Macrophages are major contributors to inflammatory responses in acute kidney injury (AKI) and rapidly alter their gene expression through epigenetic regulation. This study focused on ASXL1, a chromatin modifier regulating histone marks consisting of H3K27me3 (repressive) and H3K4me3 (activating) in M1 macrophages. We found that ASXL1-positive M1 macrophages were significantly increased in the unilateral ischemia-reperfusion injury kidneys of male mice in the acute phase. In cultured M1 macrophages, RNA sequencing revealed that Asxl1 knockdown upregulated inflammatory response genes such as Il6 and Il1b. Conversely, the expression of anti-apoptotic genes Csf3 and Lcn2 was suppressed, and pathways related to interleukin-17 signaling and Fcγ receptor-dependent phagocytosis were downregulated. In co-culture experiments, Asxl1 silencing in M1 macrophages induced more severe apoptosis and reduced proliferation of mouse renal cortical tubular cells. Mechanistically, chromatin immunoprecipitation analysis demonstrated that Asxl1 knockdown significantly decreased H3K27me3 levels at the Il6 and Il1b promoter regions and H3K4me3 levels at the Csf3 and Lcn2 promoter regions in M1 macrophages. These findings indicate that ASXL1 suppresses excessive inflammatory cytokine expression and preserves anti-apoptotic activity through histone modifications, while maintaining phagocytic capacity in M1 macrophages. ASXL1 in M1 macrophages thus attenuates inflammatory activation and macrophage-mediated renal tubular cell damage in AKI.

Cardiac lymphatic endothelial cells (LECs) regulate tissue homeostasis, immune trafficking, and remodeling, but how human cardiac LEC heterogeneity changes with physiological aging and cardiovascular disease remains poorly defined. We sought to define age- and disease-associated LEC states, their regulatory and microenvironmental programs, and the functional relevance of selected pathways.

We integrated human cardiac single-nucleus transcriptomic datasets spanning physiological aging, dilated and hypertrophic cardiomyopathy, doxorubicin-associated cardiomyopathy, and heart failure with preserved ejection fraction. Aging redistributed LECs among pre-existing states, with expansion of a homeostatic immune-surveillance state and loss of cytokine-responsive and polarity-associated states. Cardiovascular diseases showed a distinct trajectory, with depletion of a non-failing homeostatic state and expansion of shared and disease-associated remodeling states. SCENIC and NicheNet/MultiNicheNet identified state-specific regulatory programs and disease-dependent signaling networks, with recurrent BMP/TGF-β/activin-family signaling. ACVR2A was prioritized in human doxorubicin-associated cardiomyopathy; endothelial Acvr2a deletion in aged doxorubicin-treated mice was associated with improved cardiac function and increased open cardiac lymphatic vessels. Independent human spatial transcriptomic analyses supported selected aging- and disease-associated programs.

Physiological aging and cardiovascular disease remodel cardiac LECs through distinct changes in cellular state, transcriptional regulation, and microenvironmental signaling. Aging is associated with redistribution and reduced representation of specialized LEC programs, whereas cardiovascular diseases redirect LECs through disease-associated signaling environments, highlighting context-dependent remodeling of the cardiac lymphatic endothelium across aging and disease.

FTO (fat mass and obesity-associated) protein, a key N6-methyladenosine demethylase, plays a critical role in cardiovascular disease. However, its function in vascular calcification remains poorly understood.

High phosphate (Pi) was used to induce calcification in vascular smooth muscle cells (VSMCs) and aortic rings, and high-dose vitamin D₃ (vD₃) was used to induce vascular calcification in mice. FTO expression was modulated using adenovirus, adeno-associated virus, and siRNA. To identify FTO targets, we performed integrated MeRIP sequencing and RNA sequencing analyses.

