Migration may be associated with psychosocial challenges affecting adolescent mental health. This retrospective study described psychiatric hospitalizations of adolescents with a migration background in a child and adolescent psychiatry inpatient unit between December 2016 and June 2024. Forty-four adolescents were identified, accounting for 51 hospitalization episodes. Most patients were female (66%), with a mean age of 15.34 ± 1.47 years, and 91% were first-generation migrants. Suicidal ideation was the most frequent reason for admission (31.38%). Most admissions originated from the emergency department (84.32%), with a mean length of stay of 18.47 ± 10.62 days. At discharge, the most frequent diagnoses included depressive disorders (36.36%), trauma- and stressor-related disorders (22.73%), and schizophrenia spectrum and other psychotic disorders (13.64%). Most adolescents had no previous contact with mental health services (63.6%). These findings highlight the clinical relevance of this population and the need for early intervention strategies and improved coordination between healthcare, education and community services. A migração pode estar associada a desafios psicossociais com impacto na saúde mental durante a adolescência. Este estudo retrospetivo descreveu os internamentos psiquiátricos de adolescentes com antecedentes migratórios num serviço de pedopsiquiatria entre dezembro de 2016 e junho de 2024. Foram identificados 44 adolescentes, correspondendo a 51 episódios de internamento. A maioria era do sexo feminino (66%), com idade média de 15,34 ± 1,47 anos, e 91% eram migrantes de primeira geração. O motivo mais frequente de internamento foi a ideação suicida (31,38%). A maioria dos internamentos teve origem no serviço de urgência (84,32%), com um tempo médio de internamento de 18,47 ± 10,62 dias. À data da alta, os diagnósticos mais frequentes eram os de perturbações depressivas (36,36%), perturbações relacionadas com trauma e fatores de stress (22,73%) e perturbações do espetro da esquizofrenia e outras perturbações psicóticas (13,64%). A maioria dos adolescentes não havia tido contacto prévio com serviços de saúde mental (63,6%). Estes resultados destacam a relevância clínica desta população e a necessidade de estratégias de intervenção precoce e de articulação entre serviços de saúde, escola e comunidade.
To compare early response prediction across accelerated and standard intermittent theta-burst stimulation (iTBS) protocols for major depressive disorder, examining whether predictive performance differs when assessments are matched by cumulative pulse exposure versus calendar time. Pooled analysis of two prospective iTBS trials conducted at Instituto de Psiquiatria, Hospital das Clínicas, Universidade de São Paulo: the open-label BRAEN-MAP trial (once-daily; N = 65; 20 sessions over 4 weeks) and the active arm of the triple-blind, sham-controlled randomized TTT trial (accelerated; N = 50; 45 sessions over 3 weeks). Assessments were matched by cumulative pulses (18,000 pulses), calendar time (Weeks 1 and 2), or session count (15 sessions). Early improvement was defined as ≥ 20% HDRS-17 reduction. Positive predictive values (PPV) and negative predictive values (NPV) were compared using bootstrap resampling. Response rates did not differ between trials (BRAEN-MAP: 55.4%; TTT: 54.0%; p = 0.95). For response prediction, PPV ranged from 66.7% to 75.0% across protocol-timepoint combinations, with no significant differences between protocols at pulse-matched (66.7% vs. 68.9%, p = 0.84), time-matched, or session-matched (66.7% vs. 68.8%, p = 0.86) comparisons (all bootstrap p > 0.43). NPV for non-response prediction ranged from 69.0% to 82.4%, also without significant between-protocol differences. Trajectory analyses demonstrated that early improvers maintained steeper improvement through endpoint. Early symptom improvement predicts iTBS response consistently across accelerated and standard protocols regardless of whether assessments are matched by cumulative pulses, calendar time, or number of sessions. These preliminary findings support early response assessment as a protocol-independent clinical tool, though the accuracy levels observed (PPV 67-75%) are insufficient to justify treatment discontinuation and may be most useful within adaptive, measurement-based care frameworks.
