OBJECTIVE: This study investigated the long-term detrimental effects of early stressful life experiences on physical and cognitive health outcomes in later adulthood, with a particular focus on the mediating role of psychological processes across the life course. METHODS: We used multigenerational data from the Longitudinal Study of Generations (LSOG; N = 561) and applied structural equation modeling to examine the long-term associations between early stressful life experiences (1971-1985) and later health outcomes (2021), with depressive symptoms and self-esteem across adulthood (1994, 1997, 2000, 2005, and 2016) as mediators. RESULTS: Early stressful life experiences predicted higher depressive symptoms, which in turn were associated with poorer physical health, greater limitation in physical functioning, and greater perceived health decline in later adulthood, supporting depression as a key life-course mediator. Self-esteem was not associated with early stressful experiences. CONCLUSION: Early stressful life experiences and adverse family circumstances have lasting detrimental effects on health, primarily through persistently elevated depressive symptoms across adulthood, increasing vulnerability to physical and cognitive health problems in later life. By integrating contemporaneous reports from individuals and their mothers collected nearly 50 years ago, this study provides unique life-course evidence linking early stress to later-life health.

BACKGROUND: Inflammatory bowel diseases (IBD) remain understudied in Black populations despite studies suggesting a disproportionate rising incidence and worse health outcomes for this demographic when compared to White populations in the United States. Perceived stigma impacts outcomes in other chronic disease states but is poorly studied in IBD. Thus, we aimed to assess the impact of perceived stigma in Black participants with IBD. METHODS: A web-based questionnaire was administered from July through August 2022 in partnership with the Color of Gastrointestinal Illnesses. Poisson regression was used to estimate relative risks (RR) and 95% confidence intervals (CIs) for the association between perceived stigma and primary outcomes of medication nonadherence, perception of care, anxiety, and depression. All models were multivariate adjusted and restricted to Black respondents. RESULTS: This study included 1142 Black participants with IBD. The majority of respondents were male (57.9%), held a diagnosis of ulcerative colitis (58.9%), were from the South (33.7%), completed high school as their highest level of education (31.2%), and endorsed moderate stigma levels (57.4%). Perceived stigma was associated with medication nonadherence (moderate stigma: RR 0.95 [0.91-0.99]; low stigma 0.79 [0.70-0.89]). While moderate stigma had higher RR for poor perception of care (1.14; 1.10-1.19), low stigma had lower RR (0.88; 0.82-0.94). Mood outcomes were not significantly associated with perceived stigma. CONCLUSIONS: Perceived stigma significantly impacted healthcare perception and utilization for Black participants with IBD. Future studies are needed for better understanding of the interplay between perceived stigma and IBD health outcomes.

OBJECTIVE: Stress-related mental illnesses, including depression, are associated with altered glucose metabolism. However, it is unclear how chronic stress alters glucose metabolism along with depression-related behaviors, and how antidiabetic drugs normalize these alterations. METHODS: Using a mouse model of social defeat stress, we compared stress-induced glycemic responses among strains that differ in stress susceptibility (C57BL/6N, C57BL/6J, and BALB/c). Blood glucose was measured before stress and after the last stress exposure of acute and chronic stress. Circulating metabolic hormones and inflammatory cytokines were quantified, and depression-related behaviors (social avoidance, anhedonia-like behavior and cognitive deficits) were assessed. In C57BL/6N mice, the antidiabetic drug glyburide or liraglutide was administered 30 min before each of the ten stress exposures, and their effects on glycemic responses and behavioral outcomes were evaluated. RESULTS: Acute stress elevates blood glucose in the relatively stress-resilient C57BL/6N and C57BL/6J strains, but not in the more stress-susceptible BALB/c strain. After chronic stress, this stress-induced hyperglycemic response was abolished in C57BL/6N and C57BL/6J mice, whereas BALB/c mice showed stress-induced hypoglycemia. Chronic stress also produced largely coordinated changes in circulating metabolic hormones and inflammatory cytokines, with strain-dependent differences in a subset of these molecules. In C57BL/6N mice, treatment with glyburide or liraglutide, antidiabetic drugs with distinct primary mechanisms of action, before each stress exposure reduced the development of anhedonia-like behavior and cognitive deficits without affecting social avoidance, while restoring stress-induced hyperglycemia. CONCLUSION: These results demonstrate that chronic stress drives a hypoglycemic shift accompanied by depression-related behaviors, and that the development of both metabolic and behavioral alterations can be prevented by antidiabetic drugs with distinct primary mechanisms administered during the stress period. Thus, this study supports metabolically targeted interventions as a potential preventive strategy for stress-related mental illnesses, whereas their efficacy against an already established phenotype remains to be tested.

