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Abstract Objective Women with type 2 diabetes experience higher cardiovascular and mortality risk than men possibly because of a sub-optimal cardio-protective treatment. We evaluated whether an intensive multifactorial therapy (MT) produces similar protective effect on development of adverse outcomes in women and men. Research design and methods Nephropathy in Diabetes type 2 study is an open-label cluster randomized trial comparing the effect of Usual Care (UC) or MT of main cardiovascular risk factors (blood pressure

Abstract Background The impact of rosuvastatin versus atorvastatin on new-onset diabetes mellitus (NODM) among patients treated with high-intensity statin therapy for coronary artery disease (CAD) remains to be clarified. This study aimed to evaluate the risk of NODM in patients with CAD treated with rosuvastatin compared to atorvastatin in the randomized LODESTAR trial. Methods In the LODESTAR trial, patients with CAD were randomly assigned to receive either rosuvastatin or atorvastatin using a 2-by-2 factorial randomization. In this post-hoc analysis, the 3-year incidence of NODM was compared between rosuvastatin and atorvastatin treatment in the as-treated population with high-intensity statin therapy as the principal population of interest. Results Among 2932 patients without diabetes mellitus at baseline, 2377 were included in the as-treated population analysis. In the as-treated population with high-intensity statin therapy, the incidence of NODM was not significantly different between the rosuvastatin and atorvastatin groups (11.4% [106/948] versus 8.8% [73/856], hazard ratio [HR] = 1.32, 95% confidence interval [CI] = 0.98 to 1.77, P = 0.071). When the risk of NODM with rosuvastatin versus atorvastatin was assessed according to the achieved low-density lipoprotein cholesterol (LDL-C) level, the risk of NODM began to increase at a LDL-C level below 70 mg/dL. The incidence of NODM was significantly greater in the rosuvastatin group than it was in the atorvastatin group when the achieved LDL-C level was

Abstract New anti-diabetic medications, including glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose cotransporter 2 (SGLT2) inhibitors are recommended in guidelines to reduce cardio-renal events in type 2 diabetes mellitus (T2DM), independent of glucose control. Yet they might be underused in real world. This study aims to address the knowledge gap, prescription patterns and barriers faced by Chinese doctors. Cardio-Metabolic Survey was a cross-sectional study conducted among doctors managing diabetic patients in clinical practice, via a designated online questionnaire from May 1st, to Dec. 31th, 2022. A total of 358 doctors from 57 hospitals across Beijing participated in this survey, 34.9% from tertiary hospitals. Only 30–40% doctors demonstrated somewhat understanding of the mechanism and clinical applications of GLP-1RA or SGLT2 inhibitors. There is no difference in understanding of these two medications overall (p = 0.336). However, doctors in tertiary hospitals have a higher understanding of GLP-1RA and SGLT2 inhibitors compared to those in non-tertiary hospitals (p = 0.049, and 0.008, respectively). 40.2% doctors have never prescribed GLP-1RA, and 36.6% for SGLT2 inhibitors. The frequency of prescribing SGLT2 inhibitors was significantly higher than prescribing GLP-1RA (p = 0.005). The main barriers on prescription include high cost, poor adherence, side effects concern, and insufficient knowledge about these medications. Chinese doctors currently have limited understanding and low prescription frequency for GLP-1RA and SGLT2 inhibitors. Multifaceted approaches are needed to improve doctors' knowledge and strengthen their ability to manage T2DM effectively.

Abstract Cancer therapy-related cardiac dysfunction (CTRCD), which commonly includes left ventricular dysfunction and heart failure, is the main adverse effect of anticancer therapy. In recent years several candidate genes studies and genome-wide association studies have identified common genetic variants associated with CTRCD, but evidence remains limited and few genetic variants are robust. A genome-wide meta-analysis of CTRCD was performed with 852 oncology patients receiving cancer therapy. DNA samples were genotyped and imputed to perform a GWAS meta-analysis for case–control (N = 852 (380 cases and 472 controls) and extreme phenotypes (N = 618 (78 cases and 472 controls) looking for genetic variants that predispose to CTRCD. The results were validated in a replicate cohort of 1,191 oncology patients (245 cases and 946 controls). Functional mapping of the replicated loci was then performed. The meta-analysis showed 9 and 17 loci suggestively associated (P-value

Abstract Background A stent with characteristics of a hybrid design may have advantages in improving the patency of symptomatic iliofemoral vein obstruction. This study assessed the safety and effectiveness of the V-Mixtent Venous Stent in treating symptomatic iliofemoral outflow obstruction. Methods Eligible patients had a Clinical-Etiologic-Anatomic-Physiologic (CEAP) C classification of ≥ 3 or a Venous Clinical Severity Score (VCSS) pain score of ≥ 2. The primary safety endpoint was the rate of major adverse events within 30 days. The primary effectiveness endpoint was the 12-month primary patency rate. Secondary endpoints included changes in VCSS from baseline to 6 and 12 months, alterations in CEAP C classification, Chronic Venous Disease Quality of Life Questionnaire (CIVIQ-14) scores at 12 months, and stent durability measures. Results Between December 2020 and November 2021, 171 patients were enrolled across 15 institutions. A total of 185 endovenous stents were placed, with 91.81% of subjects receiving one stent and 8.19% receiving 2 stents. Within 30 days, only two major adverse events occurred (1.17%; 95% confidence interval [CI], 0.14–4.16%), below the literature-defined performance goal of 11% (P

Abstract Aims Interleukin‐16 (IL‐16) has been reported to mediate left ventricular myocardial fibrosis and stiffening in patients with heart failure with preserved ejection fraction (HFpEF). We sought to elucidate whether IL‐16 has a distinct impact on pathophysiology and prognosis across different subphenotypes of acute HFpEF. Methods and results We analysed 211 patients enrolled in a prospective multicentre registry of acute decompensated HFpEF for whom serum IL‐16 levels after stabilization were available (53% female, median age 81 [interquartile range 75–85] years). We divided this sub‐cohort into four phenogroups using our established clustering algorithm. The study endpoint was all‐cause death. Patients were subclassified into phenogroup 1 (‘rhythm trouble’ [n = 69]), phenogroup 2 (‘ventricular‐arterial uncoupling’ [n = 49]), phenogroup 3 (‘low output and systemic congestion’ [n = 41]), and phenogroup 4 (‘systemic failure’ [n = 52]). After a median follow‐up of 640 days, 38 patients had died. Among the four phenogroups, phenogroup 2 had the highest IL‐16 level. The IL‐16 level showed significant associations with indices of cardiac hypertrophy, diastolic dysfunction, and congestion only in phenogroup 2. Furthermore, the IL‐16 level had a significant predictive value for all‐cause death only in phenogroup 2 (C‐statistic 0.750, 95% confidence interval 0.606–0.863, P = 0.017), while there was no association between the IL‐16 level and the endpoint in the other phenogroups. Conclusions Our results indicated that the serum IL‐16 level had a significant association with indices that reflect the pathophysiology and prognosis of HFpEF in a specific phenogroup in acute HFpEF.

Abstract Aims A considerable proportion of candidates for transcatheter aortic valve implantation (TAVI) have underlying heart failure (HF) with preserved ejection fraction (HFpEF), which can be challenging for diagnosis because significant valvular heart disease should be excluded before diagnosing HFpEF. This study investigated the long‐term prognostic value of the pre‐procedural H2FPEF score in patients with preserved ejection fraction (EF) undergoing TAVI. Methods and results Patients who underwent TAVI between October 2013 and May 2017 were enrolled from the Optimized CathEter vAlvular iNtervention–Transcatheter Aortic Valve Implantation Japanese multicentre registry. After excluding 914 patients, 1674 patients with preserved EF ≥ 50% (median age: 85 years, 72% female) were selected for calculation of the H2FPEF score and were dichotomized into two groups: the low H2FPEF score [0–5 points; n = 1399 (83.6%)] group and the high H2FPEF score [6–9 points; n = 275 (16.4%)] group. Patients with high H2FPEF scores were associated with a higher prevalence of New York Heart Association Functional Class III/IV (59.3% vs. 43.7%, P

Abstract Aims This study aimed to elucidate age‐stratified clinical profiles and outcomes in patients with heart failure (HF) with preserved left ventricular ejection fraction (LVEF) (HFpEF). Methods and results The Chronic Heart Failure Registry and Analysis in the Tohoku District‐2 (CHART‐2) Study included 2824 consecutive HFpEF patients with LVEF ≥ 50% (mean age 69.0 ± 12.3 years; 67.7% male) with a median follow‐up of 9.8 years. We stratified them into five age groups: ≤54 (N = 349, 12.4%), 55–64 (N = 529, 18.7%), 65–74 (N = 891, 31.6%), 75–84 (N = 853, 30.2%), and ≥85 years (N = 202, 7.2%), and we categorized these age groups into younger (≤64 years) and older (≥65 years) groups. We compared the clinical profiles and outcomes of HFpEF patients across age groups. Younger HFpEF groups exhibited a male predominance, elevated body mass index (BMI), and poorly controlled diabetes (haemoglobin A1c > 7.0%). Older HFpEF groups were more likely to be female with multiple comorbidities, including coronary artery disease, hypertension, renal impairment, and atrial fibrillation. The positive association between elevated BMI and HFpEF was more pronounced with lower classes of age from ≥85 to ≤54 years, especially in males. With higher classes of age from ≤54 to ≥85 years, mortality rates increased, and HF death became proportionally more prevalent (Ptrend