The cortisol awakening response (CAR) is thought to represent an anticipatory mechanism to prepare for upcoming demands. In sport, competition increases in the CAR have been reported, although findings remain inconsistent. A study on amateur athletes identified a divergent CAR between individual-sport (IS) and team-sport (TS) athletes, thereby highlighting sport type as a confounding factor. Our aim was to determine whether competition-related changes in the CAR are robust in elite athletes and whether sport type moderates this response. Using a within-subject crossover design, 190 elite athletes (58 women) from seven sports (soccer, field hockey, handball, badminton, athletics, swimming, and judo) provided saliva samples upon awakening (T0) and 30 min after awakening (T30) on both a competition day and a rest day. The CAR was quantified as a change score (T30 - T0) based on log-transformed and raw values. Both sets of analyses revealed a significant trial effect (p < 0.001). The CAR was greater on competition days (back-transformed mean = 82.1%, 4.81 ng/mL raw units) than on resting days (mean = 24.7%, 0.99 ng/mL), representing large effect size differences. No significant effect of sport type, nor a trial × sport type interaction, was detected. In conclusion, we observed a robust elevation in CAR on competition mornings in elite athletes, compatible with anticipatory processes and potential training-related influences. In contrast to findings in amateur athletes, the CAR did not differ between IS and TS athletes, suggesting a relatively consistent CAR pattern across sports played at the elite level.
Serotoninomics, a nascent emerging discipline within the field of omics, provides a transdisciplinary framework for understanding reproductive toxicology via serotonergic signalling. This research investigates the neuroendocrine effects of permethrin, a commonly used pyrethroid insecticide often considered to pose a low risk to humans, and positions it as a model compound for evaluating reproductive susceptibility beyond conventional endocrine endpoints. It is hypothesized that serotonin, traditionally examined in neuropsychiatric contexts, plays an essential role in gonadal function, hormonal regulation, and emotional resilience. Although permethrins are generally regarded as safe, acute exposure may subtly interfere with serotonergic pathways, potentially resulting in molecular, biochemical, behavioural, and reproductive alterations. These effects could extend beyond immediate exposure, including during gestation, considering permethrins' ability to cross the placental barrier and influence foetal development. By synthesizing evidence across molecular, organismal, and environmental domains, we advocate for a serotonergic approach to facilitate a more comprehensive assessment of risk and resilience. We emphasize the importance of fostering a transdisciplinary dialogue to redefine reproductive health through the perspectives of serotonergic vulnerability and systemic resilience.
Despite well-documented harms of prenatal alcohol exposure, evidence-based treatment guidelines for alcohol use disorder (AUD) during pregnancy remain limited. We systematically reviewed international clinical practice guidelines to examine how they address the full cascade of AUD care during pregnancy, including diagnosis, engagement, treatment initiation, and retention. We searched over 40 clinical practice guideline databases (including PubMed and Guidelines International Network) and gray literature sources globally, identifying 1045 records. Using the Population, Interventions, Comparators, Attributes, Recommendation Characteristics (PICAR) framework, we evaluated guidelines from medical organizations in English-speaking nations addressing alcohol use and AUD management in pregnancy. Our final analysis included 18 guidelines from the United States, Canada, the United Kingdom, Australia/New Zealand, and the World Health Organization published from 2014 to the present. Two reviewers independently assessed each guideline using the Appraisal of Guidelines Research and Evaluation-Recommendations Excellence (AGREE-REX) framework to evaluate quality and risk of bias. We used narrative synthesis to summarize findings across key concepts and care cascade stages. Nearly all guidelines (94%) described risks of alcohol exposure and recommended counseling on cessation (89%), yet few extended beyond these early cascade stages. Only 44% mentioned medications for AUD (MAUD), and merely 17% discussed specific psychosocial treatments. Among guidelines addressing MAUD, only one cautiously supported use, while three explicitly recommended against it. Most guidelines (61%) ended treatment recommendations at referral to specialty care, with half limiting guidance to acute alcohol withdrawal management. Taken together, our findings reveal a stark misalignment between screening emphasis and treatment guidance. While guidelines consistently recommend universal screening and brief intervention, they provide minimal actionable frameworks for managing AUD throughout pregnancy. This gap leaves clinicians without evidence-based pathways for comprehensive AUD treatment during the prenatal period, highlighting an urgent need to strengthen both the evidence base and clinical guidance for AUD management in pregnancy.
