Journal of Parkinson’s Disease

Background: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic risk factor for Parkinson's disease (PD). G2019S, the most common pathogenic variant, has been linked to milder motor symptoms, but the effects of other LRRK2 variants on disease trajectory remain incompletely characterized. R1441G, the second most common pathogenic variant, co-occurs with the PD risk variant M1646T on a shared haplotype. Whether this haplotype confers a distinct rate of motor progression has not been established. Methods: We analyzed up to 12 years of longitudinal data from 603 participants in the Parkinson's Progression Markers Initiative (PPMI) with PD and available whole-genome sequencing data: 394 sporadic PD, 169 G2019S carriers, 20 R1441G+M1646T carriers, and 20 M1646T carriers. Motor symptom progression (MDS-UPDRS III) was assessed using linear mixed-effects models with genotype-by-time interactions, adjusted for age at onset, disease duration at baseline, sex, race, baseline score, and levodopa equivalent daily dose. Results: R1441G+M1646T carriers exhibited 76% slower progression in OFF-state MDS-UPDRS III than sporadic PD (0.50 vs. 2.04 points/year; {beta}=-1.54 [95% CI: -2.48, -0.60]; p=0.001). G2019S carriers exhibited 26% slower progression (1.52 points/year; {beta}=-0.52 [-0.99, -0.06]; p=0.03). M1646T carriers did not differ from sporadic PD (p=0.60). Slower progression in R1441G+M1646T carriers was characterized by attenuated bradykinesia (64% slower; p=0.008), axial decline (76% slower; p=0.002), and a lack of orofacial symptom progression (p<0.001). R1441G+M1646T carriers also exhibited 55% slower self-reported motor decline (MDS-UPDRS II; p=0.04) Conclusions: R1441G+M1646T carriers exhibit substantially slower motor progression than sporadic PD while M1646T carriers do not.

Objective and scalable approaches for detecting subtle motor impairment in isolated REM sleep behavior disorder (iRBD), a prodromal stage of Parkinson's disease, remain limited. We investigated whether markerless motion capture from single RGB-camera videos can identify gait abnormalities in people living with iRBD and provide interpretable digital biomarkers. We retrospectively analyzed 93 standardized walking videos from three clinical sites. Human pose estimation extracted 12 body markers and 14 kinematic time series. Thirty-five machine learning approaches classified healthy controls (HC) and people with iRBD. The Movement Disorder Society Unified Parkinson's Disease Rating Scale Part 3 (MDS-UPDRS III) served as the clinical baseline. The best-performing model (tsfresh+XGBoost) achieved an AUROC of 0.739, significantly outperforming the MDS-UPDRS III sum score when trained on data from all three sites. Harmonized multi-site training improved performance. SHAP identified hip-related temporal features as key contributors, which differed between groups and showed stronger associations with regional dopaminergic deficits than clinical scores. Single-camera gait analysis may provide scalable digital biomarkers for low-cost screening and monitoring of prodromal PD.

Dopamine replacement therapy (DRT) alleviates motor symptoms in Parkinson's disease (PD) but can trigger hallucinations in a subset of patients, yet the neural basis of this selective vulnerability is unknown. Hallucinations are among the most disabling non-motor symptoms of PD, linked to social isolation, dementia and institutionalization. Using a validated robotic paradigm to induce and quantify hallucinations in real-time, combined with resting-state fMRI in a crossover On/Off DRT design, we studied patients with PD with (PD-H) and without (PD-nH) hallucinations. DRT selectively amplified sensitivity to robot-induced hallucinations in patients with pre-existing hallucinatory phenotype (PD-H, but not PD-nH) and was accompanied by cortico-striatal and large-scale network hyperconnectivity. Rather than supporting a uniform hallucinogenic effect of dopamine in PD, these findings indicate that DRT interacts with an intrinsic neural vulnerability that varies in patients. Prospective studies will establish whether this pharmacological-behavioural signature identifies patients at risk before clinical hallucinations emerge.

