BACKGROUND: The COVID-19 pandemic profoundly disrupted education in South Africa, yet quantitative investigations into its mental health impact among learners in late adolescence remain scarce. This study examined associations between COVID-19-related cognitive appraisals and psychological outcomes among late-adolescent learners (aged 18-19 years), a group navigating the transition to adulthood amid substantial educational and social uncertainty. METHOD: A convenience sample of 239 late-adolescent learners (mean age = 18.13 years; 72% female) from seven public schools in informal and semi-urban communities in the Western Cape completed an online survey between March and August 2022. Standardised measures assessed symptoms of depression, anxiety, posttraumatic stress disorder (PTSD), alcohol use, fear of COVID-19, perceived vulnerability to disease, and COVID-19-related worry. RESULTS: High levels of psychological distress were observed within the sample: 59% reported clinically significant depressive symptoms, 39% severe anxiety, 35% clinically significant PTSD symptoms, and 13% alcohol use suggestive of dependence. Hierarchical regression analyses indicated that fear of COVID-19 was a significant predictor of all four mental health outcomes ( < 0.001). Perceived vulnerability to disease independently predicted PTSD symptoms ( < 0.001) and alcohol use ( < 0.01). : These findings highlight the importance of school-based mental health interventions that target learners' cognitive appraisals of threat and vulnerability during periods of educational disruption, with implications for strengthening preparedness for future public health emergencies.

BACKGROUND: Adolescence (ages 10 to 19 years) is a critical developmental stage marked by biological, psychological, and social transitions that heighten vulnerability to depression. During this period, depression is often under-recognised and may persist in adulthood, negatively affecting academic performance, social relationships, and well-being. Social determinants shape vulnerability and resilience, yet research on these factors, especially in low- and middle-income countries, remains limited. OBJECTIVE: This scoping review aimed to examine the role of social factors in influencing adolescent depression in low- and middle-income countries. METHOD: Following the Arksey and O'Malley framework, empirical studies published in English between 2010 and 2023 were reviewed. Forty-seven eligible studies were identified through searches of Google Scholar, PubMed, PsychINFO, Web of Science, Sociological Abstracts, Embase, and manual sources. Data were coded and synthesised using thematic and narrative analyses. Reporting adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews. RESULTS: Socio-structural factors such as gender, socioeconomic status, ethnicity, and family structure were identified as risk factors. Stressors within the family, school, and neighbourhood, including conflict, harsh parenting, maltreatment, academic pressure, peer rejection, bullying, and neighbourhood violence, also contributed to depressive symptoms. In contrast, social support from family, peers, and teachers emerged as a protective factor. CONCLUSIONS: Most studies relied on atomisation, which overlooks how social factors contribute to cumulative stress by shaping adolescents' social settings and leading to depressive symptoms. Critical gaps remain, particularly the under-exploration of neighbourhood influences and out-of-school adolescents.

BACKGROUND: Medication prescribing in Long-Term Care Facilities (LTCFs) is characterised by widespread polypharmacy and frequent exposure to potentially clinically relevant drug-drug interactions (DDIs). METHODS: Data from the Italian Prescription Day in LTCFs 2024, a national multicentre point-prevalence study conducted in 82 LTCFs, were analysed. Prescriptions were classified using the Anatomical Therapeutic Chemical system, and DDIs were identified using an international consensus list. Resident-level variables were assessed using validated tools, and associations with DDI burden were examined using univariate mixed-effects Poisson regression models. Facility-level organisational characteristics were described by centre-level DDI burden. RESULTS: The analysis included 3,174 residents (mean age 84.8 years; 74.1% women), with a mean of 7.7 prescribed drugs. Drugs acting on the nervous system, alimentary tract and metabolism, and cardiovascular system were most frequently prescribed; furosemide, paracetamol, pantoprazole, quetiapine, and macrogol were the most commonly used active substances. Overall, 42.2% of residents were exposed to at least one potentially clinically relevant DDI, most commonly involving centrally acting drugs, cumulative anticholinergic burden, serotonergic combinations, and potassium-related interactions. Higher DDI burden was associated with greater pharmacological complexity, depression, sleep disorders, cardiopulmonary disease, and behavioural and psychological symptoms of dementia, whereas older age, severe cognitive impairment, malnutrition, and dysphagia were associated with fewer DDIs. Facility-level and staffing characteristics showed limited differentiation, with assisted living facilities under-represented at higher DDI burden. CONCLUSIONS: Potentially clinically relevant DDIs are common in Italian LTCFs and are primarily associated with resident-level clinical complexity, highlighting targets for medication review and deprescribing to improve medication safety.