Interictal psychosis has long been described as a neuropsychiatric condition secondary to epilepsy. However, there is no chronological relationship with seizures. It differs from schizophrenia since negative symptoms are less prominent, and deterioration of the patient's personality is uncommon. Forced normalization, an antagonistic relation between seizures and psychosis, may be observed, and it is sometimes called alternating or alternative psychosis when there is no electroencephalogram available. The treatment relies on a balance between antipsychotics and antiseizure medications. Surgery is still controversial. This review aims to analyze the existing literature regarding case reports of interictal psychosis. The search performed in the PubMed database for the terms ((psycho*[Title/Abstract]) OR (schizo*[Title/Abstract])) AND ((interictal [Title/Abstract]) OR (inter-ictal [Title/Abstract])) presented 703 articles, 112 of which met the eligibility criteria. Forty-six other studies from other sources were included. Eligible articles were sorted according to their format into case reports and non-case reports. Sixty-nine patients, on average 34.7 ± 12.9 years old, were studied. More than half (50.7%) displayed neuropsychiatric comorbidities, with psychoses (23.2%) and head trauma (15.9%) being the most reported. Fourteen (20.3%) patients were mistakenly diagnosed with primary psychosis. Twenty (29.0%) had a left hemisphere focus, the majority in the temporal lobe. The largest single subgroup of patients whose neuroimaging exams were available (17.4%) had no abnormalities. A significant percentage (62.3%) presented abnormal electroencephalograms, 12 of those with episodes of forced normalization (17.4%). The delay between epilepsy and interictal psychosis was 13.8 ± 10.2 years (Median 13.5 years). Many patients have their symptoms treated as primary, and forced normalization also complicates the treatment. It is urgent to implement guidelines for diagnosis, theragnosis, and prognosis of this fascinating entity.
Characterization of HIV acquisitions during ImPrEP study. Implementation study among MSM and transgender women in Brazil, Mexico, and Peru (February 2018 to December 2020). Participants used HIV rapid tests at enrollment and follow-up visits. HIV viral load on enrollment blood samples was used to identify acute HIV infections retrospectively. Participants with an HIV-negative rapid test at enrollment initiated oral PrEP. Adjusted logistic regression model assessed factors associated with acute HIV infections. We described characteristics of participants who acquired HIV during follow-up according to country, PrEP adherence measures, and virological outcomes. Acute HIV prevalence at enrollment was 0.5% (n = 43/9552). Factors associated included younger age and having any STI. Among 8714 participants (12 185.25 person-years of follow-up; median age 29 years; MSM: 94.8%; transgender women: 5.2%), 104 (1.2%) were diagnosed with HIV during follow-up. Among these, median HIV viral load was 12 257 copies/ml [interquartile range (IQR) 851-114 118]. One (1.8%) participant had K65R mutation and six (10.5%) M184V/I mutations. Median time from first PrEP dispensation to HIV diagnosis was 360 days, varying by country (P = 0.012). Only five participants (8.6%) had tenofovir intracellular levels consistent with at least four doses per week at HIV diagnosis visit. Our findings highlight low detection of acute HIV infection among those starting oral PrEP. Significant challenges in PrEP adherence were verified among young MSM and transgender women who acquired HIV during PrEP follow-up. Innovative approaches, such as long-acting PrEP formulations and tailored adherence support strategies, could play a crucial role in reducing HIV incidence among people using PrEP in Latin America.
Current research suggests that genetic risk for psychiatric disorders is largely due to distinct combinations of many common variants shared by different disorders. This points to the existence of latent components affecting different dimensions of psychopathology. The aim of this study is to identify and characterise latent genetic components involved in psychopathology using a data-driven approach and evaluate their potential as principal component-based polygenic scores (PC-PGSs). Singular value decomposition was applied to a matrix of summary statistics from the largest available genome-wide association studies (GWASs) for eight psychiatric disorders to identify latent components. The components were characterised by gene mapping of the top contributing variants, enrichment analysis and genetic correlation with external traits. PC-PGSs were evaluated in the FinnGen dataset by computing group-wise PGSs from summary statistics using Reconstructing Allelic Count. The different components were mainly involved in synapse organisation and neurodevelopment. The first latent component (PC1) explained 30.5% of the total variance and represented a broad transdiagnostic dimension. Neuroticism was the most strongly correlated external trait. Substance use traits and other psychiatric disorders were positively correlated, whereas cognitive traits were negatively correlated. The second latent component (14.7% of the variance) contrasted thought disorders with childhood-onset neurodevelopmental disorders. Educational attainment and creativity were the most correlated external traits. Other components were more related to a single disorder or differentiated between two related disorders. PC-PGSs in FinnGen largely showed associations in the expected direction, indicating a consistent overall trend for the different PC-PGSs. PC1-PGS was associated with all disorders. Other PC-PGSs showed the expected association in case-case comparisons. Decomposing GWAS summary statistic matrices can reveal functionally coherent dimensions of psychiatric genetic risk that could be clinically relevant, offering a potential framework to refine diagnosis, improve prediction and inform personalised treatment.
