Citations

Abstract INTRODUCTION Loss‐of‐function variants of the ABCA7 gene are associated with an increased risk of Alzheimer's disease (AD). How neuronal ABCA7 contributes to AD pathogenesis is unknown. METHODS Using neuron‐specific Abca7 KO mice (n Abca7 −/− ) with or without 5×FAD amyloid model background and post mortem AD brains, we investigated AD‐related phenotypes through comprehensive approaches including transcriptomics and lipidomics. RESULTS Lipidomics analysis detected altered lipid profiles in the brains and synaptosomes of 5×FAD; n Abca7 −/− mice compared to controls. Transcriptomics profiling revealed that neuronal ABCA7 deficiency altered the expression of genes and pathways related to mitochondrial homeostasis and apoptosis, particularly in excitatory neurons. Consistently, synaptosomes isolated from 5×FAD; n Abca7 −/− mice showed diminished mitochondria respiration and reduced synaptic protein levels, which is further supported by results from human AD brains. DISCUSSION Our findings reveal that neuronal ABCA7 plays a critical role in mitochondrial homeostasis important for neuronal function and survival in the presence of AD pathology. Highlights Neuronal ABCA7 deficiency exacerbates Aβ pathology and neuronal damage in 5×FAD mice. Neuronal ABCA7 deficiency alters brain transcriptomes and lipidomes of 5×FAD mice. Neuronal ABCA7 deficiency disturbs mitochondria functions in synaptosomes from 5×FAD mice. Neuronal ABCA7 expression associates with genes and pathways related to mitochondrial homeostasis in AD brains.

Heart failure with reduced ejection fraction is a major cause of morbidity and mortality. Cardiac resynchronization therapy (CRT) improves outcomes but faces challenges such as unsuccessful lead placement and suboptimal responses. The Wireless Stimulation Endocardially for CRT (WiSE-CRT) system, a novel leadless left ventricular (LV) pacing technology, uses ultrasonic energy to deliver electrical stimulation directly to the LV endocardium, potentially improving the response rates. A comprehensive literature search was performed across multiple databases from inception until August 2024. The outcomes of interest included the New York Heart Association (NYHA) functional score, LV ejection fraction (LVEF), LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), and QRS duration. Statistical analysis involved pooling the mean differences (MDs) and their corresponding 95% confidence intervals (CIs) from each study using the inverse-variance random-effects model in RevMan version 5.4.1 software. Seven studies, including 468 patients with heart failure treated with the WiSE-CRT system, were included. The pooled analysis showed significant improvements in NYHA functional score (MD: −0.44; 95% CI: −0.67 to −0.21; P = 0.0002; I 2 = 77%), LVEF (MD: 5.71; 95% CI: 4.54 to 6.87; P < 0.001), LVEDV (MD: −24.49; 95% CI: −33.24 to −15.73; P < 0.001), and LVESV (MD: −24.47; 95% CI: −32.80 to −16.14; P < 0.001). The QRS duration also decreased significantly (MD: −38.62; 95% CI: −46.76 to −30.49; P < 0.001; I 2 = 60%). The WiSE-CRT system significantly improved NYHA functional score, LVEF, QRS duration, LVEDV, and LVESV in patients with heart failure. This leadless pacing technology offers a promising alternative for ineligible candidates or for those who do not respond to conventional CRT.

Abstract Background and Aims Classification and risk stratification in aortic (AR), mitral (MR), and tricuspid regurgitation (TR) remains a significant clinical challenge. This study aimed to develop an artificial intelligence (AI) system to assess valvular regurgitation and stratify MR-progression risk. Methods Using transthoracic echocardiograms (TTEs) at two sites (internal development/test, external test), the DELINEATE-Regurgitation system was developed to classify AR, MR, and TR severity using colour Doppler videos. Methods of summating video-level classifications into study-level predictions were tested, comparing single-view with multiview approaches integrating predictions across multiple videos. Model agreement with cardiologists was assessed by weighted kappa. A separate AI system (DELINEATE-MR-Progression) analysing colour Doppler videos was developed to predict which patients with mild, mild–moderate, and moderate MR were most likely to progress to moderate–severe or severe MR with analysis by Kaplan–Meier and Cox proportional hazards models. Results A total of 71 660 TTEs with 1 203 980 colour Doppler videos were included. The weighted kappa in internal/external test sets for regurgitation classification was 0.81/0.76 for AR, 0.76/0.72 for MR, and 0.73/0.64 for TR using a multiview approach taking all colour Doppler videos in a study, demonstrating substantial agreement with cardiologist interpretation with superiority of multiview over single view approaches. In the progression analysis, the AI score stratified MR-progression risk even when controlled for clinical factors known to be associated with MR progression [internal test set hazard ratio 4.1 (95% confidence interval 2.5–6.6)]. Conclusions An AI system can accurately classify AR, MR, and TR and predict MR progression beyond currently known risk factors.

