Bipolar disorder affects around 2% of the population and is linked with reduced life expectancy and socioeconomic burden. Depressive episodes are difficult to treat and typically more prevalent, enduring and burdensome than manic episodes. The use of antidepressants alone has limited effect and is associated with significant clinical risk through polarity switch. Current National Institute for Health and Care Excellence guidelines recommend quetiapine, olanzapine (with or without fluoxetine) and lamotrigine; however, these medications have limited efficacy, tolerability and acceptability. The ASCEnD study aims to assess the clinical and cost-effectiveness of aripiprazole plus sertraline compared with quetiapine, offering potential improvements for outcomes in bipolar depression. The study is funded by the National Institute for Health and Care Research Health Technology Assessment programme (NIHR132773). ASCEnD is a prospective, two-arm, superiority, individually 1:1 randomised, controlled, pragmatic, parallel group, type A open-label clinical trial of aripiprazole/sertraline medication combination compared with quetiapine for bipolar depression. The study is conducted in the UK National Health Service setting with the aim of recruiting and randomising 270 participants followed-up for 24 weeks. Adults with bipolar disorder self-refer or are recruited through primary and secondary care services. The primary outcome is change in depressive symptoms 12-16 weeks after randomisation. Secondary outcomes include measures of symptom change, treatment satisfaction, tolerability, medication adherence, concomitant medication use, psychosocial functioning, quality of life and cost-effectiveness and informal carer measures of quality of life and costs of caring. The exploratory outcome is change in participant reward and punishment responsiveness. Analysis will follow a prespecified statistical analysis plan. A nested qualitative study is included to examine feasibility and acceptability of the trial design. A Clinical Trial Authorisation from Medicines and Healthcare products Regulatory Agency, and approval from the Health Research Authority (IRAS 1007468) and North East - Newcastle and North Tyneside 1 Research Ethics Committee (23/NE/0132) were obtained. Results will be disseminated through peer-reviewed publications, conference presentations and lay summaries for participants and patient and public groups. ISRCTN63917405.
People with severe mental illness (SMI) have a higher risk of HIV infection than the general US population. Despite this increased prevalence, robust efforts to engage this population in routine HIV testing, timely linkage to and ongoing engagement in care, and treatment adherence have been challenging. We sought to identify solutions at the health care delivery system level, as well as policies at the state and local level, that might affect HIV-related health outcomes for this key population, particularly those that featured integrated care models. We recruited key stakeholders in 10 states within the United States, based on HIV prevalence and approaches to HIV and mental health services. From June 2018 to May 2021, we conducted 64 in-depth interviews with key informants which lasted 45-90 minutes. Interviews were recorded and transcribed. Informants included state and county-level public administrators in HIV and/or behavioral health; HIV and behavioral health clinic administrators, medical providers, and case managers; service providers at non-profit agencies serving those with SMI and/or HIV; and academics. Interview topics included HIV testing policies and systems, HIV linkage and treatment policies and organization of SMI and HIV health care systems, funding streams, recent care integration efforts, and electronic data sharing. Transcripts were coded for broad themes, and segments were further reduced for key content. Key factors leading to improvements in HIV-related outcomes for those with SMI include state and local efforts to integrate physical and mental health services, funding requirements for grantees to perform HIV testing, shared electronic health records, ability to combine funding streams, expansion of telehealth services to deliver psychiatric and behavioral health care, and charismatic leaders at the state or local level championing care integration. Fragmented and decentralized physical and behavioral health care systems that disincentivized care integration, policies that limited data sharing, stigma, a depleted workforce, and a lack of collegial working relationships between behavioral health and infectious disease leaders were perceived barriers to improved HIV outcomes for those with SMI. Scaling up facilitators of implementation and addressing the present challenges has the potential to promote successful implementation of integrated care models and positively impact the health and well-being of individuals living with HIV and SMI.