Abstract Aims The incidence and prognosis of symptomatic heart failure following acute myocardial infarction (AMI) in the primary percutaneous coronary intervention era have rarely been reported in the literature. This study aimed to (i) determine the incidence of heart failure admission among AMI survivors, (ii) compare 1 year outcomes between patients with heart failure admission and those without, and (iii) identify the independent risk factors associated with heart failure admission. Methods and results The Japan Acute Myocardial Infarction Registry is a prospective multicentre registry from which data on consecutively enrolled patients with AMI from 50 institutions between 2015 and 2017 were obtained. Among the 3411 patients enrolled, 3226 who survived until discharge were included in this study. The primary endpoint was all‐cause mortality. The secondary endpoints were major adverse cardiovascular events (defined as cardiovascular mortality, non‐fatal myocardial infarction, or non‐fatal cerebral infarction) and major bleeding events corresponding to Bleeding Academic Research Consortium Type 3 or 5. Clinical outcomes were compared between the patients who were and were not admitted for heart failure. Over a median follow‐up of 12 months, 124 patients (3.8%) were admitted due to heart failure. Independent risk factors for heart failure admission included older age, female sex, Killip class ≥2 on admission, left ventricular ejection fraction

Abstract Introduction Cefiderocol is a siderophore cephalosporin showing activity against various carbapenem-resistant Gram-negative bacteria (CR-GNB). No data currently exist about real-world use of cefiderocol in terms of types of therapy (e.g., empirical or targeted, monotherapy or combined regimens), indications, and patient characteristics. Methods In this multicenter, prospective study, we aimed at describing the use of cefiderocol in terms of types of therapy, indications, and patient characteristics. Results Cefiderocol was administered as empirical and targeted therapy in 27.5% (55/200) and 72.5% (145/200) of cases, respectively. Overall, it was administered as monotherapy in 101/200 cases (50.5%) and as part of a combined regimen for CR-GNB infections in the remaining 99/200 cases (49.5%). In multivariable analysis, previous isolation of carbapenem-resistant Acinetobacter baumannii odds ratio (OR) 2.56, with 95% confidence interval (95% CI) 1.01–6.46, p = 0.047] and previous hematopoietic stem cell transplantation (OR 8.73, 95% CI 1.05–72.54, p = 0.045) were associated with administration of cefiderocol as part of a combined regimen, whereas chronic kidney disease was associated with cefiderocol monotherapy (OR 0.38 for combined regimen, 95% CI 0.16–0.91, p = 0.029). Cumulative 30-day mortality was 19.8%, 45.0%, 20.7%, and 22.7% in patients receiving targeted cefiderocol for infections by Enterobacterales, A. baumannii, Pseudomonas aeruginosa, and any metallo-β-lactamase producers, respectively. Conclusions Cefiderocol is mainly used for targeted treatment, although empirical therapies account for more than 25% of prescriptions, thus requiring dedicated standardization and guidance. The almost equal distribution of cefiderocol monotherapy and cefiderocol-based combination therapies underlines the need for further study to ascertain possible differences in efficacy between the two approaches.

Abstract Tuberculous meningitis (TBM) is the most lethal form of tuberculosis. Clinical features, such as coma, can predict death, but they are insufficient for the accurate prognosis of other outcomes, especially when impacted by co-morbidities such as HIV infection. Brain magnetic resonance imaging (MRI) characterises the extent and severity of disease and may enable more accurate prediction of complications and poor outcomes. We analysed clinical and brain MRI data from a prospective longitudinal study of 216 adults with TBM; 73 (34%) were HIV-positive, a factor highly correlated with mortality. We implemented an end-to-end framework to model clinical and imaging features to predict disease progression. Our model used state-of-the-art machine learning models for automatic imaging feature encoding, and time-series models for forecasting, to predict TBM progression. The proposed approach is designed to be robust to missing data via a novel tailored model optimisation framework. Our model achieved a 60% balanced accuracy in predicting the prognosis of TBM patients over the six different classes. HIV status did not alter the performance of the models. Furthermore, our approach identified brain morphological lesions caused by TBM in both HIV and non-HIV-infected, associating lesions to the disease staging with an overall accuracy of 96%. These results suggest that the lesions caused by TBM are analogous in both populations, regardless of the severity of the disease. Lastly, our models correctly identified changes in disease symptomatology and severity in 80% of the cases. Our approach is the first attempt at predicting the prognosis of TBM by combining imaging and clinical data, via a machine learning model. The approach has the potential to accurately predict disease progression and enable timely clinical intervention.

Abstract Background Growing interest has motivated recent studies to examine differences in recovery after sport-related concussion (SRC) by sex. However, heterogeneity in study design, participants, and recovery outcomes has led to mixed findings. Further work is needed to evaluate potential differences by sex and to investigate the role of related characteristics, such as sport contact-level, in recovery timelines. This study aimed to investigate whether concussion recovery trajectories differ by sex, considering a priori clinical and demographic covariates, and accounting for the sequence of recovery outcomes. Our secondary question was whether sport contact-level modifies the relationship between sex and time to outcomes. Using data from the Ivy League–Big Ten Epidemiology of Concussion Study, we included SRCs reported across five academic years; 2015–2020 (February 2020). We used Cox proportional hazards regressions to estimate associations between sex and time from injury to three outcomes: (1) symptom resolution, (2) return to academics, (3) return to full play, accounting for measured confounders. Results Among 1160 SRCs (male, n = 667; female, n = 493) with complete data, median age overall was 20 years (25th-75th percentiles:19–21), and most occurred among athletes playing high-contact sports (78.0%). Males were slightly more likely to complete symptom resolution over time compared to females (HR = 1.18, 95%CI = 1.05–1.33), but results were attenuated in fully adjusted models (HR 1.13, 95%CI = 0.99–1.29). Similarly, the HR of full academic return for males compared to females was 1.22 (95%CI = 1.07–1.38), but was attenuated in fully adjusted models (HR = 1.11, 95%CI = 0.97–1.28). The HR of full return to play for males compared to females was 1.14 (95%CI = 1.02–1.28), and was attenuated after adjustment (HR = 1.06, 95%CI = 0.93–1.20) as well. The interaction between sex and playing a high/low-contact sport was not statistically significant across models, though differences were apparent. Conclusions Among a cohort of collegiate athletes with SRC, recovery timelines appeared similar between male and female athletes, adjusting for measured confounders. Differences by sex, considering sport contact-level, were evident and may be important clinically and in future studies. This study used robust methods, accounting for nesting in the sequence of RTP outcomes. Results inform concussion management protocols and planned qualitative work to further elucidate how collegiate athletes experience concussion recovery. Key Points Heterogeneity in study design, participants, and recovery outcomes has led to mixed findings in determining differences in recovery trajectories after concussion by sex. We found that having longer time to symptom resolution, and also the sequence of having academic return before symptoms resolve and longer time to academic return were confounders in the relationship between sex and RTP timelines. Time to sequential recovery outcomes appeared similar between male and female athletes, adjusting for observable confounders. Further differences by sex were evident when considering contact-level, and may be important to consider clinically and in future research. Results indicate that differences in concussion recovery trajectories by sex may be largely attributed to and driven by differences in sports with a men’s or women’s team only, such as football, and this should be explored further.

Abstract Background Cardiac arrest is a common and devastating emergency of both the heart and brain. More than 380,000 patients suffer out-of-hospital cardiac arrest annually in the USA. Induced cooling of comatose patients markedly improved neurological and functional outcomes in pivotal randomized clinical trials, but the optimal duration of therapeutic hypothermia has not yet been established. Methods This study is a multi-center randomized, response-adaptive, duration (dose) finding, comparative effectiveness clinical trial with blinded outcome assessment. We investigate two populations of adult comatose survivors of cardiac arrest to ascertain the shortest duration of cooling that provides the maximum treatment effect. The design is based on a statistical model of response as defined by the primary endpoint, a weighted 90-day mRS (modified Rankin Scale, a measure of neurologic disability), across the treatment arms. Subjects will initially be equally randomized between 12, 24, and 48 h of therapeutic cooling. After the first 200 subjects have been randomized, additional treatment arms between 12 and 48 h will be opened and patients will be allocated, within each initial cardiac rhythm type (shockable or non-shockable), by response adaptive randomization. As the trial continues, shorter and longer duration arms may be opened. A maximum sample size of 1800 subjects is proposed. Secondary objectives are to characterize: the overall safety and adverse events associated with duration of cooling, the effect on neuropsychological outcomes, and the effect on patient-reported quality of life measures. Discussion In vitro and in vivo studies have shown the neuroprotective effects of therapeutic hypothermia for cardiac arrest. We hypothesize that longer durations of cooling may improve either the proportion of patients that attain a good neurological recovery or may result in better recovery among the proportion already categorized as having a good outcome. If the treatment effect of cooling is increasing across duration, for at least some set of durations, then this provides evidence of the efficacy of cooling itself versus normothermia, even in the absence of a normothermia control arm, confirming previous RCTs for OHCA survivors of shockable rhythms and provides the first prospective controlled evidence of efficacy in those without initial shockable rhythms. Trial registration ClinicalTrials.gov NCT04217551. Registered on 30 December 2019.

