BACKGROUND:Safety and efficacy of supervised exercise training (ET) remain unclear in left ventricular assist device (LVAD) patients. A systematic review with an individual participant data (IPD) meta-analysis was performed to determine: (1) safety, (2) the effects of ET on peak oxygen consumption (peakVO2), 6 min walk distance (6MWT) and quality of life (QoL) and (3) the effects of ET on different subgroups of patients with LVAD (age, sex, body mass index (BMI), time post LVAD implantation, baseline exercise performance). METHODS:IPD were retrieved from all published randomised, controlled trials that compared the efficacy of ET versus standard care in LVAD patients. One-stage and two-stage (sensitivity analysis) meta-analyses were used to determine the effects of ET overall and for subgroup and ET effects interactions. RESULTS:Four trials that included 119 LVAD patients (89.1 % males; age: mean (SD), 53 (14) years; BMI: 28 (5) kg/m2; ejection fraction: 19 (6)%) were analysed. ET was safe and improved peakVO2 (mean difference (95% CI) +1.43 (0.39 to 2.45) mL/kg/min, p=0.004), 6MWT distance (+48 (95% CI 24 to 73) m, p<0.001), QoL (+0.66 (95% CI 0.26 to 1.05) standardised units, p<0.001) more than standard care. Males, older patients, 1 year post LVAD implantation and those with lower baseline BMI and (sub)maximal exercise performance had larger benefit of ET. CONCLUSIONS:ET is safe and improves (sub)maximal exercise performance and QoL in LVAD patients, and should be considered in management of LVAD. PROSPERO REGISTRATION NUMBER:CRD42023480119.

Nightmares are a hallmark of post-traumatic stress disorder (PTSD), yet pharmacological treatments remain limited. Here we conducted a multicenter, double-blind, randomized, placebo-controlled trial to evaluate the efficacy and safety of dronabinol (BX-1; Δ9-tetrahydrocannabinol (THC)) for PTSD-related nightmares. Adults with PTSD and recurrent nightmares were randomly assigned to receive dronabinol (2.5-15 mg) or placebo, once daily before bedtime, for 10 weeks. The primary endpoint was change from baseline to week 10 in the Clinician-Administered PTSD Scale for DSM-IV (CAPS-IV) B2 item assessing nightmare frequency and intensity. A total of 171 patients underwent randomization (mean age, 37.9 ± 12.8 years; 79.3% female), with 87 assigned to dronabinol and 84 to placebo. At week 10, reduction in CAPS-IV B2 scores was significantly greater with dronabinol than with placebo (between-group difference -1.50; 95% confidence interval -2.28 to -0.71; Cohen's d = 0.65; P < 0.001). Adverse events occurred in 78 patients (89.7%) receiving dronabinol and 64 (77.1%) receiving placebo. Treatment discontinuation due to adverse events occurred in five (5.7%) and six (7.2%) patients, respectively. Serious adverse events occurred in seven patients (8.0%) receiving dronabinol and in none receiving placebo. This trial provides evidence that dronabinol reduces the frequency and intensity of PTSD-related nightmares, although long-term efficacy and safety require further evaluation. ClinicalTrials.gov: NCT04448808 .

Efficient detection of breathing impairment is critical for treatment and prognosis in neuromuscular disorders. However, standard pulmonary function tests often yield ambiguous results. This prospective study evaluates whether advanced real-time MRI (RT-MRI) combined with deep learning-based image segmentation provides sensitive outcome measures for respiratory dysfunction in late-onset Pompe disease (LOPD), a model disease for diaphragmatic weakness. Eleven Pompe patients (mean age 52.2 years; 55% female) and 11 controls (mean age 50.9 years; 55% female) were included. RT-MRI with a temporal resolution of 50 ms, combined with U-Net-supported lung segmentation, revealed significantly reduced diaphragmatic motion in Pompe patients compared to controls and unmasked paradoxical diaphragmatic motion in Pompe patients (7 of 11). Reduced diaphragmatic sniff velocity and pathological diaphragmatic/thoracic synchronicity were detected in Pompe patients with still normal results in standard pulmonary function tests. Fatty involution of the diaphragm as quantified by fast T1 mapping correlated significantly with functional parameters from RT-MRI and pulmonary function tests. RT-MRI combined with deep learning-based lung segmentation offers novel biomarkers for early detection of respiratory muscle weakness. This new technique provides useful outcome measures for clinical care as well as treatment studies in patients with neuromuscular breathing impairment. The technique can also be used to characterize physiologic breathing patterns in healthy individuals.