Scarce human resources for health and high injury-related mortality coincide with inequities in accessing quality trauma education programs in low- and middle-income countries. Existing observational studies restrict assessments of trauma training program impacts on providers' knowledge. Evaluation of trauma education programs outside clinical trial settings hinders their effectiveness in influencing clinical practice and policy changes for patient outcomes. This study aimed to assess the impact of the Rural Trauma Team Development Course (RTTDC) on clinical processes and patient outcomes of motorcycle-accident-related neurological and/or musculoskeletal injuries in selected Ugandan hospitals. This was a pragmatic 2-arm, parallel, multiperiod, cluster randomized controlled trial. The participants were trauma care frontline personnel and patients aged 2-80 years at 3 intervention and 3 control Ugandan hospitals (1:1 allocation). Hospitals were randomly allocated to intervention or control groups using permuted block sequences. Sequence codes were generated off-site by an independent statistician using Sealed Envelope (version 1.23.1; Sealed Envelope Ltd). Both patient participants and outcome assessors were blinded to allocation. Hospital allocation codes were concealed until the point of assignment. In the intervention arm, 500 trauma care frontliners received RTTDC, whereas patients received standard care. In the control arm, patients received standard care without RTTDC for staff. The primary outcomes were time from accident to admission and from referral to dispatch. The secondary outcomes were all-cause 90-day mortality and morbidity related to neurological and/or musculoskeletal injuries. We followed the CONSORT (Consolidated Standards of Reporting Trials) guidelines for reporting cluster randomized trials. We analyzed 1003 participants (501 intervention and 502 control). The intervention arm had a shorter median (IQR) prehospital time of 1 hour (0.50-2) and referral-to-dispatch interval during interfacility transfers of 2 hours (1.25-2.75). This contrasted with 2 hours (1.50-4) and 4 hours (2.50-4.10) in the control arm, respectively (P<.001). The 90-day mortality was more than halved in the intervention (5%, 24/457) vs in the control arm (13%, 58/430) (P<.001). Fewer participants in the intervention group had unfavorable Glasgow Outcome Scale scores (9%, 42/457) vs (20%, 87/430) (P<.001). No difference was found in musculoskeletal injury morbidity outcomes (P=.57). Rural trauma team development training demonstrated potential for improved organizational time efficiency and clinical outcomes for neurological injuries without negatively impacting musculoskeletal injury morbidity outcomes. Evidence from this trial supports that locally contextualized, trainee-led rural trauma team development interventional programs are feasible in low- and middle-income countries. However, despite being a multicenter study conducted across 6 geographically distinct hospitals, the research is limited in generalizability due to its focus on a single health care system within 1 country, retrospective trial registration, exclusion of prehospital deaths, and a relatively small number of clusters, which could introduce measurement bias.
Autism spectrum disorder (ASD) remains underexplored in Southeast Asia, with limited characterization of its molecular underpinnings and clinical heterogeneity. This study investigated transcriptomic variation and its relationship to clinical diversity in Thai children with ASD using integrated molecular and phenotypic analyses. Peripheral blood transcriptomic profiling was performed in 150 ASD and 70 typically developing (TD) children to identify differentially expressed transcripts (DETs), followed by pathway enrichment, unsupervised molecular clustering, and integrative multiomics modeling. Clinical data from 200 ASD and 110 TD participants were analyzed in parallel to evaluate screening performance and derive phenotype-based subgroups. Differential expression analysis identified 1,407 DETs with significant enrichment of autism-associated genes. Pathway analysis consistently implicated dysregulation of protein-synthesis machinery. Unsupervised transcriptome-based clustering revealed three molecular subgroups characterized by translational, innate-immune, and interferon-associated signatures, which did not directly correspond to clinical severity, age, or cognitive level, indicating structured biological heterogeneity beyond symptom-based classification. Integration of transcriptomic and phenotypic data demonstrated moderate cross-domain correspondence. Among recurrent molecular signals, MBD2 showed consistent upregulation across subgroups and strong associations with social-interaction measures (r = 0.74). In parallel, clinical machine-learning models showed high within-cohort screening performance, while a refined 17-transcript panel achieved robust discriminative accuracy, supporting the complementary role of molecular features in ASD stratification. Transcriptomic stratification reveals biologically structured heterogeneity in ASD that is only partially reflected in clinical presentation, supporting a multilayered framework integrating molecular and phenotypic dimensions.
Bipolar disorder (BD), a psychiatric condition with significant illness burden, is associated with high suicide risk. To date, there are relatively fewer studies examining clinical factors including psychotropic drug use and dosing associated with suicide attempts in patients with BD, especially within Asia. We conducted a cross-sectional survey across 13 Asian sites on both outpatients and inpatients with BD to examine the prevalence of lifetime suicide attempts and clinical correlates, such as demographic features, treatment setting, and illness characteristics (including illness course, psychotropic drug use and dose). Univariate analysis was performed to identify factors associated with lifetime suicide attempts, and multivariable logistic regression analysis was performed to control for confounders. A total of 2114 patients with BD (47.7% male, mean age 42.4 ± 15.2 years) were surveyed, with lifetime suicide attempt rate of 17.2%. Univariate analysis found that lifetime suicide attempts were associated with demographic (younger age, females), illness features (depressed and mixed illness phases, recurrent illness course, depression at illness onset, lifetime rapid cycling), and treatment factors (ECT in past year, antidepressant prescription). Multivariable logistic regression showed that factors associated with lifetime suicide attempt included inpatient status, depressive and mixed phases of BD, presence of rapid cycling in the past year and depression at illness onset. Our study noted a significant lifetime suicide attempt rate in BD patients across Asian sites and identified germane clinical factors. This allows for better identification and monitoring of relevant BD patients, allowing for optimisation of care for these individuals.