Abstract Background Type 2 diabetes (T2D) patients have an increased risk of heart failure (HF). There are limited data on the association between HF and T2D in specific healthcare settings. This study sought to analyse the prevalence and incidence of HF in a contemporary cohort of T2D patients attending cardiology and endocrinology outpatient clinics. Methods We conducted an observational multicentre prospective study (DIABET-IC) that enrolled patients with a T2D diagnosis attending cardiology and endocrinology outpatient clinics in 30 centres in Spain between 2018 and 2019. The prevalence at the start of the study and the incidence of HF after a 3 year follow-up were calculated. HF was defined as the presence of typical symptoms and either: a) LVEF

Abstract Background Oesophageal adenocarcinoma (OAC) is a highly heterogeneous cancer with poor survival. Standard curative treatment is chemotherapy with or without radiotherapy followed by oesophagectomy. Genomic heterogeneity is a feature of OAC and has been linked to treatment resistance. Methods Whole-genome sequencing data from 59 treatment-naïve and 18 post-treatment samples from 29 OAC patients was analysed. Twenty-seven of these were enrolled in the DOCTOR trial, sponsored by the Australasian Gastro-Intestinal Trials Group. Two biopsies from each treatment-naïve tumour were assessed to define ‘shared’ (between both samples) and ‘private’ (present in one sample) mutations. Results Mutational signatures SBS2/13 (APOBEC) and SBS3 (BRCA) were almost exclusively detected in private mutation populations of treatment-naïve tumours. Patients presenting these signatures had significantly worse disease specific survival. Furthermore, mutational signatures associated with platinum-based chemotherapy treatment as well as high platinum enrichment scores were only detected in post-treatment samples. Additionally, clones with high putative neoantigen binding scores were detected in some treatment-naïve samples suggesting immunoediting of clones. Conclusions This study demonstrates the high intra-tumour heterogeneity in OAC, as well as indicators for treatment-induced changes during tumour evolution. Intra-tumour heterogeneity remains a problem for successful treatment strategies in OAC.

Abstract Background Difelikefalin, a potent and highly selective agonist of kappa opioid receptors, is used to treat moderate-to-severe pruritus in hemodialysis patients. Methods This was a 52-week, open-label phase 3 trial following a 6-week randomized double-blind placebo-controlled treatment period to investigate the efficacy and safety of difelikefalin in Japanese hemodialysis patients. Having completed the 6-week double-blind period, patients received difelikefalin 0.5 μg/kg three times per week intravenously for 52 weeks. Efficacies were assessed using numerical rating scale (NRS) scores, proportion of patients whose NRS score improved by ≥ 3 points and ≥ 4 points, Shiratori severity score, proportion of patients with a nighttime Shiratori severity score of ≤ 2, the Skindex-16 score, 5-D itch scale score, and patient global impression of change (PGIC). Safety was assessed on the basis of adverse events, clinical laboratory tests, vital signs, body weight, 12-lead electrocardiography, and dependency. Results The number of patients who entered the extension treatment period from the difelikefalin (MR–MR) and placebo (P-MR) groups was 85 and 83, respectively. The weekly mean NRS scores (mean ± SD) in the MR–MR group at baseline, week 6, and week 58 were 6.57 ± 1.32, 4.04 ± 2.24, and 2.36 ± 1.86, respectively. The weekly mean scores in the P-MR group, at baseline, week 6, and week 58 were 6.42 ± 1.29, 4.85 ± 1.90, and 2.73 ± 2.14, respectively. In patients receiving difelikefalin, there was a decline in the score from treatment initiation, and this decline continued until week 58. Similarly, improvements were seen until week 58 in the proportion of responders, Shiratori severity score, proportion of responders based on the Shiratori severity score, the Skindex-16 score, 5-D itch scale score, and PGIC. A correlation was seen between the change in NRS and itch-related quality of life (QOL), including the Shiratori severity score, Skindex-16 score, 5-D itch scale score, and PGIC. Difelikefalin was well tolerated and safe even when used long term. Conclusions Difelikefalin improved itching and itch-related quality of life during long-term treatment in hemodialysis patients with moderate-to-severe pruritus whose response to conventional medications had been inadequate. It also demonstrated excellent safety and tolerability. Trial registration: ClinicalTrials.gov; NCT04711603. Registered 15 January 2021, https://www.clinicaltrials.gov/study/NCT04711603?term=NCT04711603&rank=1 .

Abstract Background Endovascular treatment (ET) options for acute stroke due to distal middle cerebral artery occlusions are rapidly evolving, but data on outcome and safety are sparse. We therefore performed an analysis of patients undergoing ET for primary M3 occlusions in routine clinical practice in a nationwide registry. Methods Patients enrolled between 01/20 and 12/21 in the prospective, multicenter German Stroke Registry-Endovascular Treatment (GSR-ET) were screened for mechanical thrombectomy performed for primary M3 occlusion. We analyzed neurological deficit as measured by the National Institute of Health Stroke Scale (NIHSS), symptomatic intracranial hemorrhage (sICH), thrombectomy technique, successful reperfusion (modified Thrombolysis in Cerebral Infarction [mTICI] score of 2b-3) and functional outcome as measured by the modified Rankin Scale (mRS) at discharge and 90 days. Results Out of 5574 patients, 11 patients (0.2%, median age 80 years, 54.5% female) underwent ET for primary M3 occlusion. All patients had pre-admission mRS ≤ 1, median NIHSS on admission was 8, and successful reperfusion was achieved in 6/11 patients (54.5%). While no vasospasm, dissection or perforation was reported, symptomatic intracranial hemorrhage occurred in 2 patients (18.2%). Favorable outcome (mRS ≤ 2) was achieved in 6/11 patients (54.5%) at 90-day follow-up. Conclusions ET for primary M3 occlusions is rarely performed. While technically feasible, the procedure’s potential benefits must be carefully weighed against its associated risks, including clinically relevant complications. Caution and further research is needed to optimize patient selection for this intervention. Trial Registration GSR-ET; ClinicalTrials.gov Identifier: NCT03356392; Trial Registration Date: 11/29/2017.

Abstract Huntington’s disease (HD) is a hereditary neurodegenerative disorder caused by the extension of the CAG repeats in exon 1 of the HTT gene and is transmitted in a dominant manner. The present study aimed to assess whether patients’ sex, in the context of mutated and normal allele length, contributes to age on onset (AO) of HD. The study population comprised a large cohort of 3723 HD patients from the European Huntington’s Disease Network’s REGISTRY database collected at 160 sites across 17 European countries and in one location outside Europe. The data were analyzed using regression models and factorial analysis of variance (ANOVA) considering both mutated allele length and sex as predictors of patients’ AO. AO, as described by the rater’s estimate, was found to be later in affected women than in men across the whole population. This difference was most pronounced in a subgroup of 1273 patients with relatively short variants of the mutated allele (40–45 CAG repeats) and normal alleles in a higher half of length distribution—namely, more than 17 CAG repeats; however, it was also observed in each group. Our results presented in this observational study point to sex-related differences in AO, most pronounced in the presence of the short mutated and long normal allele, which may add to understanding the dynamics of AO in Huntington’s Disease. Trial registration: ClinicalTrials.gov identifier NCT01590589.

Abstract Background One of the major hurdles in clinical genetics is interpreting the clinical consequences associated with germline missense variants in humans. Recent significant advances have leveraged natural variation observed in large-scale human populations to uncover genes or genomic regions that show a depletion of natural variation, indicative of selection pressure. We refer to this as “genetic constraint”. Although existing genetic constraint metrics have been demonstrated to be successful in prioritising genes or genomic regions associated with diseases, their spatial resolution is limited in distinguishing pathogenic variants from benign variants within genes. Methods We aim to identify missense variants that are significantly depleted in the general human population. Given the size of currently available human populations with exome or genome sequencing data, it is not possible to directly detect depletion of individual missense variants, since the average expected number of observations of a variant at most positions is less than one. We instead focus on protein domains, grouping homologous variants with similar functional impacts to examine the depletion of natural variations within these comparable sets. To accomplish this, we develop the Homologous Missense Constraint (HMC) score. We utilise the Genome Aggregation Database (gnomAD) 125 K exome sequencing data and evaluate genetic constraint at quasi amino-acid resolution by combining signals across protein homologues. Results We identify one million possible missense variants under strong negative selection within protein domains. Though our approach annotates only protein domains, it nonetheless allows us to assess 22% of the exome confidently. It precisely distinguishes pathogenic variants from benign variants for both early-onset and adult-onset disorders. It outperforms existing constraint metrics and pathogenicity meta-predictors in prioritising de novo mutations from probands with developmental disorders (DD). It is also methodologically independent of these, adding power to predict variant pathogenicity when used in combination. We demonstrate utility for gene discovery by identifying seven genes newly significantly associated with DD that could act through an altered-function mechanism. Conclusions Grouping variants of comparable functional impacts is effective in evaluating their genetic constraint. HMC is a novel and accurate predictor of missense consequence for improved variant interpretation.

