on treatment occurred in one (3%) patient in the DA-EPOCH-R group (due to dyspnoea; possibly related to treatment) and six (17%) patients in the DA-EPOCH-R plus venetoclax group (four due to sepsis [three at least possible related and one unrelated], two due to cardiac arrest [at least possibly related]), prompting early closure of the double-hit lymphoma cohort. The most common grade 3-4 non-haematological adverse event was febrile neutropenia, occurring in 15 (43%) of 35 patients in the DA-EPOCH-R plus venetoclax group and 11 (37%) of 30 patients in the DA-EPOCH-R group. The median overall survival has not been reached in either group. The 24-month overall survival estimates were 72% (95% CI 52-85) in the DA-EPOCH-R group compared with 52% (95% CI 33-68) in the DA-EPOCH-R plus venetoclax group (HR 2·49, 95% CI 1·03-6·04; p=0·038). INTERPRETATION: The addition of venetoclax to DA-EPOCH-R resulted in excess mortality, prompting early study closure. Robust accrual shows that prospective multicentre trials are feasible in double-hit lymphoma, and the outcomes in the DA-EPOCH-R group serve as a benchmark for future studies. FUNDING: National Cancer Institute of the National Institutes of Health.

Humans↗

PubMed2026

Effects of a situational interest-based rotational fitness training program on positive affect in university students: A randomized controlled trial.

BACKGROUND: To evaluate whether a 12-week situational interest-based rotational fitness program improved positive emotional states in university students, to compare module-specific effects, and to examine whether the intervention moderated the heart rate-emotion association. METHODS: In this 2-arm randomized controlled trial, 560 freshmen from 10 Chinese universities were assigned to an experimental (n = 280) or control group (n = 280). The experimental group completed weekly 90-minute sessions covering strength, endurance, speed, and agility modules; controls received regular physical education. Positive emotional states were assessed using the positive well-being subscale of the Subjective Exercise Experiences Scale through ecological momentary assessment at 3 points per session, yielding over 14,000 observations. Linear mixed-effects models tested group, time, group × time, heart rate, and heart rate × group effects. Assessors and analysts were blinded. Ethical approval for the trial was granted by the Institutional Review Board of Capital University of Physical Education and Sports (2025A055). RESULTS: Improvement was greater in the experimental group than in controls (EMM change: 1.843 vs 0.505; difference = 1.338, 95% confidence interval [CI]: 1.275-1.400, P < .001). At week 12, the raw between-group difference was 1.85 (d = 2.23), and all group × week interactions from weeks 2 to 12 were significant. Heart rate positively predicted emotional states in controls (B = 0.005, 95% CI: 0.003-0.007), but this association was attenuated in the experimental group (interaction B = -0.008, 95% CI: -0.011 to -0.005). Strength and agility showed significant improvements, while endurance produced consistently higher emotional states across assessment points. Heart rate moderation was significant for strength and endurance, but not speed or agility. CONCLUSION: The rotational program improved positive emotional states more than regular physical education, although effects varied by module. Strength showed the most robust benefit. The program also weakened, but did not eliminate, the heart rate-emotion association during more demanding activities.

Humans↗

PubMed2026

Photobiomodulation as an Adjunct to Resistance Training in Older Adults: A Systematic Review and Meta-Analysis.

BACKGROUND: Photobiomodulation (PBM) has been proposed as an adjunct to resistance training to enhance strength adaptations; however, findings from randomized controlled trials (RCTs) remain inconsistent. This study aimed to evaluate whether adjunctive PBM improves maximal strength gains when combined with periodized resistance training in older adults. METHODS: RCTs were identified through systematic searches of PubMed, Scopus, Embase, PEDro, Web of Science, the Cochrane Library, and CNKI from inception to January 2026. Eligible studies examined PBM delivered via low-level laser therapy or light-emitting diodes in combination with resistance training or other strength-oriented loading tasks. Prespecified meta-analyses were restricted to trials combining PBM with periodized resistance training that reported one-repetition maximum (1RM) outcomes; other studies were included in a narrative synthesis. RESULTS: Eleven RCTs (n = 456) were included. Five trials (PBM plus resistance training: n = 74; control: n = 72) met the criteria for meta-analysis. PBM combined with resistance training did not significantly improve maximal muscle strength compared with sham PBM (SMD = 0.26, 95% CI -0.08 to 0.59; p = 0.14; I2 = 4%). Subgroup analyses showed a nonsignificant trend favoring PBM for unilateral 1RM, with no effect for bilateral outcomes and no significant subgroup differences. Sensitivity analyses indicated that the unilateral effect was dependent on individual studies. In nonresistance training contexts, some studies reported potential benefits for fatigue-, recovery-, or function-related outcomes, particularly in frail or critically ill older adults, although findings were inconsistent. CONCLUSION: Current evidence does not demonstrate a clear additional benefit of PBM on maximal strength when combined with resistance training in older adults, although a small effect cannot be excluded. PBM may have selective value in improving recovery-related outcomes and supporting training tolerance in vulnerable populations. Larger, well-designed RCTs are needed to clarify its role.