BACKGROUND: Chronic pain is neurophysiologically heterogeneous and may be obscured by group-average EEG metrics. We hypothesized that chronic pain would be characterized by reduced cortical complexity relative to a healthy-control-derived normative reference, defined as the age- and sex-conditioned expected distribution of EEG features, and that larger negative deviations would be associated with greater pain intensity. METHODS: Resting-state EEG from 147 participants, including 78 patients with chronic pain and 69 healthy controls, was analyzed. Complexity was quantified using Higuchi fractal dimension (HFD) across seven scalp regions. A Gaussian process regression normative model was trained exclusively on healthy controls, using age and sex as covariates, to estimate expected HFD values and predictive uncertainty. Individual deviations were expressed as W-scores, with more negative values indicating reduced complexity relative to the normative reference. In patients, regional W-scores were correlated with average pain intensity using Pearson correlations with false discovery rate correction. Robustness was examined after adjustment for age, sex, depression, and anxiety, and spectral power measures were evaluated as exploratory benchmarks. RESULTS: More negative frontal HFD W-scores were associated with higher pain intensity (r = -0.545, P_FDR < 0.001). Significant HFD-pain associations were observed across multiple regions, with correlation coefficients ranging from -0.441 to -0.545 among FDR-significant HFD features. The parietal association also survived correction (r = -0.523, P_FDR < 0.001). Compared with the examined spectral power benchmarks, HFD-based deviations showed larger descriptive associations with pain intensity. The frontal HFD-pain association persisted after adjustment for age, sex, depression, and anxiety (r = -0.520, two-tailed P < 0.001). Exploratory subgroup analyses suggested larger negative latent deviation scores in neuropathic conditions, particularly PNP and PHN. CONCLUSION: Normative deviation mapping of EEG complexity may provide a candidate research marker for quantifying inter-individual variability in chronic pain severity. These findings support further validation of HFD-based normative modeling for mechanism-informed stratification, while requiring replication in larger, harmonized, and longitudinal datasets.

BACKGROUND: COVID-19 is a new disease with high transmission and mortality rates and can cause or exacerbate a myriad of psychological sequelae, particularly in patients with underlying serious illness. Palliative care patients' experiences have been widely studied, but research on their experiences during COVID-19 pandemic is scanty. AIM: To determine the prevalence of and factors associated with anxiety and depression among palliative care patients and explore palliative care patients' experiences during the COVID-19 pandemic. MATERIALS AND METHODS: This cross-sectional mixed-methods study used the Hospital Anxiety and Depression Scale (HADS) and face-to-face audio-recorded interviews to collect data from participants between April and May, 2022. Quantitative data were analysed using STATA v.17. Chi-square test and multivariate logistic regression were performed to examine factors associated with depression and anxiety. Qualitative data were analysed using thematic analysis. RESULTS: Of the 96 participants, 74% (n=71) were female. Patients who earned ≥100,000 Ugandan shillings (OR=0.18, p=0.026, CI 0.040-0.818) had lower odds of depression compared to patients who earned less, while patients who missed clinic appointment sometimes (OR=26.02, P=0.025, CI 1.503-450.226) and those who reported change in sleep pattern (OR=15.91, p=001, CI 3.030-83.567) had higher odds of depression. Male participants had lower odds of anxiety (OR=7.93, p=0.003, CI 2.004-31.370) while those who missed medicines very often (OR=6.79, p=0.024, CI 1.288-35.852) and those who reported change in sleep pattern (OR=10.21, p=0.000, CI 2.790-37.393) showed higher odds of anxiety. Three main themes emerged from the qualitative interviews: (1) Navigating multidimensional suffering before and during a pandemic, (2) the healthcare system as a precipitant of suffering, and (3) finding hope and meaning amidst uncertainty and suffering. CONCLUSION: Mental health morbidities were great in this cohort, occurring in a multifaceted manner, with disruptions to the psychological, social, financial, and physical dimensions of patients' quality of life. Palliative care continuity and mental health, psychosocial and spiritual support services should be integrated into humanitarian emergency health care package in future outbreaks.

BACKGROUND: Gynecological examination anxiety can be influenced by women's mental state and genital self-image. This study aimed to examine the relationship between gynecological examination anxiety, genital self-image, and depression, anxiety, and stress in women. METHODS: This descriptive and correlational study included 281 women reached through social media. Data were collected using a personal information form, the female genital self-image scale (FGSIS), the gynecological examination anxiety scale, and the Depression Anxiety Stress Scale-21. RESULTS: The mean age of the women was 42.18 ± 11.57. It was found that 63% of the women were university graduates, 29.5% had chronic diseases, 13.5% had gynecological diseases, 59.1% did not have regular gynecological examinations, and 46.3% had undergone a gynecological examination in the last year. The prevalence rates for severe and very severe depression, anxiety, and stress were 7.5%, 15.7%, and 6.4%, respectively. This study found a low-level negative correlation between genital self-image and gynecological examination anxiety ( = -0.141,   < 0.05). According to the multiple linear regression analysis, previous negative experiences during gynecological examinations were associated with higher anxiety ( = 0.129, = 0.033), whereas higher female genital self-image was associated with lower anxiety ( = -0.140, = 0.027). CONCLUSION: Previous negative experiences with gynecological examinations can increase gynecological examination anxiety, while a more positive genital self-image can play a protective role in reducing anxiety.