Background: Posttraumatic stress disorder (PTSD) is a severe and frequent affection that is highly comorbid to major depressive disorder. Comorbid PTSD and depression increase the risk of treatment-resistant depression (TRD), with a high risk of functional impairment and suicide. Esketamine nasal spray is a recent validated treatment for TRD, but its efficacy on comorbid TRD-PTSD remains insufficiently documented. In particular, it is unknown whether traumatic re-experiencing may occur during esketamine treatment and if so, how it influences clinical outcomes.Objectives: Our objective was to describe trauma re-experiencing episodes during esketamine sessions and their impact on clinical trajectories within an ecological sample of patients with comorbid TRD-PTSD.Methods: We retrospectively collected clinical data of patients receiving esketamine nasal spray for TRD for whom at least one trauma re-experiencing episodes had been identified by clinicians during esketamine sessions across 11 psychiatric departments.Results: Between February 2020 and March 2023, 22 adult patients with TRD met inclusion criteria. In sixteen patients (72.7%) trauma re-experiencing episodesdisappeared as the sessions progressed. In six patients (27.3%), esketamine treatment was stopped because of trauma re-experiencing episodes. When esketamine was continued, favourable clinical outcomes were observed both for depression and PTSD (depression response rate: 45.5% and remission rate: 22.7%; PTSD improvement rate: 45.5% and remission: 18.2%).Limitations: The retrospective design of the study and the absence of a comparator group are the main limitations of our study.Conclusions: Our results suggest that esketamine can be safely administered to patients with comorbid PTSD and TRD, and that the occurrence of trauma re-experiencing episodes does not hinder clinical response. Esketamine nasal spray is validated for treatment-resistant depression, but it is efficacy on comorbid post-traumatic stress disorder is poorly documented.Trauma re-experiencing episodes can occur during esketamine administration.Esketamine could be safely administered to patients with comorbid PTSD and TRD.Esketamine-related flashback does not hinder its clinical response. Antecedentes: El Trastorno de Estrés Postraumático (TEPT) es una afección grave y frecuente que presenta una alta comorbilidad con el Trastorno Depresivo Mayor. La comorbilidad entre TEPT y Depresión incrementa el riesgo de Depresión Resistente al Tratamiento (DRT), con un elevado riesgo de deterioro funcional y suicidio. El espray nasal de esketamina es un tratamiento recientemente validado para la DRT, pero su eficacia en la DRT-TEPT comórbidos sigue insuficientemente documentada. En particular, se desconoce si durante el tratamiento con esketamina pueden presentarse reexperimentaciones traumáticas y, de ser así, cómo influyen en los resultados clínicos. Objetivos: Nuestro objetivo fue describir los episodios de reexperimentación del trauma durante las sesiones con esketamina y su impacto en las trayectorias clínicas dentro de una muestra ecológica de pacientes con DRT-TEPT comórbidos. Métodos: Recopilamos retrospectivamente los datos clínicos de pacientes que recibieron esketamina en spray nasal para el Tratamiento de la Depresión Resistente (DRT), en quienes los clínicos identificaron al menos un episodio de reexperimentación del trauma durante las sesiones de esketamina en 11 servicios de psiquiatría. Resultados: Entre febrero de 2020 y marzo de 2023, 22 pacientes adultos con DRT cumplieron los criterios de inclusión. En dieciséis pacientes (72,7%), los episodios de reexperimentación del trauma desaparecieron a medida que avanzaban las sesiones. En seis pacientes (27,3%), el tratamiento con esketamina fue interrumpido debido a los episodios de reexperimentación del trauma. Cuando el tratamiento con esketamina se continuó, se observaron resultados clínicos favorables tanto en la depresión como en el TEPT (tasa de respuesta en depresión: 45,5% y tasa de remisión: 22,7%; tasa de mejoría en TEPT: 45,5% y remisión: 18,2%). Limitaciones: El diseño retrospectivo del estudio y la ausencia de un grupo comparador constituyen las principales limitaciones de nuestro estudio. Conclusión: Nuestros resultados sugieren que la esketamina puede administrarse de forma segura a pacientes con TEPT y DRT comórbidos, y que la aparición de episodios de reexperimentación del trauma no interfiere con la respuesta clínica.
