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PubMed2026

Balanced Fluid or 0.9% Saline in Children Treated for Septic Shock.

BACKGROUND: Whether treatment with balanced crystalloid fluid leads to better outcomes than 0.9% saline in children treated for septic shock is debated. METHODS: In this pragmatic clinical trial conducted at 47 emergency departments in five countries, patients (2 months to <18 years of age) with suspected septic shock and abnormal perfusion were randomly assigned to receive fluid resuscitation with either balanced fluid or 0.9% saline for up to 48 hours. The primary outcome was a major adverse kidney event (a composite of death, new renal-replacement therapy, or persistent kidney dysfunction) at 30 days after enrollment or hospital discharge, whichever occurred first. RESULTS: Of 9041 enrolled patients, 277 (6.1%) in the balanced-fluid group and 282 (6.2%) in the 0.9%-saline group withdrew from the trial, leaving 4235 and 4247 patients, respectively, for analysis. A primary-outcome event occurred in 137 patients (3.4%) in the balanced-fluid group and in 124 (3.0%) in the 0.9%-saline group (difference, 0.4 percentage points; 95% confidence interval [CI], -0.5 to 1.3; risk ratio, 1.10; 95% CI, 0.88 to 1.40; P = 0.85). The median number of hospital-free days during 28 days after enrollment was 23 (interquartile range, 19 to 25) in both groups. Hyperchloremia occurred in 868 patients (31.4%) in the balanced-fluid group and in 1383 (49.0%) in the 0.9%-saline group; hypernatremia in 52 (1.8%) and 89 (3.1%), respectively; and hyperlactatemia in 260 (19.8%) and 228 (16.7%). No differences in other safety outcomes or adverse events were seen. CONCLUSIONS: Among children treated for septic shock, no significant difference was seen in the incidence of death, new renal-replacement therapy, or persistent kidney dysfunction when fluid resuscitation was administered with balanced fluid as compared with 0.9% saline. (Funded by Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; PRoMPT BOLUS ClinicalTrials.gov number, NCT04102371.).

Adolescent↗

PubMed2026

Pragmatic gynecologic cancer clinical trials: statements and roadmap from the Gynecologic Cancer InterGroup Chicago Brainstorming Meeting.

Randomized controlled trials remain fundamental to evidence generation in oncology but are increasingly complex, costly, and often misaligned with real-world practice. Traditional explanatory trials, designed under ideal, controlled conditions, frequently enroll highly selected populations, limiting generalizability and underrepresenting key groups such as older adults, patients with comorbidities, and those from low- and middle-income countries. Pragmatic clinical trials offer an alternative by evaluating interventions under routine care conditions, with broader eligibility, simplified procedures, and patient-centered outcomes. To address these challenges, the Gynecologic Cancer InterGroup convened an international brainstorming meeting in May 2025 with multi-disciplinary experts, patients, and advocates to define priorities and develop a roadmap for pragmatic trials in gynecologic oncology. Key discussions emphasized embedding trial design within routine care, aligning eligibility criteria and procedures with standard practice, minimizing non-essential data collection, and prioritizing outcomes meaningful to patients, including quality of life. Innovative designs such as registry-based randomized trials, trials-within-cohorts, and cluster randomization were highlighted as feasible approaches to improve efficiency while preserving internal validity. Integration of patient-reported outcomes and real-world data was considered achievable when carefully streamlined. Major challenges identified included regulatory heterogeneity, consent complexity, data interoperability, and funding limitations, particularly in multi-national settings. Proposed solutions include simplified consent models, centralized ethics processes, hybrid funding strategies, and the responsible use of artificial intelligence to enhance patient identification, recruitment, and potential development of synthetic control arms. Patient engagement was recognized as essential to ensure relevance, feasibility, and equity. Incorporation of patient-reported outcomes was discussed as key to informing acceptance and tolerability. In summary, pragmatic trials within Gynecologic Cancer InterGroup represent a critical pathway to generate efficient, inclusive, and practice-changing evidence in gynecologic cancers across diverse health care settings.

Humans↗

PubMed2026

Role of routine surveillance stress testing in patients with or without imaging-guided or physiology-guided PCI.

OBJECTIVE: The optimal follow-up strategy for high-risk patients who underwent imaging-guided or physiology-guided percutaneous coronary intervention (PCI) remains uncertain. We investigated whether routine surveillance stress testing after PCI provides clinical benefit when the procedure is guided by intravascular ultrasonography (IVUS) or fractional flow reserve (FFR). METHODS: In the Pragmatic Trial Comparing Symptom-Oriented vs Routine Stress Testing in High-Risk Patients Undergoing PCI randomised trial, 1706 high-risk patients who underwent PCI were assigned to either routine functional testing at 1 year or standard care alone. In this prespecified subgroup analysis, patients were subsequently categorised according to whether IVUS or FFR was used at the index procedure. The primary outcome was a composite of death, myocardial infarction or hospitalisation for unstable angina over 2 years. RESULTS: Among the randomised population, 74% underwent IVUS-guided intervention and 36% underwent FFR-guided intervention. At 2 years, rates of the primary outcome were similar between routine testing and standard care both in patients treated with IVUS guidance (5.3% vs 6.7%; HR 0.79; 95% CI 0.50 to 1.24) and without IVUS guidance (5.7% vs 3.8%; HR 1.52; 95% CI 0.63 to 3.68; interaction p=0.21). Comparable results were observed in patients with FFR guidance (2.6% vs 3.9%; HR 0.65; 95% CI 0.26 to 1.58) and without FFR guidance (7.0% vs 7.1%; HR 0.99; 95% CI 0.63 to 1.55; interaction p=0.59). Routine functional testing was consistently associated with higher use of invasive coronary angiography and repeat revascularisation, without improvement in clinical outcomes. CONCLUSIONS: Among high-risk patients who underwent PCI, routine surveillance stress testing did not reduce the risk of death, myocardial infarction or unstable angina, regardless of the use of IVUS or FFR at the index procedure. Routine functional testing increased downstream invasive procedures without clinical benefit. These findings support guideline recommendations against routine surveillance testing after PCI. TRIAL REGISTRATION NUMBER: NCT03217877.