BACKGROUND: Depression and obesity are common chronic conditions in adolescence with major health consequences. While adverse childhood experiences (ACEs), socioeconomic disadvantage, and sexual minority (SM) identity are linked to higher mental health-obesity (MH-OB) comorbidity, evidence on predictors of change during adolescence is limited. METHODS: Data came from 10,353 UK adolescents (49% male, 80.9% White, 9.1% SM) in the Millennium Cohort Study. MH-OB comorbidity was defined using overweight/obesity (International Obesity Task Force criteria) and depression/anxiety symptoms (Strengths and Difficulties Questionnaire emotional symptoms subscale) at ages 14 and 17. Change in comorbidity was categorised as none, persistent, resolved, or newly developed. Predictors included sex at birth, ethnicity, sexual identity, socioeconomic position, and cumulative ACEs. Multinomial logistic regression estimated adjusted relative risk ratios (aRRRs). RESULTS: At age 14, 7.7% of adolescents were obese, 19.5% overweight, and 27.8% reported depression/anxiety symptoms. By age 17, 2.5% had persistent MH-OB comorbidity, 6.2% newly developed comorbidity, and 2.8% resolved; 88.0% had no comorbidity. Female sex, SM identity, lower household income, and increasing ACE exposure were associated with persistent and newly developed comorbidity. Associations were strongest among SM adolescents and females. Exposure to three or more ACEs increased risk of persistent comorbidity. CONCLUSION: Adolescents who experienced socioeconomic disadvantage, exposure to adversity, and with SM identity were more likely to show persistent or new-onset MH-OB comorbidity, with associations generally stronger in females than in males. These findings highlight the importance of early, integrated interventions that address both mental health and weight-related risks in structurally disadvantaged groups.

BACKGROUND: People with tuberculosis (TB) have a suicide risk up to 25 times higher than the general population. It may be due to stigma, isolation, prolonged treatment, and psychological distress from the disease. Hence, empowering healthcare workers (HCWs) who are involved in TB care with suicide prevention skills is essential. NOVELTY: This study will be integrating suicide prevention into TB care and will be evaluating an asynchronous learning management solution (LMS)-based training model against traditional in-person gatekeeper training for HCWs of high-risk population. OBJECTIVES: This study will examine the effectiveness of the gatekeeper suicide prevention training online e-module compared to in-person training for National Tuberculosis Elimination Program (NTEP) HCWs. METHODS: HCWs in the Karnataka State NTEP program will be randomly assigned to two training groups using parallel cluster-randomization at the district level. The online training group (intervention group) will receive training through customized and locally adapted e-modules hosted on an LMS. The In-person training group (control group) will undergo training through presentations, role-play simulations, and discussions. Training effectiveness will be assessed using the Kirkpatrick model, with statistical evaluation and comparison of pre- and post-test scores to measure knowledge acquisition, skill retention, and application (number of referrals) across both groups. EXPECTED OUTCOME: The study anticipates that e-module training will be as effective as in-person training for developing competence and confidence in suicide prevention and early identification and referral of suicidality.

BACKGROUND: Neurodivergent children and young people, including those with autism, attention-deficit/hyperactivity disorder and intellectual disability, experience higher rates of mental health difficulties than their neurotypical peers. Despite this increased need, many families encounter barriers when accessing child and adolescent mental health services (CAMHS). These barriers may occur across the service pathway, including referral, triage, assessment, treatment, and discharge. Patient and Public Involvement and Engagement, and professional contributions are essential to ensuring that CAMHS and research reflect the needs and priorities of those who use them. This paper describes a programme of PPIE and professional contribution activities undertaken to co-develop practical guidance for mental health professionals supporting neurodivergent children and young people. METHODS: We - a partnership between a PhD researcher, a parent with lived experience, a young person with lived experience and two PhD supervisors undertook a programme of PPIE activities, using a co-designed 'Co-production, Accessibility, Participation and Engagement' approach, over 12 months (December 2024 to November 2025). NW is a doctoral student, and HTr is a PPIE parent and lived experience partner. Together, we facilitated co-production activities with PPIE members, discussions at parent carer conferences, and with professional contributors to support inclusive participation and prioritise ideas. Parents, carers, neurodivergent children and young people, and professionals from health, education, and social care participated in workshops, co-production activities, and discussions exploring experiences of accessing CAMHS and identifying opportunities for service improvement. Insights shared during these activities informed the co-development of practical guidance for mental health professionals. RESULTS: A total of 60 PPIE and professional contributors took part in co-production activities. Contributors highlighted barriers including communication challenges, misunderstandings of neurodevelopmental differences vs. mental health conditions, fragmented services and limited clinician training in neurodiversity-affirming approaches. These insights informed the development of an open-access guidance resource outlining practical recommendations to support more inclusive communication, service approaches, family participation, and ongoing evaluation of service accessibility. CONCLUSIONS: Collaborative involvement with lived-experience contributors enabled the development of practical guidance to improve accessibility and inclusivity within child and adolescent mental health pathways for neurodivergent children and young people. This work demonstrates how structured PPIE and professional contribution approaches can support the development of resources grounded in lived experience and contribute to ongoing discussions about inclusive child and adolescent mental health service design.