Humans↗

PubMed2026

Pilot randomized trial of intermittent theta-burst stimulation versus H-Coil transcranial magnetic stimulation for treatment-resistant depression.

BACKGROUND: Intermittent theta burst stimulation (figure-8-coil iTBS) and H7-coil repetitive transcranial magnetic stimulation (rTMS) are FDA-cleared treatments for major depression; yet their comparative effectiveness in treatment-resistant depression (TRD) has not been evaluated in randomized trials. This pilot randomized trial was designed to obtain preliminary comparative estimates and to explore whether baseline cognitive functioning relates to early remission. METHODS: Twenty-eight adults with TRD were randomized to six weeks of figure-8-coil iTBS delivered to the dorsolateral prefrontal cortex (DLPFC) (n = 15) or H7-coil rTMS delivered to the dorsomedial prefrontal cortex (DMPFC) (n = 13). The primary outcome was change in 17-item Hamilton Depression Rating Scale (HRSD-17) score from baseline to week 6, analyzed with ANCOVA. Additional outcomes included response, remission, and symptom trajectories through week 18. Exploratory analyses examined the association between baseline cognitive functioning, such as executive functions and memory, and remission. RESULTS: Twenty-five participants completed all 30 sessions. Adjusted week-6 HRSD-17 scores did not differ between groups (mean difference -0.40, 95% CI -5.23 to 4.43; p=.865). Response rates were 40.0% for figure-8-coil iTBS and 50.0% for H7-coil rTMS (p>.60), and remission rates were identical across groups (20.0%). Remitters showed higher baseline executive functioning than non-remitters in exploratory analyses, although these associations were not confirmed in adjusted models. CONCLUSION: In this pilot trial, figure-8-coil iTBS and H7-coil rTMS showed symptom improvement, with no clear between-group differences. Exploratory findings suggest a potential signal involving executive functioning that warrants further investigation. These results inform the feasibility and design of larger comparative trials. TRIAL REGISTRATION: ClinicalTrials.gov (NCT05902312).

Adult↗

PubMed2026

Chemoradiotherapy versus short-course radiotherapy for response-adapted organ preservation in early-stage and intermediate-stage rectal cancer (STAR-TREC): 12-month results of an international, multicentre, open-label, parallel-group, randomised, phase 2/3 trial.