Posttraumatic stress disorder (PTSD) is a chronic and disabling condition and identifying beneficial therapies is timely and important. We aimed to estimate the efficacy of 3,4-methylenedioxymethamphetamine-assisted therapy (MDMA-AT) compared with control on clinical and functional outcomes in PTSD. A PRISMA-compliant search (PROSPEROCRD42022353261) up to August 14, 2025, covered nine databases and manual searches to identify randomised controlled trials (RCTs). Methodological quality was assessed using the Cochrane Risk of Bias tool (RoB2), and the certainty of the evidence for each outcome was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. Of 1035 records identified, 14 studies met inclusion criteria for qualitative synthesis; eight trials provided sufficient data for quantitative synthesis (k = 24). Random-effects meta-analyses indicated that MDMA-AT was associated with reductions in PTSD symptom severity (n = 298, k = 9, SMD = -1.19, 95 % CI [-1.95, -0.42]; I² = 68.8 %, τ2 = 1.02), dissociative symptoms (n = 148, k = 5, SMD = -0.37, 95 % CI [-0.70, -0.04]; I² = 0.0 %, τ2 = 0), and may improve functioning (n = 227, k = 4, SMD = -0.83, 95 % CI [-1.47, -0.19]; I² = 61.2 %, τ2 = 0.27). No clear evidence of benefit was observed for depressive symptoms. Most studies showed a high risk of bias in the measurement of the outcome, and some concerns due to deviations from the intended intervention; the overall certainty of the evidence was very low. The number of trials remains limited, with considerable heterogeneity in certain outcomes, small sample sizes, and the absence of active controls in most studies, which likely compromised blinding integrity. Current findings suggest that MDMA-AT may warrant further investigation as a potential treatment for PTSD; however, larger, higher-quality RCTs with active controls and long-term follow-up are needed to determine its efficacy.
Introduction/background: Individuals with Down syndrome (DS) face a higher and earlier risk of overweight and/or obesity than the general population, influenced by factors like limited physical activity, suboptimal diet, stress, and sleep disorders. Despite the impact these lifestyle factors can have, there is a significant lack of robust, evidence-based guidelines for managing overweight and obesity in these individuals, particularly for the adult population. Results: Based on findings from an observational study across three European sites, within the EU Horizon-2020 GO-DS21 project, in this short communication, we highlight some key insights for developing effective prevention and management strategies for overweight and obesity in people with Down syndrome. Conclusions: In general terms, effective overweight and obesity management demands a holistic approach, integrating tailored diet and physical activity and actively addressing co-occurring health conditions. Moreover, the active participation of the family and peers is crucial for promoting sustainable healthy habits and for enhancing the overall quality of life of people with Down syndrome.
Sleep is essential for overall health and well-being, but assessing sleep architecture is often costly and time-consuming, relying primarily on polysomnography (PSG). While wrist-worn wearables offer alternatives, they face limitations regarding user compliance, such as battery charging and physical discomfort. Nearable devices address these burdens, but they regularly lack rigorous validation, especially in real-world settings. This study evaluates the accuracy and reliability of the Withings Sleep Analyzer (WSA), a contactless sleep monitoring device, compared to PSG in a home setting using a large and diverse cohort of healthy individuals. A total of 117 healthy volunteers (69 women; mean 39.9, SD 11.4 years), prospectively recruited from the general population, underwent home-based PSG and simultaneous WSA recording. The study was conducted under free-living conditions, without constraints on substance intake, prebedtime activity, or forced sleep schedules. The main outcomes were the device's performance in sleep-wake distinction and sleep stage identification using accuracy, kappa, sensitivity, specificity, and the mean absolute error of sleep measures on the entire population and demographic, clinical, and environmental subgroups. WSA demonstrates high sensitivity (93%, 95% CI 92%-94%) for sleep detection and moderate sensitivity (73%, 95% CI 69%-77%) for wakefulness, achieving an overall accuracy of 87% (95% CI 86%-87%) for sleep-wake distinction. The device showed consistent performance across various demographic subgroups, including different age, BMI, mattress, and sleep arrangements (with or without bed partner) categories. Challenges were noted in accurately classifying specific sleep stages, particularly in distinguishing between light and deep sleep, with a mean accuracy of 63% (95% CI 62%-65%) and a Cohen κ of 0.49 (95% CI 0.47-0.51). The WSA tended to overestimate total sleep time (20 min, 95% CI 10 min to 31 min) and light sleep (1 h 21 min, 95% CI 1 h 8 min to 1 h 36 min) while underestimating rapid eye movement (-15 min, 95% CI -23 min to -8 min) and deep sleep (-46 min, 95% CI -59 min to -34 min) durations. Disagreements between expert reviewers were mirrored in part by the WSA's misclassifications. Participants reported altered perceived sleep quality during the night with the PSG, suggesting discomfort during sleep. Being contactless and placed under the mattress, the WSA offers a promising approach to long-term sleep monitoring in natural home environments. It shows competitive performance in sleep-wake and sleep stage identification compared to other consumer devices. Progress in wearable and nearable devices is necessary to enhance their accuracy to better support the monitoring of populations with impaired sleep, although limited by an imperfect gold standard. This work also emphasizes the importance of using large, diverse, and challenging datasets, as well as the need for a standardized methodology for accurate sleep stage classification.