OBJECTIVES: In Canada, approximately 85% of pediatric emergency visits occur in general emergency departments lacking specialized pediatric resources. Through a national co-developed knowledge mobilization strategy, the Translating Emergency Knowledge for Kids (TREKK) network creates evidence-based resources to bridge this gap. This study evaluated the usability of TREKK resources as perceived by healthcare providers. METHODS: Between February 2023 and February 2024, a concurrent triangulation mixed-methods design was used to evaluate eight pediatric clinical resources across seven topics (diabetic ketoacidosis (DKA), bronchiolitis, aerosol-generating medical procedures, pneumonia, respiratory distress, eating disorders, and anxiety). Four iterative survey rounds each assessed two resources on nine usability dimensions (e.g., usefulness, simplicity, and clinical confidence) using an eleven-point Likert scale (0 = strongly disagree; 10 = strongly agree). Survey respondents were invited to semi-structured interviews on three resources (DKA and bronchiolitis Bottom Line Recommendations and the DKA algorithm); purposive sampling ensured diverse professional roles across urban, rural, and remote settings. Interviews were analyzed using reflexive thematic analysis. RESULTS: The survey sample comprised 432 respondents across four rounds. Mean usability scores across nine dimensions ranged from 7.81 to 9.61 (out of 10). The DKA algorithm was rated most positively on clinical usefulness (mean = 9.61), while the aerosol-generating medical procedures Fact Sheet was rated least positively on intention-to-use (mean = 7.2) and provider confidence (mean = 7.0). Thematic analysis of 21 interviews generated four themes: trusted resources, diverse utilization patterns, effective design, and organizational awareness gaps. Triangulation indicated that, although providers rated the resources as highly usable, limited organizational awareness was the primary barrier to uptake in practice. CONCLUSIONS: TREKK resources are valued for evidence-based credibility and bedside usability, yet limited organizational awareness impedes their uptake in practice. Ongoing, active strategies to increase uptake, such as knowledge brokering and curricular integration, are essential to bridge the knowledge-to-practice gap.

OBJECTIVES: Loneliness is a well-established longitudinal predictor of depression in later life, yet the mechanisms through which this association unfolds remain unclear. This study examined the direct and indirect effects of loneliness on subsequent depressive symptoms in late life, with particular emphasis on persistent loneliness over time. METHODS: Community-dwelling, older Israeli adults (N = 1216; M age = 81.1 years) completed annual assessments of loneliness and depressive symptoms over three years. Structural equation modelling was used to estimate autoregressive pathways, prospective effects of loneliness on subsequent depressive symptoms, and indirect effects operating through the persistent loneliness. Models were adjusted for age, sex, education, marital status, financial status, self-rated health, living arrangement, religiosity, and Holocaust survivor status. RESULTS: Loneliness and depressive symptoms both demonstrated substantial temporal stability over time. After adjusting for prior depressive symptoms and sociodemographic covariates, loneliness remained a significant prospective predictor of subsequent depressive symptoms. Decomposition of longitudinal effects, however, indicated that indirect pathways, transmitted through persistent loneliness, accounted for a greater proportion of the total longitudinal association than direct prospective effects. In fact, direct prospective effects were not statistically significant after accounting for indirect pathways. Baseline loneliness and depressive symptoms did not predict study attrition, supporting the robustness of the longitudinal findings. CONCLUSIONS: The association between loneliness and subsequent depressive symptoms in later life appears to operate primarily through persistent loneliness rather than through direct prospective effects. These findings suggest that chronic loneliness functions as a longitudinal pathway sustaining depressive symptoms over time. Interventions that mitigate loneliness in late life may also reduce depression among older adults.

In low-income, high HIV prevalence settings, caregiving for a young child who is HIV exposed and uninfected (HEU) can place additional demands on a mother living with HIV while she manages her own health and the well-being of her child. We compared caregiver burden associated with infants' healthcare needs, perceived by mothers of infants who were HEU and HIV-unexposed, uninfected (HUU). This nested sub-study of a prospective cohort study was conducted within the public primary healthcare setting in Western Cape, South Africa. Eligible mothers were enrolled antenatally with known HIV status and with a child confirmed HIV negative at age 12 months by 20 May 2025. The primary exposure was maternal-child HIV status, and primary outcome was caregiver burden according to the modified 12-item Zarit Caregiver Burden Scale questionnaire (ZCBS; range 0-48), measured by maternal interview at child's age 12 months. Logistic regression was used to compare caregiver burden (no-to-mild [ZCBS 0-10] vs moderate-to-high [ZCBS 11-48]), unadjusted and adjusted for maternal and household confounders. Among 187 mothers included (n = 91 of infants HEU, n = 96 of infants HUU), the median (interquartile range) ZCBS was 3(1-8); 22/91 (24.2%) mothers with HIV and 11/96 (11.5%) mothers without HIV perceived moderate-to-high caregiver burden (unadjusted odds ratio 2.46, 95% confidence interval (CI) = 1.12-5.43, P = .025). After adjusting for maternal age, income, number of cohabitating adults in the family and maternal depression, the adjusted odds ratio was 2.06, 95% CI = 0.85-4.98, P = .108. Living with HIV while caring for an infant who is HEU increases mothers' caregiving burden during the critical period of early motherhood.

