Metabolic syndrome (MetS) comprises a cluster of interconnected metabolic abnormalities that collectively elevate the risk of cardiovascular disease and mortality. With its global prevalence escalating, understanding the molecular underpinnings of MetS has become increasingly imperative. Protein arginine methyltransferases (PRMTs), classically studied for their epigenetic functions and oncogenic properties, are now recognized as pivotal regulators of metabolic homeostasis. Emerging research reveals that these enzymes coordinate crucial aspects of cellular metabolism through multiple mechanisms, including methylation of metabolic transcription factors, modulation of nutrient-sensing pathways, and direct regulation of enzymatic activities in glucose and lipid metabolism. This review summarizes current knowledge on the metabolic roles of PRMTs, specifying their roles in the development and function of major metabolic tissues and their associations with various metabolic disorders. We further review how PRMTs influence metabolic processes by modifying key transcriptional networks and signaling cascades through methylation of different substrates. By integrating these insights, we establish PRMTs as central players in metabolic regulation and assess their potential as therapeutic targets for metabolic diseases beyond their established roles in cancer biology, thereby providing a framework for future research and clinical development.

Varicocele remains the most common potentially correctable cause of male infertility. Data from clinical guidelines, systematic reviews, meta-analyses, and original studies on the clinical and economic efficiency of varicocele treatment are summarized in this review. In men with clinical varicocele and impaired spermatogenesis, surgical repair improves semen parameters, including the number of progressively motile spermatozoa, and increases the likelihood of natural pregnancy. Before assisted reproductive technologies (ART), surgery is associated with higher clinical pregnancy and live birth rates and may be economically beneficial by improving ART efficacy. In men with severe oligozoospermia, microsurgery may allow some patients to proceed to intrauterine insemination or postpone IVF/ICSI. In non-obstructive azoospermia (NOA), surgery may result in the appearance of spermatozoa in the ejaculate and increase the likelihood of successful sperm retrieval by micro-TESE; however, no consistent economic advantage of a "surgery-first" strategy over immediate micro-TESE+ICSI has been demonstrated. Antioxidant therapy moderately improves semen parameters and reduces sperm DNA fragmentation, but its effect on clinical pregnancy and live birth remains insufficiently established. Among the available techniques for varicocele repair, microsurgical subinguinal varicocelectomy demonstrates the most favorable profile in terms of efficacy, safety, and recurrence rates. Laparoscopic and endovascular techniques remain valid alternatives, whereas robot-assisted and exoscopic technologies require further evidence regarding their clinical and economic efficiency. Overall, the evidence base remains heterogeneous; large prospective studies with clinical pregnancy and live birth as endpoints are required to clarify the effectiveness and cost-effectiveness of different approaches.

Transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) therapies include both TTR gene silencers and TTR stabilizers. The role of TTR gene silencers added to background TTR stabilizer therapy is unknown, and the effects of silencer treatment in the absence of stabilizer use is unclear. In the CARDIO-TTRansform study, 1,432 patients, (n=135 [9.4%] female and n=1297 [90.6%] male), with ATTR-CM were randomized (1:1) and treated with the antisense oligonucleotide eplontersen (45 mg every 4 weeks) targeting TTR or with placebo for up to 140 weeks. Fifty-seven percent of patients were taking TTR stabilizers at baseline. In the overall study, treatment with eplontersen did not significantly reduce the primary composite endpoint. Here, in a prespecified analysis, we show that the primary endpoint (a composite of cardiovascular mortality and recurrent cardiovascular events) was modified by baseline stabilizer use (P_interaction = 0.017). Benefit was seen in those patients not on stabilizers at baseline (RR 0.71, 95% CI, 0.54-0.93, P = 0.012), whereas no benefit seen in those on stabilizers at baseline (RR 1.14, 95% CI, 0.85-1.53, P = 0.39). The safety profile of eplontersen was favorable, irrespective of baseline stabilizer use. Treatment with eplontersen versus placebo demonstrated a clinically meaningful benefit among patients not receiving background stabilizers but provided no additional clinical benefit in those on background stabilizer therapy. These findings of a strong treatment effect modification may offer insight for therapeutic decision-making in clinical practice. ClinicalTrials.gov registration: NCT04136171.