BACKGROUND: Total mesorectal excision (TME) is the standard treatment for most early-stage and intermediate-stage rectal cancer but can cause substantial perioperative morbidity, functional impairment, and reduced quality of life. We assessed whether long-course chemoradiotherapy (LCCRT) or short-course radiotherapy (SCRT) could increase organ preservation and reduce surgery, toxicity, and quality-of-life harms without compromising oncological outcomes. METHODS: STAR-TREC is an international, multicentre, open-label, parallel-group, randomised, phase 2/3 trial in five European countries. Eligible patients were aged 16 years or older in the UK or aged 18 years or older elsewhere, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and rectal adenocarcinoma (≤40 mm staged as mrT1-T3bN0). In phase 2, participants were randomly assigned (1:1:1) to LCCRT-based organ preservation (LCCRT-OP; 50 Gy in 25 fractions plus oral capecitabine 825 mg/m2 twice daily), SCRT-based organ preservation (SCRT-OP; 25 Gy in five fractions), or primary TME. Phase 2 assessed feasibility, with recruitment at months 12 and 24 as the primary endpoint and feasibility thresholds of four or more and six or more randomisations per month, respectively. Phase 3 adopted a partially randomised patient-preference design, allowing participants to choose either organ preservation or TME. Participants that chose organ preservation were randomly assigned (1:1) to receive LCCRT-OP or SCRT-OP using centralised, computer-generated assignment, with stratification by country and MRI T category (≤T3a vs T3b) using minimisation. The phase 3 primary endpoint was organ-preservation 30 months after treatment initiation, defined as absence of TME, stoma, or local recurrence, which was assessed in the modified intention-to-treat population, which included participants in phase 2 and phase 3. After a planned interim analysis of unmasked phase 2 data, the trial steering committee and independent data monitoring committee recommended reporting a 12-month, modified intention-to-treat analysis of implementation outcomes for participants recruited before Aug 8, 2023. This study is registered with ISRCTN (14240288) and is closed. FINDINGS: Between June 14, 2017, and April 8, 2024, 503 participants were enrolled at 37 sites. Phase 2 enrolled 120 participants, with recruitment rates of three and six participants per month at months 12 and 24, respectively. Overall, 12-month TME-free survival was 60% (47 of 78 participants). After phase 3 recruitment ended, interim analysis of unmasked phase 2 data showed an early TME-free survival benefit with LCCRT versus SCRT (12-month median TME-free survival not reached [95% CI not reached-not reached] vs 7·6 months [95% CI 6·4-not reached]; hazard ratio [HR] 3·7 [95% CI 1·7-8·0]; posterior probability of superiority >99·5%). The trial steering committee and independent data monitoring committee therefore recommended expanded analysis of 426 participants recruited before Aug 8, 2023: 120 from phase 2 and 306 from phase 3. 17 participants withdrew before treatment, leaving 409 in the modified intention-to-treat population: 163 allocated to LCCRT, 168 to SCRT, and 78 to primary TME. 116 (28%) participants were female and 293 (72%) were male. Among participants who opted for organ preservation, 12-month TME-free survival was 78·5% (95% CI 72·4-85·1) with LCCRT and 60·6% (53·6-68·4) with SCRT (HR 1·90 [95% CI 1·29-2·81]). The most common grade 3-4 serious adverse events were gastrointestinal disorders (four [2%] with LCCRT vs six [4%] with SCRT vs six [8%] with TME) and procedural complications (three [2%] with LCCRT vs five [3%] with SCRT vs five [6%] with TME). One participant allocated to primary TME died after an anastomotic leak. INTERPRETATION: These early results support a response-adapted organ-preservation approach, with LCCRT appearing more effective than SCRT at 12 months. Organ-preservation might also reduce treatment-related toxicity compared with primary TME. Longer follow-up is needed for the prespecified 30-month endpoint and definitive functional and oncological outcomes. FUNDING: Cancer Research UK, Stand Up to Cancer, Dutch Cancer Society, Danish Cancer Society, Kom Op Tegen Kanker, Cancerfonden, ALF Region Stockholm, RCC Region Stockholm.

Humans↗

PubMed2026

Beyond Glycaemia: Fear of Hypoglycaemia, Cognition and Functional Mobility After Advanced Hybrid Closed-Loop Therapy in Older Adults With Type 1 Diabetes: A Prespecified Secondary Analysis of a Randomised, Single-Centre Study.

