Citations

Abstract Background Arrhythmogenic mitral valve prolapse (AMVP) is increasingly recognized as a cause of sustained ventricular arrhythmias (VA) and sudden cardiac death. Although prior studies have identified clinical and imaging risk markers in AMVP, it remains unclear whether the arrhythmogenic phenotype differs between women and men. Purpose To investigate sex-specific differences in clinical profiles, structural substrates, and arrhythmia presentations in patients with AMVP who experienced sustained VA. Methods We conducted a sex-based sub-analysis of a multicenter cohort (35 centers from 15 countries) of patients with AMVP and sustained VA. Participants were grouped by sex and by initial arrhythmia type (sustained monomorphic ventricular tachycardia [SMVT] vs ventricular fibrillation [VF]). Data collected included clinical history, ECG findings, echocardiographic measurements, and cardiac MRI (CMR) markers, such as late gadolinium enhancement (LGE) patterns and mitral annular disjunction (MAD). These factors were compared across groups. Results The study comprised 129 women (57%) and 96 men (43%). Women were diagnosed at younger ages (39±16 years vs. 49±16 years, p<0.03) and had more frequently a family history of MVP (22% vs 10%, p=0.027). MAD was significantly more common in women (66% vs 48%, p=0.015) while LGE was more frequently observed in men than women (N=39 (72%) vs N=41 (53%), p=0.028), with no significant regional patterns (myocardial and/or papillary muscle). ECG T-wave inversion (p=0.627), PVC burden (p>0.03) and arrhythmia types were similar in men and women. However, stress was a more often commonly recognized as the initiating trigger for VA in men than in women (38% [N=24] vs. 18% [N=18], p<0.05). The overwhelming majority of VA were initiated by PVCs in both sexes with no differences in the initiating mechanisms. Conclusion In patients with AMVP presenting with sustained VA, the arrhythmic phenotype and initiating mechanisms are similar between sexes, although stress was a significantly stronger trigger for VA in men. Women more often exhibited MAD, whereas LGE was more frequent in men. These findings suggest that structural and tissue-based markers, rather than sex alone, contribute to the development of malignant arrhythmias in AMVP.

Abstract Introduction: Surveillance biopsies after kidney transplantation provide an opportunity to assess early renal disease processes, including diabetic nephropathy, before clinical manifestation. This study aimed to identify proteomic alterations in renal allografts at 5 years post-transplant (5yrPT) and their associations with histologic features in diabetic/obese (DM/OB) versus non-diabetic/non-obese (nDM/nOB) recipients. Methods: We studied protocol biopsies from 17 DM/OB and 14 nDM/nOB kidney transplant recipients at Mayo Clinic (2000–2012). Laser capture microdissection followed by mass spectrometry was used for proteomic profiling. Histologic assessment included Banff and Tervaert scoring and morphometric analysis. Statistical comparisons were performed using ANOVA with Tukey post-hoc testing. Results: DM/OB recipients demonstrated greater histologic and metabolic injury at 5yrPT. Proteomic analysis identified 101 glomerular and 86 non-glomerular proteins differentially expressed between groups. Significant alterations were observed in proteins associated with mitochondrial dysfunction, including VDAC1 (fold change [FC] 2.6, p = 0.03), NDUFB9 (FC 0.15, p = 0.009), and NDUFA9 (FC 1.72, p = 0.01). Extracellular matrix remodeling proteins COL6A1, COL6A2, and COL6A3 were upregulated (FC 1.6–1.8, p < 0.05). Immune and inflammatory markers C9 (FC 1.6, p < 0.03) and TGFBI (FC 1.7, p < 0.001), as well as oxidative stress–related CLU, were increased. GGACT showed the greatest decrease (FC 0.30, p < 0.001), implicating altered energy metabolism. Conclusion: Distinct proteomic signatures at 5yrPT in DM/OB recipients highlight early mitochondrial, metabolic, immune, and extracellular matrix pathways involved in diabetic kidney disease. These changes precede clinical disease and identify candidate biomarkers and therapeutic targets to improve graft longevity.