BACKGROUND:Autologous haematopoietic stem cell transplantation (aHSCT) represents a treatment option for highly aggressive multiple sclerosis (MS). Here, we report outcome analyses from the two largest German centres performing aHSCT in MS. METHODS:In this retrospective analysis, people with (pw) MS who underwent aHSCT between 2007 and 2025 were included. Outcomes comprise no evidence of disease activity (NEDA-3), 3-month confirmed disability changes on the Expanded Disability Status Scale and transplantation-related mortality (TRM). Predictors of treatment response were evaluated according to the European Committee for Treatment and Research in Multiple Sclerosis and the European Society of Blood and Marrow Transplantation consensus criteria. RESULTS:A total of 109 pwMS were included: 55 (50.5%) with relapsing-remitting MS (RRMS), 23 (21.1%) with secondary progressive MS (SPMS) and 31 (28.4%) with primary progressive MS (PPMS). Median follow-up after aHSCT was 20.1 months. Overall, 82.8% (SE 4.9%) of pwMS maintained NEDA-3. PwRRMS had significantly higher NEDA-3 rates (Kaplan-Meier (KM) estimate 91%, SE 5%) than those with SPMS (KM 80.1%, SE 10.5%, p=0.018) or PPMS (KM 70.6%, SE 11.4%, p=0.035). Patients meeting core consensus criteria achieved NEDA-3 more often (KM 94.4%, SE 5.4%) than those meeting the extended criteria (KM 84.4%, SE 8.5%, p=0.199) or those outside the criteria (KM 73.7%, SE 8.8%, p=0.004). In progressive MS, a disease duration of <5 years indicated a potential prediction of NEDA-3 stability. TRM was 0.9% (n=1/109). CONCLUSIONS:In this heterogeneous cohort, comprising a substantial proportion of people with progressive MS, aHSCT provided sustained NEDA-3 stability and a marked reduction in inflammatory disease activity, particularly in RRMS, with a potential benefit in progressive MS.

For randomized controlled trials to be conclusive, it is important to set the target sample size accurately at the design stage. Comparing two normal populations, the sample size calculation requires specification of the variance other than the treatment effect and misspecification can lead to underpowered studies. Blinded sample size re-estimation is an approach to minimize the risk of inconclusive studies. Existing methods proposed to use the total (one-sample) variance that is estimable from blinded data without knowledge of the treatment allocation. We demonstrate that, since the expectation of this estimator is greater than or equal to the true variance, the one-sample variance approach can be regarded as providing an upper bound of the variance in blind reviews. This worst-case evaluation can likely reduce a risk of underpowered studies. However, blinded reviews of small sample size may still lead to underpowered studies. We propose a refined method accounting for estimation error in blind reviews using an upper confidence limit of the variance. A similar idea had been proposed in the setting of external pilot studies. Furthermore, we developed a method to select an appropriate confidence level so that the re-estimated sample size attains the target power. Numerical studies showed that our method works well and outperforms existing methods. The proposed procedure is motivated and illustrated by recent randomized clinical trials.

OBJECTIVES:To prevent heart failure (HF), the global longitudinal strain (GLS) emerged as a promising systolic function parameter for targeted pre-HF screening and prevention measures. This analysis investigated the cost-effectiveness of a GLS-based screening and prevention program for pre-HF in a German at-risk population. METHODS:A patient-level simulation model was developed from the perspective of the German statutory health insurance. By comparing the lifetime costs and consequences of a GLS-based screening program with those of standard of care without screening, the incremental cost-effectiveness ratio (ICER) was calculated. Input parameters were obtained from HERZCHECK trial data and the literature. Results were presented as costs per quality-adjusted life-year (QALY) and costs per life-year (LY) gained. Deterministic and probabilistic sensitivity analyses examined the robustness of the results, and a model validation was performed. An option value was calculated to reflect the impact of the potential costs and benefits of future innovations. RESULTS:Compared with standard of care, the GLS-based screening program resulted in both additional costs (€7031) and benefits (0.10 QALYs/0.12 LY), with an ICER of €69 543/QALY and €59 552/LY. The probabilistic sensitivity analysis showed that the GLS-based screening program was cost-effective with a probability of 67% at a willingness-to-pay threshold of €100 000/QALY. While screening only men or patients aged ≥60 years decreased the ICER by 25% and 21%, respectively, considering the option value increased the ICER by 59%. CONCLUSION:Our results indicate that a GLS-based screening program could be offered at an acceptable cost-effectiveness ratio. Specifying the target population may improve the cost-effectiveness.

