Plant-derived exosome-like nanovesicles (PDEVs) are emerging as breakthrough platforms for the treatment of age-related diseases (ARDs). These endogenous nanocarriers contain a variety of bioactive molecules, including microRNAs, proteins, lipids, and phytochemicals, which play crucial roles in therapy. PDEVs have strong potential to treat chronic inflammation, oxidative stress, cellular senescence, and mitochondrial dysfunction, all of which are related to aging. Their pleiotropic effects support wide therapeutic applications in neurodegenerative, cardiovascular, and metabolic diseases; sarcopenia; cachexia; and skin ageing. PDEVs have several advantages over synthetic nanoparticles and mammalian exosome-like nanovesicles, including good biocompatibility, low immunogenicity, and excellent in vivo stability. Being of natural origin, they can be produced on a large scale at low cost, and drugs can be effectively delivered via various routes, including oral, intravenous, and intramuscular routes. However, translating PDEVs into the clinic presents several challenges, including mass production, batch-to-batch consistency, standardized isolation and characterization methods, and regulatory issues. By combining natural plant compounds with modern nanomedicines, safe, effective, and targeted therapies for complex ARDs can be developed. However, oral delivery faces key limitations due to gastrointestinal barriers, including acidic pH, enzymatic degradation, bile salts, and mucus layers, which can compromise vesicle stability and bioavailability. Variability in intestinal uptake and microbiota interactions further affects therapeutic consistency. Protective strategies, including encapsulation, enteric coating, and surface engineering, may enhance stability and absorption. Emerging approaches such as ligand-functionalized PDEVs, hybrid nanovesicles, and stimuli-responsive delivery systems offer safer and more precise therapeutic options, improving targeting, controlled release, and translational potential.

The natural history and response to tafamidis treatment in women with wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) remain insufficiently characterised. Current study aimed to explore sex-differences in clinical presentation, natural course and tafamidis treatment efficacy, focusing on women with ATTRwt-CM.

An international, multicentric cohort of ATTRwt-CM subjects was evaluated, including for all-cause mortality. In total 1454 patients were studied (mean age 81±7y), including 307 (21.1%) females. At presentation, females were ∼3 years older than males with slightly worse phenotype, including higher indexed left ventricular wall thickness and National Amyloidosis Centre (NAC) disease stage (p<0.050). Heart failure with preserved ejection fraction and hypertension coincided more often in women (p=0.001). Natural disease course was poor without sex-difference, even when age-corrected (p=0.210). Tafamidis was initiated in 1055 patients, 12% less in females (p<0.001), although reasons for non-initiation and discontinuation did not show heterogeneity by sex (p=0.116 and p=0.304, respectively), indicating structural undertreatment. After 1.9 (0.9-3.3) years of median follow-up, 409 (28.1%) patients died. Tafamidis related to lower mortality in the overall and propensity score-matched cohort (n=742, HR 0.44, 95%CI 0.32-0.61, p<0.001), without sex-difference (female HR 0.76, 95%CI 0.52-1.11, p=0.150) nor sex-based treatment efficacy interaction (p=0.381). NAC disease stages strongly related to mortality under tafamidis treatment (HR 2.13%, 95%, 1.81-2.50, p<0.001), but female sex did not (HR 0.82, 95%CI 0.53-1.27, p=0.365).

Women with ATTRwt-CM are prone to underdiagnosis and undertreatment, despite similar poor natural course and tafamidis treatment efficacy. Initiatives to increase diagnostic awareness and disease modifying treatment initiation in women are urgently needed.

Pw1, a maternally imprinted gene, is expressed in various stem cell populations, underscoring its crucial roles in tissue development, maintenance, and regeneration. While our recent work has revealed its regulatory function in cardiac fibrosis following ischemic injury, whether PW1⁺ cells exhibit stem cell properties in the heart remains unclear.

We utilized genetic lineage tracing with Pw1^pCreER/m+;R26-tdT and Pw1^p2A-CreER/m+;R26-tdT mouse models. The adipogenic and fibrogenic potential of PW1⁺ cells was assessed in vitro using sorted tdTomato⁺ cells subjected to differentiation assays. In vivo fate mapping was performed during postnatal development and after myocardial infarction (MI) induced by permanent coronary artery ligation. Single-cell RNA sequencing data from adult mouse hearts were reanalyzed to characterize Pw1 expression across cardiac cell types.

