Citations

Abstract The impact of early-life traumatic experiences on late-life morbidity remains partly unknown. We tested the hypothesis that adverse childhood experiences (ACE) and specifically abuse (physical, verbal or emotional, or sexual) experienced during childhood or early adulthood are associated with a higher rate of accumulation of multi-morbidity in women. Here we show strong evidence in support of the hypothesis. We studied 1,026 women aged 21–45 years randomly selected from the general population in Olmsted County, Minnesota and used the Rochester Epidemiology Project medical records-linkage system to measure the rate of development of 18 chronic conditions. The women had a median age of 41 years at inclusion in the study and were followed historically for a median of 21 years. Women with an ACE score ≥ 2 had higher incidence of 10 of the 18 chronic conditions considered separately and an accelerated accumulation of multi-morbidity measured as a score compared to women with ACE score 0. In addition, women exposed specifically to abuse in childhood or early adulthood had accelerated accumulation of multi-morbidity. We excluded the possible confounding effect of socioeconomic status and explored a series of possible mediation events or characteristics. We discuss several possible biological and social or behavioral mechanisms underlying these associations.

Abstract Allogeneic hematopoietic cell transplantation (allo-HCT) is potentially curative for older adults with hematologic malignancies. Concerns on nonrelapse mortality (NRM) in older adults limit allo-HCT utilization. We executed a prospective, observational study BMT-CTN 1704 (Blood and Marrow Transplant Clinical Trials Network) enrolling allo-HCT recipients aged ≥60 years from 49 centers in the United States. We analyzed associations between 13 measurements of older adult health and NRM within 1 year to construct a comprehensive health assessment risk model (primary-CHARM) using multivariate Fine-Gray model and grouped penalized variable selection. Two machine learning (ML) models (Cox and pseudo-value boosting) were also explored. Models’ performances were compared using area under the curve (AUC), with bootstrap and cross-validation sampling to correct for optimism, decision curve analysis (DCA), calibration, and Brier scores. Among 1105 patients with median age of 67 (range, 60-82) years who received allo-HCT, NRM was 14.4% and overall survival (OS) 71.7% at 1 year. Factors statistically selected for inclusion in primary-CHARM were higher comorbidity burden, lower albumin, higher C-reactive protein, older age, higher weight-loss percentage, lower patient-reported performance score, and cognitive impairment. Primary-CHARM scores were independently associated with higher NRM (hazard ratio [HR], 2.72; P < .0001) and worse OS (HR, 2.09; P < .0001). Bootstrap bias–corrected AUC for primary-CHARM was 0.591. Comparing primary-CHARM with HCT-comorbidity index and 2 ML-CHARM models, calibration, Brier score, and DCA analysis favored primary-CHARM. Primary-CHARM, with mostly simple and readily available parameters, risk stratifies older adults for allo-HCT. Adopting primary-CHARM in practice may promote broader use of HCT by quantifying risk and enhance the design of strategies to improve outcomes. This trial was registered at www.ClinicalTrials.gov as #NCT03992352.

ABSTRACT Background Mitral annular disjunction (MAD) carries an increased risk of complex ventricular arrhythmias, which can lead to sudden cardiac death. Many of these patients undergo implantable cardioverter defibrillator (ICD) implantation, but their ICD outcomes are not known. Objective The aim of this study was to assess the outcomes of ICD implantation and the predictors of appropriate ICD therapies in patients with MAD. Methods The study included patients with MAD who underwent ICD implantation. Clinical, electrocardiographic, cardiac imaging, and device therapy data were collected. Results Forty‐nine patients with MAD and ICD were included. Median age was 49 (21) years, and 29 (59%) were female. 13 (27%) patients underwent ICD implantation for primary prevention and 36 (73%) patients for secondary prevention. Over a median follow‐up of 27.3 (35.3) months, 23 (47%) patients received ICD therapies. 18 (37%) patients had appropriate ICD therapies, and 5 (10%) patients had inappropriate ICD shocks. Median time to first appropriate therapy was 22.3 (63.3) months. In patients with a secondary prevention ICD indication, the rate of appropriate ICD therapies was 44%, while in patients with a primary prevention ICD indication, it was 15%. Among patients with appropriate ICD therapies, the first therapies were delivered for monomorphic ventricular tachycardia (VT) in 7 (39%) patients and polymorphic VT or ventricular fibrillation (VF) in 11 (61%) patients. Patients with appropriate ICD therapies were more likely to have a history of SCA ( p = 0.003) and/or low left ventricular ejection fraction (LVEF) ( p = 0.022) before ICD implantation as compared to patients without appropriate ICD therapies. Conclusions In our cohort of patients with MAD and ICD, appropriate ICD therapies were common. Most appropriate ICD therapies were delivered for polymorphic VT or VF. Larger studies are needed to elucidate the mechanisms of VAs and refine risk stratification in MAD.