BACKGROUND: Multimorbidity-the co-occurrence of two or more chronic health conditions-has become a major public health challenge in ageing societies. However, most research continues to frame it as a clinical or epidemiological issue, overlooking the role of social determinants and healthcare system dynamics. This study investigates the patterns, experiences, and structural implications of multimorbidity in southern Spain, aiming to uncover how health inequalities shape disease profiles and care experiences in one of the most deprived regions of the country. METHODS: We employed a mixed-methods sequential explanatory design. The quantitative phase was based on a cross-sectional telephone survey of 1,592 individuals aged 50 and over with multimorbidity. Latent Class Analysis (LCA) was used to identify multimorbidity patterns based on 33 chronic conditions. Associations with sociodemographic factors and healthcare utilisation were analysed using chi-square tests. The qualitative phase consisted of 18 semi-structured interviews with healthcare professionals and patients, analysed thematically to explore lived experiences, care trajectories, and institutional barriers. RESULTS: Five multimorbidity patterns were identified: unspecific, cardiometabolic, musculoskeletal, musculoskeletal-mental, and complex multimorbidity. These patterns showed clear social stratification: complex and musculoskeletal-mental profiles were more prevalent among low-income individuals, women, and residents in deprived areas. Healthcare utilisation also varied across patterns, with higher service use in more complex profiles. Qualitative findings revealed that multimorbidity was experienced as a cycle of physical decline, emotional vulnerability, and systemic neglect. Patients faced difficulties in treatment adherence, experienced long waiting times, and often relied on informal caregiving, predominantly by women. Healthcare professionals highlighted systemic fragmentation, lack of coordination, and the inadequacy of clinical guidelines for complex cases. CONCLUSIONS: Multimorbidity in this context is not merely a clinical challenge but a socially embedded condition shaped by structural inequality and institutional failures. Health systems must move beyond single-disease logic and adopt integrated, equity-oriented models of care that consider the syndemic nature of multimorbidity. This study highlights the need to incorporate social determinants into chronic care strategies and to prioritise the lived experiences of patients and caregivers in future health policy and planning.

The treatment of chronic oral ulcer healing, particularly in diabetic patients, presents a significant clinical challenge. Current therapeutic strategies have inadequately addressed the complexities associated with diabetic oral ulcers, underscoring the urgent need for innovative solutions. In this study, nanoparticles were extracted from edible spirulina powder (SP-NPs) and incorporated into adhesive chitosan-based oral gel (CSgel), resulting in the development of an advanced functional hydrogel (SP-NPs@CSgel) designed to manage chronic oral ulcers in diabetes. The SP-NPs, rich in proteins involved in antioxidant and anti-inflammatory processes, demonstrated significant potential in repairing cellular damage by mitigating oxidative stress and modulating inflammation through the inhibition of the NF-κB pathway in macrophages, with the percentage of M2 macrophage increasing to 27% versus merely 12% in the control group. Additionally, the CSgel exhibited excellent injectable and adhesive properties, which prolonged the retention of SP-NPs in the oral mucosa for over 8 h, representing a four-fold increase compared to merely 2 h for free SP-NPs, thereby significantly accelerating the healing of chronic oral ulcers with complete wound closure achieved within 8 days in diabetic rats and 14 days in diabetic mice with severe ulcers. Furthermore, the SP-NPs@CSgel showed promising effects in alleviating depression-related behaviors and regulating the oral microbiota in severe oral ulcers, creating a conducive environment for ulcer healing. In conclusion, by harnessing the synergistic effects of edible SP-NPs and adhesive CSgel, this hydrogel system represents a safe and effective approach with substantial potential for clinical transformation, offering a promising solution for chronic oral ulcer management in diabetic patients.