INTRODUCTION:The majority of clinical studies investigating patients with heart failure and a reduced ejection fraction (HFrEF) exclusively included patients with symptomatic heart failure. There is a paucity of information concerning the clinical characteristics, progression to symptomatic heart failure, heart failure hospitalization rates and survival in patients with asymptomatic systolic left ventricular dysfunction (ASLVD). We address this knowledge gap by describing the baseline characteristics of participants in the prospective observational TransitionCHF study of patients with reduced left ventricular Function in New York Heart Association (NYHA) functional Class I and comparing them to those of other recent trials in HFrEF. METHODS:In total, 1005 individuals with ASLVD NYHA I with an ejection fraction ≤ 40% were recruited. Patient characteristics were compared with other studies involving patients with symptomatic heart failure. Multivariable linear regression and Pearson coefficients were used to determine the association between quality of life, mental health, markers of organ function, N-terminal prohormone of brain natriuretic peptide (NT-proBNP) plasma levels, and exercise performance. RESULTS:The mean age of participants was 60 ± 14 years and 18% were women. The mean ejection fraction was 36% and the mean left ventricular end-diastolic diameter was 59 mm. When compared with studies involving patients with symptomatic heart failure, the age was ≈ 5 years younger and the frequency of comorbidities was lower. The Short Form Health Survey-36 physical functioning score was moderately correlated with the Maastricht Vital Exhaustion Questionnaire (MQ; r = -0.44 and weakly with 6-min walking distance (r = 0.32), peak VO2 at ergospirometry (r = 0.28), and Heart Focus Anxiety (HAF17; r = -0.34). NT-proBNP levels showed a weak association with peak VO2 (r = -0.29) and the 6-min walk distance (r = -0.21). CONCLUSIONS:Patients included in the TransitionCHF study are younger and suffer from fewer comorbidities as compared with symptomatic heart failure patients. Associations between NT-proBNP levels and markers of exercise performance were weak.

BACKGROUND AND AIM:Randomized trials conducted in the early 2000s established the survival benefit of primary prevention implantable cardioverter-defibrillator (ICD) therapy in patients with reduced left ventricular ejection fraction (LVEF) after myocardial infarction. However, management of myocardial infarction and heart failure has substantially evolved since that time. We investigated whether the estimated association between primary prevention ICD implantation in post-myocardial infarction patients with reduced LVEF and mortality reduction has changed over time. METHODS:We analyzed individual participant data from 32,214 patients with LVEF ≤35% after myocardial infarction included in the PROFID pooled cohort, comprising 7,477 patients carrying a primary prevention ICD (ICD patients) and 24,737 patients without an ICD (non-ICD patients). The primary endpoint was all-cause mortality. Propensity scores were estimated using multivariable logistic regression including age, sex, LVEF, renal function, and diabetes, and overlap weighting was applied to balance treatment groups. Time period-specific analyses were performed across three prespecified time periods defined by inclusion year: 1995-2004, 2005-2014, and 2015-2020. Weighted cumulative mortality curves were generated for each time period. Temporal changes in the estimated association between ICD implantation and mortality reduction were assessed using a weighted Cox proportional hazards model. RESULTS:A total of 12,097 deaths occurred during a mean follow-up of 43.7 months. The estimated association between ICD implantation and mortality changed significantly across time (P for interaction <0.001). In weighted time period-specific analyses, the estimated mortality reduction associated with ICD implantation progressively decreased over more recent periods. The hazard ratio for ICD versus non-ICD patients was 0.54 (95% CI 0.47-0.62; P<0.001) in 1995-2004, 0.67 (95% CI 0.62-0.72; P<0.001) in 2005-2014, and 0.89 (95% CI 0.73-1.07; P=0.221) in 2015-2020, with negligible separation of the weighted cumulative mortality curves in the most recent time period. CONCLUSIONS:In this analysis including a large cohort of post-myocardial infarction patients with reduced LVEF, the estimated mortality reduction associated with primary prevention ICD implantation progressively decreased over time.