INTRODUCTION: Alcohol-associated hepatitis (AH) is a severe condition with high short-term mortality. Identifying key predictors of poor outcomes is critical for guiding therapeutic strategies. Mean arterial pressure (MAP), a key determinant of tissue perfusion and systemic hemodynamics, may play a pivotal role in prognosis. METHODS: We analyzed a multicenter, prospective cohort of 323 patients hospitalized with AH, with validation in an independent cohort of 290 patients. Survival was evaluated using Kaplan-Meier curves and compared with the log-rank (Mantel-Cox) test. Cox proportional hazards models were used to estimate hazard ratios for mortality, adjusted for Model for end stage liver disease score. Mechanistic insights were explored through assessment of cardiovascular biomarkers. RESULTS: A baseline MAP <80 mm Hg was associated with significantly higher mortality at both 28 days (27.3% vs 8.0%) and 90 days (40.3% vs 15.6%; P < 0.001 for both). This association persisted after adjusting for Model for end stage liver disease score, age, and baseline hepatic encephalopathy. The incidence of infections during follow-up was similar across MAP groups (27.6% vs 22.8%), but acute kidney injury occurred more frequently in the MAP <80 mm Hg group (62% vs 38%, P < 0.001). In the validation cohort, patients with MAP <80 mm Hg also demonstrated significantly lower 28-day transplant-free survival. Although B-type natriuretic peptide and plasma renin levels were altered in patients with AH, they did not correlate with MAP values. DISCUSSION: A baseline MAP <80 mm Hg is an independent predictor of short-term and mid-term mortality in patients with AH. Strategies aimed at restoring hemodynamic stability may improve outcomes in this high-risk population.

Abstract Patients with extremely rare pathogenic variants pose unique challenges to current healthcare systems. Nano-rare mutations have been defined as mutations with a known prevalence of &lt;30 patients worldwide, but because of the small fraction of humans who have undergone genetic testing, neither the precise prevalence of individual mutations nor the total prevalence of patients with nano-rare mutations is known. n-Lorem is a non-profit founded in 2020 with the mission of equitably discovering, developing, and providing bespoke experimental antisense oligonucleotides (ASOs) for free, for life, to patients with nano-rare mutations that are amenable to ASO treatment. In this perspective, we provide an overview of the n-Lorem processes and systems, the characteristics of the first 329 patients who have applied for treatment for whom initial assessment was completed and suitability for ASO treatment determined, and a summary of the results of ASO treatment for patients treated to date. Detailed data on individual patients and the overall clinical safety and tolerability profiles of the ASOs for which there are clinical data are the subjects of other manuscripts.

Abstract Background The amygdala is closely connected to the olfactory bulb and involved in olfactory processing as well. It is a particularly susceptible region that accumulates a‐synuclein pathology in Parkinson's disease (PD). Our previous work revealed olfactory bulb gene alterations related to neuroinflammation, and neurotransmitter dysfunction to be associated with olfactory function. We aimed to extend this work and assess gene expression changes, affected pathways and co‐expression networks by transcriptomic profiling of the amygdala in subjects with and without clinicopathologically defined PD. Method Bulk RNA sequencing was performed on frozen human amygdala of 20 PD and 20 controls without dementia or any other neurodegenerative disorder, from the Arizona Study of Aging and Neurodegenerative Disorders. Result Differential expression analysis, corrected for age, sex and post‐mortem interval revealed 40 significantly differentially expressed genes (DEGs) in PD. Downregulated genes were mainly related to altered hemoglobin expression while upregulated genes included inflammatory markers and glutamine transporter. Significantly enriched pathways were involved in oxygen and carbon dioxide transport, cellular oxidant detoxification and regulation of glutamine secretion. Cell enrichment revealed these genes to be mainly expressed in neurons. Co‐expression network analysis using Weighted correlation network analysis (WGCNA ) subsequently identified four significant modules correlated with both PD and premortem olfactory dysfunction which were involved in pathways related to neuroinflammatory processes, mitochondrial, endoplasmic reticulum and lysosomal dysfunction. Conclusion These preliminary results suggest cellular alterations in the amygdala related to mitochondrial dysfunction, altered oxygen homeostasis, oxidative stress, inflammation as well as glutamatergic neurotransmitter dysfunction that may contribute to neurodegeneration in PD.

