Frontiers in Human Neuroscience

Resting-state electroencephalography (EEG) has been proposed as a scalable source of biomarkers for chronic pain, but its clinical potential remains uncertain. To systematically evaluate this potential, we benchmarked nine modeling strategies, spanning conventional machine learning with handcrafted features to state-of-the-art deep learning. Across 72 configurations of signal representations and model architectures, we trained models to predict self-reported pain intensity, using chronological age decoding as a positive control. Pain prediction performance was limited (R=0.15), with the best results achieved by conventional connectivity-based models. In contrast, age was robustly decoded from the same dataset (R=0.53), confirming technical efficacy. These findings indicate that resting-state EEG contains limited information about inter-individual differences in chronic pain intensity, making it unlikely to yield clinically actionable biomarkers in cross-sectional settings. Instead, its potential may lie in intra-individual modeling of pain dynamics, which could advance individualized mechanistic insights and more personalized treatment of chronic pain.

Background and objectives STXBP1-related disorder (STXBP1-RD), caused by pathogenic variants in the STXBP1 gene, is a rare neurodevelopmental condition, characterized by early-onset seizures, developmental delay, intellectual disability (ID), and prominent motor dysfunction. Despite the high prevalence of motor symptoms, systematic gait characterization remains limited. We therefore aimed to quantitively assess gait in individuals with STXBP1-RD. Methods In this cross-sectional study, we included ambulatory patients aged 6 years or older with genetically confirmed STXBP1-RD. Instrumented 3D Gait Analysis (i3DGA) was performed to objectively quantify gait. Functional mobility was assessed with the Functional mobility scale (FMS) and Mobility Questionnaire 28 (MobQues28). Caregiver health-related quality of life was evaluated using the PedsQL-Family Impact Module (PedsQL-FIM). We explored associations between gait, functional mobility, STXBP1-variant type and clinical features (ID, age at seizure onset, seizure frequency, age at onset of independent walking). Correspondence between i3DGA and the Edinburgh Visual Gait Score (EVGS), an observational gait assessment, was investigated. Results Eighteen participants were included. Compared to typically developing peers, individuals with STXBP1-RD had significantly reduced walking speed, step and stride length. Gait patterns were highly variable, with the most frequent pattern being an externally rotated foot progression angle (FPA), present in 11/18 participants. At home, 93.75% of the participants (16/18) walked independently, yet community mobility was more variable: 11/16 (68.75%) walked independently, 2/16 (12.50%) with aid and 3/16 (18.75%) used a wheelchair, indicating increasing limitations with distance and environmental complexity. Earlier acquisition of independent walking strongly predicted later unassisted ambulation at community level (p<0.001). Median MobQues28 score was 57.14% and median PedsQL-FIM score was 60.42%, indicating a moderate level of mobility limitations and reduced health-related quality of life of caregivers. EVGS was highly positive correlated with i3DGA (p= 0.001). Discussion Quantitative gait analysis in individuals with STXBP1-RD demonstrates heterogenous kinematic deviations, with an externally rotated FPA emerging as the most common pattern. Age at independent walking was a clinically relevant predictor of later functional mobility. EVGS showed strong correspondence with i3DGA and may offer a more practical, semi-quantitative assessment for broader use. These findings inform clinical decision-making and guide the selection of scalable outcome measures for natural history studies and interventional trials.