Apathy and impulsivity are common in syndromes associated with frontotemporal lobar degeneration (FTLD). They are associated with high carer distress and poor patient outcomes. There are limited treatment options and progress has been hindered by a lack of appropriate outcome measures. This study aimed to develop a carer-rated questionnaire oriented to people with syndromes associated with FTLD. Principal component and Rasch analysis were conducted on carer-, clinician- and patient-reported questionnaires and performance-based tests of behavioural change in the "Pick's Disease and Progressive Supranuclear Palsy Prevalence and Incidence" (PiPPIN) study. We identified two key components which informed subsequent item development for a novel scale which we call the Cambridge Questionnaire for Apathy and Impulsivity Traits (CamQUAIT). The resulting scale comprised two subscales assessing "motivation and support" (CamQUAIT-M) and "impulsivity and challenging behaviours" (CamQUAIT-C). An independent sample of 132 carers for people with FTLD-associated syndromes completed the CamQUAIT, along with a battery of existing measures. The CamQUAIT was reduced to 15 items following Rasch analysis. Both subscales showed good construct validity as assessed by high Person separation index (CamQUAIT-M = 0.9; CamQUAIT-C = 0.7) and Cronbach's alpha (CamQUAIT-M = 0.9; CamQUAIT-C = 0.8). The subscales correlated moderately with each other (r = 0.376, p < 0.001), and with existing measures of behavioural change. The CamQUAIT is a targeted measurement tool to assess apathy, impulsivity, and related behavioural change in the context of FTLD-related syndromes. The scale demonstrates good measurement properties and is sensitive to group differences, providing a suitable outcome measure to evaluate novel symptomatic treatments.
BackgroundBlood pressure is a major modifiable risk factor for both cardiovascular disease and dementia, yet its relationship with blood-based biomarkers of Alzheimer's disease (AD) and neurodegeneration remains unclear.ObjectiveTo evaluate associations of systolic blood pressure, diastolic blood pressure (DBP), and pulse pressure with plasma biomarkers of AD and neurodegeneration, and to examine whether these associations differ across Non-Hispanic White, Non-Hispanic Black, and Hispanic participants.MethodsParticipants were 2636 cognitively normal older adults enrolled in the Health and Aging Brain Study-Health Disparities. Participants with hypotension or hypertensive crisis were excluded. The outcomes were plasma biomarkers including phosphorylated Tau181, phosphorylated tau217 (p-Tau217), amyloid-β 42 to 40 ratio, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP). Adjusted multivariable linear regression models evaluated associations between blood pressure measures and log transformed plasma biomarker concentrations. Additional models examined the American Heart Association blood pressure categories as a predictor.ResultsHigher DBP was associated with lower concentrations of neurodegeneration related plasma biomarkers, including p-Tau217, NfL, and GFAP, after correction for multiple comparisons. Analyses using American Heart Association blood pressure categories demonstrated that stage 1 and stage 2 hypertension were associated with lower GFAP concentrations compared with normal blood pressure, with patterns that were broadly consistent across racial and ethnic subgroups.ConclusionsIn this multi-racial ethnic cohort of cognitively normal older adults without hypotension or hypertensive crisis, higher DBP and clinical blood pressure categories were associated with lower levels of select plasma biomarkers of neurodegeneration (NfL and GFAP).
Previous studies of antidepressant prescribing patterns largely were limited to a single location or time, and very few involved Asia. This Asian Psychotropic Prescription Patterns Consortium study investigated pharmacoepidemiologic trends and factors associated with use and dosing of newer antidepressants across 12 Asian sites in 2003, 2013, and 2023. Data from each site included demographic, treatment setting, clinical features, and type and dosage of antidepressants prescribed. Sociodemographic and clinical variables were examined using univariate methods, followed by multivariable logistic and linear modeling. Of 8357 adult participants (59.8% female), 82.8% received at least one modern antidepressant. Use of these drugs was strongly associated with more recent year, younger age, inpatient status, and affective or anxiety-related disorders. Higher daily antidepressant doses were associated with inpatient status, male gender, more recent year, and younger age. This large, multisite study provides a two-decade overview of evolving antidepressant-prescribing patterns in 12 Asian sites and highlights patient characteristics associated with prescription of newer antidepressants and their dosage. Needed are further studies of psychotropic prescribing practices related to specific illness subtypes and their impact on psychosocial functioning over time among Asian patients.