Abstract Objectives In an effort to maintain the technical aspects of traditional prosthetic surgical aortic valve replacement (AVR) while reducing invasiveness and facilitate options for concomitant operations, transaxillary lateral mini-thoracotomy endoscopic robotic-assisted aortic valve replacement (RAVR) has been introduced. The present data highlight the contemporary international collaborative experience. METHODS All consecutive patients undergoing standardized RAVR across 10 international sites (1/2020–7/2024) were evaluated using a central database with 1 year follow-up. RESULTS A total of 300 patients were analysed with a median predicted risk of 1.6% with aortic stenosis in 85.7%, nearly half with bicuspid valves. Biological prostheses were implanted in 220 (73.3%) with a median valve size 23 mm, 10% receiving aortic root enlargement, with 17% of all patients undergoing concomitant procedures. Median cross-clamp 120 min with no conversions to sternotomy. Median length of stay was 5 days, 4.3% with prolonged ventilation, 1.7% renal failure, 1.0% stroke and 8.3% required re-thoracotomy for evacuation of haemothorax. There were two 30-day operative mortalities (0.7%). The new permanent pacemaker rate for the full cohort was 2.6%. Of 163 patients with complete 1-year clinical and echocardiographic follow-up, mean aortic valve gradient was 10 mmHg and all but 2 patients (1.2%) had trace to no prosthetic or paravalvular insufficiency. CONCLUSIONS RAVR is safe and effective, providing the reproducible benefits of surgical AVR while affording a less invasive approach that permits the opportunity for concomitant procedures. For low and intermediate risk patients with aortic valve disease, RAVR is a potential reproducible alternative for patients and heart teams.

OBJECTIVE Core outcome sets (COSs) are needed to promote data consistency across studies as well as data synthesis and comparability. The goal of the current study was to utilize a modified Delphi process to develop a COS–sciatic injury and neuropathy evaluation (COS-SINE). METHODS A five-stage approach was utilized to develop the COS-SINE: stage 1, consortium development; stage 2, literature review to identify potential outcome measures; stage 3, Delphi survey to develop consensus on outcomes for inclusion; stage 4, Delphi survey to develop definitions; and stage 5, consensus meeting to finalize the COS and definitions. The study followed the Core Outcome Set–STAndards for Development recommendations. RESULTS The Core Outcomes in Nerve Surgery (COINS) Consortium comprised 23 participants, all neurological surgeons, representing 13 countries. Three participants were excluded on the basis of agreed upon participation rules. The final COS-SINE consisted of 36 data points/outcomes covering the domains of demographics, diagnostics, patient-reported outcomes, motor and sensory outcomes, and complications. Appropriate instruments, methods of testing, and definitions were set. The consensus minimum duration of follow-up was 24 months, with consensus optimal time points for assessment identified as preoperatively and 3, 6, 12, 24, and 36 months postoperatively. CONCLUSIONS The COINS Consortium developed a consensus COS and provided definitions, methods of implementation, and time points for assessment. The COS-SINE should serve as a minimum set of data that should be collected in all future neurosurgical studies on sciatic nerve injury and neuropathy. Incorporation of this COS should help improve consistency in reporting and data synthesis and comparability and should minimize outcome-reporting bias.

Summary Background Colorectal cancer (CRC) results from the accumulation of mutations and epigenetic changes in gut epithelial cells likely due to gut microbiota dysbiosis. However, limited research has been done to explore the link between host tumour dysbiosis and disease outcome. Methods The mechanisms influencing outcomes of 97 colorectal cancer (CRC) patients, including 13 with Lynch syndrome, 20 with inflammatory bowel disease (IBD), and 64 sporadic cases, were analyzed using a multiomics approach. These patients were categorized into two groups: “disease-free/stable disease” and “progression disease” survival outcomes. The analysis included tumor adherent microbiota composition (16S rRNA), somatic gene mutations (WES), gene expression (RNAseq), immune markers (RNAscope), and immune infiltrate cells (immunohistochemistry). Results IBD-CRC patients had worse outcomes than those with Lynch or sporadic CRC, regardless of TNM staging or treatment. Symbiotic bacteria like Lactococcus lactis were significantly reduced in IBD-CRC tissues. Patient outcomes were influenced by the abundance of virulent ( Escherichia coli ) relative to beneficial bacteria ( Lactococcus lactis ). Although no significant increase in deleterious somatic mutations was found in IBD-CRC. 16sRNA revealed increased virulent- and decreased anti-inflammatory symbiotic-bacteria correlating with the upregulation of oncogenes and downregulation of anti-oncogenes like PHLPP1. The multiplex in situ hybridization of CD8, IFNγ and PHLPP1 an anti-oncogene revealed significant decrease of immune cells with detectable PHLPP1 expression in IBD-CRC tumour tissues as compared to sporadic CRCs. Conclusion The poor outcomes in IBD-CRC patients are likely due to gut dysbiosis and immune cell alterations, possibly triggered by microbiota-related epigenetic pathways. What You Need to Know BACKGROUND AND CONTEXT Colorectal cancer (CRC) is associated with gut microbiota dysbiosis. Inflammatory bowel disease-related CRC (IBD-CRC) is classified as an environment-related condition. NEW FINDINGS In relation with patient outcomes, tumour tissues from three types of CRC (Sporadic-, IBD-, and Lynch syndrome-CRC) were analyzed using a multiomic approach. This included examining tissue adherent virulent bacteria, gene analyses, and quantifying immune cell infiltration in the mucosa. IBD-CRC patients had the worst outcomes, associated with the down regulation of PHLPP1 gene, virulent/symbiotic imbalance, and immune response failure. LIMITATIONS Lack of animal experiments using FMT of fresh stool from IBD-CRC patients. CLINICAL AND TRANSLATIONAL RESEARCH RELEVANCE Among the different types of CRC, IBD-CRC patients showed a greater imbalance between harmful and beneficial bacteria, along with immune response failure. Lay summary This study compares the pathological and clinical characteristics of patients with colorectal cancer (CRC) across three distinct etiologies: sporadic CRC, inflammatory bowel disease (IBD)-associated CRC, and Lynch syndrome-associated CRC (LS-CRC). Distinct differences in tumor-adherent microbiota, gene expression and immune response profiles were observed. Notably, IBD-CRC patients demonstrated the poorest prognosis depending on microbe-host gene interaction highlighting potential biomarkers for disease prognosis and treatment strategies.