Multiple sclerosis (MS) is a chronic neurodegenerative disease characterised by progressive neurological disability and heterogeneous symptom trajectories. Current clinical monitoring methods, including magnetic resonance imaging (MRI) and episodic neurological assessments, provide limited insight into subtle disease progression and functional changes. Digital health technologies integrating multimodal biosignals and behavioural assessments may enable continuous monitoring and personalised rehabilitation in patients with MS. This study aims to evaluate the clinical utility of the BodyMirror Clinical MS platform, a multimodal SaMD that combines wearable biosensors, neuroscience-based games, and machine learning to remotely monitor disease progression and deliver personalised neurorehabilitation for individuals with multiple sclerosis. This study is a prospective, randomised, double-blind, controlled, multisite clinical trial enrolling 400 participants (300 individuals with multiple sclerosis and 100 healthy controls). MS participants will be randomly assigned (1:1) to either an adaptive neurorehabilitation intervention group or a control group receiving non therapeutic digital activities matched for engagement and exposure. Participants will perform three 30-minute sessions per week over 24 months using the BodyMirror platform. The system integrates multiple biosignals, including electroencephalography (EEG), electromyography (EMG), inertial measurement unit (IMU) motion data, speech analysis, and behavioural performance metrics to generate digital biomarkers of neurological function. The primary endpoint is a change in Expanded Disability Status Scale (EDSS) score from baseline to 24 months. Secondary outcomes include changes in Multiple Sclerosis Functional Composite (MSFC), MRI brain volume, cognitive performance, patient-reported outcomes, adherence to digital rehabilitation, and health economic outcomes.

Background: Quadriceps weakness may reduce sagittal plane shock absorption during landing, shifting load toward the frontal plane and increasing knee abduction moment (KAM), a biomechanical risk factor for anterior cruciate ligament (ACL) injuries. Purpose: The purpose of this study was to evaluate the association between isokinetic quadriceps strength and peak KAM during drop vertical jump landing in adolescent athletes. Study Design: Secondary analysis of previously collected data. Methods: Healthy adolescent athletes completed quadriceps strength testing using an isokinetic dynamometer and a biomechanical assessment during a drop vertical jump task. Quadriceps strength was quantified as peak concentric torque and the peak external KAM was calculated during the landing phase on the dominant limb. Both strength and KAM were normalized to body mass. Linear regression was used to examine the association between normalized quadriceps strength and peak external KAM on the dominant limb. Results: The association between quadriceps strength and peak normalized KAM on the dominant limb was not statistically significant ({beta} = -0.053 (95% CI [-0.137 to 0.030]), F(1,119) = 1.62, R2 = 0.013, p = 0.206). Quadriceps strength explained only 1.3% of the variance in peak KAM, indicating a negligible association between these variables in this cohort. Discussion: Quadriceps strength was not associated with peak normalized KAM during landing, suggesting that frontal-plane knee loading during a drop vertical jump is not meaningfully explained by maximal concentric quadriceps strength alone. KAM appears to be driven more by multi-joint movement strategy and neuromuscular coordination than by the capacity of a single muscle group.

Background: Psychological readiness to return to sport and subjective knee function are critical outcomes following ACL reconstruction (ACLR), yet they do not always progress in parallel. An athlete may demonstrate high subjective knee function but low psychological readiness, suggesting a mental barrier to return, or conversely, report high readiness despite persistent functional limitations, raising concerns of overconfidence and reinjury risk. Understanding how these domains change together during recovery is essential for identifying mismatches that may require targeted intervention. Purpose: The purpose of this study is to examine the relationship between changes in psychological readiness (ACL-RSI) and subjective knee function (IKDC) from early to late recovery following ACLR. Study Design: Secondary analysis of prospectively collected data. Methods: Athletes (N = 48, Age at ACLR = 17.7 {+/-} 1.8 y) aged 15-25 years who underwent ACLR with an ipsilateral autograft, had a pre-injury MARX score > 8, and completed the ACL-RSI and IKDC questionnaires at 3.5 {+/-} 1 and 7 {+/-} 1 months post-ACLR were included. Percent changes in ACL-RSI and IKDC scores between early and late recovery were calculated. Spearman's rank correlation was used to examine the association between changes in psychological readiness and subjective knee function. Significance was set to p < .05. Results: The mean percent change in ACL-RSI was 40.7 {+/-} 57.1% and the mean percent change in IKDC was 24.8 {+/-} 18.1% from 3.5 {+/-} 1 months to 7 {+/-} 1 months post-ACLR. The percent changes in ACL-RSI and IKDC scores from 3.5 {+/-} 1 months to 7 {+/-} 1 months post-ACLR were moderately correlated ({rho} = 0.350 (95% CI [0.089, 0.584]), p = 0.012). Discussion: The main finding of this study was that subjective knee function and psychological readiness to return to sport changed in parallel from 3.5 to 7 months following ACLR. Clinicians can use this information regarding the concordant progression of psychological readiness to return to sport and subjective knee function to personalize ACL rehabilitation for future patients. Overall, clinicians can understand that if psychological readiness improves, subjective knee function will likely improve over the 3.5- to 7-month post-ACLR time frame, and vice versa. Therefore, focusing on both of these components at multiple time points during the recovery process may be influential to ensure the greatest likelihood of returning to sport in athletes following ACLR.