Background The efficacy of EVOKE therapy, a closed-loop spinal cord stimulation (SCS) system, has been demonstrated in a double-blinded randomized controlled trial (RCT). RCT evidence, however, may not be generalizable to clinical practice, while limitations of real-world evidence may affect its validity. The aim of this study was to evaluate the effectiveness of EVOKE therapy in routine clinical practice employing a rigorous data collection approach. Methods The ECAP study was a prospective, multicenter, single-arm, pragmatic study that enrolled SCS candidates with chronic, intractable trunk and/or limb pain in 22 US investigational sites. PROMIS-29 questionnaire and objective neurophysiological metrics were collected, and minimal clinically important differences (MCIDs) were used to characterize baseline dysfunction and response to EVOKE therapy both at trial end and maximal analgesic effect post-implant visit. Pre-specified subgroup analyses were conducted based on diagnosis. Results EVOKE therapy observed included a dose ratio of 1.3 and neural dose accuracy of 2.8 μV. Improvements of >1 MCID were observed for all domains and improvements of ≥2 MCIDs were observed for six of the seven domains. Improvements observed at trial end were maintained or improved at post-implant visit, with statistically significant improvement in holistic MCID (MD 0.2, 95% CI 0.1 to 0.4, p=0.004), and a significantly greater proportion of patients considered holistic MCID responders (p=0.047). Subgroup analysis by diagnosis showed similar outcomes. Conclusions EVOKE therapy was associated with clinically meaningful improvements in a real-world chronic pain population across different subgroups and disease pathologies, with effects observed at trial end reproduced at post-implant visit.

Introduction Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA) used to treat type 2 diabetes mellitus (T2D), has potential associations with higher rates of diabetic retinopathy (DR) complications including proliferative DR (PDR) and diabetic macular edema (DME). The purpose of this study was to determine whether an association exists between semaglutide and PDR and treatment-requiring DR/DME. Research design and methods This was a retrospective cohort study of 14 databases (six administrative claims and eight electronic health records) in the Observational Health Data Sciences and Informatics Evidence Network. Adults with T2D on semaglutide, other GLP-1RA (dulaglutide, exenatide), or non-GLP-1RA medications (empagliflozin, sitagliptin, glipizide) from 1 December 2017 to 31 December 2023 were included. The association between semaglutide and PDR or treatment-requiring DR/DME was assessed using an active-comparator cohort design comparing new users of semaglutide as second-line T2D treatment to those on other GLP-1RAs and non-GLP-1RAs. Propensity score-adjusted Cox proportional hazards models were used to estimate hazard ratios (HRs). Network-wide HR estimates were generated using a random-effects meta-analysis. Results The study included 810 390 new semaglutide users for T2D. PDR risk for semaglutide was similar to dulaglutide (HR 0.81, 95% CI 0.42 to 1.54, p=0.51), empagliflozin (HR 0.83, 95% CI 0.53 to 1.30, p=0.41) and sitagliptin (HR 0.83, 95% CI 0.45 to 1.55, p=0.57) but was lower than glipizide (HR 0.59, 95% CI 0.39 to 0.88, p=0.01). The risk for treatment-requiring DR/DME for semaglutide was similar to empagliflozin (HR 0.66, 95% CI 0.43 to 1.02, p=0.06) but lower than dulaglutide (HR 0.53, 95% CI 0.31 to 0.91, p=0.02), sitagliptin (HR 0.46, 95% CI 0.26 to 0.81, p=0.008) and glipizide (HR 0.55, 95% CI 0.33 to 0.91, p=0.02). Conclusions and relevance We did not identify increased risk for either PDR or treatment-requiring DR/DME comparing semaglutide with other GLP-1RAs or non-GLP-1RAs. Patients with T2D should still undergo close eye care follow-up, particularly when initiating new antihyperglycemic medications.