Humans↗

PubMed2026

Psychotherapy vs antidepressants in heart failure: Impact of adherence.

BACKGROUND: Depression affects nearly half of patients with heart failure (HF), which is associated with increased morbidity and reduced health-related quality of life (HRQoL). This secondary per-protocol analysis of a previously published randomized trial evaluated the behavioral activation (BA) versus antidepressant medication (MEDS) among patients with depression and HF who adhered to study interventions. METHODS: This analysis is based on a pragmatic randomized comparative-effectiveness trial conducted from 2018 to 2022, with a 1-year follow-up. 416 participants diagnosed with HF and a DSM-5 depressive disorder were randomized to BA or MEDS, and the current analysis examined outcomes according to treatment adherence. OUTCOMES: The primary outcome was depressive symptom severity (PHQ-9) at 6 months, and the secondary outcomes were physical and mental HRQoL (SF-12v2-PC and SF-12v2-MC, respectively) and HF-specific HRQoL (Kansas City Cardiomyopathy Questionnaire; KCCQ) overall and clinical scores (KCCQ-OS and KCCQ-CS), at 3, 6, and 12 months. High adherence was defined as completion of >75-100% of intervention components. Overall adherence rates were similar between BA and MEDS. At 6 months, among patients with >75-100% adherence who followed treatment as directed in both arms, BA was associated with higher Mental HRQoL (SF-12v2-MC: 5.22; 95% CI: 0.72 to 9.72; p = 0.023) and higher HF-specific HRQoL (KCCQ-OS: 16.08; 95% CI: 7.20 to 24.97; p < 0.001); (KCCQ-CS: 16.04; 95%CI: 7.05 to 25.02; p < 0.001) compared to MEDS. There were no significant differences in depressive symptoms or physical HRQoL at 6 months. INTERPRETATION: Both BA and MEDS were equally effective treatments for depression in HF. However, among highly adherent patients, BA was associated with greater improvements in mental and HF-specific HRQoL than MEDS. FUNDING/SUPPORT: The study was funded by PCORI Award Number: 2017C2-7716.

Humans↗

PubMed2026

Swab Testing to Optimize Pneumonia Treatment With Empiric Vancomycin: A Randomized Controlled Trial.

BACKGROUND: Fear of methicillin-resistant Staphylococcus aureus (MRSA) as a cause of community-acquired pneumonia (CAP) frequently leads to empiric vancomycin coverage. Data evaluating the use of MRSA polymerase chain reaction (PCR) nasal swab testing to guide vancomycin de-escalation is limited for patients in the intensive care unit (ICU). METHODS: Swab Testing to Optimize Pneumonia Treatment With Empiric Vancomycin (STOP-Vanc) is a pragmatic, prospective, single-center, non-blinded randomized trial in which adult ICU patients with suspicion of CAP were randomized 1:1 to receive usual care either with (intervention) or without (control) the addition of MRSA nares PCR testing following ICU admission. The primary outcome was vancomycin-free hours alive, defined as the expected number of hours alive and free of vancomycin use within the first 7 days of trial enrollment as estimated using a longitudinal proportional odds state transition model adjusted for baseline covariates. RESULTS: A total of 277 adult ICU patients were randomized. Methicillin-resistant Staphylococcus aureus PCR nasal swab testing had a negative predictive value (NPV) of 98.9% in the intervention arm. The primary endpoint, vancomycin-free hours alive, was 105.7 in the control arm and 109.7 in the intervention arm (adjusted difference, 4 hours; 95% CI, -9.5-18.2; P = .458). CONCLUSIONS: Despite MRSA PCR nasal swab testing demonstrating a high NPV in this critically ill population, MRSA PCR nasal swab testing did not decrease the duration of vancomycin use or 30-day mortality among ICU patients with suspected CAP. Additional clinician education and antimicrobial stewardship interventions might be needed to reduce vancomycin use in this patient population. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov NCT06272994 (STOP-Vanc).

Humans↗

PubMed2026

Long-term motor outcomes after parent-administered early physiotherapy in children born very preterm.