Importance: Dementia is common in Parkinson's disease (PD), causing greater disability than other symptoms, but varies in timing. Although visual deficits are linked with PD dementia, how these interact with genetic factors to predict PD dementia has not been characterised. Objective: To investigate whether visual deficits and genetic factors predict PD dementia. Design: Large prospective longitudinal case-control study, mean follow-up 32.7 (SD=12.3) months. Setting: Cases were recruited between 2017-2020 at 35 UK PD clinics. Participants: People with PD without dementia at baseline were included. Main outcomes and measures: Visual function was measured using a web-based platform. The main outcome measure was global cognition, measured as the Montreal Cognitive Assessment (MoCA). Blood samples were collected for genetics. Results: 450 patients with PD were included. Mean age of PD patients was 71.7 (SD=7.8), 68% male. Mean baseline MoCA was 27.7 (SD=1.7). 263 patients with PD were classed as poor-vision based on baseline visual tests: mean age 74.4 (SD=6.8) compared to 69.7 (SD=7.5) with good-vision. Poor-vision PD patients had higher rates of progression to mild cognitive impairment (PD-MCI) (HR=2.34, CI=1.58-3.48, pFDR=0.00062, age- and sex-corrected). The combination of genetic factors together with vision influenced outcomes. In good-vision PD patients, high-risk GBA1 gene variants were linked with greater progression to PD-MCI (HR=4.61, CI=1.73-12.28, pFDR=0.0068). Polygenic Risk Score (PRS) for both PD and Alzheimer's disease (AD) also modified cognitive survival when combined with vision status. High PD-PRS was associated with greater progression to PD-MCI in good-vision patients (HR=2.66, CI=1.21-5.81, pFDR=0.0381); and high AD-PRS with greater progression to PD-MCI in poor-vision PD patients (HR=1.91, CI=1.10-3.32, pFDR=0.04999). Combining high PD- and AD-PRS, compared to low PD- and AD-PRS in good-vision PD showed even higher progression to PD-MCI (HR=6.14, CI=1.36-27.83, pFDR=0.046). Simulations showed that adding visual and genetic stratification reduced sample size from n=705 to n=160 for clinical trials. Conclusions and relevance: Poor vision in PD predicts progression to PD-MCI and dementia. This combines with the effects of genetic factors including GBA risk variants and PD- and AD-PRS. These findings can enable enrichment of clinical trials for patients at higher risk of PD dementia, for more efficient trial design for interventions to slow progression.

We propose a lesion-centric phenotype learning pipeline for interpretable breast ultrasound (BUS). Predicted lesion masks are used for mask-weighted pooling of segmentation-encoder latents, producing compact embeddings that suppress background influence; a lightweight calibration step improves cross-dataset consistency. We cluster embeddings to discover latent phenotypes and relate phenotype structure to morphology descriptors (compactness, boundary sharpness). On BUSI and BUS-UCLM with external testing on BUS-BRA, lesion-centric pooling and calibration improve separability and enable strong malignancy probing (AUC 0.982), outperforming radiomics and a standard CNN baseline. A simple rule-gated generator further improves BI-RADS-style descriptor consistency on difficult cases.