Youth mental health-related problems and disorders have garnered increased attention due to global prevalence estimates that have, in some cases, increased following the COVID-19 pandemic. Various methodologies have been proposed to leverage artificial intelligence (AI) for detecting mental health problems in the general population; however, research specifically focused on AI methods for youth remains limited. Shortcomings in modern AI include limited training data modalities (i.e., types of input data used for model training), reliance on offline training, and the use of static models. This scoping review provides an overview of evidence that uses AI methods applied to youth mental health (YMH) and provides an assessment of the current state of research that integrates multimodal AI (i.e., models that incorporate multiple data modalities) and/or online learning (i.e., incremental or continual model training from streaming data) for the diagnosis, monitoring, and treatment of YMH-related problems. The findings indicate that research in AI applied to YMH is limited in the areas of multimodal AI and online learning. The number of studies in this field is steadily growing. Studies incorporating online learning demonstrate that this approach enhances model performance and adaptability, which is crucial for developing translational models capable of addressing real-world challenges effectively. Despite these advances, key challenges remain, including the availability and long-term validity of multimodal data, the lack of participant-related information in certain databases and studies, the ethical and logistical difficulties of collecting data from minors, and the computational costs of training robust AI models.

Cisplatin is widely used in oncology yet causes dose-limiting, irreversible hearing loss through cochlear hair-cell injury. Although mitochondrial dysfunction is central to this ototoxicity, how the outer mitochondrial membrane (OMM) fails in hair cells remains unclear. We identify BAX-associated mitochondrial membrane rupture and abnormal permeabilization as key drivers. In HEI-OC1 cells and murine cochlear explants, super-resolution and transmission electron microscopy revealed cisplatin-induced BAX translocation and oligomerization on the OMM, forming ring-like assemblies with ultrastructural damage (rupture, herniation, fragmentation). Subcellular fractionation and functional assays demonstrated consequent mitochondrial outer membrane permeabilization, cytochrome c release, loss of membrane potential, and accumulation of reactive oxygen species (ROS). Pharmacologic inhibition of BAX oligomerization with BAX inhibitor peptide V5 (BipV5) preserved mitochondrial integrity, reduced ROS, and limited hair-cell loss in vitro. In vivo, repeated transtympanic delivery of BipV5 conferred sustained functional protection and reduced outer hair cell loss. These findings establish a structural mechanism linking mitochondrial membrane rupture to redox imbalance and apoptosis in cochlear hair cells and nominate BAX oligomerization as a drug-targetable node for preventing cisplatin ototoxicity without compromising anticancer therapy.