Isolated rapid eye movement sleep behavior disorder (iRBD) is characterized by nigro-striatal deficits, comprising dopaminergic denervation of the striatum and loss of dopaminergic cells in the substantia nigra (SN), that may herald phenoconversion to clinically manifest synucleinopathy. While phenoconversion has repeatedly been shown to relate to pre-synaptic dopaminergic deficits in the striatum, potential involvement of loss of dopaminergic cells in the SN remain unclear. In addition, phenoconversion may independently relate to noradrenergic deficits, stemming from cell loss in the locus coeruleus/subcoeruleus (LC/LsC) complex. Fifty-six iRBD patients were included and clinically followed over an 11-years as part of the ICEBERG study. Putamen dopamine denervation was quantified using 123I-FP-CIT single-photon emission computed tomography. Cell loss in the SN and LC/LsC was quantified using neuromelanin-sensitive magnetic resonance imaging (MRI). SN cell loss was additionally characterized as free water, derived from diffusion-weighted MRI. The primary outcome was time to phenoconversion. Cox proportional hazards regression was used to investigate relationships between phenoconversion risk and imaging predictors, estimated as hazard ratios (HRs). Out of 56 patients, 24 (41%) converted to a clinically manifest synucleinopathy [PD=14 (58%), DLB=8 (33%), MSA=2 (8%)] over a maximum period of 11 years. We replicated the well-established finding that reduced putamen DaT confers an increased phenoconversion risk [HR (95%CI)=3.1 (1.7-5.5), P<0.001]. We extend on this by showing a similar relationship for SN neuromelanin [HR (95%CI)=2.5 [1.3-4.6], P=0.004], SN free water [HR (95%CI)=1.54 (1.06-2.24), P=0.025], and LC/LsC neuromelanin [HR (95%CI)=2.1 (1.2-3.7), P=0.011], demonstrating involvement of the broader nigro-striatal dopaminergic system along with potential involvement of noradrenergic neurotransmission. When adjusting for putamen DaT, the relationship between phenoconversion risk and SN neuromelanin was attenuated [P=0.16], suggesting partial overlap between the metrics. In contrast, when modelled together, SN neuromelanin [HR (95%CI)=2.8 (1.4-5.6), P=0.003] and LC/LsC neuromelanin [HR (95%CI)=2.3 (1.1-4.8), P=0.037] contributed to phenoconversion risk independently of each other, indicating a differential contribution of dopaminergic and noradrenergic neurotransmitter deficits to iRBD phenoconversion. We demonstrate that phenoconversion in iRBD relates similarly to dopaminergic denervation of the putamen and cell loss in the SN. This opens possibilities for using NM-MRI, which can simultaneously capture dopaminergic and noradrenergic deficits, as an alternative to nuclear imaging techniques when estimating phenoconversion risk in iRBD.

Parkinsons disease (PD) arises through disruption of multiple interconnected cellular processes, but the genetic contributions to these processes may differ across ancestries. We investigated functional convergence among genes harboring pathogenic or likely pathogenic (P/LP) variants and variants of uncertain significance (VUS) in a multicenter Indian cohort recruited through the Genetics of Parkinsons Disease in India Young Onset Parkinsons Disease project (GOPI YOPD). The cohort included 668 participants (463 males 69.3%) with a mean age at motor onset of 39.4+/-8.8 years. P/LP variants and VUS identified through previously reported whole-exome or whole genome sequencing were retained as separate evidential categories. The P/LP-associated gene set comprised 11 unique genes and the VUS associated set comprised 40 unique genes. Separate STRING functional-enrichment analyses evaluated Gene Ontology Biological Process, Molecular Function and Cellular Component terms, KEGG pathways, WikiPathways and STRING local network clusters. Terms meeting a Benjamini Hochberg false discovery rate threshold of <0.05 were organized into eight non-mutually-exclusive ontology/pathway categories. Gene to pathway mappings were subsequently projected to individual participants to estimate pathway representation and examine clinical associations. At least one reportable P/LP variant or VUS was identified in 336/668 participants (50.3%): 35 had a P/LP variant alone, 282 had VUS alone and 19 had a P/LP variant together with VUS in one or more additional genes. The most frequently represented categories were mitochondrial organization (247/336, 73.5%), autophagy related processes (228/336, 67.9%) and regulation of synaptic vesicle transport (201/336, 59.8%). PRKN was the most frequent P/LP-associated gene, occurring in 29/54 P/LP carriers, followed by PLA2G6 and PINK1. Lysosomal transport was represented exclusively by VUS-associated genes, particularly GBA1, VPS13C and LRRK2. Among P/LP carriers, additional VUS in distinct genes were not associated with age at onset (P = 0.81) or family history (52.6% versus 31.4%; P = 0.15). No pathway phenotype association remained significant after correction for multiple testing. Genetic findings in this Indian cohort converged across an interconnected mitochondrial autophagic lysosomal vesicular network, with different contributions from P/LP-associated and VUS associated gene sets. This study provides the first pathway resolved South Asian genetic profile and a framework for comparative studies across populations.