BACKGROUND: Adolescent mental health is shaped by multiple factors. This study examined the association between intersectional identity based on gender and family-socioeconomic status (SES) and mental health and whether this association differs by the function of health behaviors (ie, physical activity, screen time, and sleep) among Korean adolescents. METHODS: Nationally representative, cross-sectional, self-reported data from the 2023 Korea Youth Behavior Web-Based Survey (N = 52,880, 12-18 y) were used. Intersectional identity included gender and family SES. Mental health factors included stress, depressive symptoms, and loneliness. Health behaviors included physical activity, recreational screen time, and sleep. Covariates were age, academic performance, and parental educational attainment. Decision tree models, logistic regressions, and moderation analyses were conducted. RESULTS: Compared with boys, more girls reported high stress (31% vs 44%), depressive symptoms (21% vs 31%), and loneliness (49% vs 63%). A statistically significant interaction between gender × family SES was observed only for loneliness, with girls with low-family-SES reporting the highest likelihood (odds ratio [OR] = 3.60; 95% CI, 3.28-3.95). Physical activity and sleep moderated the association between intersectional identity and loneliness, with sleep showing more salient results. Specifically, not meeting the sleep recommendation was associated with greater loneliness, especially for more marginalized identity groups in a linear manner (boys × mid-family-SES: OR = 1.65; boys × low-family-SES: OR = 2.75; girls × high-family-SES: OR = 2.46; girls × mid-family-SES: OR = 3.01; and girls × low-family-SES: OR = 5.24). CONCLUSION: Meeting sleep recommendations may buffer intersectionality-linked loneliness particularly for girls across SES levels and boys with mid-family-SES. Sleep-focused strategies may offer opportunities to address the adolescent loneliness epidemic in Korea.

BACKGROUND: Treatment-resistant schizophrenia (TRS) affects 20-30% of individuals with schizophrenia, with persistent symptoms, functional impairment, and reduced quality of life. Clinical identification remains dependent on sequential antipsychotic trials despite reported structural brain differences between TRS and treatment-responsive schizophrenia (TxR). This study evaluated whether structural MRI features could discriminate clinically defined TRS from TxR using machine learning. METHODS: A total of 225 participants (122 TRS, 103 TxR) from multi-site studies in Canada and Japan were included. Cortical thickness, brain volume, surface area, and intrinsic curvature were derived from T1-weighted MRI using FreeSurfer, with feature engineering generating volumetric-cortical thickness interaction terms. A voting ensemble was evaluated under a primary leakage-controlled NeuroComBat harmonization and a secondary exploratory full-dataset harmonization. Performance was assessed using ROC-AUC, F1 score, precision, and recall. RESULTS: In the leakage-controlled analysis, the voting ensemble achieved a held-out ROC-AUC of 0.57 and macro F1 of 0.56; training cross-validation yielded ROC-AUC of 0.715. The full-dataset harmonization analysis yielded ROC-AUC of 0.60 and macro F1 of 0.62, interpreted cautiously due to leakage. Temporal-occipital cortical thickness and choroid plexus volume interaction terms contributed most to model performance. CONCLUSION: Structural MRI features may support cross-sectional discrimination of TRS from TxR. The divergence between harmonization strategies highlights the importance of leakage-aware preprocessing in neuroimaging. Validation in independent cohorts is required to establish whether these features contribute to earlier identification of treatment resistance.

Individuals with bipolar disorder (BD) face elevated rates of chronic kidney disease (CKD) and premature mortality yet remain underrepresented in cardiorenal trials. Although sodium-glucose cotransporter-2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have established renoprotective benefits in the general population, their comparative effectiveness in BD with comorbid CKD is unknown. This observational cohort study examined risks of kidney replacement therapy (KRT) and healthcare utilization (HCU) (inpatient hospitalization and emergency department visits) among adults with BD and CKD Stage ≤3 initiating SGLT2i versus GLP-1 RA. Electronic health record data from the TriNetX network (2014-July 2026) identified eligible adults with documented treatment prescriptions; 3971 SGLT2i and 5608 GLP-1 RA users were identified, with 1:1 propensity score matching (PSM) yielding 2557 patients per arm. Cox proportional hazards regression generated adjusted hazard ratios (aHR) in the full cohort; Kaplan-Meier analyses were conducted in the matched cohort. In full cohort, SGLT2i use was associated with non-significantly lower KRT risk (aHR 0.87, 95% CI 0.71-1.06) and slightly higher HCU risk (aHR 1.18, 95% CI 1.10-1.28) relative to GLP-1 RA. In the matched cohort, 132 of 2557 SGLT2i users and 181 of 2557 GLP-1 RA users experienced KRT, with a borderline, non-significant difference favoring SGLT2i (86.88% vs. 83.48%; p = 0.06). For HCU, 990 of 2557 SGLT2i users and 965 of 2557 GLP-1 RA users experienced the outcome; 5-year HCU-free survival was slightly higher for SGLT2i users than GLP-1 RA users (36.42% vs. 33.27%; p = 0.004), reflecting convergence and late crossover of the Kaplan-Meier curves despite SGLT2i's higher hazard over most of the follow-up period. Residual confounding cannot be excluded, and competing mortality risk may have attenuated the observed hospitalization difference. Among patients with BD and CKD, SGLT2i use showed a non-significant trend toward lower KRT risk but was associated with significantly higher healthcare utilization compared with GLP-1 RA in the full cohort. Confirmation in prospective registries, large longitudinal studies, and randomized trials is needed.