Background: Nursing interns are at high risk of psychological distress due to academic and clinical stressors. While poor sleep quality is linked to anxiety and depression, the buffering role of social support remains underexplored in this population. Aims: To explore the role of social support in regulating the relationship between sleep and mental health among nursing interns. Methods: A total of 396 nursing interns completed self-administered questionnaires including the Pittsburgh Sleep Quality Index (PSQI), Social Support Rate Scale (SSRS), Generalized Anxiety Disorder-7 (GAD-7), and Patient Health Questionnaire-9 (PHQ-9). Hierarchical regression and simple slope analyses were used to test moderation effects. Results: Poor sleep quality was significantly associated with higher anxiety ({beta}=0.449, P<0.001) and depression ({beta}=0.535, P<0.001). Social support significantly moderated these relationships. Under low social support, the effects of sleep quality on anxiety ({beta} = 0.602) and depression ({beta} = 0.779) were stronger than under high support (anxiety: {beta} = 0.396; depression: {beta} = 0.515). Conclusions: Social support buffers the adverse psychological effects of poor sleep among nursing interns. Interventions should integrate sleep hygiene education with strategies to enhance social support.

Protocadherin-12 (PCDH12), a cell-adhesion protein belonging to the non-clustered protocadherin family, plays a crucial role in the establishment and regulation of neuronal connections and communication. Bi-allelic loss-of-function (LoF) variants in the PCDH12 gene have been associated with several neurodevelopmental disorders (NDDs) such as diencephalic-mesencephalic junction dysplasia (DMJD) syndrome, cerebral palsy, and cerebellar ataxia, often accompanied by ocular abnormalities. However, genotypes exhibit variable expressivity. Affected individuals sharing the same PCDH12 variant presenting differing phenotypic severities have posed major challenges towards identification of the underlying pathogenic mechanisms. Here, we report three affected individuals from two families, each harbouring non-truncating pathogenic missense variants in PCDH12. The patients are compound heterozygous, with each individual carrying one extracellular [c.1742T>G (p.Val581Gly) and c.1861_2del/insCA (p.Ile621His)] and one intracellular variant [c.3370C>T (p.Arg1124Cys) and c.3445G>A (p.Asp1149Asn] on each allele. The children present with a range of phenotypes similar to those associated with LoF variants. One child exhibited microcephaly and seizures, while the two siblings displayed developmental delays and severe behavioral disorders. All three children experienced some degree of visual impairment. The missense variants provided new insights into the neurodevelopmental consequences of compromised PCDH12 function by distinguishing the specific consequences associated with dysfunction in the extracellular versus intracellular domains of PCDH12. All identified missense variants are predicted to be deleterious and destabilizing. The expression of PCDH12 in HEK293T and HeLa cells demonstrated that PCDH12 is expressed effectively, regardless of the presence of missense variants. However, the extracellular variants p.Val581Gly and p.Ile621His compromised the stability of PCDH12's homophilic adhesion. Additionally, we found evidence of an interaction between PCDH12 and the extracellular domain of the epilepsy-associated PCDH19 protein. PCDH12 extracellular missense variants also negatively impact this interaction. Our study provides evidence that PCDH12 mediates both homophilic and heterophilic interactions. Our findings also highlight the importance of stable PCDH12-mediated adhesion, emphasizing the need to further study the functional consequences of PCDH12 missense variants on brain and visual system development.