Abstract Background One single-center randomized clinical trial showed that INTELLiVENT-adaptive support ventilation (ASV) is superior to conventional ventilation with respect to the quality of ventilation in post-cardiac surgery patients. Other studies showed that this automated ventilation mode reduces the number of manual interventions at the ventilator in various types of critically ill patients. In this multicenter study in patients post-cardiac surgery, we test the hypothesis that INTELLiVENT-ASV is superior to conventional ventilation with respect to the quality of ventilation. Methods “POStoperative INTELLiVENT-adaptive support VEntilation in cardiac surgery patients II (POSITiVE II)” is an international, multicenter, two-group randomized clinical superiority trial. In total, 328 cardiac surgery patients will be randomized. Investigators screen patients aged > 18 years of age, scheduled for elective cardiac surgery, and expected to receive postoperative ventilation in the ICU for longer than 2 h. Patients either receive automated ventilation by means of INTELLiVENT-ASV or ventilation that is not automated by means of a conventional ventilation mode. The primary endpoint is quality of ventilation, defined as the proportion of postoperative ventilation time characterized by exposure to predefined optimal, acceptable, and critical (injurious) ventilatory parameters in the first two postoperative hours. One major secondary endpoint is ICU team staff workload, captured by the ventilator software collecting manual settings on alarms. Patient-centered endpoints include duration of postoperative ventilation and length of stay in ICU. Discussion POSITiVE II is the first international, multicenter, randomized clinical trial designed to confirm that POStoperative INTELLiVENT-ASV is superior to non-automated conventional ventilation and secondary to determine if this closed-loop ventilation mode reduces ICU team staff workload. The results of POSITiVE II will support intensive care teams in their choices regarding the use of automated ventilation in postoperative care of uncomplicated cardiac surgery patients. Trial registration Clinicaltrials.gov NCT06178510 . Registered on December 4, 2023.

Abstract Background Patients with advanced critical illness often receive more intensive treatment than they would choose for themselves, which contributes to high health care costs near the end of life. The purpose of this study was to determine whether a family support intervention delivered by the interprofessional ICU team decreases hospitalization costs and hospital readmissions among critically ill patients at high risk of death or severe functional impairment. Results We examined index hospitalization costs as well as post-discharge utilization of acute care hospitals, rehabilitation and skilled nursing facilities, and hospice services for the PARTNER trial, a multicenter, stepped-wedge, cluster randomized trial of an interprofessional ICU family support intervention. We determined patients’ total controllable and direct variable costs using a computerized accounting system. We determined post-discharge resource utilization (as defined above) by structured telephone interview at 6-month follow-up. We used multiple variable regression modelling to compare outcomes between groups. Compared to usual care, the PARTNER intervention resulted in significantly lower total controllable costs (geometric mean: $26,529 vs $32,105; log-linear coefficient: − 0.30; 95% CI − 0.49, − 0.11) and direct variable costs ($3912 vs $6034; − 0.33; 95% CI − 0.56, − 0.10). A larger cost reduction occurred for decedents ($20,304 vs. $26,610; − 0.66; 95% CI − 1.01, − 0.31) compared to survivors ($31,353 vs. $35,015; − 0.15; 95% CI − 0.35,0.05). A lower proportion in the intervention arm were re-admitted to an acute care hospital (34.9% vs 45.1%; 0.66; 95% CI 0.56, 0.77) or skilled nursing facility (25.3% vs 31.6%; 0.63; 95% CI 0.47, 0.84). Conclusions A family support intervention delivered by the interprofessional ICU team significantly decreased index hospitalization costs and readmission rates over 6-month follow-up. Trial registration Trial registration number: NCT01844492

Abstract Introduction Recurrent Clostridioides difficile infection (rCDI) often occurs after standard-of-care antibiotics. VOWST oral spores (VOS, previously SER-109), an FDA-approved orally administered microbiome therapeutic, is indicated to prevent rCDI following antibiotics for rCDI. Objective, Design, and Patients To evaluate safety and efficacy of VOS from two phase 3 trials, (randomized, placebo-controlled [ECOSPOR III: NCT03183128] and open-label, single arm [ECOSPOR IV: NCT03183141]) of 349 adults with rCDI and prevalent comorbidities. Methods VOS or placebo [ECOSPOR III only] (4 capsules once daily for 3 days). Integrated analysis of treatment-emergent adverse events (TEAEs) collected through week 8; serious TEAEs and TEAEs of special interest collected through week 24; and rates of rCDI (toxin-positive diarrhea requiring treatment) evaluated through weeks 8 and 24. Results TEAEs were mostly mild or moderate and gastrointestinal. Most common treatment-related TEAEs were flatulence, abdominal pain and distension, fatigue, and diarrhea. There were 11 deaths (3.2%) and 48 patients (13.8%) with serious TEAEs, none treatment-related. The rCDI rate through week 8 was 9.5% (95% CI 6.6–13.0) and remained low through 24 weeks (15.2%; 95% CI 11.6–19.4). Safety and rCDI rates were consistent across subgroups including age, renal impairment/failure, diabetes, and immunocompromise/immunosuppression. Conclusions VOS was well tolerated and rates of rCDI remained low through week 24 including in those with comorbidities. These data support the potential benefit of VOS following antibiotics to prevent recurrence in high-risk patients. Trial Registration ClinicalTrials.gov identifier, NCT03183128 and NCT03183141.

INTRODUCTION: Antithrombotic therapy prevents adverse ischemic events following acute ischemic stroke (AIS). Intravenous tirofiban provides desirable antiplatelet effects, especially in patients who are vulnerable to neurological deterioration (ND). AIM: The aim of the study was to test the hypothesis that intravenous administration of tirofiban, initiated within 24 h of ictus and continued for consecutive 72 h, would be more effective than aspirin in reducing the risk of ND within 72 h of enrollment among patients with potentially atherothrombotic ischemic stroke. METHODS: The Safety and Efficacy of Tirofiban in Preventing Neurological Deterioration in Acute Ischemic Stroke (TREND) trial is an investigator-initiated, multicenter, prospective, randomized, open-label, masked endpoint study. Its eligibility criteria included AIS secondary to potential atherosclerosis, a National Institutes of Health Stroke Scale (NIHSS) score ranging from 4 to 20 points, ineligibility for recanalization therapy, and administration within 24 h postsymptom onset. Randomization was performed at a 1:1 ratio to allocate 420 patients into two groups to receive an intravenous tirofiban bridge to oral antiplatelet drugs or direct oral antiplatelet drugs. OUTCOMES: The primary outcome is the proportion of patients with a ≥4-point increase in NIHSS score within 72 h of intervention compared to the score at enrollment. The key secondary outcomes include changes in NIHSS score, modified Rankin scale (mRS) score at 90 days, and dichotomized mRS scores (0–2 vs. 3–6 and 0–1 vs. 2–6) at 90 days. The safety variables are symptomatic intracerebral hemorrhage, any intracerebral hemorrhage, and systemic hemorrhage within 72 h after randomization and 90-day mortality. CONCLUSIONS: The TREND trial may identify the suitability of intravenous tirofiban as a routine clinical strategy to prevent ND in patients with AIS within 24 h of the onset of symptoms. TRIAL REGISTRATION: http://www.clinicaltrials.gov (identifier: NCT04491695).