OBJECTIVE: This observational follow-up study investigated whether early parent-administered physiotherapy during the neonatal period was associated with motor outcomes in childhood, and compared these outcomes between two preterm groups and a term-born control group. STUDY DESIGN: This is a follow-up of a pragmatic randomised controlled trial that initially included 153 infants born very preterm (≤32 weeks' gestation), randomised to either early parent-administered physiotherapy or standard care, between 34 and 37 weeks' gestation. At 7-10 years, motor outcomes were assessed in 92 children (intervention, n = 43; standard care, n = 49) and in 83 term-born controls. The primary outcome was the Movement Assessment Battery for Children-Second Edition (MABC-2). Group differences were analysed using linear mixed models adjusted for age, sex, and parental education. Odds ratios (ORs) were calculated for scores ≤5th and ≤ 15th percentiles to estimate the likelihood of having or being at risk for movement difficulties. RESULTS: Mean MABC-2 total score was 9.0 (SD3.0) in the intervention group, 9.6 (SD3.0) in the standard care group, and 10.8 (SD2.9) in the control group. Adjusted mean difference between the intervention and the standard care groups did not differ but both the intervention and standard care groups had lower scores than the control group (-1.2; 95% CI: -2.3 to -0.2 and -0.6; 95% CI: -1.6 to 0.3, respectively). Adjusted ORs for scoring ≤5th or ≤15th percentile did not differ in either preterm group compared with the control group. CONCLUSION: At 7-10 years, motor outcomes did not differ between children born very preterm who received three-week parent-administered physiotherapy and those who received standard care during the neonatal period. However, both preterm groups had lower motor scores than term-born peers.

Humans↗

PubMed2026

Virtual Reality Education for Hospitalized Pediatric Patients Improves Intrinsic Motivation: A Prospective, Randomized Crossover Study.

Hospitalized children experience educational disruption and reduced motivation during prolonged admissions. Despite the availability of in-hospital schools, many cannot participate due to illness severity or isolation precautions. This pragmatic, randomized crossover trial evaluated whether bedside virtual reality (VR) lessons improve intrinsic motivation among inpatients aged 5 to 25 years unable to attend the hospital school. Participants completed both VR-based educational sessions and standard of care (SOC) conditions on consecutive days. The primary outcome was intrinsic motivation, with secondary outcomes including educational self-efficacy, well-being, self-esteem, and parental experience. Of 156 enrolled patients, 100 were analyzed (mean age 11.5 [SD = 4.1 years]; 43.9% female). Intrinsic motivation scores were higher in the VR condition than SOC (P = .0048), and parental satisfaction was also greater (P = .0008). Bedside VR education represents a feasible, acceptable, and scalable adjunct to inpatient learning, supporting intrinsic motivation and caregiver satisfaction during hospitalization.Trial Registration: ClinicalTrials.gov NCT05725395, date first registered November 22, 2022.

Humans↗

PubMed2026

Genotype-Guided Antidepressant Prescribing for Patients With Depression: A Randomized Clinical Trial.

IMPORTANCE: The effectiveness of pharmacogenetics to guide prescribing of selective serotonin reuptake inhibitors (SSRIs) for depression remains unclear, despite the well-established association between SSRI pharmacokinetics and genetic variation. OBJECTIVE: To determine whether pharmacogenetic-guided prescribing of SSRIs improves treatment response in patients with depression. DESIGN, SETTING, AND PARTICIPANTS: The ADOPT PGx (A Depression and Opioid Pragmatic Trial in Pharmacogenetics) Depression pragmatic randomized clinical trial was conducted from August 10, 2021, through April 27, 2024, at primary care, psychiatry, or family medicine clinics at enrolling sites throughout the US. Patients were aged 8 years or older and had experienced depression for 3 months or longer. INTERVENTION: Patients were randomized to genotype-guided SSRI prescribing (intervention group) or usual care (control group). Actionable drug metabolism phenotypes were defined as those for which pharmacogenetic clinical guidelines recommend alternative medication selection or dose adjustment. MAIN OUTCOMES AND MEASURES: The primary outcome was change in Patient-Reported Outcomes Measurement Information System (PROMIS) depression T scores at 3 months among patients with the actionable phenotype. Secondary end points included adverse effect severity of SSRIs at 3 months and depression remission (measured with PROMIS depression scores and Patient Health Questionnaire-8 [PHQ-8] scores) at 6 months. RESULTS: This study of 1460 patients included 1239 adults (84.9%) (mean [SD] age, 40.6 [16.7] years) and 221 children (15.1%) (mean [SD] age, 14.6 [1.8] years). Most patients were female (1096 [75.1%]). A total of 692 patients (47.4%) had an actionable phenotype; 351 (50.7%) were assigned to the intervention, and 341 (49.3%) were assigned to usual care. At baseline, 463 of the 692 patients (66.9%) reported having depressive symptoms for more than 2 years, 603 (87.1%) were receiving pharmacologic treatment, and 354 (51.2%) were receiving nonpharmacologic treatment. At 3 months, no significant differences were observed between the intervention and usual care groups in change in PROMIS depression T scores (mean [SD] change, -4.3 [8.4] vs -4.0 [8.1]; P = .68), medication adverse effect burden (mean [SD] change, 8.2 [4.3] vs 7.8 [4.5]; P = .37), or Patient Health Questionnaire-8 score change (mean [SD] change, -3.3 [5.2] vs -2.7 [4.8]; P  = .13). However, at 6 months, the PROMIS depression T-score remission rate (score ≤16) was higher in the intervention group compared with the usual care group (153 of 317 patients [48.3%] vs 122 of 310 patients [39.4%]; P = .02). CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, genotype-guided prescribing of SSRIs did not improve control of depression symptoms at 3 months compared with usual care but was associated with higher depression remission rates at 6 months. These findings suggest a possible longer-term clinical benefit and indicate that future studies should focus on the durability and long-term impact of genotype-guided prescribing in the management of depressive symptoms. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT04445792 (Master Protocol Research Program platform trial) and NCT05966155 (ADOPT PGx Depression trial).