Background: The primary neuroanatomical site of Huntington-s disease (HD) pathology resides in the striatum and its atrophy identifies important disease progression from HD-ISS Stage 0 to Stage 1. Immune-associated proteins may capture variation in HD that is incompletely represented by markers of neuroaxonal injury. Objectives: To determine whether cerebrospinal-fluid myeloperoxidase contributes information about striatal volume loss beyond genetic disease burden and neurofilament light. Methods: Cross-sectional data from 88 persons with HD were analyzed. Cerebrospinal-fluid myeloperoxidase and neurofilament light were measured with a nucleic acid-linked immunosandwich assay. Normalized putamen volume was derived from structural magnetic resonance imaging. Linear regression adjusted for genetic disease burden and sex. Results: Higher neurofilament light was associated with smaller normalized putamen volume (standardized {beta} = -0.322, (P=.0066)). Higher myeloperoxidase was associated with larger normalized putamen volume after adjustment for genetic disease burden, sex, and neurofilament light (standardized {beta} = 0.183, (P=.0386)). Adding myeloperoxidase increased explained variance in striatal loss. Conclusions: Cerebrospinal fluid myeloperoxidase contributed modest incremental information about striatal volume in this cross-sectional sample. Independent longitudinal studies are needed to determine its biological source, temporal behavior, and potential biomarker value. Findings advance efforts to characterize multicomponent biological markers of HD.

INTRODUCTION: Biomarkers for monitoring disease activity and treatment response in peripheral neuropathies remain limited. Big tau, a high-molecular-weight isoform of tau, is predominantly expressed in the peripheral nervous system (PNS). We investigated serum levels of big tau, brain-derived tau (BD-tau), and neurofilament light chain (NfL) in peripheral neuropathies, multiple sclerosis (MS), Alzheimer disease (AD), and healthy controls (HC). METHODS: Ultra-sensitive blood-based assays run on an HD-X Single Molecule Array analyser (Quanterix) were used to measure big tau and BD-tau in serum from patients with Guillain-Barr&eacute syndrome (GBS, n=81), Miller Fisher syndrome (MFS, n=20), Charcot-Marie-Tooth disease (CMT, n=102), chronic inflammatory demyelinating polyneuropathy (CIDP, n=43), MS (n=159), AD (n=20), and HC (n=41). NfL was measured in patients with neuropathies using an SR-X Single Molecule Array analyser (Quanterix). RESULTS: Serum big tau levels were higher in GBS than in AD (11.4 vs 2.4 pg/mL, p<0.0001) and MS (11.4 vs 9.0 pg/mL, p=0.01), and similar to CIDP and CMT. Contrarily, serum BD-tau levels in GBS were higher than in CIDP (3.0 vs 2.3 pg/mL, p=0.006) and MS (3.0 vs 1.7 pg/mL, p<0.0001), but similar to CMT, and lower than in AD (3.0 vs 9.8 pg/mL, p<0.0001). Serum NfL levels were higher in GBS than in CIDP (32.5 vs 13.0 pg/mL, p=0.0002), CMT (32.5 vs 12.3 pg/mL, p<0.0001), and HC (32.5 vs 7.6 pg/mL, p<0.0001). Compared with GBS, MFS patients showed higher BD-tau (12.7 vs 3.0 pg/mL, p=0.003), lower big tau (5.4 vs 11.4 pg/mL, p=0.002), and higher NfL levels, although the latter did not reach statistical significance (118.3 vs 32.5 pg/mL, p=0.16). The NfL/big tau ratio was significantly higher in MFS than in GBS, CIDP, and CMT. In GBS, BD-tau correlated with early clinical severity (MRC at 1 week; I-RODS at 4 weeks; maximum GBS-DS and GBS-DS at 4 weeks), whereas neither tau biomarker showed long-term clinical correlations. Higher BD-tau and big tau levels were associated with the need for mechanical ventilation (BD-tau: 8.6 vs 2.9 pg/mL, p=0.019; big tau: 19.7 vs 10.7 pg/mL, p=0.007), while higher BD-tau levels were associated with mortality (10.9 vs 2.9 pg/mL, p=0.003). CONCLUSIONS: Higher big tau levels in peripheral neuropathies than in CNS diseases support its role as a PNS-specific biomarker. In MFS, increased serum BD-tau, reduced big tau, and an elevated NfL/big tau ratio suggest CNS involvement with relative preservation of the PNS.