Early assessment of depressive symptoms is essential for scalable and personalized mental health care. We developed a hybrid clinical decision support system (CDSS) that combines interpretable logistic regression with fine-tuned large language models (LLMs) to classify depressive symptom status using wearable-derived behavior, clinical features, and environmental exposures. This study aimed to develop a hybrid clinical decision support system by fine‑tuning a GPT‑based large language model with odds ratio-derived statistical reasoning to classify depressive symptom status from wearable‑derived behavioral metrics, clinical characteristics, and environmental exposures. We compared the diagnostic accuracy, interpretability, and operational efficiency of this OR‑based fine‑tuned model against both traditional nomogram‑based statistical models and label‑supervised fine‑tuned LLM approaches. We further evaluated the incremental predictive value of wearable‑derived behavioral features beyond readily available demographic and clinical variables using matched feature-set comparisons. We analyzed data from 2437 adults at Chonnam National University Hospital, South Korea (August 2021-January 2023) who wore wrist actigraphy devices continuously for 7 days. Depressive symptoms were assessed using PHQ-9, with a score ≥ 10 indicating higher symptom burden. We extracted temporal behavioral features including morning steps (06:00-12:00), non-daylight steps, and vigorous physical activity minutes, stratified by weekday/weekend. Meteorological data (temperature, precipitation) were integrated with behavioral metrics. Multivariable logistic regression identified significant predictors with odds ratios (ORs). Five LLMs (GPT-4o, o3-mini, Claude 3.5-sonnet, Gemini 2.0-flash, Llama 3.3) were evaluated under zero-shot conditions. The GPT-based model was selected for supervised fine-tuning using two strategies: label-based (binary outcome only) and OR-based (embedding statistical reasoning into prompts). The system was deployed as a chatbot interface. Among 2437 participants (mean age 60.2 years, 67.5% female), 317 (13.0%) were classified as having elevated depressive symptoms (PHQ-9 ≥ 10). Prespecified incremental-value analyses using matched feature sets (clinical-only, wearable-only, and combined) demonstrated that wearable-derived behavioral features provided additive predictive value beyond demographic and clinical variables. In the OR-based fine-tuned LLM framework, balanced accuracy increased from 0.635 (clinical-only) to 0.735 (wearable-only) to 0.787 (combined) on weekdays, and from 0.589 to 0.647 to 0.680 on weekends. In the nomogram framework, adding wearable features to the clinical model significantly improved risk reclassification (continuous NRI: 0.469, p < 0.001 on weekdays; 0.372, p = 0.002 on weekends) and integrated discrimination improvement (IDI: 0.037, p < 0.001 on weekdays; 0.018, p = 0.002 on weekends). The combined OR-based fine-tuned model achieved 90.3% accuracy and 94.5% specificity on weekdays and 88.8% accuracy and 96.4% specificity on weekends, outperforming both nomogram and label-based fine-tuned models. This hybrid framework demonstrates that odds ratio-anchored fine-tuning can improve classification performance while preserving predictor traceability for PHQ-9-defined elevated depressive symptoms. Wearable-derived behavioral features provided statistically significant incremental predictive value beyond demographic and clinical variables, with larger gains observed on weekdays than on weekends. Prospective external validation across diverse populations is required before clinical implementation.

Maternal physical activity during pregnancy has been shown to confer benefits on the brain functions of offspring. This study investigated the positive effects of maternal exercise during pregnancy on enhancing hippocampal synaptic plasticity and resilience to stress-induced depressive behavior in adult murine offspring. Using a mouse model with mother mice engaged in voluntary wheel running during pregnancy, we assessed changes in long-term potentiation (LTP) in the hippocampal dentate gyrus, synaptic protein expression, and behavioral responses to chronic stress in adult male and female offspring from exercised dams compared with those from sedentary dams. We found that maternal exercise enhanced LTP in offspring of both sexes. Western blot analysis of hippocampal synaptoneurosome extractions revealed significant main effects of maternal exercise on increasing the expression of brain-derived neurotrophic factor (BDNF), PSD-95, synaptophysin, and phosphorylation of N-methyl-D-aspartate receptor subunit GluN2A and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit GluA1. Maternal exercise significantly increased synaptophysin levels in both male and female offspring, with sex-specific effects on increasing PSD-95 levels in male offspring and increased p-GluN2A levels in female offspring from exercised dams. Golgi staining revealed a significant increase in hippocampal dendritic spine density in female offspring only. Maternal exercise-induced improvements in hippocampal synaptic plasticity were associated with reduced depression-like behaviors in both male and female offspring exposed to chronic unpredictable stress. Additionally, male offspring displayed reduced anxiety-like behavior, while female offspring showed no significant anxiolytic changes. These findings elucidate the sex-specific effects of maternal exercise on enhancing hippocampal synaptic plasticity, which may contribute to increased resilience against stress-induced depressive behaviors in adult offspring.