This 2026 consensus report from the European Association for the Study of Diabetes (EASD) and the American Diabetes Association (ADA) builds on the 2021 consensus report to provide guidance for managing type 1 diabetes in adults. Reflecting the rapid advances in the field, this update places particular emphasis on the integration of new technologies, while all sections have been revised to incorporate new evidence, advances in clinical practice, and novel therapies, including interventions to delay the onset of stage 3 type 1 diabetes. It also broadens its scope to screening for long-term diabetes complications, and the management of obesity and cardiovascular risk factors. Psychosocial care and diabetes self-management education and support (DSMES) remain key elements.

Objective: To analyze the clinical characteristics, diagnosis, and treatment of infectious endocarditis (IE) with septic pulmonary embolism (SPE) in children. Methods: A case series study was conducted. Clinical data of 10 children with IE complicated by SPE admitted to the Department of Cardiovascular Medicine, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine from January 2023 to September 2025 were analyzed. The detection rates of three pathogen detection methods, including blood culture, metagenomic next-generation sequencing (mNGS), and vegetation culture, were compared. The clinical diagnosis, treatment, and follow-up outcomes were summarized. Results: Among the 10 children, there were 3 males and 7 females, with an age at presentation of 8.5 (6.6, 11.0) years. Congenital heart disease was present in 9 cases, and intracardiac implants were present in 4 cases. The main clinical manifestations included fever in 10 cases, cough in 4 cases, dyspnea in 4 cases, and chest pain in 3 cases. Six cases had dental caries. A total of 10 pathogens were detected in 9 children, including 2 fungi, 7 bacteria, and 1 Coxiella burnetii. Blood culture was positive in 7 cases, mNGS was positive in 8 cases, and vegetation culture was positive in 4 cases. Echocardiography revealed right-sided vegetations in all cases, and cardiac CT angiography showed multiple pulmonary lesions, including pulmonary artery filling defects, patchy opacities, and streaky shadows. Nine children underwent surgical treatment, and the duration of antimicrobial therapy was 3.0 (2.5, 8.0) months. Under multidisciplinary management, 4 cases were cured, 5 cases improved, and 1 case was under control at discharge. After 6 months of follow-up, pulmonary lesions resolved in 9 cases, and valvular regurgitation improved in 8 cases. Conclusions: Embolization of right-sided IE vegetations is an important cause of SPE in children. Adjunctive mNGS testing, when required, contributes to a higher pathogen detection yield in patients with IE.For right-sided IE, early surgical intervention is often required in addition to antimicrobial therapy.

Disruption of MYBPC3 precursor mRNA splicing is a frequent genetic cause of hypertrophic cardiomyopathy (HCM). Most often, it reflects changes at canonical sites or the creation of novel splice sites. Prediction tools usually prioritize splice variants with lower efficiency when they are distant from canonical sites. These elusive variants may explain HCM in patients considered genotype-negative after DNA testing.

Massively parallel sequencing identified the previously unreported deep-intronic variant MYBPC3 c.2308+227G>A in a cohort of genotype-negative patients with HCM from Salamanca, Spain. SpliceAI predicted a benign effect (Δ score, 0.03). However, its recurrent detection prompted us to conduct extensive analyses to investigate its pathogenicity, including genetic testing, clinical assessment, family studies, splicing assays, and haplotype reconstruction.

We identified 35 unrelated HCM probands carrying c.2308+227G>A, plus 46 relatives from 27 families, yielding 81 confirmed carriers. Of these, 56 (69%) met diagnostic criteria for HCM (66% male; mean age, 53±15 years). By age 60 years, cumulative penetrance was estimated to be 81% in women and 96% in men. The combined logarithm of the odds score of 5.51 across 20 informative families provided strong evidence of cosegregation. During follow-up of probands, no significant differences were observed in heart failure, arrhythmic events, atrial fibrillation, or mortality when compared with cohorts carrying other pathogenic MYBPC3 variants. Blood splicing assays, confirmed in cardiac tissue, showed that c.2308+227G>A disrupts splicing by the use of pre-existing cryptic donor (c.2308+299) and acceptor (c.2309-580) splice sites, generating 2 misspliced mRNAs with partial intron retention or cryptic exon inclusion, which encode truncated proteins. These cryptic sites are the leading natural, unannotated missplicing events in intron 23, and some of the most frequent across the whole MYBPC3 precursor mRNA, as revealed by SpliceVault analysis of RNA sequencing databases. This deep-intronic variant does not alter essential splice motifs but promotes the use of pre-existing cryptic sites, likely through gain of splicing regulatory enhancer elements. The identification of a shared haplotype among HCM probands carrying this variant explains its recurrent detection, consistent with an ancient founder effect.