Background Sleep, mood, and affective states are mutually connected. There is a paucity of studies, however, that have considered bidirectional relationships between daily sleep-affective dyads in naturalistic settings, particularly for shift workers. Objective To evaluate the dynamic and temporal interplay of daily smartphone-based self-reported sleep measurements, dimensions of affective experience and cognitive processing in UK shift working nurses. Methods The EClocker Study prospectively monitored 102 National Health Service (NHS) nurses (aged 25-61 years, 83.3% female) working standard (day shift) and non-standard (fast rotating shifts) schedules over a two-week period. Smartphone-based Experience Sampling Methodology (ESM) recorded daily sleep, mood, momentary affect and cognitive attentional functioning. Self-reported burnout, emotional dysregulation, emotion reactivity and affective dimensions (positive and negative) were also collected. Findings Overall, NHS nurses reported a high prevalence of depressive symptoms, stress, burnout and sleep-circadian rhythm disturbances. Generalised Additive Modelling (GAMs) revealed that NHS nurses higher perceived sleep quality predicted better next-day mood state, while better daytime mood was associated with reduced sleep onset latency, such that participants reported falling asleep faster. In contrast, daytime mood or affect (positive and negative) had no substantial, direct impact on nurses subjective sleep parameters (sleep quality, sleep duration, sleep efficiency). Exposure to fast rotating night shifts across the two-week study was associated with more frequent response errors on a Choice Reaction Time (CRT) cognitive task, while daytime somnolence did not adversely influence nurses momentary reaction time speeds or attentional function. Conclusions Clinically relevant sleep impairments, insomnia-related symptoms, elevated stress, and poor mood were pervasive in a sample of UK NHS nurses, regardless of shift type. Sleep quality impacted next-day mood and daytime mood impacted sleep latency, while rotating shifts led to an increase in cognitive errors. Recognising the impact of shiftwork and designing interventions to promote better sleep quality offer potential to enhance mood and performance in healthcare professionals. Clinical implications We need to implement and evaluate interventions that regularise sleep patterns and promote sleep quality to alleviate mood symptoms among frontline NHS shift workers.

Background: Shiftwork disrupts natural sleep-wake cycles, alters light exposure patterns, and contributes to circadian misalignment. Detrimental health consequences associated with shift work include elevated risk for metabolic disorders, cardiovascular disease, cancer and all-cause mortality. Healthcare workers have one of the highest rates of shift work exposure, yet there are relatively few non-pharmacological interventions (with good evidence) developed to improve sleep outcomes in this population. Objective: A pre-post pilot interventional study assessed the acceptability and perceived effectiveness of commercial noise-masking earbuds on improving subjective sleep characteristics among National Health Service (NHS) healthcare staff working fast rotating shifts. Methods: Noise-masking sleep earbuds (Kokoon NightBuds) were worn for a pilot six-week intervention by twenty-seven NHS nurses (aged 26-43 years, 88.9% female) working fast rotating shifts from the EClocker Study. Sensors inside the earbuds were paired with a smartphone app to monitor sleep. An audio library in the smartphone app delivered personalised relaxation exercises and sleep techniques drawn from cognitive behavioural therapy for insomnia (CBT-I). A pre-post two-week monitoring period with daily smartphone-based Experience Sampling Methods (ESM) captured perceived daily sleep patterns. Acceptability and perceived effectiveness of the earbuds in promoting better sleep outcomes was assessed. Results: Use of the noise-masking sleep earbuds over a six-week period was associated with positive sleep improvement trends and elicited promising acceptability. Almost two thirds of NHS fast rotating shift nurses (63%) subjectively reported reductions in general sleep disturbance symptoms (PSQI Global), one in four experienced perceived sleep quality improvements (SQ; 25.9%), one in five reported sleeping longer (TST; 22.2%), and a third perceived falling asleep faster (SOL; 33.3%), had better sleep efficiency (SE; 33.3%) and improved daytime dysfunction (33.3%) (PSQI subcomponent scores). Sleep diaries (CSD) collected daily using smartphone-based ESM also demonstrated small improvements post-sleep earbud use; nurses reported sleeping an average 18 minutes longer (TST) and fell asleep more easily, on average 11 minutes faster (SOL). Sleep earbuds were generally well tolerated; 56% of nurses reported the earbuds as (somewhat to very) helpful, 52% reported (somewhat to strongly) falling asleep more easily (SOL), 44% felt (somewhat to strongly) their sleep quality was improved (SQ) and 30% agreed (somewhat to strongly) they slept longer (TST) and had less disturbed sleep. Conclusions: To our knowledge, this is the first study in Europe to pilot noise-masking earbuds as a potential non-pharmacological aid to improve sleep-wake behaviours or mitigate fatigue for healthcare staff. Preliminary results showed promising acceptability and (small) perceived sleep improvement trends following a targeted six-week earbud intervention in NHS fast rotating shift nurses.