BACKGROUND: Maltreatment associated psychiatric problems (MAPP) in children and adolescents can be highly variable and commonly include both trauma related difficulties and neurodivergence. Treatment guidelines for this population require further development. The Relationships in Good Hands Trial (RIGHT) is a multi-site randomised controlled trial comparing Dyadic Developmental Psychotherapy (DDP) with services as usual (SAU) for children with MAPP in permanent foster or adoptive care. This qualitative study is a part of the RIGHT process evaluation. OBJECTIVE: To understand the experience of supporting a child with MAPP, considering both parent and professional perspectives. PARTICIPANTS AND SETTING: Parents and professionals (social workers, therapist and teachers) supporting children with MAPP within the RIGHT trial. METHODS: Six case-studies were identified representing both trial arms at different trial sites. Qualitative interviews with parents and professionals supporting each child were conducted and interpreted using multi-perspectival Interpretative Phenomenological Analysis (IPA). RESULTS: Six themes were interpreted from the data: the nature and far-reaching impact of MAPP; experiences navigating and building parent - professional relationships; trying to flexibly meet the child's needs despite an inflexible system; frustration and disappointment in statutory services; constantly facing difficult decisions; and apprehension with hope for the child. CONCLUSIONS: There is significant interaction between the child, parent and the wider context including statutory services. This is explored within a syndemics framework, whereby the effects of maltreatment and neurodivergence co-occurring within their context increases overall difficulties beyond that of comorbidity. Supporting the child therefore requires supporting the whole system around the child.

Preterm birth (i.e., before 37-week gestation) is a global health concern, with most prematurity occurring between 32 - 36.6 weeks gestation, yet research has primarily focused on extreme prematurity (i.e., before 32-weeks gestation). As such, less is known about the developmental and psychological outcomes associated with moderate-to-late preterm birth. This study examines how infant temperament and infant physical wellbeing are associated with maternal mental health, and whether moderate-late prematurity moderates these relationships in a low-income sample. Using a matched case-control design, we collected data from 100 low-income mothers of infants aged 12-18 months (50 preterm, 50 full-term), assessed maternal stress, anxiety, and depression, infant temperament (including anger and fear), and physical health indicators (e.g., colds, doctor visits, injuries). Infant anger was significantly associated with poorer maternal mental health regardless of prematurity. Infant fear and minor injuries were also associated with worse maternal mental health, but this effect was lessened among mothers of preterm infants, underscoring the differential experiences of mothers with premature infants. These findings highlight the potential value of the targeted supports often offered to mothers of preterm infants and suggest that extending such supports to all mothers, including those with full-term infants, may help improve maternal wellbeing across the perinatal population.

This study examines how distance to specialized pediatric cancer treatment may shape the psychosocial consequences experienced by families of children with cancer. Drawing on a time geographic perspective, the study is based on 16 qualitative interviews with parents in Denmark. Although no parent expressed willingness to compromise on treatment quality for a shorter distance, those facing extended travel reported more pronounced negative experiences. The findings suggest that longer travel exacerbates family separation, disrupts routines, and reduces opportunities for meaningful activities, with particular consequences for siblings' mental well-being and participation in leisure activities. This study highlights potential territorial challenges arising from the centralization of healthcare in Denmark by demonstrating that while the universal welfare model ensures free and equal access to treatment, geographical disparities impose constraints on families. These findings indicate the value of a strategic distribution of treatment centers across the country to ensure more geographically equitable access due to psychosocial factors.

BACKGROUND: Negative symptoms of schizophrenia are highly disabling and remain insufficiently responsive to pharmacological treatment. High-definition transcranial direct current stimulation (HD-tDCS) targeting the left dorsolateral prefrontal cortex (DLPFC) may improve these symptoms, but its neurophysiological correlates remain unclear. METHODS: This study was a secondary fNIRS analysis of a randomized, double- blind, sham-controlled trial. Sixty clinically stable patients with schizophrenia and predominant negative symptoms received active or sham online HD-tDCS over the left DLPFC while performing a two-back working memory task. Functional near-infrared spectroscopy was used to assess prefrontal activation during the two-back task and verbal fluency task (VFT), as well as resting-state functional connectivity. Graph- theoretical analyses quantified global efficiency (Eg) and local efficiency (Eloc). Negative symptoms were assessed using the PANSS factor score for negative symptoms (FSNS) and the Scale for the Assessment of Negative Symptoms (SANS). RESULTS: Active HD-tDCS was associated with significantly greater increases in left DLPFC activation during both the two-back task and VFT compared with sham stimulation. Resting-state Eg and Eloc did not differ significantly between groups. Changes in task-evoked fNIRS signals were not significantly correlated with improvements in negative symptoms. However, lower resting-state Eloc was significantly associated with greater negative symptom severity. CONCLUSIONS: Online HD-tDCS enhanced task-evoked left DLPFC activation in schizophrenia, but these changes were not directly related to clinical improvement. Resting-state local efficiency may better reflect the severity of negative symptoms than task-based activation, suggesting a potential role for intrinsic prefrontal network organization in schizophrenia.