Introduction: Patients experiencing an out-of-hospital cardiac arrest (OHCA) frequently do not receive bystander cardiopulmonary resuscitation (CPR), especially in low- and middle-income countries (LMIC). In this study we sought to determine the prevalence of OHCA patients in Vietnam who received bystander CPR and its effects on survival outcomes. Methods: We performed a multicenter, retrospective observational study of patients (≥18 years) presenting with OHCA at three major hospitals in an LMIC from February 2014–December 2018. We collected data on the hospital and patient characteristics, the cardiac arrest events, the emergency medical services (EMS) system, the therapy methods, and the outcomes and compared these data, before and after pairwise 1:1 propensity score matching, between patients who received bystander CPR and those who did not. Upon admission, we assessed factors associated with good neurological survival at hospital discharge in univariable and multivariable logistic models. Results: Of 521 patients, 388 (74.5%) were men, and the mean age was 56.7 years (SD 17.3). Although most cardiac arrests (68.7%, 358/521) occurred at home and 78.8% (410/520) were witnessed, a low proportion (22.1%, 115/521) of these patients received bystander CPR. Only half of the patients were brought by EMS (8.1%, 42/521) or private ambulance (42.8%, 223/521), 50.8% (133/262) of whom had resuscitation attempts. Before matching, there was a significant difference in good neurological survival between patients who received bystander CPR (12.2%, 14/115) and patients who did not (4.7%, 19/406; P

Abstract Background Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting over 300,000 people worldwide. It is characterized by the progressive decline of the nervous system that leads to the weakening of muscles which impacts physical function. Approximately, 15% of individuals diagnosed with ALS have a known genetic variant that contributes to their disease. As therapies that slow or prevent symptoms continue to develop, such as antisense oligonucleotides, it is important to discover novel genes that could be targets for treatment. Additionally, as cohorts continue to grow, performing analyses in ALS subtypes, such as primary lateral sclerosis (PLS), becomes possible due to an increase in power. These analyses could highlight novel pathways in disease manifestation. Methods Building on our previous discoveries using rare variant association analyses, we conducted rare variant burden testing on a substantially larger multi-ethnic cohort of 6,970 ALS patients, 166 PLS patients, and 22,524 controls. We used intolerant domain percentiles based on sub-region Residual Variation Intolerance Score (subRVIS) that have been described previously in conjunction with gene based collapsing approaches to conduct burden testing to identify genes that associate with ALS and PLS. Results A gene based collapsing model showed significant associations with SOD1, TARDBP, and TBK1 (OR = 19.18, p = 3.67 × 10–39; OR = 4.73, p = 2 × 10–10; OR = 2.3, p = 7.49 × 10–9, respectively). These genes have been previously associated with ALS. Additionally, a significant novel control enriched gene, ALKBH3 (p = 4.88 × 10–7), was protective for ALS in this model. An intolerant domain-based collapsing model showed a significant improvement in identifying regions in TARDBP that associated with ALS (OR = 10.08, p = 3.62 × 10–16). Our PLS protein truncating variant collapsing analysis demonstrated significant case enrichment in ANTXR2 (p = 8.38 × 10–6). Conclusions In a large multi-ethnic cohort of 6,970 ALS patients, collapsing analyses validated known ALS genes and identified a novel potentially protective gene, ALKBH3. A first-ever analysis in 166 patients with PLS found a candidate association with loss-of-function mutations in ANTXR2.

Abstract Background Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure and cardiovascular death with type 2 diabetes; however, their effect on arrhythmias is unclear. The purpose of this study was to investigate the effects of empagliflozin on ventricular arrhythmias in patients with type 2 diabetes. Methods A total of 150 patients with type 2 diabetes who were treated with an implantable cardioverter-defibrillator or cardiac resynchronization therapy defibrillator (ICD/CRT-D) were randomized to once-daily empagliflozin or placebo for 24 weeks. The primary endpoint was the change in the number of ventricular arrhythmias from the 24 weeks before to the 24 weeks during treatment. Secondary endpoints included the change in the number of appropriate device discharges and other values. Results In the empagliflozin group, the number of ventricular arrhythmias recorded by ICD/CRT-D decreased by 1.69 during treatment compared to before treatment, while in the placebo group, the number increased by 1.79. The coefficient for the between-group difference was − 1.07 (95% confidence interval [CI] − 1.29 to − 0.86; P

Abstract The efficacy of an implantable cardioverter-defibrillator (ICD) in patients with a non-ischaemic cardiomyopathy for primary prevention of sudden cardiac death is increasingly debated. We developed a multimodal deep learning model for arrhythmic risk prediction that integrated late gadolinium enhanced (LGE) cardiac magnetic resonance imaging (MRI), electrocardiography (ECG) and clinical data. Short-axis LGE-MRI scans and 12-lead ECGs were retrospectively collected from a cohort of 289 patients prior to ICD implantation, across two tertiary hospitals. A residual variational autoencoder was developed to extract physiological features from LGE-MRI and ECG, and used as inputs for a machine learning model (DEEP RISK) to predict malignant ventricular arrhythmia onset. In the validation cohort, the multimodal DEEP RISK model predicted malignant ventricular arrhythmias with an area under the receiver operating characteristic curve (AUROC) of 0.84 (95% confidence interval (CI) 0.71–0.96), a sensitivity of 0.98 (95% CI 0.75–1.00) and a specificity of 0.73 (95% CI 0.58–0.97). The models trained on individual modalities exhibited lower AUROC values compared to DEEP RISK [MRI branch: 0.80 (95% CI 0.65–0.94), ECG branch: 0.54 (95% CI 0.26–0.82), Clinical branch: 0.64 (95% CI 0.39–0.87)]. These results suggest that a multimodal model achieves high prognostic accuracy in predicting ventricular arrhythmias in a cohort of patients with non-ischaemic systolic heart failure, using data collected prior to ICD implantation.

Abstract Subclinical leaflet thrombosis (SLT) can be one of the causes of transcatheter heart valve (THV) failure after transcatheter aortic valve implantation (TAVI). We sought to clarify the formation process of SLT and thrombogenicity during the perioperative period of TAVI. This multicenter, prospective, single-arm interventional study enrolled 26 patients treated with edoxaban for atrial fibrillation and who underwent TAVI for severe aortic stenosis between September 2018 and September 2022. We investigated changes in maximal leaflet thickness detected by contrast-enhanced computed tomography between 1 week and 3 months after TAVI in 18 patients and measured the thrombogenicity by Total Thrombus-formation Analysis System (T-TAS) and flow stagnation volume by computational fluid dynamics (CFD) (n = 11). SLT was observed in 16.7% (3/18) at 1 week, but decreased to 5.9% (1/17) at 3 months after TAVI. Patients with SLT at 1 week had a significantly decreased maximal leaflet thickness compared to those without SLT. Thrombogenicity assessed by T-TAS decreased markedly at 1 week and tended to increase at 3 months. The stagnation volume assessed by CFD was positively associated with a higher maximum leaflet thickness. This study showed the course of leaflet thrombus formation and visualization of stagnation in neo-sinus of THV in the acute phase after TAVI.

Abstract Objectives Current recommendations support surgical treatment of atrial fibrillation (AF) in patients indicated for cardiac surgery. These procedures are referred to as concomitant and may be carried out using radiofrequency energy or cryo-ablation. This study aimed to assess the electrophysiological findings in patients undergoing concomitant cryo-ablation. Methods Patients with non-paroxysmal AF undergoing coronary artery bypass grafting and/or valve repair/replacement were included in the trial if concomitant cryo-ablation was part of the treatment plan according to current guidelines. The patients reported in this study were assigned to undergo staged percutaneous radiofrequency catheter ablation (PRFCA), i.e., hybrid treatment, as a part of the SURHYB trial protocol. Results We analyzed 103 patients who underwent PRFCA 105 ± 35 days after surgery. Left and right pulmonary veins (PVs) were found isolated in 65 (63.1%) and 63 (61.2%) patients, respectively. The LA posterior wall isolation and mitral isthmus conduction block were found in 38 (36.9%) and 18 (20.0%) patients, respectively. Electrical reconnections (gaps) in the left PVs were more often localized superiorly than inferiorly (57.9% vs. 26.3%, P = 0.005) and anteriorly than posteriorly (65.8% vs. 31.6%, P = 0.003). Gaps in the right PVs were more equally distributed anteroposteriorly but dominated in superior segments (72.5% vs. 40.0%, P = 0.003). There was a higher number of gaps on the roof line compared to the inferior line (131 (67.2%) vs. 67 (42.2%), P

Abstract Background A notable increase in severe cases of COVID-19, with significant hospitalizations due to the emergence and spread of JN.1 was observed worldwide in late 2023 and early 2024. However, no clinical data are available regarding critically-ill JN.1 COVID-19 infected patients. Methods The current study is a substudy of the SEVARVIR prospective multicenter observational cohort study. Patients admitted to any of the 40 participating ICUs between November 17, 2022, and January 22, 2024, were eligible for inclusion in the SEVARVIR cohort study (NCT05162508) if they met the following inclusion criteria: age ≥ 18 years, SARS-CoV-2 infection confirmed by a positive reverse transcriptase-polymerase chain reaction (RT-PCR) in nasopharyngeal swab samples, ICU admission for acute respiratory failure. The primary clinical endpoint of the study was day-28 mortality. Evaluation of the association between day-28 mortality and sublineage group was conducted by performing an exploratory multivariable logistic regression model, after systematically adjusting for predefined prognostic factors previously shown to be important confounders (i.e. obesity, immunosuppression, age and SOFA score) computing odds ratios (OR) along with their corresponding 95% confidence intervals (95% CI). Results During the study period (November 2022–January 2024) 56 JN.1- and 126 XBB-infected patients were prospectively enrolled in 40 French intensive care units. JN.1-infected patients were more likely to be obese (35.7% vs 20.8%; p = 0.033) and less frequently immunosuppressed than others (20.4% vs 41.4%; p = 0.010). JN.1-infected patients required invasive mechanical ventilation support in 29.1%, 87.5% of them received dexamethasone, 14.5% tocilizumab and none received monoclonal antibodies. Only one JN-1 infected patient (1.8%) required extracorporeal membrane oxygenation support during ICU stay (vs 0/126 in the XBB group; p = 0.30). Day-28 mortality of JN.1-infected patients was 14.6%, not significantly different from that of XBB-infected patients (22.0%; p = 0.28). In univariable logistic regression analysis and in multivariable analysis adjusting for confounders defined a priori, we found no statistically significant association between JN.1 infection and day-28 mortality (adjusted OR 1.06 95% CI (0.17;1.42); p = 0.19). There was no significant between group difference regarding duration of stay in the ICU (6.0 [3.5;11.0] vs 7.0 [4.0;14.0] days; p = 0.21). Conclusions Critically-ill patients with Omicron JN.1 infection showed a different clinical phenotype than patients infected with the earlier XBB sublineage, including more frequent obesity and less immunosuppression. Compared with XBB, JN.1 infection was not associated with higher day-28 mortality.