Viral infections have long been proposed as environmental contributors to neurodegenerative diseases, including Parkinson's disease (PD), yet the molecular mechanisms linking infection and neurodegeneration are not well defined. Neuroinflammation and disruption of central nervous system (CNS) homeostasis have emerged as potential mediators. In this study, we used severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, as a model pathogen to investigate convergent molecular pathways between viral infection and PD. Single-nucleus RNA sequencing (snRNA-seq) was performed on post-mortem striatal tissue from 14 individuals stratified into four groups: COVID-19 only (COVID-19), PD only (PD), comorbid PD with COVID-19 (PD/COVID-19), and controls (Control). The PD/COVID-19 group exhibited an expanded astrocytic population and a pronounced interferon-associated molecular signature characterized by increased expression of canonical interferon-stimulated genes, including IFI44L (average log2FC= 3.9; adjusted p=2.3 x 10-373), IFI44 (average log2FC=2.9; adjusted p=8.0 x 10-266), ISG15 (average log2FC=3.1; adjusted p=1.2 x 10-197), and RSAD2 (average log2FC= 3.5; adjusted p=8.6 x 10-111). Pathway analyses demonstrated activation of innate immune and antiviral signaling pathways, particularly within microglia and astrocytes, including interferon signaling, pattern-recognition receptor pathways, and complement-associated responses. In parallel, genes involved in lipid metabolism, cholesterol homeostasis, synaptic maintenance, and neuronal signaling were reduced across disease groups. Proteomic analyses independently confirmed enrichment of antiviral and interferon-associated pathways and identified convergent suppression of sterol, cholesterol, and lipid metabolic processes. Our findings identify a convergent molecular signature linking PD and COVID-19, pronounced in comorbid individuals and characterized by interferon-driven innate immune activation, glial inflammatory responses, and dysregulation of lipid metabolic homeostasis. Collectively, the data support a model in which severe viral infection amplifies biological pathways already implicated in PD pathogenesis.

Mitochondria are central hubs for cellular metabolism and mitochondrial dysfunction is a hallmark of many chronic diseases. Consequently, changes in mitochondrial DNA copy number (mtDNA-CN), the number of mtDNA genomes per cell or tissue sample, are associated with diseases ranging from cancer and obesity to psoriasis and all-cause mortality. MtDNA-CN especially holds promise as a biomarker for neurodegenerative diseases, but whether and how mtDNA-CN changes with neurodegeneration is controversial. Here, we performed a systematic review and meta-analysis of 76 studies including 156 comparisons of mtDNA-CN in populations with or without a neurodegenerative disease to identify overall trends and potential moderators that explain variation among studies. Overall, mtDNA-CN was not statistically different with neurodegeneration, but heterogeneity among studies was extreme (I2 = 99.5%). The diagnosed disease explained the most variation. For example, Alzheimer's patients showed a 21% decrease in mtDNA-CN, but there was no change in mtDNA-CN with Parkinson's disease. Decreases in mtDNA-CN during neurodegeneration were also more extreme at older ages. Surprisingly, the tissue sampled for mtDNA-CN was not particularly influential, except for certain diseases. Studies published in earlier years also showed more extreme decreases in mtDNA-CN with neurodegeneration. Excessive heterogeneity persisted even after accounting for all moderators and their interactions (I2 = 85.7%). We conclude that the general perception of decreased mtDNA-CN with neurodegeneration is a vast oversimplification that may stem from legacy effects of early studies. However, mtDNA levels offer great promise as biomarkers for neurodegeneration, other diseases, and general health metrics, assuming appropriate complications can be considered.

Background: Plasma phosphorylated tau at threonine 217 (p-Tau217) is a leading blood-based biomarker for Alzheimer's disease (AD). Robust analytical characterization on high-throughput platforms is essential for research use and clinical translation. Objective: To evaluate the analytical performance of an automated plasma p-Tau217 immunoassay and characterize its discrimination of PET-defined amyloid status. Methods: We performed analytical validation of the Access Research Use Only (RUO) plasma p-Tau217 immunoassay on the Beckman Coulter DxI 9000 Access Immunoassay Analyzer and evaluated biomarker discrimination of PET-defined amyloid pathology in a subset of the Bio-Hermes-001 cohort spanning the symptomatic cognitive continuum (mild cognitive impairment or mild AD dementia; cognitively unimpaired participants excluded; n = 449). Analytical precision, sensitivity, linearity, specificity, interference, and sample stability were assessed per Clinical and Laboratory Standards Institute guidelines. Discrimination of PET-defined amyloid status was evaluated using receiver operating characteristic curve and indeterminate zone analyses. Results: The assay demonstrated high precision (within-laboratory CV </=7.1%), excellent sensitivity (limit of detection 0.018-0.021 pg/mL), linearity across the analytical measuring range (R-squared > 0.99), strong epitope specificity (</=1.0% cross-reactivity with other tau phosphoisoforms), and minimal interference from over 60 endogenous and exogenous substances. In 449 research participants plasma p-Tau217 showed strong discrimination between amyloid-positive and amyloid-negative groups (AUC 0.881; 95% CI 0.846-0.915). Application of indeterminate zones systematically improved classification metrics at the cost of fewer definitive classifications. Conclusions: These findings support the Access p-Tau217 (RUO) assay as a robust, high-throughput assay for plasma biomarker-based discrimination of PET-defined amyloid pathology in AD applications.