Adverse social conditions across the life course influence brain aging and dementia, yet their compounded impact on clinical phenotypes remains underexplored, particularly in Latin America, where social inequality and dementia burden are high. We studied 3941 individuals from six Latin American countries, including cognitively unimpaired controls (CU), Alzheimer's disease (AD), and frontotemporal lobar degeneration (FTLD). A life-course questionnaire captured eight domains of social vulnerability, used to derive a social vulnerability index and latent vulnerability profiles. Brain health was characterized across 37 cognitive, functional, mental health, and dementia severity indicators. Higher vulnerability was mostly associated with executive and memory deficits in CU, cognitive and functional impairment in AD, and social cognition and neuropsychiatric symptoms in FTLD. Multidimensional brain health was affected across groups. Compounded social vulnerability is a key determinant of clinical expression in aging and dementia, underscoring the need for life-course-informed and equity-oriented dementia models.
To assess the prevalence and clinical impact of antinuclear antibodies (ANA) and low complement levels on fetal-maternal outcomes in pregnant women within the spectrum of obstetric antiphospholipid syndrome (APS). A total of 285 ever-pregnant women with APS-related obstetric morbidity were included. Among them, 85 fulfilled APS classification criteria, 139 were classified as non-criteria APS (NC-APS), and 61 as seronegative APS (SN-APS). Patients with other autoimmune diseases were excluded. Adverse pregnancy outcomes (APO) included early pregnancy loss, fetal death, preeclampsia, abruptio placentae, and preterm birth. Successful pregnancy was defined as the achievement of a live birth. ANA positivity and complement levels were analyzed in relation to obstetric outcomes and treatment prescription patterns. Sixty patients (22.3%) were ANA positive. ANA positivity was associated with a lower number of pregnancies and live births, with the lowest ANA titers observed in the SN-APS group. Fifteen patients (6.3%) presented low complement levels. Hypocomplementemia was associated with a higher incidence of preeclampsia and early miscarriages, particularly among NC-APS patients. Additionally, all serological abnormalities were significantly associated with increased prescription of antimalarial therapy during pregnancy. ANA positivity and hypocomplementemia were associated with poorer obstetric outcomes in women within the spectrum of obstetric APS. These serological abnormalities may identify a subgroup of patients with a higher-risk obstetric profile and greater need for intensified therapeutic management, including the use of antimalarial treatment during pregnancy.
Three clinical staging models for bipolar disorder (BD) have been published, each with a different but complementary approach and focus. The International Society for Bipolar Disorders Staging Task Force aimed to integrate these models into one comprehensive three-dimensional staging model, separately rating bipolar spectrum, nonmood psychopathology, and (inter-episodic) functional impairment. Via a series of in-person and online meetings, Delphi-surveys, and email discussions, the task force members step-by-step reached consensus on the overall structure of the model and the definition of the various stages. The resulting BD staging model describes the progression of mood psychopathology, nonmood psychopathology, and functional impairment in three independently rated dimensions. The stages of the mood psychopathology are M0 (at risk for BD having a 1st or 2nd degree family member with BD); M1 (prodromal); M2 (first episode classifying for BD-I or BD-II); M3 (recurrent BD); and M4 (chronic unremitting BD), with various substages. Single or recurrent major depression in persons at familial risk for BD is positioned in stage M1. The stages for nonmood psychopathology are: N0 (no symptoms); N1 (subsyndromal symptoms); N2 (one nonmood disorder); N3 (two nonmood disorders); N4 (three or more nonmood disorders). The stages for functional impairment are: F0 (no); F1 (mild); F2 (moderate); F3 (marked); and F4 (severe impairment). Fictitious case vignettes are presented to demonstrate how to apply the model. Limitations of clinical staging are discussed. The proposed three-dimensional clinical staging model for illness progression comprehensively captures the complexity of illness presentation and heterogeneous illness progression in BD, including psychiatric comorbidities and degree of functional impairment. The model provides a framework that requires validation in research and clinical practice.