BACKGROUND: Emotional Mental Imagery (eMI) may contribute to the development and persistence of auditory verbal hallucinations (AVHs), particularly through imagery appraisals. However, empirical evidence from large clinical samples is limited. The present study examined associations between seven characteristics of eMI (i.e., frequency, quality (liveliness, compellingness), and appraisals (encapsulated beliefs and metacognitions)) and AVH severity, exploring whether levels of depression and anxiety mediate this association. METHODS: 107 individuals with subclinical (psychotic-like experiences) and clinical psychosis and current AVHs completed cross-sectional questionnaires on eMI, AVH severity, and the level of depression and anxiety. A multiple regression analysis was applied to test the association between seven aspects of eMI and AVH severity. Exploratory mediation analyses using the PROCESS macro for SPSS were applied. RESULTS: eMI characteristics were positively associated with the severity of AVHs in individuals with subclinical and clinical psychosis (η= 0.239, p < .001). Lower positive encapsulated beliefs (η= 0.072, p = .007) and higher negative metacognitions (η = 0.077, p = .005) were associated with more severe AVHs. The remaining five imagery characteristics failed to show significant associations with AVH severity. A significant indirect effect was found for negative metacognitions (η= 0.059, 99%CI [0.04, 0.36]) on AVH severity via depression levels. Indirect pathways via anxiety did not reach statistical significance. DISCUSSION: Imagery appraisals seem important in relation to AVH severity across the psychosis spectrum, potentially via a mediating role of depression levels. Future studies are needed to further examine the underlying cognitive processes driving this association.

BACKGROUND: To explore the latent profiles of digital self-harm among Chinese adolescents and to examine between-profile differences in sample characteristics and psychological variables, as well as their associations with suicidal behaviors. METHODS: A total of 5655 adolescents (mean age = 16.26 ± 0.82 years; 53.2% male) were recruited from 27 April to 19 May 2025. All participants completed self-report web-based questionnaires covering demographic characteristics, lifestyle variables, depressive symptoms, cyber-victimization, digital self-harm, physical self-harm, and suicidal behaviors. Latent profile analysis and logistic regression analysis were used to analyze the data. RESULTS: Three latent profiles of digital self-harm in adolescents were identified: high digital self-harm (7.0%), inner self-emotion harm (11.2%), and low digital self-harm (81.8%). Multivariate logistic regression indicated that sex, grade, parental marital status, history of mental disorders, and smoking status distinguished the digital self-harm subtypes. Short sleep duration, depressive symptoms, and cyber-victimization were risk factors for digital self-harm (p < 0.05). After controlling for covariates, both high digital self-harm and inner self-emotional harm were associated with physical self-harm and suicidal behaviors. Notably, inner self-emotional harm demonstrated a unique association with suicidal ideation (OR = 2.00, 95% CI = 1.60-2.51) and suicide attempts (OR = 1.70, 95% CI = 1.10-2.61) even after additionally controlling for physical self-harm. CONCLUSIONS: Healthcare and educational professionals should prioritize early screening for digital self-harm, promptly identify high-risk groups, and provide targeted psychological counselling and support to safeguard adolescent mental health and prevent suicide.