BACKGROUND:Catheter-based closure of the left atrial appendage is an alternative to oral anticoagulation for stroke prevention in patients with atrial fibrillation. The effectiveness of this strategy, as compared with physician-directed best medical care, in patients at high risk for stroke and bleeding is unknown. METHODS:In this multicenter randomized trial conducted in Germany, we assigned patients with atrial fibrillation and a high risk of stroke and bleeding to undergo left atrial appendage closure or to receive physician-directed best medical care (including direct oral anticoagulants, if eligible). The primary end point, tested for noninferiority, was a composite of stroke (ischemic or hemorrhagic), systemic embolism, major bleeding, or cardiovascular or unexplained death, assessed in a time-to-event analysis. The noninferiority margin was a hazard ratio of 1.3. RESULTS:A total of 912 adult patients underwent randomization. The primary end-point analysis included 446 patients who were assigned to undergo left atrial appendage closure (device group) and 442 who were assigned to physician-directed best medical care (medical-therapy group). The mean (±SD) age was 77.9±7.1 years; 38.6% of the patients were women, the mean CHA2DS2-VASc score was 5.2±1.5 (range, 0 to 9, with higher scores indicating a greater risk of stroke), and the mean HAS-BLED score was 3.0±0.9 (range, 0 to 9, with higher scores indicating higher risk of bleeding). After a median follow-up of 3 years (interquartile range, 1.7 to 4.7), a first primary end-point event had occurred in 155 patients (incidence per 100 patient-years, 16.8) in the device group and in 127 patients (incidence per 100 patient-years, 13.3) in the medical-therapy group (difference in restricted mean survival time, -0.36 years; 95% confidence interval, -0.70 to -0.01; P = 0.44 for noninferiority). Serious adverse events occurred in 368 patients (82.5%) in the device group and 342 (77.4%) in the medical-therapy group. CONCLUSIONS:Among patients with atrial fibrillation at high risk for stroke and bleeding, left atrial appendage closure was not noninferior to physician-directed best medical care with regard to a composite end point of stroke, systemic embolism, major bleeding, or cardiovascular or unexplained death. (Funded by the German Center for Cardiovascular Research; CLOSURE-AF ClinicalTrials.gov number, NCT03463317.).

MicroRNA-132 (miR-132) is a central regulator of adverse cardiac remodeling. Here we evaluated CDR132L, a synthetic antisense oligonucleotide miR-132 inhibitor, in a multinational, randomized, double-blind, placebo-controlled phase 2 trial (HF-REVERT) in patients with recent myocardial infarction (MI) and left ventricular (LV) systolic dysfunction. Within 3-14 days after MI, 294 patients were randomized to receive CDR132L 5 mg kg-1, CDR132L 10 mg kg-1 or placebo as three intravenous doses at 4-week intervals plus guideline-directed therapy. In total, 280 patients (245 men and 35 women) who received at least one dose of the study drug were included in the modified intention-to-treat population. CDR132L was well tolerated, with no hepatic, renal, hematologic or cardiac toxicity signals. The primary endpoint-the percentage change in LV end-systolic volume index at 6 months-improved in all groups but did not differ significantly between the CDR132L groups (5 mg kg-1 and 10 mg kg-1) and the placebo group. Secondary endpoints, including LV ejection fraction, global longitudinal strain and N-terminal pro B-type natriuretic peptide, were also not significantly different between the CDR132L and placebo groups. Prespecified exploratory analyses suggested potential benefits of CDR132L treatment in patients with advanced adverse remodeling at baseline, supporting further evaluation of CDR132L, including in chronic heart failure conditions. ClinicalTrials.gov: NCT05350969 .