Patients with atrial fibrillation (AF) who experience an ischemic stroke despite oral anticoagulation (OAC) face a high risk of recurrence and bleeding. We aimed to compare 90-day outcomes between patients with and without competing stroke etiologies after a breakthrough ischemic stroke while on OAC for AF. ASPERA-R retrospectively enrolled adults (>18 years) with AF who experienced a breakthrough ischemic stroke, defined as either first or recurrent event, occurring on continuous OAC (last intake ≤48 hours), across 35 centers from February 2020 to February 2025. Patients' eligibility required imaging-confirmed ischemic stroke, baseline vessel imaging, and a standardized 90-day follow-up. Patients with inadequate anticoagulant dosing or poor adherence were excluded. Competing etiologies were defined as any additional mechanism coexisting with cardioembolism and plausibly contributing to the index stroke. The primary outcome was 90-day recurrent ischemic stroke; secondary outcomes included modified Rankin Scale shift, myocardial infarction, and vascular and all-cause death. Bleedings were also evaluated. We performed inverse probability weighting to balance baseline covariates and applied Cox or regression models to compare outcomes. Among 1,649 patients (mean age 78 years, 47.8% male), 24.3% had competing etiologies, most commonly large artery atherosclerosis (59.9%). Considering the weighted population, 90-day recurrent ischemic stroke occurred more often in those with competing etiologies (6.0% vs 2.7%; adjusted hazard ratio [aHR] 2.62, 95% CI 2.01-3.42; p < 0.001). Risk was greatest for large artery atherosclerosis and other determined causes. Competing etiologies also had worse disability distribution (adjusted odds ratio 1.30, 95% CI 1.08-1.55; p = 0.005) and higher all-cause mortality (aHR 1.58, 95% CI 1.18-2.12; p = 0.002). Moderate-to-severe bleeding was higher with competing etiologies (aHR 1.82, 95% CI 1.08-3.09; p = 0.026), whereas 24-hour hemorrhagic transformation was less frequent (adjusted risk difference -4.3%, 95% CI -7.8% to -0.7%; p = 0.020). Other outcomes did not differ. One in 4 patients with AF and breakthrough ischemic stroke on OAC had competing etiologies, most often large artery atherosclerosis. These patients showed higher risk of recurrent stroke, functional dependence, mortality, and bleeding, highlighting the need for development of individualized secondary prevention. Main study limitations include observational retrospective design and incomplete data on on-treatment anticoagulation quality. ClinicalTrials.gov NCT06823466.
Adverse childhood experiences (ACEs) are well-established risk factors for mental disorders, yet their impact within vulnerable occupational groups remains insufficiently understood. Women engaged in sex work and social care are disproportionately exposed to violence and emotional stressors, potentially compounding the effects of early-life adversity. We conducted a mixed-methods study in Berlin, Germany, including 560 women (403 engaged in sex work, 157 in social care). Childhood adversity was assessed using the Childhood Trauma Questionnaire (CTQ-SF), and current psychiatric disorders were diagnosed via structured clinical interviews (MINI-DIPS). Severe ACE exposure was defined as moderate-to-severe trauma in at least two CTQ domains. Multivariable logistic regression models examined associations between ACE exposure and mental health outcomes, adjusting for age, socioeconomic indicators, and occupational stressors. In addition, 10 semi-structured interviews explored experiences with mental health care, coping strategies, and resilience. Severe ACE exposure was reported by 47% of women in sex work and 16% of women in social care work. Higher ACE exposure was associated with increased odds of depression [adjusted OR (aOR) 3.8, 95% CI 2.3-6.3], panic disorder (aOR 2.7, 95% CI 1.6-4.7), post-traumatic stress disorder (aOR 5.7, 95% CI 3.1-10.7), and substance use disorders (aOR 4.0, 95% CI 2.3-7.1). Qualitative findings highlighted the interplay of early adversity and occupational stress, alongside resilience through peer support and advocacy. ACEs substantially contribute to psychiatric morbidity among women in violence- and stress-exposed occupations. Trauma-informed approaches that integrate early-life adversity and occupational context are essential for prevention and care in these high-risk groups.