MYBPC3 c.2308+227G>A is a pathogenic splice-altering variant that causes HCM by amplifying natural missplicing events. These background splicing errors help explain how this elusive variant disrupts splicing without creating novel essential splice sites, thereby expanding the known mechanisms by which deep-intronic variants alter MYBPC3 splicing and ultimately contribute to HCM pathogenesis. Elusive MYBPC3 splice-altering variants should be considered in HCM patients with an unresolved genetic origin of disease.

Tourniquet-associated lower limb ischemia-reperfusion can induce skeletal muscle inflammation, edema, and early functional impairment, in which autophagy dysregulation may be involved. The present study was designed to investigate the effects of esketamine (ESK) on skeletal muscle injury following lower limb ischemia-reperfusion in mice and its relationship with autophagy regulation. A mouse model of left hindlimb ischemia for 3 hours followed by 24 hours of reperfusion was established, and changes in hindlimb perfusion, functional outcomes, tissue injury, inflammatory response, and autophagy-related markers were examined after intervention with ESK alone or in combination with chloroquine phosphate (CQ). The results showed that ESK attenuated the abnormally elevated perfusion after reperfusion, improved motor performance and partial muscle contractile function, yet exerted limited effects on mechanical pain threshold and nerve stimulation-induced muscle contraction. Concurrently, ESK alleviated histological damage, edema, and sarcolemmal integrity disruption in the gastrocnemius muscle, reduced serum Tumor Necrosis Factor-alpha and Interleukin-6 levels, and downregulated the expression of several inflammation-related genes. With respect to autophagy, ESK increased the microtubule-associated protein 1 light chain 3 II/I ratio while decreasing sequestosome 1 levels and the phosphorylated mechanistic target of rapamycin/total mechanistic target of rapamycin ratio; these protective effects were partially abrogated by CQ. Collectively, these findings indicate that ESK mitigates acute-phase skeletal muscle injury and improves selected early functional outcomes after lower limb ischemia-reperfusion in mice, and that its protective actions may be associated with suppression of inflammation and modulation of autophagy.

Pathogenic variants in RBM20 cause severe dilated cardiomyopathy. Loss-of-function variants disrupt splicing; neomorphic gain-of-function (GoF) variants also mislocalize RBM20 to cytoplasmic ribonucleoprotein granules and are associated with more aggressive disease. The mechanism by which RBM20 mislocalization drives cardiac dysfunction remains unknown.

We investigated the effects of Rbm20 GoF and loss-of-function (LoF) variants using proteomic profiling, protein solubility assays, mitochondrial respiration and calcium flux analyses, and ultrastructural imaging in mouse models. Human induced pluripotent stem cell-derived cardioids were used to validate variant-specific phenotypes.

Rbm20 GoF, but not LoF, variants caused posttranscriptional downregulation of soluble mitochondrial proteins, including the calcium efflux regulator TMEM65 (transmembrane protein 65), and reduced solubility of mitochondrial membrane proteins. Electron microscopy revealed enlarged mitochondria with cristae disorganization. Functional assays confirmed impaired oxidative phosphorylation, reduced mitochondrial membrane potential, and abnormal calcium handling in Rbm20 GoF models. Human cardioids reproduced these findings, demonstrating that cytoplasmic mislocalization, rather than splicing deficiency, drives mitochondrial dysfunction.

Cytoplasmic mislocalization of RBM20 disrupts mitochondrial function by reducing mitochondrial protein abundance, leading to oxidative phosphorylation failure and abnormal mitochondrial calcium handling. This mechanism distinguishes RBM20 GoF from LoF variants and may explain the more severe heart failure phenotype observed in patients with RBM20 GoF variants. These insights advance the mechanistic understanding of RBM20-related cardiomyopathy and identify mitochondrial mRNA/protein regulation as a key node in cardiac energetics.