Abstract Background The cluster randomized controlled trial interprof ACT evaluated the effects of a complex intervention designed to improve collaboration between general practitioners (GPs) and registered nurses (RNs) in nursing homes (NHs). The intervention includes six components (“Name badges”, “Mandatory availability rules”, “Designated contact persons”, “Standardized GPs’ home visits”, “Pro re nata medication”, “Shared goal setting”). The findings showed a nonsignificant reduction in hospital admissions in the intervention group (IG) compared to the control group (CG) within twelve months. The aims of this process evaluation were to describe (1) the dose, reach and fidelity of implementation (“implementation performance”), (2) the effects on the quality of RN-GP collaboration, and (3) potential moderating factors. Methods Process evaluation with a mixed-methods triangulation design involving all clusters (17 NHs per IG and CG) and 323 nursing home residents (NHRs) (n = 166 IG, n = 157 CG): We collected quantitative and qualitative data from multiple perspectives (e.g., RNs, GPs, NHRs) at several measurement points. We quantitatively compared groups by means of medians, interquartile ranges, proportions (all outcome domains) or Mann‒Whitney U tests (implementation performance) and analyzed qualitative data inductively via content analysis. The key findings were triangulated narratively and via a joint display. Results Compared to those in the CG, we noted relevant improvements in the implementation of “Name badges”, “Mandatory availability rules”, “Designated contact persons” and “Pro re nata medication” in ≥50% of the IG clusters, of which the group difference for “Mandatory availability rules” reached statistical significance. The implementation performance of IG clusters was moderated by resource-related and other organizational attributes of NHs and GP offices and attributes of involved professionals, especially their attitudes and awareness. Implementation of the components induced greater standardization of care processes together with positive changes in interprofessional communication and coordination among GPs and RNs. Conclusions Implementation of the interprof ACT components varied between components and NHs but showed potential for improving RN-GP collaboration. The standardization of shared care procedures emerged as a key mediator for improvement. For larger and more sustainable implementation we recommend a stronger focus on locally available resources and communication of potential benefits for all involved parties. Trial registration ClinicalTrials.gov, NCT03426475; registered 07 February 2018, https://www.clinicaltrials.gov/study/NCT03426475?lead=NCT03426475%26;rank=1 .

INTRODUCTION:Post-COVID-19 syndrome (PCS) is characterised by persistent symptoms, such as fatigue, dyspnoea, depression and sleep problems, following SARS-CoV-2 infection. The long-term course and impact on quality of life remain unclear. This review aims to synthesise evidence on longitudinal changes in symptom prevalence, severity and health-related quality of life (HRQoL) in adults with PCS. METHODS AND ANALYSIS:This systematic review will include longitudinal studies (randomised controlled trials, non-randomised trials, prospective and retrospective cohort studies) of adults (≥18 years) with PCS, defined by symptoms persisting beyond 4 weeks after acute infection. Eligible studies must report changes in prevalence or severity of fatigue, dyspnoea, depression, sleep problems or HRQoL from baseline to at least one follow-up visit.We will systematically search MEDLINE, Embase, PsycINFO, Web of Science, Scopus, CINAHL and Epistemonikos, with no restrictions on language, date or publication status. Two reviewers will independently screen studies, extract data and assess risk of bias using validated tools appropriate to study design. Disagreements will be resolved by consensus or a third reviewer.A narrative synthesis will summarise study characteristics and symptom trajectories. Where sufficient data are available, random-effects meta-analyses will be conducted to estimate pooled changes in symptom prevalence (ORs), severity ((standardised) mean differences) and HRQoL ((standardised) mean differences). Meta-regression and subgroup analyses will explore potential effect modifiers. Certainty of evidence will be evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. ETHICS AND DISSEMINATION:No ethical approval is required. Findings will be disseminated via peer-reviewed publication, conference presentations and plain language summaries. PROSPERO REGISTRATION NUMBER:CRD420251011612.