FTO expression was significantly downregulated in calcified VSMCs, mouse arteries, and human arteries relative to their noncalcified counterparts. Silencing of Fto increased high Pi-induced osteogenic gene expression and calcification in VSMCs. Conversely, overexpression of Fto resulted in the opposite effect. These results were confirmed in high Pi-induced rat aortic ring calcification and a vD₃-induced mouse model of vascular calcification through treatment with the FTO inhibitor F,B-2,3. Intriguingly, the ALP (alkaline phosphatase) inhibitor TNAP-IN-1 or levamisole hydrochloride partially reduced FTO inhibition-induced increases in VSMC calcification, rat aortic ring calcification, and vascular calcification in mice. Adeno-associated virus-mediated VSMC-specific overexpression of Fto significantly attenuated vascular calcification in mice with overloaded vD₃. Integrated MeRIP sequencing and RNA sequencing identified that Pcsk9 is a potential target of FTO. Knockdown of FTO increased N6-methyladenosine methylation and mRNA stability of Pcsk9, and its secretion by VSMCs. In addition, knockdown of Fto enhanced the activation of NF-κB (nuclear factor-κB) signaling and increased the expression of inflammatory cytokines, including IL-6, Icam1, and Vcam1, which were attenuated by concomitant knockdown of Pcsk9. Finally, knockdown of Pcsk9 or p65 abolished silencing of the Fto-induced increase in osteogenic transition and calcification in VSMCs.

Our results suggest that FTO may inhibit vascular calcification at least in part through Pcsk9-mediated modulation of NF-κB signaling and altered ALP activity. FTO may therefore be an attractive target for the treatment of vascular calcification.

Evidence-based health information often fails to reach everyday sports practice, leaving a gap between research and real-world application. Digital platforms can help bridge this research-practice gap by disseminating accessible and sport-specific health guidance to coaches, parents, and athletes. Frisk Friidrott, developed by the Swedish Athletics Federation, is a digital health platform providing evidence-based information on injury prevention, training, nutrition, and mental health in youth athletics.

To evaluate the diffusion and user experience of Frisk Friidrott among one group of intended end users, coaches and parents, for youth aged 12-15 years in Swedish Athletics.

A multimethods, cross-sectional study was conducted among coaches and parents of athletes aged 12-15 years. Quantitative data (n = 267) were collected through a web-based survey and analyzed descriptively. Qualitative data were obtained from open-ended survey responses (n = 40) and semistructured interviews (n = 5) and analyzed thematically. Two dimensions from the Reach, Effectiveness, Adoption, Implementation and Maintenance Sports Setting Matrix (RE-AIM-SSM framework), reach and adoption, were used to evaluate diffusion, while constructs from the Technology Acceptance Model, perceived usefulness and perceived ease of use, were applied to assess user experience.

Thirty-one percent of respondents had heard of the platform, and 27% had initially adopted it. Adoption was higher among coaches, especially those with training in sports medicine or athletics. Adopters reported high perceived usefulness and credibility but identified navigation and structural limitations as barriers to ease of use.

Passive diffusion resulted in modest reach. Integrating the platform into coach education and improving usability and promotion may enhance adoption and sustained engagement within Swedish Athletics.

Posttraumatic Stress Disorder (PTSD) symptoms amongst people with serious mental illness (SMI) are prevalent in Ethiopia and throughout the world, yet treatment is scarce, particularly in low-resource settings with few mental health providers. This study describes the process of adapting a PTSD treatment, originally designed to be delivered by mental health providers in specialty mental health clinics in the US, to be appropriate, acceptable and sustainable when delivered by non-specialist providers in routine care in rural Ethiopian primary care clinics. Methods included a literature review, qualitative interviews (N=48), an adaptation workshop (N=12), and theater, cognitive, and usability testing (N=14) with people with SMI, caregivers of people with SMI, health care providers, and community leaders. Participants found the intervention to be appropriate and acceptable, while also noting multiple patient, family, provider, clinic and community-level barriers that might impact successful delivery and receipt of the intervention. The intervention was adapted to address as many barriers as possible, while maintaining adherence to the original intervention's theoretical and conceptual model. While many of these barriers could be addressed with adaptations, others such as high rates of poverty and limited population-level mental health awareness, require policy and community-based solutions and systemic change. Future research is needed to assess whether the intervention is feasible and effective in this setting.

Caregiver engagement in behavioral parent training (BPT) interventions can have a significant impact on treatment outcomes and retention. Yet, low-income families of color often experience low rates of engagement in treatment due to structural and sociocultural barriers. BPT models partnering with community health workers (CHWs) have shown promise in addressing these barriers and increasing treatment engagement. The current study examines the engagement strategies utilized by CHWs when providing support to families receiving Parent-Child Interaction Therapy (PCIT + CHW) by identifying common CHW engagement strategies utilized in treatment (e.g., active listening, psychoeducation) and how they influence components of engagement (e.g., alliance, attendance).