BACKGROUND: Evidence on psychological, cognitive and functional outcomes of advanced diabetes technologies in older adults with long-standing type 1 diabetes (T1D) remains limited. We evaluated whether initiation of advanced hybrid closed-loop (AHCL) therapy was associated with changes in fear of hypoglycaemia, diabetes distress, psychological well-being, cognition, frailty-related measures and mobility-related function in adults aged ≥ 65 years with T1D. METHODS: This prespecified, exploratory secondary analysis was conducted within a single-centre, open-label, randomised, controlled, parallel-group trial including adults aged ≥ 65 years with long-standing T1D. Participants were randomly assigned (1:1) to initiate AHCL therapy using the MiniMed 780G system or to continue standard diabetes treatment. The secondary outcomes included WHO-5, the 17-item Diabetes Distress Scale (DDS), Hypoglycemia Fear Survey-II (HFS-II), Montreal Cognitive Assessment, Digit Symbol Substitution Test, Fried frailty phenotype and performance-based functional measures. No formal sample-size calculation was performed for these secondary outcomes. RESULTS: Thirty-one participants were randomised and 29 completed 12 months of follow-up and were included in the treatment-effect analyses. In the baseline-adjusted primary analysis, AHCL therapy was associated with a lower HFS-II score than standard treatment (adjusted mean difference -18.9; 95% CI: -32.4 to -5.4; nominal p = 0.008), although this finding did not remain statistically significant after Holm correction (adjusted p = 0.104) or in an exploratory model additionally adjusted for sex (difference -13.6; 95% CI: -32.2 to 5.0; p = 0.145). Diabetes distress, psychological well-being, global cognition and processing speed did not differ between groups. In sex-adjusted sensitivity analyses, the between-group differences remained statistically significant for 6-min walk distance (92.6 m; 95% CI: 36.8 to 148.3; p = 0.002) and Timed Up and Go performance (-2.27 s; 95% CI: -4.28 to -0.27; p = 0.028), but not for gait speed (0.27 m/s; 95% CI: -0.05 to 0.59; p = 0.099). At 12 months, 12 of 14 AHCL participants were robust and 2 were pre-frail; in the control group, 11 of 15 were robust and 4 were pre-frail. No participant was classified as frail at follow-up. CONCLUSIONS: In this small, selected cohort, AHCL therapy was associated with a nominally lower fear-of-hypoglycaemia score and better performance on selected mobility-related tests over 12 months. The fear-of-hypoglycaemia finding did not remain statistically significant after correction for multiple comparisons or additional adjustment for sex. Six-minute walk distance and Timed Up and Go remained statistically significant in the exploratory sex-adjusted sensitivity analyses, whereas the gait-speed difference did not. No measurable between-group deterioration in global cognition or processing speed was observed. These exploratory findings require confirmation in larger studies with balanced representation by sex and direct measurement of physical activity. These findings also support a person-centred clinical message: older age alone should not be regarded as a barrier to AHCL when treatment is introduced with individualised education and appropriate ongoing support.

Humans↗

PubMed2026

[Moxibustion combined with Jianpi Wenshen formula for cancer-related anorexia of spleen-kidney yang deficiency: a randomized controlled trial].

OBJECTIVE: To observe the clinical efficacy of moxibustion combined with Jianpi Wenshen formula in treating cancer-related anorexia of spleen-kidney yang deficiency. METHODS: A total of 80 patients with cancer-related anorexia of spleen-kidney yang deficiency were randomized into an observation group and a control group, with 40 cases in each group.Jianpi Wenshen formula was given orally in the control group. On the basis of the treatment in the control group, moxibustion was applied at bilateral Zusanli (ST36), Neiguan (PC6) and Zhongwan (CV12), Guanyuan (CV4), Mingmen (GV4) in the observation group, once daily for the first 15 days, then once every other day. Both groups were treated for 4 weeks. The scores of appetite, Karnofsky performance status (KPS), nutritional risk screening 2002 (NRS-2002), and patient-generated subjective global assessment (PG-SGA), as well as the serum levels of interferon-γ (IFN-γ) and C-reactive protein (CRP)were observed before and after treatment, and the clinical efficacy was evaluated after treatment in the two groups. RESULTS: After treatment, the scores of appetite, NRS-2002, PG-SGA, and the serum levels of IFN-γ and CRP were decreased compared with those before treatment in the two groups (P<0.001, P<0.05, P<0.01), and the above indexes in the observation group were lower than those in the control group (P<0.05, P<0.001); the KPS scores were increased in the two groups compared with those before treatment (P<0.001, P<0.05), and the KPS score in the observation group was higher than that in the control group (P<0.001). The marked response rate was 57.5% (23/40) in the observation group, which was higher than 30.0% (12/40) in the control group (P<0.05). CONCLUSION: Moxibustion combined with Jianpi Wenshen formula can effectively improve appetite and overall status, and reduce the levels of IFN-γ and CRP in patients with cancer-related anorexia of spleen-kidney yang deficiency.

Humans↗

PubMed2026

Efficacy and safety of JAK inhibitors for vitiligo: an updated systematic review and meta-analysis of randomized controlled trials.