Postoperative delirium (POD) affects ∼20% of older surgical patients. It is associated with poor clinical outcome and increased mortality. We aimed to identify the major POD risk factors and to develop and validate a multivariate algorithm for individual POD risk prediction and risk evaluation in the very early postoperative period. BioCog is a prospective cohort study conducted in the anaesthesiology departments of two tertiary care centres in Germany and The Netherlands. Patients aged ≥65 yr with no preoperative dementia (Mini-Mental Status Examination ≥24) undergoing surgery with an expected duration of at least 60 min were enrolled and screened for POD according to DSM 5 until the seventh postoperative day. Clinical, neuropsychological, neuroimaging data, and blood were measured before and after surgery. We evaluated several models by sequentially adding blocks of variables. Gradient-boosted trees (GBT) with nested cross-validation were used for POD prediction. Model accuracy (area under the receiver-operating curve, AUC) and calibration were assessed (Brier score). Out of 929 patients, 184 (20%) experienced POD. A GBT algorithm using both preoperative data, characteristics of the intervention, and postoperative changes in laboratory parameters achieved the highest AUC (0.83, [0.79-0.86]) with a Brier score of 0.12 (0.12-0.13). Models combining preoperative with precipitating factors during surgery predict POD with high accuracy. This suggests that the resulting algorithms eventually may become useful to support clinical decision-making. NCT02265263.
Ketamine and esketamine have been increasingly used as adjunctive treatments for treatment-resistant depression (TRD), yet evidence on pharmacological interactions with commonly prescribed psychotropic medications remains limited. This study evaluated the association between concomitant lamotrigine, lithium, and benzodiazepine use and antidepressant outcomes during subcutaneous esketamine treatment in patients experiencing treatment-resistant depressive episodes, including unipolar and bipolar depression. We analyzed real-world clinical data from 178 patients treated between 2017 and 2023 at the Esketamine Clinic of the Mood Disorders Program, Universidade Federal de São Paulo. Participants received six weekly subcutaneous esketamine administrations (0.5-1.0 mg/kg), adjusted according to clinical response and tolerability. Changes in Montgomery-Åsberg Depression Rating Scale (MADRS) scores were examined using linear regression and linear mixed-effects models to assess associations between concomitant medication use and outcomes over time. MADRS scores decreased significantly from baseline to endpoint at week 6 (p < 0.001). Mixed-effects models showed a significant effect of time (β = -2.82 MADRS points per week, p < 0.001), indicating consistent symptom improvement. Concomitant benzodiazepine use was associated with higher MADRS scores across treatment weeks (β = 4.46, 95% CI [0.53-8.39], p = 0.026). Lamotrigine (β = 1.04, p = 0.777) and lithium (β = 1.70, p = 0.343) showed no significant effects, and no medication-by-time interactions were detected. Subcutaneous esketamine was associated with significant symptom reduction. Benzodiazepine use was associated with higher depressive symptom severity during treatment, whereas lamotrigine and lithium were not associated with differential trajectories. Prospective studies are needed to clarify medication-specific interactions.
Distressing dreams were previously reported to predict future all-cause dementia among predominantly white US participants aged 79-89 years, particularly in men. We investigated whether disturbing dreams (nightmares and bad dreams) were associated with all-cause and Alzheimer dementia (AD) among individuals aged 60-89 years from diverse international regions. Data were from six longitudinal cohort studies across Brazil, China, France, Italy, South Korea, and Taiwan (n = 10,238, 42.5% men). Cox regressions with a random effect for study investigated associations between disturbing dreams and incident dementia, with all participants and stratified separately by sex and baseline age. Analyses examined (i) any disturbing dreams and (ii) disturbing dreams at least once a week. Fully adjusted analyses included three studies with covariates for sleep problems, medications, mental and physical health, cognition, and APOE ε4 status. Disturbing dreams were reported by 24.2% overall and all-cause dementia, and AD incidence was 10.8 and 5.3 per 1000 person-years, respectively. In fully adjusted analyses, having any disturbing dreams was associated with increased incidence of all-cause dementia among 60-69-year-olds (hazard ratio [HR] 3.93, 95% confidence interval [CI] 1.32-11.67). There were no significant effects for older individuals. In fully adjusted sex-stratified analyses, having disturbing dreams at least once a week was associated with AD only among men (HR 3.59, 95% CI 1.44-8.96). We found some evidence for disturbing dreams being associated with incident all-cause dementia among individuals aged 60-69 years and with AD among men. The mechanisms potentially underlying these associations remain to be clarified.
Prenatal stress affects up to 74% of expectant mothers and has been implicated in shaping early child development. This study aims to examine the associations between both subjective (self-reported) and objective prenatal stress and infant temperament at 12 months of age. Additionally, we investigate whether maternal postpartum depression (PPD) mediates these associations. We analyzed data from 1,510 mother-infant dyads in the French EDEN birth cohort. Prenatal stress was assessed using the State Anxiety Inventory (STAI), the Center for Epidemiological Studies Depression Scale (CES-D), and a measure of negative life events (NLEs). Infant temperament at 12 months was measured using the Emotionality Activity Sociability (EAS) questionnaire. Adjusted logistic regression models and mediation analyses were used to assess direct and indirect effects. Prenatal anxiety was associated with greater infant sociability, while prenatal depression predicted increased emotionality and shyness. Objective stress was related to lower infant activity. Mediation analyses revealed that PPD partially mediated the effects of prenatal depression and anxiety on infant emotionality and shyness, accounting for approximately 32% of the association between prenatal depression and infant emotional temperament. No mediation effect was found for the activity domain, although a small inverse direct association was observed. Our findings suggest that maternal prenatal stress influences infant temperament in a trait-specific manner and that PPD plays a mediating role in certain domains. These results highlight the importance of addressing both prenatal and postnatal maternal stress when considering early emotional and behavioral development in children. not applicable.