Existing adolescent pregnancy prevention programs have demonstrated modest effects. Evaluation is needed for interventions aimed at improving intermediary outcomes linked to behaviors associated with adolescent pregnancy prevention, including intentions, communication skills, decision-making skills, access to information, and supportive adult relationships. These intermediary outcomes often serve as mechanisms that decrease sexual behaviors associated with unintended pregnancy and sexually transmitted infection risk and enhance understanding of how interventions influence behavior. The United States federal government announced a funding cycle aimed at assessing innovative programs for underserved youth. As one of the 12 grantees, we will evaluate Using the Connect (UTC), a novel game-based learning intervention offering opportunities to improve participants' intention to delay sex, skills related to communication, decision-making, and accessing information, and strengthen their connection to a trusted adult.

Our article describes the clustered randomized controlled trial protocol to assess the effectiveness of UTC on middle-school youths' intention to delay sex, individual-level skills (communication, decision-making, and accessing information), and perception of connection to a trusted adult.

This multi-site trial had planned enrollment for 1,150 youth ages 10-14 years from 46 community-based organizations in Texas, Alabama, and Illinois. Sites will be randomized to either UTC or business-as-usual control consisting of routine youth programming (e.g., physical activity, career education, and mental health awareness). UTC consists of four interactive games, one wrap-up activity, and one take-home activity focused on communication, decision-making, accessing sexual health information and resources, and strengthening connections with trusted adults. Participants will complete electronic surveys at baseline, immediate post-test, 3-month follow-up, and 9-month follow-up. Outcomes will be assessed using adapted survey measures of intention to delay sexual intercourse, communication skills, decision-making skills, skills to access sexual health information and resources, and perceived connection to trusted adults. To decrease attrition, we will use an evidence-based retention model. We will conduct sensitivity analyses to assess the robustness of findings.

Funding was received in September 2021 through the Personal Responsibility Education Innovative Strategies (PREIS) funding opportunity within the Personal Responsibility Education Program of the Department of Health and Human Services. Site recruitment and enrollment began in June 2023. Between June 15, 2023, and May 31, 2025, 1,338 youth have been enrolled in the study. Follow-up data collection was completed in April 2026. As of July 2026, all study activities have concluded, and data from 1,231 participants were included in the final analysis, which is being completed. The final evaluation report will be submitted by September 2026. Findings will be disseminated through scientific conferences and peer-reviewed publications.

This study will evaluate and contribute evidence regarding a novel, game-based intervention to strengthen protective factors associated with adolescent pregnancy prevention in middle school-aged youth.

This trial was registered at ClinicalTrials.gov (NCT05927194) on June 6, 2023.

Online mental health services (MH) are playing a pivotal role by increasing MH literacy, enabling accessibility, and reducing logistical barriers, especially for women from developing nations like Bangladesh. However, the psychological burden and service needs of women using online MH platforms remain understudied despite their heightened vulnerability. Therefore, this study investigated the prevalence and determinants of anxiety and depression among women who received counseling from the online MH service platform,Women Support Initiative Forum (WSIF)through a cross-sectional study conducted between 5th September 2023 and 26th August, 2024. Data were collected by WSIF psychologists using a structured client information form covering socio-demographics, history of MH condition, health conditions, and presenting MH symptoms. Anxiety and depression levels were assessed using the Generalized Anxiety Disorder-7 (GAD-7) and Patient Health Questionnaire-9 (PHQ-9). Multivariate logistic regression was used to identify associated factors. Out of 375 women, 59.2% and 58.1% had experienced mild to severe anxiety and depression, respectively, with 25.6% having both conditions. Women with graduate-level education had 66% lower, and those with one or more siblings had 50-54% lower likelihoods of anxiety compared with women without graduate-level education and siblings. In contrast, women with graduate-level or postgraduate-level education and reporting hormonal conditions had 3.41 times, 2.63 times and over 10 times higher likelihoods of depression, respectively, compared with women who were not graduates and without a hormonal condition. Conversely, women with a history of MH and reported migraine, headache and allergic conditions had 52% and 65% lower odds compared with women without these conditions. Distress, negative thinking, and feelings of worry were highly prevalent among women with anxiety and among those with depression. Our findings highlight a significant MH burden among women who accessed online psychological counseling, indicating the importance of targeted actions in designing MH interventions by relevant stakeholders and policymakers.