BACKGROUND AND OBJECTIVE:Pediatric patients with myocarditis present with heterogeneous symptoms, disease courses and outcomes. Late Gadolinium Enhancement (LGE) in cardiovascular magnetic resonance imaging (CMR) is a routine diagnostic tool, but relationships between LGE patterns and patient characteristics are typically assessed qualitatively. We investigate the use of radiomic features to quantify LGE texture and location to identify signatures that stratify pediatric myocarditis cases. METHODS:We compared radiomic features in a digital phantom across different resampling strategies to address variability in patient size and imaging parameters. Non-negative matrix factorization (NMF) was applied to spatially resolved radiomic features of the left myocardium to identify distinct radiomic signatures in a pediatric cohort with confirmed myocarditis. Clinical parameters were compared across the resulting groups, and correlations between image meta-features and outcomes explored. A user-friendly software tool offers feature extraction and signature calculation on unseen data and comparison of new patients to the existing cohort. RESULTS:The phantom experiments showed improved comparability of radiomic features when resampled to uniform voxel density (voxel count per myocardial diameter) rather than uniform voxel size. After appropriate pre-processing, NMF identified four patient groups with distinct LGE signatures within 195 patients (median age 16 years, 19% female). One group separates out patients with signs of heart failure, correlating with left-ventricular ejection fraction (r=-0.38, 95% CI [-0.50,-0.25]) and log(NT-proBNP) (r=0.36,[0.21,0.50]). A second group's dominant meta-feature correlates with myocardial edema (r=0.27,[0.13,0.40]) and ventricular tachycardia (r=0.19,[0.05,0.32]); a third indicates mild presentation. The clinical relevance of the fourth remains unclear. CONCLUSIONS:Spatially resolved radiomic features from suitably resampled LGE CMR images yield quantitative LGE signatures associated with clinical characteristics in pediatric myocarditis, supporting improved stratification and personalized management in the long run.

BACKGROUND:Heart failure (HF) is a significant public health concern. Early detection, particularly during the asymptomatic stage, is essential for prompt intervention and preventing progression. Conventional measures, such as left ventricular ejection fraction (LVEF) have limited sensitivity. However, left ventricular global longitudinal strain (GLS) can detect subclinical myocardial dysfunction. Preliminary data from the previous HERZCHECK study showed that 23% (1023/4509) of participants in rural Germany had GLS-defined subclinical pre-HF (stage B HF) when examined with mobile cardiac MRI units. Yet, the prevalence of asymptomatic HF in urban populations remains unclear. The WE-CARE-HF-CMR trial aims to address this issue. STUDY DESIGN AND METHODOLOGY:The WE-CARE-HF-CMR trial is a single-center prospective observational study with a cross-sectional baseline assessment and an exploratory longitudinal follow-up conducted in five urban German cities (Berlin, Cologne, Frankfurt, Hamburg, Munich; NCT07185100). Asymptomatic patients between the ages of 40 and 69 with cardiovascular risk factors but without a history of symptomatic HF are enrolled via outpatient physician referral or self-referral. Participants undergo a standardized diagnostic evaluation including a medical history review, laboratory testing, cardiovascular magnetic resonance (CMR) imaging with GLS analysis, and quality-of-life questionnaires. CMR examinations are performed using both stationary and mobile magnetic resonance imaging (MRI) units. Subclinical pre-HF (stage B HF) is defined as GLS ≥ -15%. The primary endpoint is the prevalence of subclinical pre-HF (stage B HF) in the urban population. Secondary endpoints assess therapy adherence, quality of life, and the prevalence of chronic kidney disease. CMR images are analyzed centrally following standardized protocols to ensure comparability with HERZCHECK rural data. CONCLUSION:The WE-CARE-HF-CMR trial will provide critical data on the prevalence of subclinical pre-HF (stage B HF) in urban populations. Using CMR-based GLS analysis with stationary and mobile units, and building on the HERZCHECK trial methodology, the study will close the diagnostic gap between rural and urban areas. These findings may ultimately support the implementation of targeted screening programs for subclinical pre-HF (stage B HF) to enable early intervention and prevent the progression to symptomatic HF. CLINICALTRIALS: GOV IDENTIFIER:NCT07185100.

Meta-analytic-predictive (MAP) priors have been proposed as a generic approach to deriving informative prior distributions, where external empirical data are processed to learn about certain parameter distributions. The use of MAP priors is also closely related to shrinkage estimation (also sometimes referred to as dynamic borrowing). A potentially odd situation arises when the external data consist only of a single study. Conceptually this is not a problem, it only implies that certain prior assumptions gain in importance and need to be specified with particular care. We outline this important, not uncommon special case and demonstrate its implementation and interpretation based on the normal-normal hierarchical model. The approach is illustrated using example applications in clinical medicine.

