Trimethylamine N-oxide (TMAO) and its related metabolites have been linked to cardiovascular disease (CVD), but their impact on DNA methylation remains unclear. Investigating these relationships may clarify the role of epigenetic mechanisms in diseases. This study analyzed data from 1,356 adults from the Cardiovascular Health Study (CHS) and the Multi-Ethnic Study of Atherosclerosis (MESA). Using stable-isotope dilution liquid chromatography with on-line electrospray ionization tandem mass spectrometry (LC–MS), we quantified TMAO and five related metabolites. DNA methylation levels were measured using Illumina BeadChip arrays. Epigenome-wide association analyses and meta-analyses were conducted across approximately 430,000 CpG sites. To explore the functional significance of the identified CpGs, we performed gene set enrichment analysis and Mendelian randomization (MR) analyses. We identified 143 metabolite-CpG pairs at FDR < 0.05, including four CpGs for TMAO (P ≤ 4.03e-7), 12 for betaine (P ≤ 1.19e-6), 53 for γ-butyrobetaine (P ≤ 6.11e-6), five for carnitine (P ≤ 5.42e-7), six for choline (P ≤ 2.81e-7), and 63 for crotonobetaine (P ≤ 7.25e-6). CpGs associated with γ-butyrobetaine showed moderate correlation with crotonobetaine-associated CpGs. In total, these metabolite-linked CpGs were mapped to 108 genes. Gene set enrichment analysis revealed 145 significantly enriched gene sets, including nine highly relevant to CVD risk. Furthermore, CpGs were enriched in 80 immunologic signature gene sets (FDR < 0.05). MR analysis identified three CpGs associated with coronary artery disease (CAD), including hypermethylation at cg18705301 (NDUFAF1), which was inversely associated with betaine levels and linked to a lower risk of CAD (P = 1.8e-5). This study identified specific DNA methylation sites associated with TMAO and related metabolites. These epigenetic changes may contribute to CVD risk through multiple pathways. Future research should validate these findings and explore their clinical implications.
Background: Chronic intestinal failure is a devastating rare disease in which patients require complex and life-saving parenteral nutrition or intravenous fluids delivered through a central venous catheter. There is a shortage of clinical expertise to manage chronic intestinal failure and patients in the United States lack access to the limited number of expert care centers. We developed a patient intestinal failure (PIF) ECHO intervention with patient advocates who have lived experience with the goal of connecting patients and family caregivers virtually to multidisciplinary intestinal failure experts for best practice learning. Objective: We pilot-tested the acceptability and feasibility of a direct-to-patient telelearning program based on the well-established ECHO Model focused on best practices in chronic intestinal failure care. Setting and Participants: 19 adults with chronic intestinal failure attended the pilot PIF-ECHO program for 12 consecutive weeks via Zoom between April and July 2026. All participants completed the post intervention questionnaire and 16 individuals participated in 3 focus groups. Design: A mixed methods evaluation was conducted. Questionnaires were assessed according to seven domains of the Theoretical Framework of Acceptability and qualitative data from the virtual focus groups were coded and analyzed using iterative thematic analysis. A data-derived PIF-ECHO logic model was developed to illustrate pathways between the program content and anticipated outcomes. Results: There was strong or very strong agreement that sessions were accessible, enjoyable, worth the time spent, and improved understanding of intestinal failure and its management. Information learned increased confidence for self-advocacy in navigating healthcare needs, disease and therapy self-management, and improved well-being. Interaction with facilitators, expert presenters, and peers was positive, judgement free, validating, and respectful. Participants felt empowered and reported lower levels of emotional strain due to the supportive resources and knowledge gained. Conclusions: A patient-facing tele-learning program in chronic intestinal failure is feasible, accessible, and acceptable to patients and appears to result in important short-term and medium-term benefits. The program was perceived as valuable and notably different from patient and peer-led support groups. The model could be applied more widely to other rare diseases. Lived Experience and Patient Contributions: Four patient advocates with lived experience in chronic intestinal failure were involved throughout the study including pre-study interviews and focus groups to inform PIF-ECHO design and content, recruitment, as presenters on topics of self-advocacy and role of patient support groups, and in the analysis and refinement of the program logic model. Their input shaped the relevance and acceptability of the PIF-ECHO pilot program. All four patient advocates fulfil uniform requirements for authorship and are co-authors on this paper. This work documents a meaningful partnership in the creation of a patient-facing virtual tele-learning adaptation of the ECHO model and establishes a valuable collaboration for future study of PIF-ECHO on a larger scale. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial Not registered - limited pilot telelearning intervention ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The protocol was approved by BRANY IRB with letter number STUDY-24-01292 dated November 12, 2025. and by the New York Academy of Medicine Institutional Review Board (IRB). with the letter number #011426 dated January 20, 2026. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors Agency for Healthcare Research and Quality, 1R03HS030321-01