Abstract Background: Conventional MRI cannot reliably distinguish radiation necrosis (RN) from recurrent metastasis after cranial radiotherapy, as both can show similar enhancement despite different biology. We tested whether these entities are mechanically non-equivalent in vivo and separable by MRE-derived viscoelastic metrics and perilesional interface-instability features. Methods: In a prospective, histopathology-anchored cohort, 11 post-radiotherapy enhancing lesions were classified as RN (n=3) or recurrent/progressive tumor (n=8). MRE was acquired at 3.0 T with single-frequency 60-Hz excitation to derive storage modulus (G'), loss modulus (G''), and complex shear modulus magnitude (|G*|). Co-primary endpoints were median tumor G' and |G*|, each tested one-sided (RN > tumor) with Holm correction across the two co-primary tests. Median tumor G'' was tested two-sided. A prespecified secondary 6-endpoint family (absolute and tumor/NAWM-normalized G', G'', and |G*|) was analyzed with Benjamini-Hochberg FDR control. Exploratory instability mapping in a 0- 6 mm peritumoral shell generated interface-topology metrics, including convexity. Results: Absolute tumor-core medians were higher in RN than tumor for |G*| (1.79 vs 1.32 kPa; Cliff's {delta} = 0.67; q = 0.10), G' (1.62 vs 1.09 kPa; {delta} = 0.50; q = 0.14), and G'' (0.81 vs 0.46 kPa; {delta} = 0.75; q = 0.10). NAWM normalization improved separation: tumor/NAWM |G*| (2.26 vs 1.41; {delta} = 0.92; q = 0.04) and tumor/NAWM G'' (2.67 vs 0.87; {delta} = 1.00; q = 0.04) were FDR-significant. Convexity also differentiated RN from tumor (0.49 vs 0.36; {delta} = 1.00; MWU p = 0.01). Conclusions: Tumor/NAWM G'', tumor/NAWM |G*|, convexity, and tumor G'' emerged as the strongest candidate features, indicating that RN is mechanically harder and more dissipative than recurrent metastasis. Signal strength was high (Cliff's {delta} up to 1.00) but should be interpreted cautiously given sample size. Exploratory analyses further suggest that instability mapping captures biologically relevant interface behavior. These findings support a mechanics-based RN-versus-recurrence framework and justify prespecified, preregistered external validation.

A critical challenge in endocrine neurosurgery is intraoperative discrimination between normal pituitary tissue and pituitary neuroendocrine tumors (PitNETs). Suggesting the universal persistence of near-infrared autofluorescence (NIRAF) in endocrine organs and inspired by routine clinical use of NIRAF for parathyroid gland identification, we discovered that pituitary NIRAF can be employed for label-free transsphenoidal surgery guidance. Ex vivo confocal spectral imaging of 33 specimens identified secretory granules as the dominant long-wavelength fluorescence source and showed that normal pituitary had higher granule content than PitNETs. For the first time, we made use of the pituitary NIRAF during surgery and assessed its performance for pituitary/adenoma separation in vivo for 27 surgeries and showed near-perfect separability between pituitary and non-pituitary measurement sites with ROC-AUC of 0.98. The obtained results clearly demonstrate that the suggested method, based on the solid microscopic background, has the potential for clinical translation and paves the way for enhanced gland preservation during resection.

Gait variability is a critical functional indicator of dynamic balance and neurocognitive decline in health. Its translation into clinical practice is, however, challenged by a lack of age-related normative trajectories and reference values under real-world ecological settings. Furthermore, the conventional metrics used to estimate gait variability (Coefficient of Variation, CV; Standard Deviation, SD) have a fundamental methodological flaw: the inherent sensitivity of conventional metrics to the statistical outliers and environmental noise in real-world walking. In this study, we mitigate this factor by applying a robust statistical framework to quantify gait variability. Analysing a large-scale cohort of community-dwelling older adults (n=2,193), we first demonstrate that free-living gait data follows a heavy-tailed distribution, necessitating the use of robust estimators like the Robust Coefficient of Variation (RCV-MAD) and Median Absolute Deviation (MAD). Leveraging these metrics, we established the normative trajectory and reference values of real-world gait variability across the ageing lifespan, revealing a distinct, age-dependent increase in spatio-temporal fluctuations, indicating a decline in rhythmicity and steadiness with age. We further demonstrated the clinical utility of these robust metrics: RCV-MAD consistently yielded larger effect sizes than conventional CV in discriminating between fallers and non-fallers across all gait parameters. Furthermore, we illustrate the potential of long-term unsupervised monitoring to capture intrinsic variability during real-world walking. Validated for consistency and reliability, this robust framework provides the necessary ecological validity to transform gait variability into a standardised, rapid clinical metric for assessing functional decline at an early timepoint.