Among families receiving a telehealth delivered PCIT + CHW model (n = 26), two recorded sessions (i.e., first session and a second randomly selected session throughout treatment) per family were coded for engagement strategy delivery. Families included primarily Latino children (96%) and their primary caregivers. Data about caregiver perceived therapeutic alliance, treatment attendance, homework completion, and PCIT skill acquisition were collected.

Findings suggest that, on average, CHWs utilized total strategies (i.e., sum of all strategies) and alliance-based strategies (i.e., active listening, conveying partnership, and positive regard) to a moderate extent. Alliance strategies delivered during the first session were associated with caregiver-perceived therapeutic alliance, caregiver-perceived effectiveness of the tasks guiding treatment, and caregiver homework completion in the first phase of treatment.

Findings indicate CHWs use a range of engagement strategies, and early use of alliance-based strategies influence multiple components of engagement. Implications for training and involving CHWs in children's mental health services are discussed.

Polyunsaturated fatty acids (PUFAs), including omega-3 (n-3) and omega-6 (n-6) essential fatty acids, play critical roles in brain development and function, serving as precursors to a wide range of bioactive lipid mediators involved in immune and inflammatory signaling. Emerging evidence implicates PUFA dysregulation in schizophrenia and bipolar disorder, severe psychiatric conditions that remain incompletely treated by current therapeutics. In this review, we first outline the biological roles of PUFAs relevant to neurodevelopment and psychiatric risk, with particular emphasis on their interactions with synaptic, immune, and stress-related risk pathways impinging on neurodevelopment. We synthesize preclinical evidence showing how altered PUFA availability influences neurobiological and behavioral phenotypes relevant to psychosis, alongside human observational, epidemiological, genomic and lipidomic studies that implicate disrupted PUFA metabolism in schizophrenia and bipolar disorder. Finally, we evaluate clinical trials of n-3 PUFA supplementation, considering both its therapeutic potential and current limitations. Together, we highlight PUFA metabolism as a mechanistic bridge linking neurodevelopment, immune function, and psychiatric risk, and as a potential target for future therapeutic strategies.

Background  Undocumented and self-initiated use of psychotropic medications represents a growing public health challenge in primary care. This study aimed to evaluate the prevalence of self-reported occasional use of anxiolytics and/or sedatives among primary healthcare (PHC) patients without a previously registered diagnosis of a mental disorder and without a documented prescription for these medications in their medical charts. Additionally, we investigated the associations of undocumented medication use and sociodemographic parameters with the severity of depressive and anxiety symptoms. Methods  A cross-sectional study was conducted between January 31, 2026, and March 31, 2026, at the Public Health Institution Health Center "Dr. Mustafa Šehović" Tuzla, Bosnia and Herzegovina, enrolling 221 adult PHC patients (N = 221). Depressive and anxiety symptoms were evaluated using the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7) screening tools. Participants were categorized as users (n = 60) or non-users (n = 161) based on self-reported occasional medication intake. Nonparametric statistical tests (the Mann-Whitney U test and Kruskal-Wallis H test with Bonferroni-adjusted post hoc comparisons) were used for group comparisons. Results  Occasional undocumented use of anxiolytics and/or sedatives was reported by 27.1% (n = 60) of participants. Medication users had significantly higher scores on both the PHQ-9 (median 10.0 (IQR = 7) vs. 4.0 (IQR = 5); p < 0.001) and GAD-7 (median 8.5 (IQR = 9) vs. 4.0 (IQR = 6); p < 0.001) than non-users. Among medication users, a statistically significant association was identified between educational level and depressive symptom severity (H = 6.515, df = 2, p = 0.038); post hoc analysis confirmed that participants with secondary education had significantly higher PHQ-9 scores than those with higher education (p = 0.036). Sex, age, and marital status showed no significant associations with symptom severity within the user group. Conclusion  More than a quarter of primary care patients without a documented mental disorder or prescription for anxiolytics and/or sedatives reported occasional use of these medications and had elevated depressive and anxiety symptom scores. These findings emphasize the clinical need for proactive, comprehensive medication history-taking in family medicine to identify undisclosed psychotropic medication use and underlying psychological distress.