Humans↗

PubMed2026

Effects of Transcranial Direct Current Stimulation and Individualized Physical Therapy on Pain and Function in Individuals With Chronic Knee Pain: A Pilot Study.

BACKGROUND AND PURPOSE: Noninvasive brain stimulation is a promising neuromodulatory intervention for chronic pain. This study aimed to determine the impact that transcranial direct current stimulation (tDCS) in combination with individualized physical therapy (PT) has on pain and function in individuals with chronic knee pain. METHODS: This study was a preliminary pragmatic, triple-blinded, randomized, and sham-controlled clinical trial performed in an outpatient orthopedic physical therapy clinic. Participants participated in 5 sessions of active or sham tDCS followed by individualized PT intervention. Pain outcomes included the Numeric Pain Rating Scale, Movement-Evoked Pain, pressure pain thresholds (PPT), and the Central Sensitization Inventory. Functional outcomes included the 2-minute walk test, 5-time sit-to-stand test, quadriceps strength, knee range of motion, Patient Specific Functional Scale, and the Lower Extremity Functional Scale. RESULTS: Thirty participants with chronic knee pain completed the study. There were no significant differences observed for primary patient-centered pain and functional outcomes. For secondary outcomes, the active tDCS group had a significant effect (p < 0.05) on percent change in lateral joint line PPT and a significant multivariate effect of group on PPT change scores for 3-site and 5-site clusters (p < 0.05). Exploratory responder analyses demonstrated that the active tDCS group was 12.8 times more likely to achieve the minimum detectable change in quadriceps strength improvement compared with the sham tDCS group (p < 0.05). DISCUSSION: There were no significant between-group differences for primary pain and functional outcomes. However, the active tDCS group showed improvements in pain sensitivity, as measured by PPT, and quadriceps strength, which were superior to those seen in the sham tDCS group. These preliminary findings provide insight into possible mechanisms of tDCS in addressing pain as opposed to efficacy. Given that there were no clear between-group differences in patient-centered outcomes, there is insufficient evidence for routine tDCS use for chronic knee pain. TRIAL REGISTRATION: NCT06132412.

Humans↗

PubMed2026

Accelerated Diagnostic Pathways for Suspected Acute Coronary Syndrome in Practice: A Randomized Trial of 0/1-Hour vs 0/3-Hour Troponin Testing.

BACKGROUND: For suspected acute coronary syndrome (ACS), guidelines recommend using high-sensitivity troponins (hs-cTn) in accelerated diagnostic pathways (ADPs) with 0/1-hour recommended over 0/3-hour ADP. However, implementation of these ADPs, with universal use of hs-cTns, has not been directly compared in randomized trials OBJECTIVES: This study sought to compare the efficiency and safety of the European Society of Cardiology (ESC) 0/1-hour and a 0/3-hour ADP when implemented in real-world clinical practice. METHODS: This pragmatic, randomized, noninferiority implementation trial compared the safety and efficiency of clinician decision making using these 2 pathways. To prevent incorporation bias, an independent hs-cTnI was used for formal adjudication using the fourth universal definition of myocardial infarction (MI). Efficiency was judged by the proportion of patients discharged within 4 hours. The safety endpoint was major adverse cardiac events (MACE) within 30 days (adjudicated index or representation type 1 MI, cardiovascular death, and urgent coronary revascularization) for those who were considered not to have ACS and discharged. The noninferiority margin, for absolute difference in sensitivity, between the ESC 0/1-hour and the 0/3-hour ADP was set at 3%, assessed with a 1-sided 97.5% CI. RESULTS: From December 2021 to July 2024, of 13,983 screened 3,543 individual patients with suspected ACS were recruited and consented from 2 major emergency departments in North-West England, with 100% follow-up achieved for all representations to any national hospital. The median age was 60 years (IQR: 49.5-70.5 years), 53% were men, 6.7%, and 7.6% had adjudicated index type 1 MI and MACE within 30 days, respectively. The turnaround time from sample to result for central laboratory hs-cTnT was 81 minutes (IQR: 69-101 minutes). The proportion of patients discharged within 4 hours was relatively low and did not differ substantially (21.8% vs 19.2%, P = 0.07). In addition, the 0/1-hour pathway was noninferior for safety, in patients discharged, compared with the 0/3-hour pathway, absolute difference in sensitivity was +4.2% (1-sided 97.5% CI: -2.5) in favor of the 0/1-hour pathway. The calculated sensitivities were 93.7% (95% CI: 88.4%-97.1%) vs 89.5% (95% CI: 82.7%-94.3%), respectively. CONCLUSIONS: Implementation of the ESC 0/1-hour pathway failed to discharge significantly more patients within 4 hours of presentation compared with the 0/3-hour ADP. In addition, The ESC 0/1-hour was noninferior to the 0/3-hour hs-cTn pathway for safety of discharge, although safety for both pathways was less than that imputed by observational studies. This trial demonstrates that perceived benefits to emergency department efficiency of a reduced sampling interval are mitigated by central laboratory turnaround times as well as system constraints. (Pragmatic Randomised Trial of the ESC 0/1 Versus 0/3 Hour Troponin Pathway [MACROS2]; NCT05322395).