Abstract Background Previous retrospective research has shown that maintaining prone positioning (PP) for an average of 40 h is associated with an increase of survival rates in intubated patients with COVID-19-related acute respiratory distress syndrome (ARDS). This study aims to determine whether a cumulative PP duration of more than 32 h during the first 2 days of intensive care unit (ICU) admission is associated with increased survival compared to a cumulative PP duration of 32 h or less. Methods This study is an ancillary analysis from a previous large international observational study involving intubated patients placed in PP in the first 48 h of ICU admission in 149 ICUs across France, Belgium and Switzerland. Given that PP is recommended for a 16-h daily duration, intensive PP was defined as a cumulated duration of more than 32 h during the first 48 h, whereas standard PP was defined as a duration equal to or less than 32 h. Patients were followed-up for 90 days. The primary outcome was mortality at day 60. An Inverse Probability Censoring Weighting (IPCW) Cox model including a target emulation trial method was used to analyze the data. Results Out of 2137 intubated patients, 753 were placed in PP during the first 48 h of ICU admission. The intensive PP group (n = 79) had a median PP duration of 36 h, while standard PP group (n = 674) had a median of 16 h during the first 48 h. Sixty-day mortality rate in the intensive PP group was 39.2% compared to 38.7% in the standard PP group (p = 0.93). Twenty-eight-day and 90-day mortality as well as the ventilator-free days until day 28 were similar in both groups. After IPCW, there was no significant difference in mortality at day 60 between the two-study groups (HR 0.95 [0.52–1.74], p = 0.87 and HR 1.1 [0.77–1.57], p = 0.61 in complete case analysis or in multiple imputation analysis, respectively). Conclusions This secondary analysis of a large multicenter European cohort of intubated patients with ARDS due to COVID-19 found that intensive PP during the first 48 h did not provide a survival benefit compared to standard PP.

Abstract Background The relationships between frailty and clinical outcomes in elderly Japanese patients with non‐valvular atrial fibrillation (NVAF) after catheter ablation (CA) have not been established. We evaluated the frailty rate of patients undergoing CA for NVAF, examined whether CA for NVAF improves frailty, and analyzed the CA outcomes of patients with and without frailty. Methods Elderly Japanese patients (≥65 years; mean age: 72.8 years) who participated in the real‐world ablation therapy with anti‐coagulants in management of atrial fibrillation registry and who responded to the frailty screening index survey were included (n = 213). Frailty and AF recurrence were assessed preoperatively and at 3 and 6 months after CA. Results Twenty‐six patients (12.8%) were frail, 109 (53.7%) were pre‐frail, and 68 (33.5%) were robust. Cardiovascular (frailty: 0.5%/person‐year; pre‐frailty: 0.1%/person‐year; robust: 0.1%/person‐year) and cardiac (frailty: 0.5%/person‐year; pre‐frailty: 0.1%/person‐year; robust: 0.1%/person‐year) events, as well as major bleeding (frailty: 0.3%/person‐year; pre‐frailty: 0.1%/person‐year; robust: 0.1%/person‐year), were numerically more frequent in the frailty group. No deaths from cardiovascular or stroke/systemic thromboembolic events occurred. A large proportion of patients did not experience 3‐month (frailty: 96.2%; pre‐frailty: 96.3%; robust: 88.2%) or 6‐month (frailty: 88.5%; pre‐frailty: 91.7%; robust: 86.8%) AF recurrence after CA. Weight loss, walking speed, and fatigue improved in the frailty and pre‐frailty groups after CA. Conclusion Japanese patients aged ≥65 years with frailty or pre‐frailty had improved frailty screening index components, such as weight loss, walking speed and fatigue, after CA. Therefore, elderly patients with frailty or pre‐frailty may benefit from CA for NVAF.

Abstract Background The aim of this study is to report the preliminary real-word clinical and hemodynamic performance from the MANTRA study in patients undergoing aortic valve replacement with Perceval PLUS sutureless valve. Methods MANTRA is an ongoing “umbrella” prospective, multi-center, international post-market study to collect real-life safety and performance data on Corcym devices (Corcym S.r.l, Saluggia, Italy). Clinical and echocardiographic outcomes were collected preoperatively, at discharge and at each follow up. KCCQ-12 and EQ-5D-5L quality of life questionnaires were collected preoperatively and at 30-days. Results A total of 328 patients underwent aortic valve replacement with Perceval PLUS in 29 International institutions. Patients were enrolled from July 2021 to October 2023 and enrollment is still ongoing. Mean age was 71.9 ± 6.4 years, mean EuroSCORE II was 2.9 ± 3.9. Minimally invasive approach was performed in 44.2% (145/328) of patients; concomitant procedures were done in 40.8% (134/328) of cases. Thirty-day mortality was 1.8% (6/328) and no re-interventions were reported. Pacemaker implant was required in 4.0% (13/328) of the patients. The assessment of the functional status demonstrated marked and stable improvement in NYHA class in most patients at 30-day follow-up, with significant increase of KCCQ-12 summary score (from 58.8 ± 23.0 to 71.8 ± 22.1, p

Abstract Digital measures may provide objective, sensitive, real-world measures of disease progression in Parkinson’s disease (PD). However, multicenter longitudinal assessments of such measures are few. We recently demonstrated that baseline assessments of gait, tremor, finger tapping, and speech from a commercially available smartwatch, smartphone, and research-grade wearable sensors differed significantly between 82 individuals with early, untreated PD and 50 age-matched controls. Here, we evaluated the longitudinal change in these assessments over 12 months in a multicenter observational study using a generalized additive model, which permitted flexible modeling of at-home data. All measurements were included until participants started medications for PD. Over one year, individuals with early PD experienced significant declines in several measures of gait, an increase in the proportion of day with tremor, modest changes in speech, and few changes in psychomotor function. As measured by the smartwatch, the average (SD) arm swing in-clinic decreased from 25.9 (15.3) degrees at baseline to 19.9 degrees (13.7) at month 12 (P = 0.004). The proportion of awake time an individual with early PD had tremor increased from 19.3% (18.0%) to 25.6% (21.4%; P

Abstract There are numerous prognostic predictive models for evaluating mortality risk, but current scoring models might not fully cater to sepsis patients’ needs. This study developed and validated a new model for sepsis patients that is suitable for any care setting and accurately forecasts 28-day mortality. The derivation dataset, gathered from 20 hospitals between September 2019 and December 2021, contrasted with the validation dataset, collected from 15 hospitals from January 2022 to December 2022. In this study, 7436 patients were classified as members of the derivation dataset, and 2284 patients were classified as members of the validation dataset. The point system model emerged as the optimal model among the tested predictive models for foreseeing sepsis mortality. For community-acquired sepsis, the model’s performance was satisfactory (derivation dataset AUC: 0.779, 95% CI 0.765–0.792; validation dataset AUC: 0.787, 95% CI 0.765–0.810). Similarly, for hospital-acquired sepsis, it performed well (derivation dataset AUC: 0.768, 95% CI 0.748–0.788; validation dataset AUC: 0.729, 95% CI 0.687–0.770). The calculator, accessible at https://avonlea76.shinyapps.io/shiny_app_up/ , is user-friendly and compatible. The new predictive model of sepsis mortality is user-friendly and satisfactorily forecasts 28-day mortality. Its versatility lies in its applicability to all patients, encompassing both community-acquired and hospital-acquired sepsis.