This systematic review investigates the mediating factors in the relationship between ambient air pollution exposure and cognitive aging. We identified 16 studies examining 72 unique exposure-mediator-outcome associations for six pollutants (PM2.5, PM10, NO2, NOX, black carbon, and PM1 components). The most studied pollutant was PM2.5 (65% of analyses). Cognitive outcomes included memory, cognitive processing speed, and clinically diagnosed conditions such as dementia incidence. Potential mediators spanned mental health outcomes (depression, anxiety, stress), lung function (FEV1, FVC, PEF), vascular diseases (stroke, hypertension), inflammation (CRP), metabolic factors (type 2 diabetes), sleep, and neuroanatomical changes. The quality of mediation analysis reporting was generally good, but most studies had some risk of bias, particularly in outcome assessment and confounding adjustment. Cardio and Cerebro-vascular diseases emerged as a potential key mediator. Mental health outcomes, sleep, and lung function also showed mediating potential, but further research is needed to confirm these findings. This review highlights the need for rigorous causal mediation analyses and standardized reporting to better understand the complex pathways linking air pollution to cognitive aging, in order to identify targeted preventive measures to reduce the negative impact of ambient air pollution on cognitive health.

Low back pain (LBP) is a leading cause of disability globally, with its impact amplified by the recurrent nature of the condition. It is unclear whether specific patient features are associated with future disability burden, following recovery from an episode of LBP. The current study explored prognostic factors of future disability over 12 months in patients recently recovered from an episode of LBP. Participants were adults from the no-intervention control group of the WalkBack trial. Fifteen candidate prognostic factors were collected at baseline. The outcome was disability, self-reported at 3, 6, 9 and 12 months using the Roland-Morris Disability Questionnaire and summarised as an area under the curve to quantify overall disability burden over 12 months. A single multivariable model was developed to identify prognostic factors. Three hundred and one of 350 control group participants (at least 3 of 4 disability measures available) were included. The sample had a mean age of 55 years, and most participants were female (81%). Higher body mass index (β = 0.27, 95% confidence interval [CI] 0.04-0.49; Kg/m), worse pain intensity during the previous episode (β = 1.10, 95% CI 0.28-1.92; 0-10 scale), a higher perceived risk of recurrence (β = 0.71, 95% CI 0.14-1.28; 0-10 scale), and depressive symptoms (β = 0.61, 95% CI 0.18-1.05; 0-21 depression subscale) were associated with higher overall disability burden, controlling for other candidate prognostic factors. Each factor had a small, unique effect on overall disability. The findings inform risk assessment and prevention of future LBP-related disability. Perspective: The combination of psychological vulnerability, pain experience, and body composition is associated with future overall disability burden, even after apparent recovery from low back pain.

BACKGROUND AND PURPOSE: Cerebral small vessel disease (CSVD) is a leading cause of post-stroke cognitive impairment, depression, and disability in older adults. Forkhead box O3 (FOXO3) is a key transcription factor that plays important roles in neurodegenerative and vascular diseases. This study investigated the correlation of acute-phase plasma FOXO3 levels with cognitive and depressive symptoms in CSVD patients. METHODS: This prospective cohort study recruited 183 patients with recent small subcortical infarct (RSSI) and 150 healthy controls. Plasma FOXO3 levels were measured by enzyme-linked immunosorbent assay at the acute phase (≤3 days) and day 7. Cognitive and depressive symptoms were assessed at discharge. The brain MRI was used to evaluate CSVD imaging characteristics. Mediation analysis assessed the effect of CSVD on the association between FOXO3 and cognitive function. RESULTS: Among the participants, 76 (41.53%) had cognitive impairment, and 40 (21.9%) had depressive symptoms. Plasma FOXO3 levels were profoundly higher in patients at both the acute phase (≤3 days) and day 7 compared with controls (both P < 0.001), with higher levels observed in the acute phase than at day 7 (P < 0.001). Acute-phase plasma FOXO3 was higher in patients with cognitive impairment than in those without (P < 0.001), showing a predictive area under the curve of 0.747. After adjustment, FOXO3 remained unassociated with depressive symptoms (P = 0.232). Total CSVD burden was associated with cognitive impairment (odds ratio: 1.728, 95%CI 1.084-2.756, P = 0.022). Mediation analysis showed that total CSVD burden, prominently white matter hyperintensities, mediated 36.96% of the association between FOXO3 and cognitive impairment. CONCLUSIONS: Acute-phase FOXO3 levels are associated with early cognitive impairment at discharge, whereas its long-term prognostic value requires validation in future longitudinal follow-up studies.