Cognitive decline is a major challenge in aging. Transcranial alternating current stimulation (tACS) modulates neural oscillations, potentially aiding cognition. Due to variation in late-life tACS studies, we conducted the first meta-analysis in older adults (≥ 60 years) to estimate pooled cognitive effects and determine if protocol parameters explain outcome variability. We searched Medline/PubMed, Embase, Cochrane Library, and ClinicalTrials.gov (up to September 17, 2025) for studies examining tACS effects on cognition in adults age ≥ 60 years, including healthy aging, mild cognitive impairment (MCI), and Alzheimer's disease (AD). Risk of bias was assessed using RoB 2 and ROBINS-I. Random-effects meta-analyses using Hedges' g were performed, with sensitivity analyses to handle outliers and heterogeneity. Twenty-two studies (n = 826 participants) were included. The primary meta-analysis revealed a significant moderate effect of tACS on cognition (g = 0.70, 95% CI 0.38-1.02), though with high heterogeneity (I2 = 88.5%). Excluding one influential outlier yielded a more conservative and stable estimate (g = 0.55, 95% CI 0.39-0.70, I2 = 47.1%). Subgroup analyses showed homogenous effects in MCI (g = 0.59, I2 = 0%). Memory was the most responsive domain. Meta-regressions did not identify significant associations between outcomes and specific stimulation parameters. tACS was associated with improvements in cognitive outcomes in older adults, with more consistent evidence observed for memory in individuals with MCI. However, findings in healthy older adults and AD were more variable and should be interpreted in light of substantial methodological heterogeneity. Overall, the pooled estimate reflects an average across diverse populations and intervention protocols rather than a single, clinically uniform effect. Future research should prioritize standardized, dose-response protocols to support clinical translation. PROSPERO CRD42025629824.
To identify the main fears related to childbirth in pregnant women in a University Hospital in Southern Brazil, from 2021 to 2023, according to the motivations for fear. A cross-sectional study was conducted with pregnant individuals between 28 and 37 weeks of gestation who answered two self-administered questionnaires: the Wijma Delivery Expectancy Questionnaire (Version A) and a researcher-designed instrument on specific childbirth fears. Based on scores, participants were classified into four levels of fear (low to very high). Descriptive statistics were applied, and differences in the distribution of specific childbirth-related fears across levels of fear were analyzed using the chi-square or Fisher's exact tests (p ≤ 0.05). The sample included 334 participants. Moderate fear was most prevalent (44.9%), with tokophobia occurring in 4.8%. High fear levels were significantly associated with fear of panicking, losing control, not knowing labor duration, and intense pain (p < 0.001). These findings demonstrate that the unpredictability of childbirth and the perception of lack of control over the situation are key factors in intensifying childbirth fear, emphasizing that incorporating psychological support and a structured health education program into prenatal care may help reduce fear and improve maternal and neonatal outcomes. Identificar os principais medos relacionados ao parto em gestantes em um Hospital Universitário do Sul do Brasil, de 2021 a 2023, de acordo com as motivações para o medo. Foi realizado um estudo transversal com gestantes entre 28 e 37 semanas de gestação, que responderam a dois questionários autoaplicáveis: o Wijma Delivery Expectancy Questionnaire (Versão A) e um instrumento desenvolvido pelos pesquisadores sobre medos específicos relacionados ao parto. Com base nas pontuações, os participantes foram classificados em quatro níveis de medo (baixo a muito alto). Foram aplicadas estatísticas descritivas e as diferenças na distribuição de medos específicos relacionados ao parto, de acordo com os níveis de medo, foram analisadas utilizando os testes qui-quadrado ou exato de Fisher (p ≤ 0,05). A amostra incluiu 334 participantes. O medo moderado foi o mais prevalente (44,9%), seguido pela tocofobia em 4,8% dos casos. Níveis elevados de medo estiveram significativamente associados ao medo de pânico, perda de controle, desconhecimento da duração do trabalho de parto e dor intensa (p < 0,001). Esses achados demonstram que a imprevisibilidade do parto e a percepção de falta de controle sobre a situação são fatores-chave que intensificam o medo do parto, enfatizando que a incorporação de apoio psicológico e um programa estruturado de educação em saúde no pré-natal pode ajudar a reduzir o medo e melhorar os resultados maternos e neonatais.