Acute Coronary Syndrome↗

PubMed2026

Prophylactic antibiotics to prevent chest infections in children with neurological impairment: the PARROT RCT.

BACKGROUND: Improvements in neonatal and paediatric care in recent decades have increased the survival of children with non-progressive neurological impairment. Respiratory disease in children with neurological impairment is common, with symptoms difficult to manage and lower respiratory tract infection occurring frequently. To reduce these, prophylactic antibiotics are being increasingly used, but the type, duration and dose of antibiotics can vary considerably, and there is limited evidence about their effectiveness in children and young people. A joint United Kingdom and Australia multicentre, randomised, double-blind, placebo-controlled trial comparing 52 weeks of azithromycin to placebo in children and young people with neurological impairment at risk of lower respiratory tract infection (PARROT) was planned to address this gap. PARROT was a multicentre, parallel group, blinded, pragmatic randomised controlled trial of 52-week duration with a planned sample size of 500 (250 in each arm) participants with neurological impairment. The primary outcome was the proportion of children and young people hospitalised with lower respiratory tract infection over the 52-week period. RESULTS: In total, 90 children and young people (62 in Australia, 28 in the United Kingdom) aged 3-17 years, with a diagnosed non-progressive, non-neuromuscular neurological impairment, who had persistent respiratory symptoms were randomised (1 : 1) to receive azithromycin or placebo. Baseline demographic and clinical characteristics were relatively well balanced across the two treatment groups and countries. Overall, mean (standard deviation) age was 9.2 (4.4) years, with 64% of participants having cerebral palsy, 67% being non-ambulant and 54% being totally tube-fed. At baseline, mean (standard deviation) numbers of hospital admissions with lower respiratory tract infection in the preceding year were 1.8 (2.0)/year, and general practitioner attendances 3.3 (3.0)/year. The PARROT trial was closed early to recruitment due to challenges arising from the COVID-19 pandemic. Sixty-five (72%) participants (azithromycin n = 30, placebo n = 35) completed 52 weeks of treatment and were not withdrawn early from the trial. Regarding the primary outcome, 11 (36.7%) in the azithromycin group were hospitalised with lower respiratory tract infection and 9 (25.7%) in the placebo group [absolute risk reduction 0.11 (95% confidence interval -0.12 to 0.33), relative risk 1.43 (95% confidence interval 0.68 to 2.97)]. Analysis of secondary outcome data was limited by the number of missing data, but parent-reported quality of life for young person and parent, sleep amount/quality for young person and parent, and respiratory symptoms were similar between groups and countries. LIMITATIONS: As PARROT was stopped early and was consequently underpowered, it is not possible to say whether azithromycin prophylaxis is any more effective than placebo in reducing the proportion of children admitted to hospital with lower respiratory tract infection after a 52-week period. CONCLUSIONS AND FUTURE WORK: Although we cannot comment on the effectiveness of prophylactic antibiotics in this context, we can draw some useful conclusions from this trial. Thus, the importance placed by families on hospitalisation and its prevalence in both treatment groups, even during the pandemic, would suggest that this is an appropriate primary outcome measure for future trials in this high-risk group of children and young people. Furthermore, the high attrition rate and large numbers of missing data, specifically for questionnaire-based outcomes at later follow-up points, should encourage researchers to be mindful of minimising trial burden to families for any future trials wherever possible. FUNDING: This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number 16/17/01.

Humans↗

PubMed2026

Comparative effectiveness of torsemide vs furosemide in the management of heart failure patients: Win-ratio reanalysis of the TRANSFORM-HF trial.