PW1 was expressed in multiple cardiac cell types-such as mesenchymal cells, epicardial cells, and endothelial cells-during early postnatal development. Isolated PW1⁺ cells from infant hearts differentiated into adipocytes in vitro, and lineage tracing experiments confirmed their significant contribution to cardiac adipocyte formation throughout postnatal development. Single-cell transcriptomic analysis further revealed predominant Pw1 expression in adult cardiac fibroblasts. In vitro, adult PW1⁺ cells differentiated into myofibroblasts upon TGFb1 stimulation and showed upregulated expression of extracellular matrix genes and TGFb receptors. After MI, PW1⁺ cells preferentially expanded and contributed to the myofibroblast population within the infarcted region.

This study reveals that PW1⁺ cells serve as a progenitor population capable of generating cardiac adipocytes during postnatal development and contributing to myofibroblast formation after MI. These findings offer new insights into cardiac adipogenesis and fibrogenesis, providing a potential foundation for future therapies aimed at mitigating pathological adipose accumulation and fibrosis in the heart.

Tenofovir alafenamide (TAF) is widely used in antiretroviral therapy due to its improved renal and bone safety compared to tenofovir disoproxil fumarate (TDF). However, concerns remain regarding its potential metabolic effects and cardiovascular risk. We aimed to compare lipid parameters and surrogate markers of subclinical atherosclerosis and arterial stiffness, namely carotid intima-media thickness (CIMT) and the cardio-ankle vascular index (CAVI), among people living with HIV (PLWH) receiving TAF- or TDF-based regimens and ART-naive individuals.

In this cross-sectional study, a total of 178 PLWH were included and classified into three groups: TAF-based therapy (n = 79), TDF-based therapy (n = 49), and ART-naive individuals (n = 53). Lipid profiles, CIMT, and CAVI were assessed contemporaneously during antiretroviral treatment and compared across groups. Multivariate logistic regression analysis was performed to identify factors independently associated with increased arterial stiffness.

Total cholesterol, triglyceride levels, CIMT, and CAVI were significantly higher in the TAF group compared with both the TDF and ART-naive groups (all p < 0.05). No significant differences were observed between the TDF and ART-naive groups. Subclinical atherosclerosis (CIMT ≥ 1 mm) and increased arterial stiffness (CAVI ≥ 8) were most frequently observed among individuals receiving TAF. In multivariate analysis, TAF use (p = 0.01) and age (p < 0.001) were independently associated with CAVI ≥ 8.

Although TAF provides important renal and bone safety advantages, TAF-based regimens were associated with less favorable metabolic parameters and higher subclinical vascular markers in this cross-sectional cohort. These findings should be interpreted cautiously and do not establish a causal relationship.

Not applicable.

Dairy foods are becoming one of the major dietary sources of trans fatty acids (TFA) as global initiatives to eliminate industrially produced TFA are implemented. This systematic review aimed to assess the cardiometabolic effects of TFA from dairy foods, using data from randomized controlled trials (RCTs) and prospective cohort studies (PCS). We hypothesized that TFA from dairy foods would have no effect on biomarkers for or risk of cardiovascular diseases. Searches for RCTs and PCS were conducted in PubMed and EMBASE using PRISMA guidelines. RCTs compared the impact on blood lipids of regular dairy foods with TFA-enhanced dairy fat/foods produced by altering the cow's diet. Pooled meta-analysis of RCTs using the random effects model was performed for total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL-C), total cholesterol/HDL-C, low-density lipoprotein cholesterol/HDL-C, triacylglycerols, apolipoprotein A1, and apolipoprotein B as continuous variables. Selected PCS analyzed associations between blood concentrations of trans vaccenic acid or trans palmitoleic acid and risk of cardiovascular diseases or type 2 diabetes. Among 10 RCTs, there were no significant differences in mean difference for any lipid biomarkers except for a slight decrease in HDL-C (mean difference: -0.05 mmol/L; confidence interval: -0.10 to -0.00) for TFA-enriched vs. regular dairy foods. Among 12 PCS, circulating concentrations of trans vaccenic acid or trans palmitoleic acid were not associated with increased risk of cardiovascular diseases incidence, mortality, or type 2 diabetes. Consumption of TFA (1.3-13.2 g/d) from different types of dairy foods was not linked to adverse effects on cardiometabolic health.