BackgroundThe potential for implementation science (IS) to address health inequities is limited by insufficient attention to power. Although the field emphasizes context, it remains unclear how best to examine and intervene on power relations related to the implementation of evidence-based interventions (EBIs). This scoping review aimed to determine: 1) To what extent do research projects studying EBI implementation explicitly examine power? 2) In these studies, how is power conceptualized, defined, operationalized, and understood? 3) What opportunities exist to examine and intervene upon power through IS research?MethodsFollowing established procedures, we undertook a six-step process: 1) articulating research question and purpose; 2) identifying relevant studies; 3) selecting studies; 4) extracting data; 5) summarizing data; and 6) reporting results. We characterized studies' attention to power using Fung's power framework, which attends to everyday, policy, structural, and ethical power. Based on publications available as of February 2022, we included English-language EBI implementation studies from clinical, community, and public health settings that explicitly attended to power. Data extraction included study context, IS frameworks used, definitions and measures of power, and characterizations of how power influenced implementation processes and outcomes.ResultsOf 3,531 articles screened, 28 papers explicitly discussed power in relation to EBI implementation and 11 presented a formal definition of power. Most studies explored everyday and structural power, with far less attention to policy power and almost none to ethical power. Conceptualizations and operationalizations of power varied widely, and few studies reported grounding in IS frameworks. Explicit strategies to intervene upon power were limited. Most studies focused on short-term integration goals, with limited discussion of how power dynamics shape what counts as evidence, whose interests are served, or opportunities for systems transformation.ConclusionsResearchers have the opportunity to explicitly integrate power theories and frameworks into conceptual models for IS studies to reshape IS efforts and build this evidence base. This will allow the field to move towards critical, systems-focused perspectives that examine how power shapes and can be used to reshape the evidence base, implementation systems, implementation strategies, and implementation, health, and system outcomes.
OBJECTIVE:The role of parental preconception trauma in the pathogenesis of psychiatric disorders remains unclear. The authors investigated whether offspring of Holocaust survivors, born years later, are at increased risk of schizophrenia. METHODS:Data from the Jerusalem Perinatal Study (1964-1976) were linked to Israel's National Psychiatric Registry. Parents from European countries under Nazi rule who immigrated to Israel after the anti-Jewish persecutions began were classified as exposed. Parents were further categorized by their own age (≤5 or >5 years) when the persecutions began. Unexposed parents were of European descent not living under Nazi rule. Two offspring subsamples were assembled: 14,759 offspring of 7,316 mothers and 18,085 offspring of 8,833 fathers, of whom 3,913 had exposed mothers and 5,672 had exposed fathers. For each offspring subsample, Cox models were used to analyze time to first schizophrenia hospitalization. RESULTS:In minimally adjusted models, offspring of parents who were older than age 5 at exposure showed elevated schizophrenia rates (maternal exposure: hazard ratio=2.71, 95% CI=1.60-4.61; paternal exposure: hazard ratio=1.52, 95% CI=1.01-2.28). No associations were observed in offspring whose parents were exposed earlier (≤5 years). Adjustments for sociodemographic variables diminished the association of paternal exposure at age >5, whereas association with maternal exposure remained strong (hazard ratio=2.38, 95% CI=1.20-4.70) and withstood further adjustments for mother's psychiatric hospitalization (hazard ratio=3.73, 95% CI=1.87-7.43) and other covariates. CONCLUSIONS:Offspring of mothers who were older than age 5 when Nazi persecutions began showed over a twofold increase in schizophrenia risk, underscoring the potential impact of trauma and its timing during the preconception period in the pathogenesis of schizophrenia.