Background: Multiple sclerosis (MS) is a chronic, immune-mediated disease of the central nervous system marked by demyelination and neurodegeneration. Beyond physical symptoms, MS is often linked to clinically relevant sleep disturbances. The variability and unpredictability of symptoms and disease progression can also fuel fear of relapse (FoR), undermining well-being and potentially increasing morbidity through inflammatory processes. Understanding biopsychosocial risk factors, including childhood maltreatment (CM) and sleep, in relation to FoR remains an important gap in MS management and research. Methods: Data from N = 48 participants were collected via an online survey. We used the Pittsburgh Sleep Quality Index (PSQI), the Fear-of-Relapse Scale (FoR), and the Childhood Trauma Questionnaire (CTQ) to assess the variables of interest. In addition, time points of exposure to different CM subtypes were assessed. Linear regression analyses were conducted to examine associations within the proposed negative triad. Results: A significant negative association between overall sleep quality and FoR was observed. In the total cohort, the interaction between CM and sleep was not a significant predictor of FoR. However, exploratory analysis revealed a significant interaction between CM and sleep among male participants, whereas the same interaction was not significant among female participants. Conclusion: A history of CM and impaired sleep quality introduce new stressors in managing one's own illness that have received little attention to date. However, the present study found that these factors were at least partly influential on the FoR. The results underscore the translational need for additional support services to enhance prevention and personalized care.

The Autism Spectrum Quotient (AQ-50) is widely used to assess autistic traits, yet its Hungarian version has not been psychometrically evaluated. We assessed the reliability, factor structure, temporal stability, convergent validity, and clinical utility of the Hungarian AQ-50 and a revised translation (AQ-50-HU-R) in two samples (N1 = 1967; N2 = 423), including autistic and non-autistic participants. The AQ-50-HU-R showed high internal consistency and test-retest reliability. A bifactor model provided the best fit ({chi}2[1125] = 1650.433, p < 0.001; CFI = 0.991; TLI = 0.990; RMSEA = 0.033 [90% CI = 0.030-0.037]; SRMR = 0.083), with 71% of common variance attributable to a general autistic traits factor. The total score distinguished clinically verified autistic participants from participants reporting no ASD diagnosis (AUC = 0.906), with a cutoff of 25. Associations with ADOS scores were weak or nonsignificant. The AQ-50-HU-R is best interpreted as a reliable total-score screening measure, supporting referral for comprehensive autism assessment.

Background: Exclusive breastfeeding may protect infants against common infections and support healthy growth and development. Working mothers may face constraints on exclusive breastfeeding arising from work schedules, separation from their infants, and inadequate breastfeeding support. National evidence on the individual, healthcare-related, and contextual factors associated with exclusive breastfeeding among working Ghanaian mothers appears to remain limited. Design: Cross-sectional secondary analysis. Setting: Nationally representative survey covering urban and rural communities across all 16 administrative regions of Ghana. Participants: The analysis included 620 currently working mothers whose youngest living infants were aged 0-5 completed months and lived with them. The complete-case multivariable analysis included 619 mother-infant pairs. Primary outcome measure: Current exclusive breastfeeding, defined using the standard 24-hour infant-feeding indicator. Infants were classified as exclusively breastfed when they received breast milk without water, formula, animal milk, other liquids, or solid or semi-solid foods during the preceding day or night. Oral rehydration solution, vitamins, minerals and prescribed medicines were permitted. Aim: To estimate the prevalence of exclusive breastfeeding and examine its individual, healthcare-related and contextual correlates among working mothers of infants aged 0-5 months in Ghana. Methods: Birth Recode data from the 2022 Ghana Demographic and Health Survey were analysed. Unweighted frequencies and survey-weighted percentages described the study population. Design-adjusted Wald tests assessed bivariate associations. Survey-weighted binary logistic regression estimated adjusted odds ratios (AORs) and 95% confidence intervals (CIs), accounting for sampling weights, primary sampling units, and strata. Results: The survey-weighted prevalence of exclusive breastfeeding was 54.3% (95% CI: 49.2-59.3). Ethnicity, mode of delivery, region, and community poverty appeared to be statistically significant in the bivariate analyses. In the adjusted model, region was jointly associated with exclusive breastfeeding (p = 0.004). Mothers in the Northern (AOR = 4.93; 95% CI: 1.5-16.17) and Savannah (AOR = 4.22; 95% CI: 1.08-16.41) regions had higher odds than mothers in the Western Region. Mothers in low-education communities had lower odds than those in high-education communities (AOR = 0.54; 95% CI: 0.30-0.98). Although Guan mothers had higher odds than Akan mothers, the overall association with ethnicity was non-significant, and the estimate appeared imprecise. Maternal age, individual education, religion, parity, wealth, infant sex, antenatal care, postnatal care, and residence were not independently associated with exclusive breastfeeding. Conclusion: The prevalence estimate suggests that slightly more than half of working mothers exclusively breastfed their infants. Regional and community differences appeared more pronounced than those associated with most measured individual characteristics. Regionally responsive breastfeeding support and practical community education may contribute to improved coverage. Workplace recommendations require further evidence because employment conditions were not measured directly. Keywords: Exclusive breastfeeding; working mothers; infant feeding; maternal employment; regional inequalities; community education; Ghana; 2022 Ghana Demographic and Health Survey; survey-weighted analysis.