Abstract Background Widefield radiation therapy (RT) has emerged as a treatment option for extensive skin field cancerization (ESFC), with or without keratinocyte cancer (KC). Objectives To assess the long‐term efficacy, safety, cosmesis and quality of life outcomes for patients with ESFC ± KC receiving widefield RT. Methods NDROR (National Dermatology Radiation Oncology Registry) is an open‐label, prospective, nonrandomized, multicentre registry of patients receiving widefield RT at 11 Australian radiation oncology clinics from a single organization. Field/lesion clearance efficacy and cosmesis were assessed in a cohort of patients with at least 24 months follow‐up. Patient‐reported quality of life using EQ‐5D‐5L questionnaires was performed at each visit. Toxicity analysis was performed on data from patients who completed treatment and had at least 3 months follow‐up. Results Combined investigator‐assessed field treatment success and lesion clearance at 24 months were ≥96% and 93.5%, respectively. The incidence of new KC within the treated field was 10%. Common Terminology Criteria for Adverse Event grade 1–2 radiation‐induced skin toxicities were reported in >92% of fields at the end of treatment, with 5.8% of fields exhibiting grade 3 toxicities. Toxicity resolved rapidly at the cessation of treatment, with grade 1–2 alopecia and xerosis the most prevalent toxicities after 24 months (51.8% and 43.4%, respectively). Cosmesis in treated fields was assessed as excellent or good in 98% of fields at 24 months. Quality of life significantly improved compared to baseline (baseline: mean visual analogue scale (VAS) 80.65, n = 183) at 24 months follow‐up (mean VAS 84.32, N = 83; improvement of 3.67; p = 0.026). Conclusions This analysis indicates that widefield RT is an effective and generally well‐tolerated treatment for ESFC ± KC. Treatment has a favourable safety and cosmesis profile within the period of follow‐up and is associated with significant improvements in quality of life for patients. Widefield RT may be considered for certain patients with extensive disease who have exhausted or are unsuitable for other therapies.

Abstract Aims Growth differentiation factor‐15 (GDF15), a cytokine in the transforming growth factor family, is up‐regulated in stress and inflammatory conditions and is elevated in patients with heart failure (HF). However, the age‐specific attributes and prognostic significance of GDF15 across age remain unknown in chronic HF (CHF). Methods and results Serum levels of GDF15 were examined in 942 hypertensive patients (median 68 years) with CHF from the SUPPORT trial across the four age groups [under 50 (n = 73), 51–59 (n = 158), 60–69 (n = 296), and 70–79 years (n = 415)] and in the continuous spectrum. Clinical correlates of GDF15 were explored using the classic stepwise and LASSO (least absolute shrinkage and selection operator) regression approaches. Interaction terms with age were tested in the LASSO regression approach. The associations with the composite outcome of HF hospitalization or all‐cause death were investigated across ages. Median GDF15 levels (pg/mL) increased along with aging, from 691 in under 50 years to 855 in 51–59 years, 1114 in 60–69 years, and 1516 in 70–79 years (trend P

IntroductionContinuous renal replacement therapy (CRRT) is used for the symptomatic management of acute kidney injury (AKI) and fluid overload (FO). Contemporary reports on pediatric CRRT are small and single center in design. Large international studies evaluating CRRT practice and outcomes are lacking. Herein, we describe the design of a multinational collaborative.MethodsThe Worldwide Exploration of Renal Replacement Outcomes Collaborative in Kidney Disease (WE-ROCK) is an international collaborative of pediatric specialists whose mission is to improve short- and long-term outcomes of children treated with CRRT. The aims of this multicenter retrospective study are to describe the epidemiology, liberation patterns, association of fluid balance and timing of CRRT initiation, and CRRT prescription with outcomes.ResultsWe included children (n = 996, 0-25 years) admitted to an intensive care unit (ICU) and treated with CRRT for AKI or FO at 32 centers (in 7 countries) from 2018 to 2021. Demographics and clinical characteristics before CRRT initiation, during the first 7 days of both CRRT, and liberation were collected. Outcomes include the following: (i) major adverse kidney events at 90 days (mortality, dialysis dependence, and persistent kidney dysfunction), and (ii) functional outcomes (functional stats scale).ConclusionThe retrospective WE-ROCK study represents the largest international registry of children receiving CRRT for AKI or FO. It will serve as a broad and invaluable resource for the field of pediatric critical care nephrology that will improve our understanding of practice heterogeneity and the association of CRRT with clinical and patient-centered outcomes. This will generate preliminary data for future interventional trials in this area.

Household air pollution from solid cooking fuel use during gestation has been associated with adverse pregnancy and birth outcomes. The Household Air Pollution Intervention Network (HAPIN) trial was a randomized controlled trial of free liquefied petroleum gas (LPG) stoves and fuel in Guatemala, Peru, India, and Rwanda. A primary outcome of the main trial was to report the effects of the intervention on infant birth weight. Here we evaluate the effects of a LPG stove and fuel intervention during pregnancy on spontaneous abortion, postpartum hemorrhage, hypertensive disorders of pregnancy, and maternal mortality compared to women who continued to use solid cooking fuels. Pregnant women (18-34 years of age; gestation confirmed by ultrasound at 9-19 weeks) were randomly assigned to an intervention (n = 1593) or control (n = 1607) arm. Intention-to-treat analyses compared outcomes between the two arms using log-binomial models. Among the 3195 pregnant women in the study, there were 10 spontaneous abortions (7 intervention, 3 control), 93 hypertensive disorders of pregnancy (47 intervention, 46 control), 11 post postpartum hemorrhage (5 intervention, 6 control) and 4 maternal deaths (3 intervention, 1 control). Compared to the control arm, the relative risk of spontaneous abortion among women randomized to the intervention was 2.32 (95% confidence interval (CI): 0.60, 8.96), hypertensive disorders of pregnancy 1.02 (95% CI: 0.68, 1.52), postpartum hemorrhage 0.83 (95% CI: 0.25, 2.71) and 2.98 (95% CI: 0.31, 28.66) for maternal mortality. In this study, we found that adverse maternal outcomes did not differ based on randomized stove type across four country research sites.

BackgroundPatients with non-alcoholic steatohepatitis (NASH)-related cirrhosis are at high risk of liver-related and all-cause morbidity and mortality. We investigated the efficacy and safety of the glucagon-like peptide-1 analogue semaglutide in patients with NASH and compensated cirrhosis.MethodsThis double-blind, placebo-controlled phase 2 trial enrolled patients from 38 centres in Europe and the USA. Adults with biopsy-confirmed NASH-related cirrhosis and body-mass index (BMI) of 27 kg/m2 or more were randomly assigned (2:1) to receive either once-weekly subcutaneous semaglutide 2·4 mg or visually matching placebo. Patients were randomly allocated via an interactive web response system, stratified by presence or absence of type 2 diabetes. Patients, investigators, and those assessing outcomes were masked to treatment assignment. The primary endpoint was the proportion of patients with an improvement in liver fibrosis of one stage or more without worsening of NASH after 48 weeks, assessed by biopsy in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug. The trial is closed and completed, and registered with ClinicalTrials.gov, number NCT03987451.Findings71 patients were enrolled between June 18, 2019, and April 22, 2021; 49 (69%) patients were female and 22 (31%) were male. Patients had a mean age of 59·5 years (SD 8·0) and mean BMI of 34·9 kg/m2 (SD 5·9); 53 (75%) patients had diabetes. 47 patients were randomly assigned to the semaglutide group and 24 to the placebo group. After 48 weeks, there was no statistically significant difference between the two groups in the proportion of patients with an improvement in liver fibrosis of one stage or more without worsening of NASH (five [11%] of 47 patients in the semaglutide group vs seven [29%] of 24 in the placebo group; odds ratio 0·28 [95% CI 0·06-1·24; p=0·087). There was also no significant difference between groups in the proportion of patients who achieved NASH resolution (p=0·29). Similar proportions of patients in each group reported adverse events (42 [89%] patients in the semaglutide group vs 19 [79%] in the placebo group) and serious adverse events (six [13%] vs two [8%]). The most common adverse events were nausea (21 [45%] vs four [17%]), diarrhoea (nine [19%] vs two [8%]), and vomiting (eight [17%] vs none). Hepatic and renal function remained stable. There were no decompensating events or deaths.InterpretationIn patients with NASH and compensated cirrhosis, semaglutide did not significantly improve fibrosis or achievement of NASH resolution versus placebo. No new safety concerns were raised.FundingNovo Nordisk A/S.

DESTINY-CRC01 (NCT03384940) was a multicenter, open-label, phase 2 trial assessing the efficacy and safety of trastuzumab deruxtecan (T-DXd) in patients with HER2-expressing metastatic colorectal cancer (mCRC) that progressed after ≥2 prior regimens; results of the primary analysis are published. Patients received T-DXd 6.4 mg/kg every 3 weeks and were assigned to either: cohort A (HER2-positive, immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization [ISH]+), cohort B (IHC 2+/ISH-), or cohort C (IHC 1+). Primary endpoint was objective response rate (ORR) by independent central review in cohort A. Secondary endpoints included ORR (cohorts B and C), duration of response, disease control rate, progression-free survival, overall survival, pharmacokinetics, and safety of T-DXd. 86 patients were enrolled (53 in cohort A, 15 in cohort B, and 18 in cohort C). Results of the primary analysis are published, reporting an ORR of 45.3% in cohort A. Here, we report the final results. No responses occurred in cohorts B or C. Median progression-free survival, overall survival, and duration of response were 6.9, 15.5, and 7.0 months, respectively. Overall serum exposure (cycle 1) of T-DXd, total anti-HER2 antibody, and DXd were similar regardless of HER2 status. Most common grade ≥3 treatment-emergent adverse events were decreased neutrophil count and anemia. Adjudicated drug-related interstitial lung disease/pneumonitis occurred in 8 patients (9.3%). These findings support the continued exploration of T-DXd in HER2-positive mCRC.