BACKGROUND: Loop diuretics are widely used for managing congestion in patients with heart failure (HF). The TRANSFORM-HF trial is a multicenter randomized study that enrolled heart failure patients, comparing a strategy of torsemide vs furosemide. The time-to-event analysis demonstrated neutral effects on all-cause death at 30 months and the composite of all-cause death and first rehospitalization at 12 months. We evaluated whether a hierarchical win-ratio (WR) framework integrating mortality, recurrent hospitalization, and patient-reported health status provides additional interpretive insight. METHODS: This study is a secondary analysis of the pragmatic, multicenter, open-label, randomized TRANSFORM-HF trial, conducted across 60 US hospitals that randomized 2,859 patients hospitalized with HF to torsemide or furosemide. The primary 12-month hierarchical composite outcome was defined as (1) all-cause mortality, (2) recurrent all-cause hospitalizations, and (3) lack of improvement in the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS). The primary statistical method was a WR analysis adjusting covariates via inverse probability weighting. Subgroup analyses evaluated potential heterogeneity across patient demographics and clinical characteristics. RESULTS: In the primary 12-month intention-to-treat analysis, the adjusted WR was 1.07 (95% CI, 0.98-1.16; P = .13), indicating no significant difference between torsemide and furosemide. A supplementary 30-month analysis with extended mortality follow-up yielded a similar estimate (adjusted WR, 1.06; 95% CI, 0.98-1.16; P = .14); hospitalization and KCCQ-CSS components were assessed through 12 months. As-treated sensitivity analyses were consistent with the neutral primary findings. Exploratory subgroup analyses were not adjusted for multiplicity and should be considered hypothesis-generating. CONCLUSIONS: The overall WR comparison between torsemide and furosemide showed no statistically significant difference in the primary 12-month analysis. The WR framework provided an interpretive decomposition across outcome domains but did not establish superiority of either loop diuretic strategy. All findings should be considered exploratory. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03296813, https://clinicaltrials.gov/study/NCT03296813.

Aged↗

PubMed2026

Electronic Nudges to Increase Influenza Vaccination in Immunosuppressed Adults Across the Age Spectrum: A Pooled Analysis of 2 Nationwide Randomized Trials.

BACKGROUND: Immunosuppressed individuals face higher risk of severe influenza complications, yet vaccination coverage remains low. We aimed to assess the effect of electronic letter-based nudges on influenza vaccination uptake by immunosuppression status. METHODS: We performed a participant-level pooled analysis of 2 methodologically harmonized, nationwide, pragmatic randomized clinical trials during the 2023-2024 influenza season. Adults aged ≥65 years (NUDGE-FLU-2) and adults aged 18-64 years with chronic conditions (NUDGE-FLU-CHRONIC) were included, with immunosuppression defined by an immunosuppressive diagnosis or a filled prescription for immunosuppressive therapy. Participants were randomized in a 2.45:1:1:1:1:1:1 ratio to usual care or 1 of 6 electronic letter interventions. The primary outcome was receipt of influenza vaccination by 1 January 2024 ascertained from nationwide administrative health registries. Effect modification by immunosuppression status was assessed using binomial regression. RESULTS: Among 1 181 254 participants (mean age 67 years; 73 830 [6.3%] immunosuppressed), 66.1% were vaccinated. Any letter increased vaccine uptake compared with usual care (absolute difference, 2.79% points; 95% confidence interval [CI], 2.60-2.98; P < .001), with greater effect among immunosuppressed individuals (+4.12 vs +2.70% points; Pinteraction = .002). In younger adults with chronic conditions, letter-based nudges increased vaccination rates by 11.7% points overall and by 13.3% points among those with immunosuppression (Pinteraction = .007). Among immunosuppressed individuals, nudging effects appeared greater for those with immunosuppressive conditions than for those receiving immunosuppressive treatment. CONCLUSIONS: Electronic letter-based nudges increased influenza vaccination rates, with greater benefit among immunosuppressed individuals. These findings support implementation of low-cost, letter-based nudging strategies to improve vaccine uptake in this high-risk population. Clinical Trials Registration. NCT06030726 and NCT06030739.

Adolescent↗

PubMed2026

Efficacy and safety of human albumin combined with furosemide in acute decompensated heart failure with hepatic dysfunction.

BACKGROUND: Congestion is the most common clinical presentation on admission of patients with acute decompensated heart failure (ADHF). Finding effective ways to alleviate congestion has become a pivotal management step. This study sought to investigate the efficacy and safety of intravenous (IV) albumin use in conjunction with furosemide in patients hospitalized for ADHF with hepatic dysfunction in terms of subjective regression of congestion symptoms and worsening renal function. METHODS: This prospective, open-label, randomized-pragmatic trial recruited 241 patients with hepatic dysfunction hospitalized for ADHF. Patients (78 years, 54% female) were assigned to receive IV albumin with furosemide or IV furosemide alone. The coprimary study endpoints were patients' global assessment of symptoms score, quantified as the area under the curve (AUC) of the score on a visual analog scale, and the change in creatinine levels over 72 hours from admission. RESULTS: The experimental treatment group demonstrated a greater improvement in patients' global assessment of symptoms scores (AUCbaseline-72 h 3,767 vs 3,457 points; P < .001) and a milder increase in creatinine levels (0.07 vs 0.18 mg/dL; P = .045) than the IV furosemide group. The length of stay was 1 day shorter (4 vs 5 days; P < .001) and the incidence of worsening renal function was lower (25% vs 38%; P = .037) in the experimental treatment group. CONCLUSIONS: In this hypothesis generating study, among patients with ADHF and hepatic dysfunction, concomitant use of IV albumin and furosemide for the first 72 hours resulted in a significant improvement in subjective perception symptoms of decongestion and a milder increase in creatinine levels than IV furosemide alone.

Aged↗

PubMed2026

Effectiveness of a blended care intervention in physiotherapy with exercise and education for patients with hip or knee osteoarthritis (SmArt-E): A multicentre pragmatic randomized controlled trial.