The Sociedad Española de Patología Digestiva (SEPD) has developed a position statement setting out expert-consensus recommendations considered essential for the structure, organization, and functioning of Bariatric and Metabolic Endoscopy Units (BMEU) operating within Departments of Gastroenterology, with the aim of enabling these units to carry out their activities efficiently and with high quality. The document defines the BMEU -including a proposed minimum activity volume as a certification criterion- and establishes provisional certification criteria relating to their organization, structure, service portfolio, processes, articulation with the pharmacological treatment of obesity, framework criteria for patient selection, safety, and aspects concerning training and research. The provisional certification criteria have been classified as mandatory (recommendations whose fulfilment is required to qualify for SEPD certification) and recommendations. These provisional certification criteria should be reviewed within no more than five years, on the basis of the experience gained in Spanish BMEUs and the evolution of scientific knowledge in bariatric and metabolic endoscopy and in the comprehensive management of obesity. The development of performance indicators-including patient-reported outcome measures (PROMs)-is identified as a relevant challenge, as is the generation of evidence on the association between consensus-based recommendations on BMEU structure and activity and health outcomes. The methodological limitations of the present document and the need to incorporate the patient perspective in future updates are explicitly acknowledged.
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To evaluate whether bullying, physical aggression, and peer rejection cluster among Brazilian adolescent students and whether aggressive-behavior cluster pairs are associated with leisure-time physical activity according to sex. This cross-sectional study analyzed data from PeNSE 2019, including 157,921 adolescents aged 13 to 17 years. Bullying, physical aggression, and rejection in the previous 30 days were dichotomized as present or absent. Clustering was assessed using observed/expected ratios (O/E) and 99% confidence intervals. Logistic regression models estimated associations between aggressive-behavior cluster pairs and sufficient leisure-time physical activity, defined as ≥300 min/week. Bullying, physical aggression, and rejection were reported by 39.41%, 14.60%, and 26.69% of adolescents, respectively. The simultaneous occurrence of all three behaviors exceeded expectation in the overall sample (O/E = 127.69), boys (O/E = 122.05), and girls (O/E = 170.23). In boys, physical aggression plus rejection was associated with lower odds of sufficient leisure-time physical activity (aOR = 0.99, 99%CI: 0.97-0.99). In girls, physical aggression plus rejection (aOR = 0.88, 99%CI: 0.86-0.89), bullying plus rejection (aOR = 0.97, 99%CI: 0.96-0.98), and bullying plus physical aggression (aOR = 0.98, 99%CI: 0.97-0.99) were associated with lower odds of sufficient leisure-time physical activity. Aggressive behaviors clustered among Brazilian adolescents and were associated with leisure-time physical activity, particularly among girls. Because this study was cross-sectional and several effect sizes were small, findings should be interpreted as associations rather than causal effects.
The Columbia Suicide Severity Rating Scale (C-SSRS) is widely used for assessing suicidal thoughts and behaviors, yet evidence on the validity of its scoring outputs in community-based samples from low- and middle-income countries remains scarce. Participants included 2076 young adults (mean age 23.45, 47% female) from the Brazilian High-Risk Cohort Study at 15-year follow-up. We evaluated C-SSRS Ideation Severity (0-5) and Intensity (0-25) scores using internal consistency, confirmatory factor analysis, item response theory, Guttman scalability, convergent/discriminant validity, known-groups comparisons, ROC analysis, and longitudinal associations with childhood risk factors via adjusted count regression. 37% endorsed lifetime suicidal ideation; 16% reported attempts. Internal consistency was low for severity (KR-20 = 0.57) and intensity (ω = 0.67). A two-factor model improved fit over a unidimensional structure (CFI = 0.997 vs. 0.954). Guttman scalability was acceptable (CR = 0.940) but with violations at higher severity levels. C-SSRS severity discriminated attempt history (AUC = 0.93). Prior self-harm was the strongest longitudinal predictor (IRR = 2.06), with a dose-response across risk categories. C-SSRS scores show low internal consistency and multidimensional structure, yet strong clinical discrimination and robust 15-year longitudinal associations. Caution is warranted when using these scores as continuous indices.