Background and purpose: Aortic stenosis (AS) poses significant healthcare challenges, particularly in aging populations like Lebanon. Aortic valve replacement (AVR) is the primary treatment; however the choice between transcatheter aortic valve replacement (TAVR) and surgical AVR (SAVR) varies based on patient-specific factors. This study aimed to compare clinical outcomes between TAVR and SAVR in patients with severe AS at a Lebanese tertiary care center. Methods: This retrospective study included 453 patients aged ≥60 with severe AS who underwent either TAVR or SAVR at the American University of Beirut Medical Center from 2011 to 2022. Primary outcomes were 30-day mortality and hospital readmission rates. Secondary outcomes included length of stay, complications, and changes in echocardiographic parameters. Statistical analysis included Chi-squared tests, t-tests, and propensity score matching. Results: Of the 453 patients, 306 underwent TAVR, and 147 underwent SAVR, with a mean age of 79.0 ± 6.8 years. The TAVR group had higher Society of Thoracic Surgeons (STS) scores (4.7 ± 3.2 vs. 2.6 ± 1.7; P < 0.001). TAVR patients had shorter hospital stays (2 [0-93] vs. 6 [4-41] days; P < 0.001), lower 30-day readmission rates (8.2% vs. 18.5%; P = 0.002), and similar all-cause mortality rates (hazard ratio [HR]: 0.69; 95% confidence interval [95% CI]: 0.14–3.42; P = 0.647). Post-procedural new-onset left bundle branch block (LBBB) was more common in TAVR group (13.0% vs. 0.6%; P < 0.001), and new-onset atrial fibrillation (Afib) was more frequent in the SAVR group (34% vs. 1%; P < 0.001). There were no significant differences in the rates of complete heart block (CHB) or pacemaker implantation. The effective orifice area index (EOAi) was higher in the TAVR group (1.2 ± 0.4 vs. 0.9 ± 0.2 cm2/m2; P < 0.001). Major bleeding complications were significantly lower in TAVR patients (7.9% vs. 65.8%; P < 0.001), with no significant differences in neurological events. Conclusions: Both TAVR and SAVR show comparable safety and efficacy, with TAVR offering advantages in terms of recovery time and bleeding risk. These findings support a tailored approach to procedural choice based on individual patient risk profiles.

ABSTRACT Understanding lung cancer evolution can identify tools for intercepting its growth. In a landscape analysis of 1024 lung adenocarcinomas (LUAD) with deep whole-genome sequencing integrated with multiomic data, we identified 542 LUAD that displayed diverse clonal architecture. In this group, we observed an interplay between mobile elements, endogenous and exogenous mutational processes, distinct driver genes, and epidemiological features. Our results revealed divergent evolutionary trajectories based on tobacco smoking exposure, ancestry, and sex. LUAD from smokers showed an abundance of tobacco-related C:G>A:T driver mutations in KRAS plus short subclonal diversification. LUAD in never smokers showed early occurrence of copy number alterations and EGFR mutations associated with SBS5 and SBS40a mutational signatures. Tumors harboring EGFR mutations exhibited long latency, particularly in females of European-ancestry (EU_N). In EU_N, EGFR mutations preceded the occurrence of other driver genes, including TP53 and RBM10. Tumors from Asian never smokers showed a short clonal evolution and presented with heterogeneous repetitive patterns for the inferred mutational order. Importantly, we found that the mutational signature ID2 is a marker of a previously unrecognized mechanism for LUAD evolution. Tumors with ID2 showed short latency and high L1 retrotransposon activity linked to L1 promoter demethylation. These tumors exhibited an aggressive phenotype, characterized by increased genomic instability, elevated hypoxia scores, low burden of neoantigens, propensity to develop metastasis, and poor overall survival. Re-activated L1 retrotransposition-induced mutagenesis can contribute to the origin of the mutational signature ID2, including through the regulation of the transcriptional factor ZNF695 , a member of the KZFP family. The complex nature of LUAD evolution creates both challenges and opportunities for screening and treatment plans.