Objective: Whether a scheduled antiseizure medication (ASM) continues on schedule across the ICU-to-floor transfer has not been characterized. We quantified ASM administration-gap frequency across this transfer and compared it with gap frequency during matched non-transfer intervals in the same patient and drug. Methods: In this retrospective MIMIC-IV (version 3.1) cohort study, we identified epilepsy and status-epilepticus admissions with an ICU stay followed by floor transfer and a scheduled ASM order active at ICU departure. A gap was defined as an interval exceeding 1.5 times the expected dosing interval between the last ICU dose and first floor dose, or no further dose before discharge, and compared with a matched non-transfer control interval in the same patient and drug (paired McNemar test). A multivariable model evaluated six prespecified clinical predictors; sociodemographic variables were summarized descriptively. Results: Among 2,469 ASM transition-by-drug observations (1,583 admissions, 1,335 patients), an administration gap occurred in 251 (10.2%; 95% CI, 8.7%-11.7%). Gap frequency across the transfer exceeded frequency during matched non-transfer control intervals in the same patient and drug: a paired rate difference of 5.8 percentage points (95% CI, 4.4-7.1; 7.5% vs 1.7%; P = 7.3 x 10^-22) before the transfer and 6.4 percentage points (95% CI, 4.9-7.9; 8.9% vs 2.5%; P = 1.9 x 10^-23) after. Gap rates were similar for intravenous-available (9.9%) and oral-only (11.4%) drugs (rate difference, 1.5 percentage points; 95% CI, -1.6 to 4.5; P = .34). None of six prespecified predictors reached significance after correction. Significance: An antiseizure medication administration gap occurred in approximately 1 of every 10 drug-transition observations at the ICU-to-floor transfer, exceeding matched non-transfer gap rates by 5.8 to 6.4 percentage points. This transfer-associated excess, rather than any single medication or patient characteristic, supports a structured medication-continuity check.

Stroke remains a leading cause of mortality and long-term disability worldwide, yet rapid diagnosis is often limited by the shortage of trained radiologists, particularly in resource-constrained settings. Automated analysis of CT imaging offers a potential solution, but existing methods often struggle to achieve clinically generalisable performance while jointly addressing multiple diagnostic tasks. Here we present the Intelligent Integrated Stroke Diagnosis System IISDS, an end-to-end deep learning framework built upon StrokeGNN, a graph-based architecture that integrates 3D contextual feature extraction with U-Net-based 2D lesion segmentation to enable comprehensive stroke analysis from non-contrast CT scans. IISDS performs stroke subtype classification, lesion segmentation and lesion volume estimation within a unified pipeline. To develop and validate the system, we collected and curated BGD-ISD through a collaboration between AI researchers, neurologists, radiologists and clinicians, resulting in a large multi-centre dataset comprising 1,507 CT scans from 597 stroke cases acquired across six hospitals and medical centres in Bangladesh. Across BGD-ISD and multiple publicly available datasets, IISDS achieves state-of-the-art performance on all tasks, improving segmentation accuracy by [&ge;]0.011 Dice score, reducing lesion volume estimation error by [&ge;]0.3 average symmetric surface distance (ASSD), and increasing classification performance by [&ge;]0.018 area under the receiver operating characteristic curve (AUC) compared with existing approaches. These results demonstrate the potential of graph-based deep learning to enable clinically generalisable, automated and scalable stroke diagnosis from CT imaging, supporting rapid clinical decision-making, particularly in healthcare environments with limited access to expert radiological interpretation.