Purpose: Tumor genomic testing (TGT) is standard-of-care for most patients with advanced/metastatic cancer. Despite established guidelines, patient education prior to TGT is frequently omitted. The purpose of this study was to evaluate the impact and durability of a concise 3-4 minute video for patient education prior to TGT in community versus academic sites and across cancer types. Patients and Methods: Patients undergoing standard-of-care TGT were enrolled at a tertiary academic institution in three cohorts: Cohort 1-breast cancer; Cohort 2-lung cancer; Cohort 3-other cancers. Cohort 4 consisted of patients with any cancer type similarly undergoing SOC TGT at one of three community cancer centers. Participants completed survey measures prior to video viewing (T1), immediately post-viewing (T2), and after return of TGT results (T3). Outcome measures included: 1) 10-question objective genomic knowledge/understanding (GKU); 2) 10-question video message-specific knowledge (VMSK); 3) 11-question Trust in Physician/Provider (TIPP); 4) perceptions regarding TGT. Results: A total of 203 participants completed all survey timepoints. Higher baseline GKU and VMSK scores were significantly associated with higher income and greater years of education. For the primary objective, there was a significant and sustained improvement in VMSK from T1:T2:T3 (Poverall p<0.0001), with no significant change in GKU (p=0.41) or TIPP (p=0.73). This trend was consistent within each cohort (all p[&le;]0.0001). Results for four VMSK questions significantly improved, including impact on treatment decisions, incidental germline findings, and insurance coverage of testing. Conclusions: A concise, 3-4 minute, broadly applicable educational video administered prior to TGT significantly and sustainably improved video message-specific knowledge in diverse cancer types and in academic and community settings. This resource is publicly available at http://www.tumor-testing.com, with a goal to efficiently educate and empower patients regarding TGT while addressing guidelines within the flow of clinical practice.

Despite the relevance of spatial mapping in analyzing the health situation and understanding the risk factors and determinants of leptospirosis, peripheral urban communities often remain invisible on maps, which tend to use data and methods that do not express community contribution nor promote local participation. Furthermore, in the implementation of sanitation interventions, the same happens: there is limited user participation, and a lack of identification of intervention needs based on the perception of community residents, failing the interventions. We conducted a cross-sectional study through collaborative mapping from February to October 2022 with 213 residents and self-declared heads-of-household in two peripheral urban communities. We analyzed the perception of sanitation needs indicated by residents and their relationship with the risk of leptospirosis in these communities. Based on community perception, sewage (NS: 87.1%; JSI/ME: 84.9%) and urban cleaning and solid waste management (NS: 25.9%; JSI/ME: 32.6%) were the sanitation needs. In NS, most participants indicated that the necessary interventions for sewage improvement were actions of sewer cleaning and sealing (26.5%), sewer cleaning and piping (23.5%), and implementation/installation/construction of a sanitary sewage network (41.4%). In JSI/ME, interventions included sewage sealing (48.7%) and piping (25.6%), in addition to actions to maintain sewage cleaning (93.3%). The removal of solid waste (trash) in the square (NS: 22.2%) and on the streets (JSI/ME: 69.2%), as well as community awareness (JSI/ME: 15.4%), were indicated as interventions to meet the needs of urban cleaning and solid waste management. Respondents agreed on where interventions should occur, which congregated around the local river. We found a negative correlation between the predicted leptospirosis seropositivity and perceived intervention needs in both study areas. The prevention of diseases such as leptospirosis in peripheral urban communities requires integrated basic sanitation interventions, encompassing different components and aligned with the local needs perceived by residents.