OBJECTIVE: To evaluate the effectiveness of a twelve-month smartphone-assisted physiotherapy (SmArt-E) intervention versus usual care in hip and/or knee osteoarthritis (OA), and to assess usability and patient satisfaction with the digital support. METHOD: We conducted a multicentre, pragmatic, parallel-group randomized controlled trial in 27 physiotherapy practices in Germany. Patients with physician-diagnosed hip and/or knee OA aged ≥50 (hip) or ≥38 years (knee) were randomly allocated to SmArt-E (IG; n=166) or usual care (CG; n=164). The twelve-month intervention combined supervised and smartphone-assisted training and education (blended care). Primary outcomes were pain (NRS, 0-10) and physical function (HOOS/KOOS-ADL, 0-100) at twelve months. Secondary outcomes followed OARSI domains; usability and patient satisfaction were also assessed. RESULTS: Among 330 participants (mean age 64±8 years), baseline NRS was 3.2±2.3 in the CG and 3.5±2.4 in the IG; HOOS/KOOS-ADL was 71.6±17.7 and 69.4±17.5, respectively. No significant between-group differences were found for pain (-0.36; 95% CI: -0.84 to 0.12; p=0.14) or physical function (2.66; 95% CI: -0.46 to 5.77; p=0.09). Among 13 secondary outcomes, significant differences favouring the IG emerged at three and twelve months for several domains; however, effect sizes were small and unlikely to be clinically meaningful. CONCLUSION: SmArt-E did not demonstrate superior effectiveness over usual care in mild hip and/or knee OA. Both groups improved over time, with slightly more favourable but clinically inconclusive outcomes in the IG. Findings highlight the need to refine the intervention, better identify eligible patients, and optimize digital and in-person components.

Humans↗

PubMed2025

Bivalent RSV Prefusion F Protein-Based Vaccine for Preventing Cardiovascular Hospitalizations in Older Adults: A Prespecified Analysis of the DAN-RSV Trial.

IMPORTANCE: Respiratory syncytial virus (RSV) infection is linked to elevated cardiovascular risk, particularly in individuals with preexisting cardiovascular disease (CVD). A bivalent RSV prefusion F protein (RSVpreF) vaccine was recently approved for preventing RSV-related lower respiratory tract illness, but its effectiveness against cardiovascular outcomes has not been evaluated in a randomized trial. OBJECTIVE: To investigate the vaccine effectiveness of RSVpreF compared with no vaccine against cardiovascular outcomes among adults aged 60 years or older. DESIGN, SETTING, AND PARTICIPANTS: Prespecified secondary analysis of the DAN-RSV trial, a pragmatic, open-label, individually randomized clinical trial conducted in Denmark during the 2024-2025 winter season. The first participant was enrolled on November 18, 2024. Adults aged 60 years or older were eligible for inclusion regardless of comorbidity status. INTERVENTIONS: Participants were randomized 1:1 to receive RSVpreF (n = 65 642) or no vaccine (n = 65 634). MAIN OUTCOMES AND MEASURES: Hospitalization for any cardiorespiratory disease was a prespecified secondary outcome, and hospitalizations for any CVD, heart failure, myocardial infarction, stroke, and atrial fibrillation were prespecified exploratory outcomes. Outcomes were assessed from 14 days after booked study visit through May 31, 2025. Vaccine effectiveness was calculated as 1 - incidence rate ratio, expressed as a percentage. RESULTS: Of 131 276 participants included (mean age, 69.4 [SD, 6.5] years; 50.3% male), 28 662 (21.8%) had preexisting CVD. All-cause cardiorespiratory hospitalization incidence was lower in the RSVpreF group compared with the control group (26.3 vs 29.2 events per 1000 participant-years [PY]; absolute rate reduction, 2.90 [95% CI, 0.10-5.71] per 1000 PY; vaccine effectiveness, 9.9% [95% CI, 0.3%-18.7%]; P = .04). There was no significant interaction by baseline CVD status (CVD at baseline: vaccine effectiveness, 5.0% [95% CI, -11.2% to 16.7%]; no CVD at baseline: vaccine effectiveness, 15.2% [95% CI, 2.2%-27.1%]; P = .27 for interaction). For the RSVpreF group vs control group, respectively, incidence rates of all-cause cardiovascular hospitalization were 16.4 vs 17.7 events per 1000 PY (vaccine effectiveness, 7.4% [95% CI, -5.5% to 18.8%]; P = .24), and incidence rates of stroke were 3.0 vs 3.8 events per 1000 PY (vaccine effectiveness, 19.4% [95% CI, -8.6% to 40.4%]; P = .14). There were also no statistically significant between-group differences for myocardial infarction, heart failure hospitalization, and atrial fibrillation. CONCLUSIONS AND RELEVANCE: In adults aged 60 years or older, all-cause cardiorespiratory hospitalization was significantly lower with RSVpreF than with no vaccine. The findings suggest potential downstream cardiorespiratory benefits of RSV immunization, although the effect on all-cause cardiovascular hospitalization was not statistically significant. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06684743.