Background: There is little data available in infants on the extent to which inhalational anesthetics prolong the effects of neuromuscular blocking agents compared with intravenous agents. Here, we assessed the differences between the neuromuscular blocking effects (duration and recovery time) of a single dose of rocuronium during propofol vs. sevoflurane anesthesia. Methods: The prospective study enrolled 20 infants (4–12 months of age) scheduled for craniosynostosis surgery, randomly assigned to receive general anesthesia maintenance with sevoflurane or propofol. All patients received 0.6 mg/kg rocuronium as a single bolus dose to facilitate tracheal intubation and surgery. Primary study endpoint was the clinical duration of rocuronium, from administration until spontaneous recovery to a train-of-four ratio (TOFR) > 0.90. Secondary endpoints were times for reappearance of the first, second, third, and fourth twitches of the TOF (T1, T2, T3 and T4, respectively) in the two patient groups. Results: There were no differences in the infants’ age (sevoflurane maintenance: 5.8 ± 2.4 months; propofol maintenance: 6.7 ± 3.1 months, p = 0.47) or weight (sevoflurane: 7722 ± 1644 g; propofol: 7433 ± 1782 g, p = 0.71). Rocuronium onset time was 101.0 ± 55.0 s in the sevoflurane group and 83.4 ± 47.9 s in the propofol group (p = 0.46). Total duration of anesthesia was comparable in the sevoflurane (122.0 ± 23.8 min) and propofol (107.7 ± 25.2 min, p = 0.18) groups. Rocuronium recovery to TOFR > 0.9 required 136 min (CI: 123.7–149.5 min) in the sevoflurane group and 61.5 min (CI: 58.0–101.0 min) in the propofol group (p < 0.001). Conclusions: In infants, sevoflurane maintenance enhances the neuromuscular blocking effect of a single, 0.6 mg/kg BW dose of rocuronium as compared to propofol maintenance. After discontinuation of sevoflurane, additional time is necessary to reach the acceptable TOFR >0.9 needed before tracheal extubation. The present study further underscores the importance of objective (quantitative) neuromuscular monitoring in infants to guide intraoperative management and prevent residual neuromuscular block.

Background & Aims: The clinical course and outcomes of alcohol-associated hepatitis (AH) remain poorly understood. Major adverse liver outcomes do not capture the added risk of return to drinking. We examined the natural history of AH and developed a composite endpoint using a contemporary observational cohort of AH. Approach & Results: A cohort of 1127 participants: 712 AH patients, 256 heavy drinking controls without clinically evident liver disease, and 159 healthy controls, were prospectively followed for 6 months at 8 United States centers as part of the Alcoholic Hepatitis Network (AlcHepNet) consortium. Outcomes included mortality and a composite endpoint (AlcHepNet composite index) that included death, liver transplantation, hepatic decompensation (new onset/worsening ascites, HE, variceal bleeding), liver-related hospital admission, MELD increase ≥5, and return to drinking. Of 712 AH patients (age 45±10.7 y; 59.1% male), 558 (79.0%) had severe and 148 (21.0%) had moderate AH, 232 (32.5%) died, and 86 (12.1%) underwent liver transplantation. Mortality rates in moderate AH and severe AH were 0.7% versus 17.2% (30 d), 3.4% versus 26.5% (90 d), and 8.8% versus 30.5% (180 d), respectively (all p <0.001). Composite liver/alcohol use events were noted in 459 (64.5%) AH patients. Higher MELD score, lower mean arterial pressure, and baseline leukocytosis were associated with higher 90-day mortality in AH (all p <0.05). College education and higher ALP were associated with lower mortality. Heavy drinking controls had low mortality (n=3; 1.2%). Conclusions: This large observational study showed a high incidence of composite liver and alcohol-use events within 6 months, reiterating the need for early interventions.

Background: How parental alcohol use disorder and liver disease-related mortality influence the risk and the outcomes of alcohol-associated hepatitis (AH) in the offspring is unknown. Methods: We analyzed data from 2 prospective observational studies of AH cases and heavy drinking controls (HDCs). Family history of parental alcohol use disorder and liver disease mortality was assessed at the study entry. Logistic regression and Cox proportional hazard models were used to assess the influences of family history on AH development and outcome. Results: Data from 1356 participants in two prospective cohorts (926 AH cases and 430 HDC) were combined and analyzed. Parental alcohol use disorder was found in 56.9% of AH cases and 61.1% of HDC; parental death due to liver disease was reported in 7.5% of AH cases and 5.7% of HDC. Multivariable logistic regression showed that parental liver disease-related mortality was associated with more than a doubled risk of AH development in the offspring after controlling for their demographic characteristics and drinking behavior (OR=2.26, 95% CI: [1.22, 4.20]). Moreover, among the AH cases, having a parent die of liver disease significantly increased the 90-day mortality of study participants after adjusting for the effects of other risk factors (HR=2.26, 95% CI: [1.05, 4.86]). Conclusions: The study highlights the influences of parental death due to liver disease on AH development and mortality. Identifying patients at risk of AH through family history might help facilitate discussions on reducing alcohol consumption.