Background: Aerobic exercise is recommended during stroke rehabilitation to improve cardiorespiratory fitness and support recovery; however, participation rates remain low. While institutional and system-level barriers have been widely examined, less is known about how individual patient factors influence engagement in aerobic exercise during rehabilitation. Objectives: We aimed to determine whether depressive symptoms, apathy, self-efficacy and outcome expectations for exercise, perceived barriers, or past exercise history were associated with aerobic exercise participation in stroke rehabilitation. Methods: In this prospective cohort sub-study, adults admitted to in- or out-patient stroke rehabilitation at three urban hospitals completed validated questionnaires assessing depressive symptoms, apathy, exercise self-efficacy, outcome expectations for exercise, perceived barriers to being active, and premorbid exercise history. Participants were separated into two groups for analysis: those who completed aerobic exercise during rehabilitation and those who did not. Equivalence testing and between-group comparisons were performed. Results: Sixty-two participants were enrolled; 16 participated in aerobic exercise and 46 did not. Groups were not equivalent on any individual-level factors. Compared to non-participants, those who performed aerobic exercise had significantly higher depressive symptom scores (p=0.0025) and lower self-efficacy for exercise (p=0.0087). Non-participants demonstrated significantly higher apathy (p=0.0007). No significant differences were found for outcome expectations, perceived barriers, or exercise history. Conclusion: Depressive symptoms and lower self-efficacy did not impede aerobic exercise participation during rehabilitation. Increased apathy, however, was associated with non-participation. Findings highlight the need for individually tailored aerobic exercise prescriptions that consider motivational and affective factors to optimize engagement during stroke rehabilitation.

Background and Objectives: Recurrence following burr-hole drainage of chronic subdural haematoma (cSDH) occurs in 10-25% of cases, sustained by neovascularisation of the subdural neomembrane supplied by the middle meningeal artery (MMA). MMA embolisation reduces recurrence; whether incidental burr-hole intersection of MMA branches during drainage confers similar benefit is unknown. Methods: We performed a multicentre retrospective cohort study of consecutive adults undergoing burr-hole drainage for cSDH at two UK tertiary neurosurgical centres. Postoperative thin-slice CT was used to classify burr-hole intersection of the underlying MMA groove (no hit, distal-branch hit or main-branch hit) and measure perpendicular burr-hole-to-MMA-groove distance. Co-primary outcomes were radiological recurrence and recurrence requiring intervention. Patient-clustered multivariable logistic regression adjusted for prespecified clinical covariates and treating site. Results: 227 patients (284 operated hemispheres) were included. Radiological recurrence decreased from 34.4% with no branch hit to 22.9% with main-branch intersection, with the gradient confined predominantly to unilateral cSDH. Main-branch intersection was associated with lower adjusted odds of radiological recurrence in unilateral cSDH (adjusted OR 0.30, 95% CI 0.11- 0.81; P = .018), with a similar but non-significant association in the overall cohort (adjusted OR 0.53, 95% CI 0.26-1.07; P = .075). Burr-hole-to-MMA-groove distance demonstrated a more consistent association: in the overall cohort, each 5-mm increase independently increased the odds of radiological recurrence (adjusted OR 1.38, 95% CI 1.04-1.82; P = .025). In unilateral cSDH, each 5-mm increase was independently associated with both radiological recurrence (adjusted OR 1.45, 95% CI 1.03-2.04; P = .034) and recurrence requiring intervention (adjusted OR 1.52, 95% CI 1.05-2.20; P = .027). Conclusion: Main-branch intersection of the middle meningeal artery during routine burr-hole surgery is associated with lower recurrence of unilateral cSDH, while the accompanying burr-hole-to-MMA-groove distance gradient provides biologically plausible support for a dose-response relationship. Together, these findings provide mechanistic rationale for prospective evaluation of intentional neuronavigation-guided MMA targeting (BURR-MMA; NCT07549893).

Disseminating study results to participants is an ethical responsibility for researchers but remains uncommon in low- and middle-income countries, and participants preferences for receiving study results are poorly understood. This study examined study result dissemination preferences among pregnant women in a phase III malaria prevention trial in Papua New Guinea (PNG). Participants completed an interviewer-administered questionnaire (survey) assessing their interest in and motivation for receiving trial results and preferences for dissemination methods and content. Associations between participants characteristics and dissemination preferences were explored using multivariable logistic regression analysis. Of 1172 trial participants, 96.0% (1125/1172) completed the survey, and of these 99.6% (1121/1125) wanted to learn about the trial results. The main motivation factors driving participants interest were an acknowledgment of their contribution to research (51.7%; n=579) and a better understanding of the study (45.0%; n=505). Most participants (78.9%; n=884) wanted to learn about the trial findings through written summary and a group meeting with other participants at the nearest clinic (31.1%, n=349). Multivariable regression analysis indicated that participants from rural/peri-urban clinics were more likely to choose non-electronic media dissemination approaches such as a group meeting as compared to urban-dwelling participants. Frequently selected items (>50% of participants) for content included information regarding good results of the study, purpose of the study, medical treatment advances, results specific to me, and how study was conducted. There was heterogenicity in the preference for dissemination content: compared to urban clinics rural clinics are less likely to want to learn about how and why study was conducted and medical and scientific advances. Overall, the majority wanted to learn about trial results, highlighting the importance of integrating dissemination into research activities in PNG. Variation in preferences for mode and content of dissemination between study clinics suggests that dissemination activities could be tailored to local context and preferences.