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PubMed2026

Phentermine/Topiramate in Obese, Diabetic Uric Acid Stone Formers: An Open-Label Randomized Feasibility Trial.

PURPOSE: The purpose of this study was to determine whether medical treatment of obesity, diabetes, and low urine pH with combination phentermine/topiramate affects uric acid (UA) kidney stone burden. MATERIALS AND METHODS: Participants with obesity, diabetes mellitus, normal renal function, urine pH < 5.8, and stone analysis ≥ 80% UA were block randomized (2:1 ratio) to phentermine 18.75 mg/topiramate 100 mg vs pragmatic controls for an 18-month, prospective, open-label feasibility study with dose escalation. The primary outcome was change in CT stone volume. Secondary outcomes included medication adherence; patient safety; and change in anthropometrics, laboratory studies, and body composition. RESULTS: Nineteen participants (age 62.1 ± 9.8 years; 68% male; mean BMI = 36.3 ± 2.9 kg/m2) were randomized, and 15 completed the study with 73% pill adherence and no serious adverse events. Stone volume by intention-to-treat analysis fell by 52% in the intervention group and rose by 8.6% in the control group (P = .10), with per-protocol analysis demonstrating statistically significant stone volume reduction (P = .02). At study end and compared with means of controls, the intervention group had greater weight loss (-10.2 vs +2.9 kg), reduction in hemoglobin A1c levels (-0.2 vs +0.5), lower 24-hour urine citrate (309 ± 81 vs 951 ± 782 mg), and lower UA supersaturation (0.7 ± 1.1 vs 1.8 ± 1.0), along with higher 24-hour urine pH (6.2 ± 0.5 vs 5.5 ± 0.4) and calcium phosphate supersaturation (0.9 ± 0.8 vs 0.2 ± 0.1; all P < .05). CONCLUSIONS: Among obese participants with diabetes mellitus and UA nephrolithiasis, phentermine/topiramate was well tolerated and demonstrated significant stone burden reductions by per-protocol analysis. The intervention group also had greater weight loss, higher urinary pH, and lower hemoglobin A1c and urinary citrate levels. These data provide a framework to study the impact of this novel alternative UA therapy on a wider range of patients with obesity and diabetes.

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PubMed2025

High-Dose vs Standard-Dose Influenza Vaccine and Cardiovascular Outcomes in Older Adults: A Prespecified Secondary Analysis of the DANFLU-2 Randomized Clinical Trial.

IMPORTANCE: The high-dose inactivated influenza vaccine (HD-IIV) has demonstrated superior protection against laboratory-confirmed influenza infection vs standard-dose IIV (SD-IIV); however, data regarding its effectiveness against cardiovascular (CV) outcomes are mainly from observational studies or specific high-risk groups. OBJECTIVE: To investigate the relative vaccine effectiveness (rVE) of HD-IIV vs SD-IIV against CV outcomes in the general older adult population in Denmark. DESIGN, SETTING, AND PARTICIPANTS: This was a prespecified secondary analysis of DANFLU-2, a pragmatic, open-label, individually randomized clinical trial (RCT) using nationwide administrative health registries in Denmark during the 2022/2023 to 2024/2025 influenza seasons. Older adults (age ≥65 years) were eligible for inclusion regardless of comorbidity. The trial design specified that if the primary end point was neutral, no hypothesis testing would be performed for secondary or exploratory end points. Data were analyzed from June 29 to August 12, 2025. INTERVENTIONS: Individual-level 1:1 randomization to HD-IIV or SD-IIV. Participants re-enrolling in additional seasons were rerandomized. MAIN OUTCOMES AND MEASURES: Severe CV outcomes were prespecified secondary and exploratory end points in the trial, occurring from 14 days after vaccination through May 31 the following year. RESULTS: A total of 332 438 participants (170 900 [51.4%] male; mean [SD] age, 73.7 [5.8] years) were randomized (166 218 to HD-IIV and 166 220 to SD-IIV), of whom 91 026 (27.4%) had a history of CV disease. HD-IIV did not significantly reduce the trial's primary end point of hospitalization for influenza or pneumonia. The incidence of hospitalization for any cardiorespiratory disease was lower in the HD-IIV group than the SD-IIV group (rVE, 5.7% [95% CI, 1.4% to 9.9%]; absolute difference, -0.13 [95% CI, -0.24 to -0.03] percentage points), and rVE did not differ by history of CV disease compared with no CV disease at baseline. Hospitalization for any CV disease occurred in fewer participants in the HD-IIV group than the SD-IIV group (rVE, 7.5% [95% CI, 1.5% to 12.5%]; absolute difference, -0.10 [95% CI, -0.18 to -0.02] percentage points) as did hospitalization for heart failure (rVE, 19.5% [95% CI, 3.3% to 33.1%]; absolute difference, -0.03 [95% CI, -0.06 to -0.01] percentage points). CONCLUSIONS AND RELEVANCE: This study found reduced incidence of cardiorespiratory hospitalization among those who received HD-IIV vs SD-IIV, driven by a lower incidence of CV hospitalizations, and particularly heart failure hospitalizations. These differences should be interpreted as exploratory findings in the setting of a large RCT with a neutral primary outcome. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05517174.

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