Purpose: Janus kinase (JAK) inhibitors are a promising therapeutic option for vitiligo, but previous meta-analyses have focused mainly on topical ruxolitinib versus placebo. Newer randomized controlled trials (RCTs) evaluating oral agents and head-to-head comparisons with active treatments have not been comprehensively synthesized. Materials and methods: We searched PubMed, Embase, the Cochrane Library, and Web of Science to 11 March 2026. Eligible RCTs evaluated JAK inhibitor monotherapy versus placebo or active comparators. Two reviewers screened records, extracted data, and assessed risk of bias using RoB 2.0. The primary outcome was F-VASI75. Meta-analyses used fixed-effect or random-effects models. GRADE assessed certainty of evidence. Results: Nine RCTs (1826 patients) were included. JAK inhibitors increased F-VASI75 versus placebo (RR 4.59, 95% CI 3.20-6.59; p < 0.001). For F-VASI50, they were superior to tacrolimus (RR 1.88, 95% CI 1.02-3.45) but not significantly different from dexamethasone (RR 2.17, 95% CI 0.95-4.94). Serious adverse events were comparable between groups (RR 1.15, 95% CI 0.57-2.33). Evidence certainty was moderate. Conclusions: JAK inhibitors are effective and well tolerated for vitiligo. Topical ruxolitinib is supported as a first-line option for limited facial disease; oral agents show promise but require longer-term safety data.

Humans↗

PubMed2026

Anti-inflammatory agents after hip and shoulder arthroplasty: A systematic review and meta-analysis.

BACKGROUND: Postoperative inflammation after arthroplasty contributes to pain, delayed mobilization and prolonged hospitalization. Recent randomized trials have evaluated pharmacological anti-inflammatory strategies within contemporary enhanced recovery pathways, but evidence after hip and shoulder arthroplasty remains scattered across different drug classes and perioperative regimens. OBJECTIVES: To synthesize recent randomized controlled trial (RCT) evidence on perioperative anti-inflammatory agents after hip and shoulder arthroplasty. METHODS: PubMed, Embase, Cochrane Library and Web of Science were searched for English-language RCTs published from January 2020 to March 2026. The 2020-2026 window was selected to update evidence generated under modern arthroplasty, anesthesia, multimodal analgesia and enhanced recovery after surgery (ERAS) pathways. Eligible trials included adults undergoing hip or shoulder arthroplasty and compared corticosteroids, cyclooxygenase-2 (COX-2) inhibitors, nonsteroidal anti-inflammatory drug (NSAID)-based/local anti-inflammatory regimens, or related anti-inflammatory interventions with placebo, saline, no treatment, or the same regimen without the target component. Weighted mean differences (WMDs) were pooled using random-effects models. RESULTS: Nine RCTs involving 800 patients were included. Anti-inflammatory interventions significantly reduced postoperative C-reactive protein (CRP) [WMD=-32.18, 95% confidence interval (CI) (-41.16, -23.21), P<0.001], interleukin-6 (IL-6) [WMD=-31.25, 95% CI (-41.79, -20.77), P<0.001], rest pain [WMD=-0.41, 95% CI (-0.58, -0.23), P<0.001], activity pain [WMD=-0.56, 95% CI (-0.83, -0.29), P<0.001] and hospital stay [WMD=-0.54, 95% CI (-0.92, -0.15), P=0.006]. CONCLUSION: Recent RCT evidence suggests that perioperative anti-inflammatory interventions can attenuate early inflammatory responses and improve short-term pain and recovery after hip and shoulder arthroplasty. Because data were limited and clinically heterogeneous, the findings should not be interpreted as evidence favoring a specific drug class, dose, route, or timing.

Humans↗

PubMed2026

Manual, digital, and AI tumour-infiltrating lymphocyte scoring: a secondary analysis of the APHINITY randomised trial.