BACKGROUND: Hydromethylthionine mesylate (HMTM) targets tau pathology and also has tau-independent symptomatic activity. A traditional randomised placebo-controlled trial (RCT) was precluded by loss of blinding due to urinary colouration and therapeutic activity at the minimum dose required to maintain blinding. OBJECTIVE: To evaluate the efficacy of HMTM in participants with mild cognitive impairment (MCI) and mild to moderate dementia due to Alzheimer's disease (AD). METHODS: Because a traditional RCT was not feasible without loss of blinding, we compared HMTM 16 mg/day in TRx-237-039 with propensity score matched true placebo controls from the FDA-sponsored Critical Path for AD (CPAD) database with the same inclusion/exclusion criteria (protocol TRx-237-080). We also compared HMTM 16 mg/day with matched natural history controls from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and with a meta-analysis of placebo arms from trials in comparable populations in analyses specified prior to the 104-week database lock of TRx-237-039. PARTICIPANTS: Propensity score matching yielded 127 pairs (HMTM n = 127; CPAD placebo n = 127) in the CPAD comparison, and 189 pairs in the ADNI comparison. A total of 218 receiving HMTM 16 mg/day were compared with meta-analytic controls (n = 1805-8567). INTERVENTION: HMTM 16mg/day MEASUREMENTS: Primary outcomes in TRx-237-080 were change from baseline to 78 weeks in ADAS-Cog and whole brain volume (WBV). CDR-Sum of Boxes (CDR-SB) and CDR-Global were analysed at 104 weeks. ADAS-cog and WBV were analysed in ADNI comparisons, and ADAS-cog, ADCS-ADL, CDR-SB and WBV were analysed in meta-analytic comparisons. RESULTS: Compared with matched CPAD placebo, HMTM 16 mg/day produced statistically significant differences in change on ADAS-Cog (p < 0.0001) and WBV at 78 (primary; p < 0.0001) and 104 weeks (p < 0.0001), and CDR-SB differed significantly overall (104-weeks; p < 0.001) and in MCI (p = 0.007). The odds of progressing to a more advanced CDR-Global stage were lower with HMTM (overall OR 0.31) and particularly in MCI (OR 0.15) versus CPAD placebo. Clinical and brain atrophy outcomes were similarly statistically significant in comparisons with ADNI case-matched natural history data and in meta-analytic comparisons. CONCLUSION: Comparisons of HMTM treatment with CPAD, ADNI, and meta-analytic controls provide evidence consistent with clinical benefit HMTM. It has the potential to offer an accessible oral treatment option which could be delivered with minimal patient/physician burden.

OBJECTIVE: To evaluate the efficacy of exercise training for patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). METHODS: Seven databases were searched from inception to December 2025 for randomized controlled trials (RCTs) on exercise effects in ME/CFS. A random-effects model was employed to calculate the pooled effect size, with Q, I statistic, and τ assessing a heterogeneity. Additionally, we performed moderator analyses to explore stability of results. RESULTS: A total of 17 RCTs (n = 1944) were included. Exercise interventions significantly improved fatigue (16 RCTs, n = 1673; standardized mean difference [SMD] = 0.85, 95% CI 0.65 to 1.06, I = 85.3%), sleep quality (5 RCTs, n = 806; SMD = 0.42, 95% CI 0.31 to 0.53, I = 41.2%), QoL (11 RCTs, n = 1171; SMD = 0.99, 95% CI 0.73 to 1.26, I = 89.7%), depression (9 RCTs, n = 1279; SMD = 0.56, 95% CI 0.43 to 0.69, I = 45.8%), and anxiety (9 RCTs, n = 1279; SMD = 0.14, 95% CI 0.04 to 0.24, I = 21.2%). However, the effects on cardiopulmonary function (3 RCTs, n = 150; SMD = 0.13, 95% CI -0.11 to 0.43, I = 0.0%) and functional capacity (4 RCTs, n = 459; SMD = 0.09, 95% CI -0.21 to 0.38, I = 47.4%) were not significant. These results may be influenced by potential moderators such as intervention length, frequency, session duration, and medication use. Crucially, there was no significant difference in acceptability or adverse events between two groups. CONCLUSION: Exercise significantly improves fatigue, sleep, QoL, and depression in ME/CFS patients. However, exercise does not yield significant improvements in cardiopulmonary or functional capacity. While not a cure, exercise is an effective strategy for symptom management, provided that individual energy limits are strictly respected to prevent harm.