The growing burden of mental illness and limited access to evidence-based psychotherapy have increased interest in artificial intelligence (AI)-driven conversational agents as potential supports for mental health care. In this exploratory pilot study, we examined the safety and feasibility of an intelligent virtual agent (IVA) designed to simulate psychotherapeutic interactions, with a focus on high-risk situations involving suicidality and substance use. Two licensed psychotherapists engaged in scripted interactions with the IVA across 12 predefined scenarios addressing suicidality and substance abuse. The IVA was powered by GPT-4omni and embedded in a Unity-based avatar. After each interaction, testers evaluated acceptance, usability, and human-robot interaction. Two independent psychotherapists rated the IVA's responses using a structured scale assessing guideline adherence, risk recognition, help provision, de-escalation, and empathy. No real patients were involved; all interactions were simulated for safety testing purposes. The IVA showed preliminary indications of good usability and generally empathic responses. However, problematic responses occurred in 29% of conversations, with 12.5% rated as highly critical. Responses rated as "critical" or "highly critical" referred to outputs that failed to provide adequate support, showed insufficient risk recognition, or included ethically problematic suggestions. Key concerns included inadequate recognition of risk, normalization of substance use, and insufficient referral to crisis resources, particularly in scenarios involving underage alcohol access and suicide-related inquiries. In this small, expert-based pilot safety evaluation, the findings suggest that although AI-based agents may improve access to mental health support, rigorous safety evaluation, clinical oversight, and robust safeguards are essential prior to clinical deployment. No clinical conclusions can be drawn from this simulated study.

Occupational ApplicationsThis study protocol outlines a co-design approach to develop a workplace-based intervention for radiographers to prevent and manage work-related musculoskeletal disorders (WRMSDs) and enhance overall well-being. By engaging radiographers, occupational health specialists, and other relevant stakeholders in the intervention design process, the resulting interventions will be tailored specifically to the physical, cognitive, and organizational demands of imaging work. Beyond radiography, the methodology offers a transferable, step-by-step framework for identifying occupation-specific risk factors and translating these findings into tailored, feasible solutions. The protocol advances ergonomics practice by shifting from a prescriptive, one-size-fits-all approach to a collaborative, context-specific design, thereby ensuring that any resulting intervention is both evidence-informed and operationally sustainable, and aligned with real-world workplace needs.

Autonomic control of the heart is an important indicator of self-regulation and overall mental and physical health. The vagus nerve plays a central role in this regulation, and resting-state heart rate variability (HRV), reflecting fluctuations in inter-beat intervals (IBIs), is the primary noninvasive marker of vagal activity. As males and females differ in aspects of self-regulation, HRV may help elucidate underlying neurobiological differences. However, sex differences in commonly used HRV metrics, such as natural log transformed root mean square of successive RR interval differences (lnRMSSD) and high-frequency HRV (lnHF-HRV) derived from 5-minute recordings, appear smaller in young adults than in other age groups. These metrics capture vagally mediated activity as averaged linear measures and may therefore overlook rapid, spontaneous IBI fluctuations. In the present study, we tested whether a similarity graph theory algorithm could better capture sex differences in nonlinear, rapid IBI variability within 2-5-seconds time windows.

Electrocardiogram (ECG) recordings of 269 young, healthy adults between 18 and 30 years old (M = 21.5, SD = 3.0) were pooled from three different studies. Males accounted for 52.4% of participants, indicating a comparable distribution between sexes. Similarity graph-theory metrics were computed to quantify nonlinear, rapid interbeat interval (IBI) variability using sliding windows of 2-5 s and ≥12 s. In addition, conventional linear and nonlinear heart rate variability metrics, including lnRMSSD and lnHF-HRV, were calculated. Logistic regression models were used to assess the predictive value of graph-theory and HRV metrics for sex, both separately and in combined models for comparison. All models were adjusted for age, body mass index, mean heart rate, and respiratory rate.

Males showed higher graph-metric values, indicating lower IBI variability compared with females (odds ratio 2.78; 95% CI 1.32-5.86). Neither lnRMSSD nor lnHF-HRV distinguished sexes alone; however, lnRMSSD became predictive when combined with the graph metric (odds ratio 1.73; 95% CI 1.06-2.81), although this effect was attenuated after controlling for mean heart rate.

These findings suggest that nonlinear methods sensitive to rapid spontaneous IBI changes can complement traditional short-term HRV metrics for assessing sex differences in autonomic heart regulation.