BACKGROUND: Depressive symptoms in late life are often accompanied by altered appetite and dietary behavior, yet the biological mechanisms linking metabolic signals to eating behavior remain poorly understood. Fibroblast growth factor 21 (FGF21) is a carbohydrate responsive hepatokine that suppresses sweet preference via central pathways. We examined whether depressive symptoms modify the association between FGF21 and sucrose intake in Japanese older adults, focusing on post-glucose FGF21 response. METHODS: This cross-sectional study from the Bunkyo Health Study in Tokyo, Japan, included 1433 adults aged 65-84 years. Serum FGF21 levels were measured during a 75-g oral glucose tolerance test, and post-glucose responsiveness was assessed using the incremental area under the curve (iAUC). Geriatric depressive symptoms (GDS) were defined as a Geriatric Depression Scale (GDS-15) score ≥ 5. Sucrose intake was compared using two-way Analysis of Covariance (ANCOVA) across groups stratified by GDS and FGF21 responsiveness. RESULTS: GDS were present in 303 participants (21.1%). The association between FGF21 response and sucrose intake differed significantly by GDS status (interaction p = 0.045): among those without GDS, higher FGF21 response was associated with lower sucrose intake (2.80% vs. 3.17%; p < 0.001), whereas no association was observed in participants with GDS (3.08% vs. 3.00%; p = 0.780). CONCLUSIONS: Post-glucose FGF21 response is associated with lower habitual sucrose intake in older adults, but this association is attenuated among individuals with GDS. These observations may inform integrated endocrine and psychological approaches to mitigating nutritional imbalance in late-life depression.

Seasonal morphological brain plasticity plays a key role in driving adaptive behavioural responses. Structural changes in the brain including the hippocampus and amygdala (nucleus taeniae in birds), across photoperiods are thought to underlie seasonal shifts in emotional state. For humans, this includes manifestations of short photoperiod seasonal affective disorder (SAD). While morphological brain changes are well documented, the associated transcriptomic dynamics remain poorly understood. Here, we examined the transcriptomes of the hippocampus and amygdala or nucleus taeniae in two highly photoperiodic species, the Siberian hamster (Phodopus sungorus) and the Japanese quail (Coturnix japonica), to identify transcriptomic changes which could underpin seasonal shifts in emotional state. Hamsters and quail exhibited robust physiological changes between long and short photoperiod treatment. Under short photoperiod, hamsters displayed anxiety-like behaviour (increased grooming) in the open field test. Transcriptomic analysis of the amygdala in hamsters identified 76 significantly differentially expressed (DE) transcripts (including transthyretin, TTR) and prolactin receptor, PRLR as differentially expressed, but not significantly. In the quail nucleus taeniae, we found 54 DE transcripts (including tenascin-C, TNC). In the hamster hippocampus, 14 DE transcripts were found, including mahogunin ring finger-1 (MGRN1), and 31 in the quail hippocampus, including eyes absent-2 (Eya2). These findings provide novel insights into the transcriptomic mechanisms underpinning seasonal affective states and suggest potential conserved roles for prolactin and thyroid hormone signalling in mediating seasonal changes in physiology and affective behaviour, particularly in the Siberian hamster.

BACKGROUND: Previous research findings on the association between chronotype and depressive symptoms have relied on cross-sectional studies, and the temporal relationship remains unclear. This study aimed to examine whether insomnia symptoms modify the longitudinal association between chronotype and depressive symptoms. METHODS: This study was an 8-year longitudinal study of 1549 adults who completed the baseline survey. Insomnia symptoms and chronotype were assessed using the Insomnia Severity Index and the Circadian Energy Scale. The presence of depressive symptoms was defined as a Patient Health Questionnaire-9 score of 10 or higher. RESULTS: Evening chronotype and insomnia symptoms were associated with depressive symptoms (evening: odds ratio [OR] = 1.73, 95% confidence interval [CI] = 1.08 to 2.78; insomnia symptoms: OR = 4.78, 95% CI = 3.89 to 5.87). In the incidence of depressive symptoms, the interaction between chronotype and insomnia symptoms was significant, with the presence of insomnia symptoms increasing the risk across all chronotypes (morning: relative risk [RR] = 5.20, 95% CI = 1.97 to 13.75, risk difference [RD] = 15.73%; intermediate: RR = 3.39, 95% CI = 2.54 to 4.52, RD = 12.04%; evening: RR = 1.70, 95% CI = 1.11 to 2.59, RD = 7.28%). In the persistence of depressive symptoms, only insomnia symptoms were significant (RR = 1.74, 95% CI [1.34, 2.27], RD = 18.67%). CONCLUSIONS: These findings suggest that the association between chronotype and depressive symptoms differs by insomnia status and is specific to the incidence of depressive symptoms, but not the persistence of depressive symptoms.