Anxiety disorders are associated with impaired inhibitory neurotransmission mediated by γ-aminobutyric acid type A (GABA-A) receptors. Although benzodiazepines remain effective anxiolytics, their clinical utility is limited by sedation, cognitive impairment, tolerance, and dependence, prompting the search for mechanistically distinct GABAergic modulators. Among cannabinoid-related molecules, the strongest evidence for direct GABA-A receptor modulation concerns the endocannabinoid 2-arachidonoylglycerol (2-AG), which potentiates recombinant human α1β2γ2 receptors through residues located in the M4 helix of the β2 subunit. Here, we review the structural architecture, biophysical properties, and pharmacological profile of the human GABA-A α1β2γ2 isoform as the relevant molecular framework for evaluating this mechanism, while discussing the broader relevance of cannabinoid-related ligands and selected phytocannabinoids without assuming mechanistic equivalence. We further assess the hypothesis that 2-AG reaches the β2-M4 site through a membrane-access route and identify five conceptual barriers that currently limit translation of this mechanism into anxiolytic drug development: supraphysiological effective concentrations, unresolved synaptic-versus-extrasynaptic actions, uncertain subtype selectivity, incomplete validation of lipid-environment effects, and lack of clinical evidence linking this mechanism to anxiolysis in humans. We conclude that direct modulation through β2-M4 defines a mechanistically intriguing allosteric pathway distinct from benzodiazepine action; however, its location on a shared β2 subunit and the micromolar concentrations required for modulation represent substantial obstacles to the rational design of anxioselective agents based on this mechanism.
Research on diabetic retinopathy (DR) usually emphasizes hyperglycemia and other causes like dyslipidemia, which are still not well understood. This study examined the effects of palmitic acid (PA) exposure, alone and combined with high glucose (G25), on Müller Glial Cell (MGC) dysfunction and angiogenic signaling. Primary MGC cultures were treated with G25 (25 mM), PA (250 µM), or PA + G25 for 24 and 48 h, followed by assessments of cell viability and analysis of the Vascular Endothelial Growth Factor (VEGFA)/VEGFA receptor 2 (VEGFR2) pathway through immunofluorescence, Western blot, and ELISA. Additionally, Gaussian mixture models (GMMs) were used to identify phenotypic subpopulations based on fluorescence intensity. The results showed that while hyperglycemia did not cause significant changes, PA and PA + G25 induced apoptosis-related cell death and significantly increased the expression of VEGFA, VEGFR2, HIF-α, and SP1. Although broad phenotypic diversity was observed at 24 h, by 48 h, a distinct shift towards an angiogenic phenotype was noted, with significantly elevated VEGFA/VEGFR2 levels. In summary, this research demonstrates that PA acts as a critical inducer of an angiogenic secretory phenotype in MGCs, indicating that lipid-mediated signaling plays a vital role in neovascularization in DR, possibly independent of glucose levels.
White matter hyperintensities (WMHs) are a robust marker of brain aging and dementia risk, typically attributed to vascular pathology. However, impaired astrocytic support may also contribute. The locus coeruleus (LC), which degenerates early in aging and Alzheimer's disease, provides widespread noradrenergic projections that regulate astrocytic metabolism via β2-adrenergic signaling. In a healthy aging cohort (N = 106), we quantified LC volume, WMHs, and voxel-wise (q-WMHs). Associations were tested, controlling for age, cardiovascular risk, and other subcortical nuclei. Spatial partial least squares regression related q-WMH patterns to LC volume, age, and cortical adrenergic receptor expression. LC volume was independently associated with WMH burden and mediated age-related WMH increases. A latent q-WMH pattern aligned with cortical β2-adrenergic receptor expression and mediated its association with WMH burden. LC degeneration may contribute to regional WMH vulnerability through noradrenergic mechanisms consistent with astrocytic β2-adrenergic signaling, highlighting a potential nonvascular pathway influencing white matter integrity.