ABSTRACTObjectiveTo examine the outcomes of a clinical sample of young patients with restrictive eating disorders who received Family‐Based Treatment for Primary Care (FBT‐PC).MethodsParticipants were 134 youth (mean age = 15.7 years) and their caregiver(s). Participants and caregivers completed measures of eating disorder symptomatology, quality of life, and caregiver self‐efficacy.ResultsOf the 134 patients who received at least one session of FBT‐PC, 55.9% completed treatment, 20.1% were followed until they began a higher level of care, and 23.8% were non‐completers. Weekly measures for the full sample were evaluated using intention‐to‐treat analyses. Patient‐reported scores on the ED‐15 improved by −0.1 (SE = 0.02, F (1,133)= 26.4, p < 0.0001) per week, and caregivers' ratings of patient symptoms also improved by 0.85 (SE = 0.2, F (1,133)=13.1, p = 0.0003) per week. Patient's BMI percentile increased by 1.25 points per week (SE = 0.14, F (1,133) = 83.9, p < 0.0001). For patients who completed FBT‐PC, eating disorder symptoms, per patient‐ (M = −1.43, p < 0.0001) and caregiver‐report (M = −1.33 p < 0.0001) decreased significantly from baseline to end of treatment. Patient's quality of life increased significantly from baseline to end of treatment (M = 21.6, p < 0.0001) and caregivers showed significant increases in self‐efficacy (M = 3.41, p < 0.0001, d = 0.856). At the end of treatment, 62.5% of patients with complete data met criteria for full research remission, and 44.6% met criteria for full clinical remission.DiscussionFindings provide preliminary support for FBT‐PC as an effective treatment for youth with restrictive eating disorders. Additional research is needed to replicate these findings in other primary care settings and to understand the durability of treatment effects.

Aim Cognitive and behavioral phenomena define behavioral variant frontotemporal dementia (bvFTD), but neuropsychiatric symptoms (NPS) outside the core criteria are common throughout the illness. Identifying how NPS cluster in bvFTD may guide development of future therapies. Methods Participants ( n = 354) with sporadic and genetic bvFTD were enrolled in the ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration Consortium. Dementia stage was defined as early (CDR® plus NACC FTLD ≤1) or advanced (CDR® plus NACC FTLD ≥1). Baseline and annual follow‐up visit data were analyzed to compare NPS across stages of bvFTD. Psychiatric states were captured using the Neuropsychiatric Inventory‐Questionnaire and Clinician Judgment of Symptoms. Polychoric cluster analysis was used to describe NPS clusters. Results NPS were highly prevalent (≥90%) in early and late bvFTD. Four NPS clusters were identified based on magnitude of factor loadings: affective, disinhibited, compulsive, and psychosis. Neuropsychiatric symptoms fluctuated across visits. In the affective cluster, depression showed the least visit‐to‐visit stability. In the disinhibited cluster, elation showed the least stability. Symptoms in the psychosis and compulsive clusters (hallucinations, delusions, obsessions/compulsions, and hyperorality) were largely stable, persisting from visit‐to‐visit in more than 50% of cases. Symptoms in the affective and disinhibited cluster were associated with the highest caregiver burden, while symptoms in the obsessive cluster were associated with the most functional impairment. Conclusion NPS in bvFTD are frequent and cluster into four discrete groups. The fluctuating nature of some NPS in bvFTD suggests that they may not be reliable markers of disease progression or stage.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Pediatric Central Nervous System Cancers provide multidisciplinary diagnostic workup, staging, and treatment recommendations for diffuse high-grade gliomas and medulloblastomas in children and adolescents. This article summarizes the studies and panel discussion that serve as the rationale for comprehensive care recommendations included in the NCCN Guidelines for Pediatric Central Nervous System Cancers.

Objective: This study evaluated the feasibility and satisfaction of using a wearable brain activity sensing device for stress reduction among patients experiencing Long COVID (LC). Patients and Methods: Patients with LC (N = 45) were invited to participate in an open-label pilot study. Participants were asked to use a brain-sensing electroencephalogram (S-EEG) wearable device (Muse-S™) daily for 90 days and followed for an additional 90 days (180 days total participation). Study enrollment began June 28, 2022, and ended July 28, 2023. Results: Patients were predominantly female (82%), white (96%), and with an average age of 47.6 (±12.5) years. At the end of treatment (90 days), cognition, sleep, self-efficacy, and quality-of-life quality of life improved ( P < .001 to P = .04). In addition, stress and anxiety were significantly reduced ( P < .001). These significant changes persisted by end-of-study (180 days). For stress ( P = .023) and anxiety ( P = .033), a change from the baseline during follow-up was significantly associated with the amount of S-EEG usage. The end-of-study satisfaction survey indicated that patients were very satisfied with the S-EEG device, and 97% planned to continue using it. Conclusion: Results suggest that the S-EEG device improved cognition in LC, which is one of the main severe symptoms we see in our LC clinic. In addition, it helped reduce stress and anxiety. These findings have important clinical implications for LC patients using S-EEG as an adjunct to concurrent LC clinical care which includes pharmacotherapies.