Pain is a defining symptom of endometriosis reducing quality of life and increasing the risk of psychological disorders. We conducted an open-label, randomized, controlled trial to investigate whether structured coaching on Mediterranean diet and aerobic exercise recommendation could improve pain-related symptoms in patients with endometriosis (Clinicaltrials.gov: NCT03994432). A total of 140 patients, aged 18-45 years, with symptomatic endometriosis despite hormonal treatment were randomly assigned (1:1) to an intervention or control group. Every 4 months, the intervention group received dietary and physical activity coaching in addition to hormonal therapy, while controls were monitored with no additional lifestyle advice. The primary outcome was the change in endometriosis-related pain symptoms, measured with an 11-point Numerical Rating Scale (NRS) from baseline to 12 months, between groups. Secondary outcomes included quality-of-life, psychological well-being, and patients' perception of health improvement. At 12 months follow-up, under an intention-to-treat (ITT) analysis, the intervention group showed greater improvements than controls in non-menstrual pelvic pain (-1.60 ± 2.52 vs - 0.74 ± 2.19; p = 0.03) and dyschezia (-0.86 ± 2.13 vs -0.04 ± 1.98; p = 0.02). The anxiety component also improved significantly, while depression and quality of life scores did not change significantly. In the ITT analysis, 47 % of patients (95 % CI, 35.9-58.7) in the intervention group, reported an overall improvement in their general health condition, compared with 27 % (95 % CI, 18.1-38.5) in controls (p = 0.01). These results suggest that in endometriosis patient's lifestyle interventions may complement hormonal treatment in improving symptom management and patients' well-being.

Working memory (WM) is central to mathematical development, yet its role in children with mathematical difficulties (MD) remains debated. Using a multilevel approach, this longitudinal meta-analysis synthesized 36 studies (38 samples; N = 6,015) comparing WM in children with MD and typically developing peers. Across 652 effect sizes, children with MD showed a robust, moderate deficit (Hedges' g = -0.57), evident across all WM components (central executive, phonological loop, visuospatial sketchpad) and domains (verbal, numerical, visuospatial). The largest impairment appeared in the central executive, consistent with accounts highlighting attentional control and dual-task coordination. By integrating longitudinal designs, this study extends prior cross-sectional syntheses, demonstrating that WM deficits persist across development rather than reflecting transient delays. Diagnostic thresholds systematically shaped outcomes, with stricter criteria yielding larger effects, while demographic factors did not. Measurement approaches also influenced estimates, underscoring the methodological sensitivity of reported deficits. Overall, findings indicate that WM weaknesses in MD are broad and persistent, with the magnitude of observed deficits varying systematically as a function of diagnostic criteria. This is the first meta-analysis to integrate longitudinal evidence in mathematical difficulties, clarifying both the developmental stability of WM deficits and the methodological contingencies that shape reported outcomes. These results advance developmental theory by positioning WM as an enduring vulnerability and highlight the need for early identification and instructional approaches that are sensitive to working memory constraints and that carefully calibrate cognitive demands within mathematics instruction, in order to prevent cascading disadvantages in mathematics learning and promote more equitable learning trajectories.

OBJECTIVE: Transcranial magnetic stimulation (TMS) of the dorsolateral prefrontal cortex (DLPFC) may achieve its antidepressant effect via transsynaptic activation of the subgenual cingulate (SGC). SGC activation by DLPFC TMS can be quantified by concurrent EEG (TMS-EEG) via source localization, while the connection between the DLPFC and SGC can be quantified by resting state functional connectivity (RSFC). Here, the relationship between SGC source activation and DLPFC-SGC anticorrelation is characterized in depression patients. METHODS: TMS-EEG and fMRI were collected from 42 depression patients before a course of accelerated individualized intermittent theta-burst stimulation treatment. SGC activation by single pulse TMS of the individual target was quantified by the cortical evoked activity (CEA, 20-500 ms) and the negative peak near 100 ms (N100) of the region's evoked potential. Correlations between the TMS-EEG measures and DLPFC-SGC RSFC were calculated. RESULTS: Stronger DLPFC-SGC anticorrelation was associated with smaller SGC N100 (Rho = -0.36, Pval = 0.03). There was no correlation between the baseline depression symptoms assessed with MADRS and neither the DLPFC-SGC anticorrelation nor the TEP-based SGC measures. CONCLUSIONS: Higher anticorrelation between the DLPFC and SGC enables TMS pulses delivered to the DLPFC to better modulate activity at the SGC. SIGNIFICANCE: This study adds to current understanding of the DLPFC to SGC pathway. Multimodal studies with TMS-EEG and fMRI measures of network pathways may provide missing links in understanding of depression pathophysiology.