BACKGROUND: Stromal tumour-infiltrating lymphocytes (sTILs) are prognostic in early-stage HER2-positive breast cancer, but their role in the context of dual HER2 blockade remains undefined. We evaluated manual, digital, and artificial intelligence (AI)-based sTIL quantification, together with AI-derived spatial metrics, for prognostic and treatment-benefit stratification using tumour samples from the phase 3 APHINITY trial. METHODS: In the APHINITY trial, 4805 patients were randomly assigned to receive chemotherapy plus trastuzumab with pertuzumab or chemotherapy plus trastuzumab with placebo. Median follow-up was 74·1 months (IQR 68·3-75·4). We analysed 4262 haematoxylin and eosin-stained images using manual assessment, an automated digital approach, AI-based lymphocyte quantification (AI percentage lymphocytes), and two AI-derived spatial features (AI-TIL and immune hotspot). Interobserver reproducibility was assessed in 262 randomly chosen tumour samples scored independently by five pathologists. Multivariable Cox models were used to assess associations between TIL levels and invasive disease-free survival (primary outcome in APHINITY), distant recurrence-free interval, and overall survival. The heterogeneity of pertuzumab benefit was evaluated using subgroup analyses, subpopulation treatment effect pattern plot analyses, and nested Cox models with treatment-by-biomarker interaction terms. FINDINGS: Manual scoring showed high interobserver reproducibility (intraclass correlation coefficient 0·84 [95% CI 0·79-0·88]). Concordance between manual and automated methods was modest. AI-based scoring (AI percentage lymphocytes) reclassified 120 (11·6%) of 1035 node-positive tumours from immune-low (by manual scoring) to immune-high; this subgroup of patients showed greater separation of 5-year invasive disease-free survival curves between pertuzumab and placebo groups compared with patients whose tumours were concordantly classified as immune-low by both manual and AI-based approaches. Higher levels of TILs were associated with improved invasive disease-free survival for all sTIL measurement approaches and spatial measurements (hazard ratios [HRs] 0·41-0·93). Pertuzumab was associated with improved invasive disease-free survival at higher sTIL levels across all measurement approaches (HRs 0·36-0·48), but was not associated with higher values of spatial measures. The largest 6-year absolute improvements with pertuzumab were observed in patients with node-positive disease whose tumours scored in the highest level of immune infiltration of manual sTIL scoring (≥70·0%; mean absolute improvement 12·1 percentage points [SD 2·8]). In nested prognostic and predictive models, AI-based immune hotspot scores provided the most consistent additional information when combined with any sTIL measurement (all p<0·010). INTERPRETATION: Standardised manual sTIL scoring was reproducible, and digital and AI-based methods showed consistent prognostic stratification and potential for treatment-benefit stratification despite only modest correlation between platforms. AI spatial metrics provided complementary information beyond sTIL density and could support more scalable immune assessment. Future studies are needed to validate these approaches in independent cohorts and to clarify their clinical utility for stratifying contemporary HER2-directed therapies. FUNDING: None.

Humans↗

PubMed2026

Comparative effects of pharmacological interventions in the prophylactic treatment of tension-type headache: systematic review and network meta-analysis.

BACKGROUND: Tension-type headache (TTH) is the most common neurological disorder. The comparative effect of pharmacological interventions for TTH prophylaxis remains unclear. We aimed to assess the comparative effects of pharmacological interventions in the prophylactic treatment of TTH. METHODS: Ovid Medline, Embase, and Cochrane were searched from inception to 12 December, 2025. Randomized controlled trials (RCTs) of medications compared to placebo or another medication for preventing TTH were included. The primary outcome was headache days per month. A Bayesian random-effect model was employed as the primary analysis of chronic TTH. RESULTS: Thirty-five RCTs were included, 33 (88.6%) RCTs involved chronic TTH patients, and 24 RCTs provided available data for meta-analysis. Amitriptyline 100 mg presented more reduction of monthly headache days than placebo at 4 and 8 weeks (4 weeks: MD -6.59, 95% CrI -11.22 to -0.64; 8 weeks: MD -6.14, 95% CrI -10.27 to -0.87). BTX-A 100 U can reduce monthly headache days (MD -3.79, 95% CrI -7.16 to -0.33). Amitriptyline 100 mg was the highest-ranked treatment for monthly headache days at 4 (SUCRA 0.85), 8 (SUCRA 0.85), and 24 (SUCRA 0.87) weeks; 12 weeks was lidocaine 25 ml (SUCRA 0.75). Amitriptyline 100 mg and BTX-A 500 U showed a higher adverse event rate than placebo. CONCLUSION: Amitriptyline 100 mg and BTX-A 100 U may be options to reduce monthly headache days in patients with chronic TTH. Given the low to very low certainty of evidence, high risk of bias, and high heterogeneity, more studies are needed. TRIAL REGISTRATION: PROSPERO (CRD42025639586).

Humans↗