Transgender youth are a highly vulnerabilized population, facing stigma, discrimination, family rejection, and social exclusion that elevate their risk of depression, anxiety, and suicidal ideation. Gender-affirming interventions-medical, psychological, social, and structural-have been proposed to improve health and wellbeing in this group, but evidence on their psychosocial and mental health impact remains scattered across heterogeneous contexts and intervention types. This scoping review aimed to map and synthesize available evidence on psychosocial and mental health outcomes associated with gender-affirming interventions among transgender youth.

Following JBI methodology and the PRISMA-ScR checklist, we searched PubMed, Scopus, Embase, Web of Science, and CINAHL in August 2025 for peer-reviewed, English-language articles published between January 2011 and July 2025. Eligible studies addressed gender-affirming interventions or experiences among transgender and gender-diverse individuals and reported psychosocial or mental health outcomes.

Of 1,207 records identified, 17 studies met eligibility criteria, comprising 123,428 participants (range: 15-120,617 per study). Designs included prospective cohort (n = 7), cross-sectional (n = 7), retrospective (n = 2), and qualitative (n = 1) studies, primarily from the US, UK, Australia, Sweden, Italy, and India. Evidence consistently linked gender-affirming interventions to improvements in quality of life, psychological wellbeing, emotional functioning, and social participation. Medical interventions (puberty suppression, hormone therapy, surgery) were generally associated with reduced depression, anxiety, distress, and suicidality, though one study found persistently elevated suicide risk decades post-surgery. Non-medical interventions-psychotherapy, family support, social transition, and community-based support-also improved mental health. Conversely, stigma, discrimination, family rejection, and structural healthcare barriers were consistently linked to poorer outcomes, particularly in studies from India.

Gender-affirming interventions are associated with improved psychosocial and mental health outcomes among transgender youth, but optimal wellbeing depends on more than medical intervention alone, requiring family support, inclusive education, affirmative healthcare systems, and supportive policy. Substantial gaps remain for non-Western, low- and middle-income, and non-binary/gender-diverse populations, highlighting the need for research testing whether existing frameworks translate across sociocultural contexts.

Contraception is important for preventing unintended pregnancies and reducing maternal and infant mortality. Among women living with HIV (WLHIV), it is also central to preventing vertical HIV transmission. Yet unmet need for contraception remains high among WLHIV in sub-Saharan Africa. Mental health symptoms may contribute to unmet need, but evidence among WLHIV remains limited. We examined the relationship between depression and anxiety and unmet need for contraception. We used baseline survey data from Kenyan WLHIV receiving routine HIV care participating in a cluster randomized clinical trial evaluating a reproductive health counselling intervention at 10 HIV clinics. Women who were fecund, did not desire a pregnancy within two years, and not using a modern method of contraception were considered to have unmet need for contraception and were eligible for this analysis. Surveys captured data on depression, anxiety, fertility intentions and contraceptive use. We constructed separate generalized linear models to assess the relationship between depression and/or anxiety and unmet need for contraception. Among 2,334 women in the analysis, the median age was 34; 9% (n=221) reported symptoms of at least mild depression, 9% (n=200) anxiety, 13% (n=305) either condition, and 5% (n=116) both. Overall, 84% (n=1,952) used a modern contraceptive method, 16% (n=378) had an unmet need for contraception, and 41% (n=784) used LARC. In univariate analysis, unmet need for contraception was 43% higher among women with either at least mild depression or at least mild anxiety (Prevalence Ratio [PR]=1.43, 95% Confidence Interval [CI]: 1.22-1.67); results were similar in the adjusted model (adjusted PR [aPR]=1.30, 95% CI: 1.08-1.58). No relationships were detected between anxiety or depression alone and unmet need. WLHIV with either depression or anxiety had higher unmet need which suggests that mental health conditions may pose barriers to contraceptive use and may need additional support to achieve their reproductive health goals. Additional attention to mental health needs during contraceptive counselling may support informed contraceptive decision-making.