Continuous monitoring is becoming more popular due to its significant benefits, including reducing sample sizes and reaching earlier conclusions. In general, it involves monitoring nuisance parameters (e.g., the variance of outcomes) until a specific condition is satisfied. The blinded method, which does not require revealing group assignments, was recommended because it maintains the integrity of the experiment and mitigates potential bias. Although Friede and Miller (2012) investigated the characteristics of blinded continuous monitoring through simulation studies, its theoretical properties are not fully explored. In this paper, we aim to fill this gap by presenting the asymptotic and finite-sample properties of the blinded continuous monitoring for continuous outcomes. Furthermore, we examine the impact of using blinded versus unblinded variance estimators in the context of continuous monitoring. Simulation results are also provided to evaluate finite-sample performance and to support the theoretical findings.

BACKGROUND AND AIMS:Advanced cancer may resemble a heart failure (HF)-like phenotype marked by cardiac wasting, dyspnoea, congestion, and/or physical dysfunction. The trial evaluated safety and efficacy of HF therapy among patients with advanced cancer receiving specialized palliative care to improve patients' self-care ability. METHODS:Patients with stage 4 solid tumours with a life expectancy of 1-6 months receiving specialized palliative care were enrolled. Patients were required to meet at least two cardiovascular risk criteria and at least one criterion for functional limitation. Participants were randomized 1:1 to receive optimized HF therapy (up to four drugs: sacubitril/valsartan, empagliflozin, ivabradine, ferric carboxymaltose) or placebo in a double-blind setting. The primary hierarchical endpoint included: (i) days alive and able to wash oneself, (ii) ability to walk 4 m, and (iii) self-reported patient global assessment (PGA) of subjective well-being, during the 30-day placebo-controlled phase. RESULTS:In five centres, 93 patients were randomized. The primary endpoint did not differ between groups (win ratio 0.95, 95% confidence interval [CI] 0.57-1.58; P = .83). Overall, mortality was 32% at 30 days (not different between groups). In patients alive at 30 days, HF therapy reduced N-terminal pro-B-type natriuretic peptide levels by 41% (P = .040), increased left ventricular ejection fraction by 2.9% (P = .036), and improved PGA scores (odds ratio 0.22, 95% CI 0.06-0.75; P = .016). CONCLUSIONS:In a population with advanced cancer receiving specialized palliative care and high early mortality, optimized HF therapy did not improve patients' self-care ability. Among survivors at 30 days, improvements in quality of life measures and cardiac biomarkers suggest potential benefit of individualized HF therapy, which is hypothesis generating and needs validation.

BACKGROUND:There is a growing consensus that screening for subclinical preheart failure (HF) may reduce the burden of symptomatic HF by allowing for timely preventive interventions. However, validated screening algorithms are currently lacking. The aim of this study was to evaluate a fully mobile telemedically supervised cardiac magnetic resonance, as a simple standardized, and ubiquitously applicable screening algorithm for subclinical pre-HF in rural and underresourced regions. METHODS:HERZCHECK was a cross-sectional cohort study conducted at 12 sites across rural and underresourced regions of Germany. Asymptomatic participants (40-69 years) with ≥1 cardiovascular risk factor-obesity, smoking, arterial hypertension, diabetes, hypercholesterolemia, or chronic kidney disease-were enrolled and underwent telemedically supervised contrast-free short cardiac magnetic resonance in mobile screening units. Subclinical pre-HF was diagnosed using a predefined cutoff of global longitudinal strain ≥-15%. A matched and entropy-balanced control cohort constructed from claims data was used to determine the time difference between detection of subclinical pre-HF in HERZCHECK and the first symptom-based diagnosis of HF within the standard of care. RESULTS:Between June 2021 and April 2023, 4666 participants were enrolled in the study, of which 4509 participants were included in the final analysis. The prevalence of subclinical pre-HF in the studied at-risk population was 22.7% (95% CI, 21.5%-23.9%). Global longitudinal strain-based screening identified subclinical pre-HF 6.7 years before the average onset of symptomatic HF within the standard of care (n=8420). CONCLUSIONS:Subclinical pre-HF affects approximately one-fourth of the at-risk population in rural and underresourced regions. The HERZCHECK approach identifies patients suitable for targeted preventive interventions ≈7 years earlier than the standard of care. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT05122793.