BackgroundWe aimed to clarify the association between intraoperative P2Y12 inhibitor administration during EVT and clinical outcomes in patients with anterior circulation TO stroke.MethodsAmong consecutive patients with acute ischemic stroke (AIS) enrolled in the Recovery by Endovascular Salvage for Cerebral Ultra-acute Embolic and Atherothrombotic Stroke with Large Vessel Occlusion Registry from 2016 to 2019, those with anterior circulation TOs who underwent EVT were analyzed. These patients were categorized into the following groups: those who received P2Y12 inhibitors during the perioperative period and those who did not receive P2Y12 inhibitors. The outcomes included good functional outcomes, as indicated by a modified Rankin Scale score of 0–2 at 90 days, and the incidence of symptomatic intracranial hemorrhage (SICH) was compared between the two groups. Multivariate logistic regression models were used to assess the association of outcomes with perioperative P2Y12 inhibitor administration. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using the group that did not receive P2Y12 inhibitors as the reference. The perioperative period included the period in which antithrombotic therapy was administered immediately before EVT and during the operative period.ResultsWe enrolled 242 patients with AIS with anterior circulation TOs (42 females [17.4%]; median age, 76 [interquartile range, 69–81] years). Patients who received P2Y12 inhibitors during the perioperative period (n = 131) showed a higher frequency of carotid artery stenting than those who did not receive perioperative P2Y12 inhibitors (n = 111; 86.3% vs. 42.3%, p

Background Mechanical thrombectomy has changed the landscape of acute ischemic stroke treatment, offering improved outcomes for patients with large vessel occlusions. The interplay between reperfusion techniques and occlusion sites remains a critical consideration in treatment decisions. This study investigates the impact of primary reperfusion techniques—stent retriever classic, stent retriever combination with aspiration, and direct aspiration—on procedural and clinical outcomes at different occlusion sites. Methods Using data from the ASSIST registry, a prospective multinational initiative, patients with anterior circulation acute ischemic stroke with large vessel occlusions (n = 1477) were included. Three primary occlusion sites—M1 segment of the middle cerebral artery, M2 segment of the middle cerebral artery, and the internal carotid artery—were studied. Univariate tests and multivariable logistic regression models were used to assess associations between reperfusion techniques and procedural and clinical outcomes, including the expanded thrombolysis in cerebral infarction score and the modified Rankin Scale, stratified by occlusion site. Results Achieving expanded thrombolysis in cerebral infarction ≥2c after first pass was lower in internal carotid artery occlusions (18.2%, P

BackgroundOne of the greatest challenges to conducting multicenter research studies in low and middle-income countries (LMICs) is the heterogeneity in regulatory processes across sites. Previous studies have reported variations in requirements with a lack of standardization in the Institutional Review Board (IRB) processes between centers, imposing barriers for approval, participation, and development of multicenter research.ObjectivesTo describe the regulatory process, variability and challenges faced by pediatric researchers in LMICs during the IRB process of an international multicenter observational point prevalence study (Global PARITY).DesignA 16-question multiple-choice online survey was sent to site principal investigators (PIs) at PARITY study participating centers to explore characteristics of the IRB process, costs, and barriers to research approval. A shorter survey was employed for sites that expressed interest in participating in Global PARITY and started the approval process, but ultimately did not participate in data collection (non-participating sites) to assess IRB characteristics.ResultsOf the 91 sites that sought IRB approval, 46 were successful in obtaining approval and finishing the data collection process. The survey was completed by 46 (100%) participating centers and 21 (47%) non-participating centers. There was a significant difference between participating and non-participating sites in IRB approval of a waiver consent and in the requirement for a legal review of the protocol. The greatest challenge to research identified by non-participating sites was a lack of research time and the lack of institutional support.ConclusionsGlobal collaborative research is crucial to increase our understanding of pediatric critical care conditions in hospitals of all resource-levels and IRBs are required to ensure that this research complies with ethical standards. Critical barriers restrict research activities in some resource limiting countries. Increasing the efficiency and accessibility of local IRB review could greatly impact participation of resource limited sites and enrollment of vulnerable populations.

Background The development of post-sepsis frailty is a common and significant problem, but it is a challenge to predict. Methods Data for deep learning were extracted from a national multicentre prospective observational cohort of patients with sepsis in Korea between September 2019 and December 2021. The primary outcome was frailty at survival discharge, defined as a clinical frailty score on the Clinical Frailty Scale ≥5. We developed a deep learning model for predicting frailty after sepsis by 10 variables routinely collected at the recognition of sepsis. With cross-validation, we trained and tuned six machine learning models, including four conventional and two neural network models. Moreover, we computed the importance of each predictor variable in the model. We measured the performance of these models using a temporal validation data set. Results A total of 8518 patients were included in the analysis; 5463 (64.1%) were frail, and 3055 (35.9%) were non-frail at discharge. The Extreme Gradient Boosting (XGB) achieved the highest area under the receiver operating characteristic curve (AUC) (0.8175) and accuracy (0.7414). To confirm the generalisation performance of artificial intelligence in predicting frailty at discharge, we conducted external validation with the COVID-19 data set. The XGB still showed a good performance with an AUC of 0.7668. The machine learning model could predict frailty despite the disparity in data distribution. Conclusion The machine learning-based model developed for predicting frailty after sepsis achieved high performance with limited baseline clinical parameters.

ObjectivesWe evaluated the impact of polypharmacy on the health of community-dwelling older adults.MethodsWe prospectively analyzed 5,631 individuals from the Moli-sani study (51% men, aged ≥65 years, recruitment 2005–2010, follow-up 2005–2020). Exposure was categorized as chronic polypharmacy therapy (C-PT; ≥5 therapeutic groups and >2 defined daily doses (DDDs)) or non-chronic polypharmacy therapy (NC-PT; polypharmacy but ≤2 DDDs). Hospitalization and mortality were the main outcomes. The mediating role of potentially inappropriate prescriptions (PIP) was examined.ResultsCompared to individuals not on polypharmacy, those in NC-PT and C-PT had higher hazards of mortality [21% (95% CI 7%–37%) and 30% (16%–46%), respectively] and hospitalization [39% (28%–51%) and 61% (49%–75%), respectively]. Similar results were found for cardiovascular outcomes. PIP mediated the association between polypharmacy and outcomes, with mediation effects ranging from 13.6% for mortality to 6.0% for hospitalization. Older adults without multimorbidity experienced the same harm from multiple medications as those with multimorbidity.ConclusionPolypharmacy is associated with a higher hazard of mortality and hospitalization, with PIP playing an important role. Addressing “medication without harm” requires assessing the appropriateness of drug prescriptions and monitoring for adverse effects.

BackgroundInvesting in the capabilities of adolescents is essential to achieving the United Nations Sustainable Development Goals, which focus on realising adolescent girls and young women’s (AGYW) rights to education, health, bodily autonomy and integrity, sexual and reproductive health (SRH) and well-being. Despite significant scientific and programmatic progress in understanding and responding to their unique and intersecting vulnerabilities, AGYW continue to face disproportionate risk of STIs, HIV and early pregnancy. Health promotion and preventative interventions stand to be improved by early and meaningful engagement of AGYW in intervention design and delivery.MethodsThis study employed Youth Participatory Action Research (YPAR) to co-generate lessons for future school-based SRH programming. The 5-step YPAR process included: (1) youth investigator recruitment; (2) youth investigator training and co-design of YPAR methods; (3) youth investigator-led data collection; (4) collaborative analysis and interpretation; and (5) dissemination.ResultsCollaborative analysis revealed improvements in self-concept and bodily autonomy, understanding and formation of healthy relationships and demand for girl-centred health services and information at school. Additionally, the study highlights YPAR’s positive influence on both the collaborative process and outputs of research. Further, it provides further insight into the quantitative biomedical and socio-behavioural findings of a larger experimental impact evaluation, in which it was nested.ConclusionResults from YPAR methods point to high programme acceptability and practical lessons to inform future school-based SRH programming. The inclusion of adolescent girls in the design, delivery and evaluation of intervention research that affects their lives is an important strategy for improving acceptability, and also has demonstrated value in building their health and social assets. Future recommendations include parental involvement, and employing quantitative measures for better evaluation of youth engagement, leadership and partnerships in the research process.