Management after an ischemic stroke occurring despite direct oral anticoagulant (DOAC) therapy for atrial fibrillation (AF) varies widely. Switching anticoagulation is common in clinical practice, although evidence supporting this strategy is limited. To evaluate whether continuation of treatment with the same DOAC was noninferior to switching oral anticoagulant therapy with respect to 90-day clinical outcomes. This multicenter registry-based cohort study with an emulated target trial design included consecutive adult patients with AF who experienced a breakthrough ischemic stroke while receiving uninterrupted DOAC therapy and resumed anticoagulation therapy thereafter. Patients were enrolled between February 2020 and February 2025, across 35 stroke centers in 9 countries in Europe and North Africa, with a standardized 90-day follow-up. The dataset was locked on September 1, 2025. A noninferiority comparison of switching vs continuation strategies was performed. Baseline confounding was addressed using inverse probability of treatment weighting (IPTW). The primary noninferiority margin was an absolute risk difference of 3.0 percentage points in 90-day net clinical benefit. The intervention group switched to treatment with a different DOAC or vitamin K antagonist; the comparator group continued therapy with the prestroke DOAC. The primary outcome was 90-day net clinical benefit, defined as recurrent ischemic stroke and moderate to severe bleeding. Secondary outcomes included recurrent ischemic events, symptomatic intracerebral hemorrhage, moderate to severe extracranial bleeding, all-cause mortality, and vascular death. Among 1006 patients included in the analysis (median age, 80.4 [IQR, 73.4-85.4] years; 503 female [50.0%] and 503 [50.0%] male), 463 (46.0%) continued the same DOAC therapy and 543 (54.0%) switched therapy. After IPTW adjustment, the 90-day net clinical benefit was 4.9% with switching and 5.1% with continuation, corresponding to a risk difference of -0.3 percentage points (90% CI, -2.7 to 2.1 percentage points), meeting the prespecified noninferiority criterion. For recurrent ischemic events and bleeding outcomes, the absolute differences were within the predefined noninferiority margins. Noninferiority was not demonstrated for all-cause or vascular mortality. In patients with breakthrough ischemic stroke during DOAC therapy, switching anticoagulation treatment was not associated with clinically meaningful short-term benefit compared with continuation. These findings suggest that switching does not provide additional benefit compared with continuing treatment with the same DOAC. Randomized clinical trials are needed to identify strategies to improve secondary prevention after a breakthrough ischemic stroke.
Quality of life (QoL) captures objective life conditions, subjective wellbeing, and personal aspirations. Interest is growing in ability-based, patient-centered instruments, not confounded by health outcomes. The Quality of Life and Function Five Domain Scale (QFS-5) uses a multi-dimensional approach to measure QoL emphasizing abilities and life engagement. We describe the development and validation of the QFS-5 in a large sample of community-dwelling older adults. The validation sample comprised 1610 participants aged ≥ 50 from the Canadian Platform for Research Online to Investigate Health, Quality of Life, Cognition, Behavior, Function, and Caregiving in Aging (CAN-PROTECT). Internal consistency was assessed using Cronbach's alpha and item-total correlations. Confirmatory factor analysis (CFA) evaluated domain structure. Criterion validity was tested through Pearson's correlation with the EuroQol-5D (EQ-5D). Convergent and discriminant validity were evaluated from associations with cognitive, mental health, and functional measures. Floor and ceiling effects were investigated. The QFS-5 demonstrated excellent internal consistency (α = 0.92); CFA supported the proposed domain structure with strong item loadings. Criterion validity was confirmed with correlation of -0.61 against the EQ-5D; higher symptom burden on related scales were associated with lower QFS-5 scores. Floor effects were minimal, while modest ceiling effects were observed in some domains. No significant floor or ceiling effects were found in participants with frailty. Validity and reliability are established for this ability-based QoL scale, within a sample of mostly cognitively unimpaired, community-dwelling older adults. The QFS-5 aligns with EQ-5D, demonstrating potential clinical and research utility to measure relevant patient-reported QoL outcomes.