Background Persistent inequities in immunisation coverage, particularly among zero-dose and under-immunised children, continue to challenge Pakistan's Expanded Programme on Immunization. Weak feedback loop, inconsistent data quality, and limited real-time monitoring impede effective decision-making. This Implementation Research was conducted under the MAINSTREAM Initiative funded by Alliance for Health Policy and Systems Research (AHPSR) and supported by the Aga Khan Community Health Services Department and National Institutes of Health Pakistan to design, implement, and evaluate a digital monitoring and action planning tool to strengthen data-driven decision-making within routine immunisation systems. Methodology/Principal Findings A co-creation approach was employed to design a digital monitoring solution through inclusive consultations, key informant interviews, and focus group discussions with EPI Punjab at provincial and district levels. The solution included a customised mobile application for data collection and a Power BI visualisation dashboard to map low-coverage areas, identify drivers of dropouts and zero-dose children, and capture caregivers' information sources to inform targeted communication. The intervention was piloted in 60 households across six clusters of a Union Council of District Lahore. Advanced analytics identified reasons for non-vaccination and missed opportunities, generating tailored recommendations and practical plans for program managers. The analysis assessed acceptability, adoption, fidelity, and perceived scalability through field observations, system use, and stakeholder feedback. The co-developed digital tool enhanced visibility of coverage gaps through UC-level mapping, real-time dashboards, and structured action planning. Pilot testing in Lahore showed strong acceptability, ease of use, fidelity, and adaptability among managers, supervisors, and vaccinators. Scalability and sustainability potential were demonstrated, though barriers included leadership turnover, system fragmentation, workload pressures, and resource constraints. Conclusion The tool demonstrated feasibility to strengthen immunisation equity, accountability, and responsiveness. Co-creation with stakeholders enhanced ownership, operational relevance, and adoption, while complementing existing platforms. Sustainability will depend on effective integration, local ownership, capacity building, and accountability, while scalability requires interoperability, resource commitment, policy support, and alignment with existing workflows.

Understanding host susceptibility to Mycobacterium tuberculosis (Mtb) is critical for the development of new vaccines. Certain individuals "resist" becoming infected with Mtb despite intensive exposure; however, it is unknown whether there is a genetic basis for "resistance" to Mtb infection across populations. Here we conducted a genome-wide association study (GWAS) of resistance to Mtb infection by carefully characterizing exposure to TB patients among 4,058 close contacts in India, Brazil, and South Africa. 476 (12%) "resisters" remained free of Mtb infection despite substantial exposure to highly infectious TB patients. GWAS identified a novel chromosome 13 locus (rs1295104126) associated with resistance across the multi-ancestry meta-analysis. Comparing Mtb-infection to all uninfected contacts, irrespective of exposure, yielded a different locus on chromosome 6 (rs28752534), near the HLA-II region. These findings demonstrate a common genetic basis for resistance to Mtb infection across multi-ancestral cohorts with potential to elucidate novel mechanisms of protection from Mtb infection.

The use of semaglutide (SE), a glucagon-like peptide-1 receptor agonist (GLP-1RA) with glucose-lowering and weight-loss effects, has risen rapidly, particularly among women of reproductive age. While preclinical studies suggest benefits for ovarian function via the hypothalamic-pituitary-ovarian axis, its impact on the endometrial-embryo interface remains unclear. Here, we show that GLP-1R is dynamically expressed in fertile human endometrium, restricted to epithelial cells and markedly upregulated during the mid-secretory phase of the menstrual cycle. In a preclinical model of endometrial epithelial organoids, SE at physiological concentrations activates intracellular cAMP signaling, enhances epithelial metabolism, and upregulates receptivity markers without steroid hormone priming, whereas higher concentrations modestly reduce expression of a key receptivity marker PAEP/glycodelin and shift metabolism towards oxidative phosphorylation. By contrast, in stromal cells lacking detectable GLP-1R, SE disrupts decidualization, induces endoplasmic reticulum stress and suppresses cell-cycle at G2/M phase. Human embryo models, blastoids, expressed GLP-1R and underwent concordant SE-mediated transcriptional remodeling in epiblast and trophectoderm lineages, encompassing changes in metabolism and epigenetic regulation, but without shifts in lineage proportions. Notably, SE increased blastoid attachment to the endometrial epithelium in the absence of exogenous steroid hormones, suggesting enhanced epithelial-embryo interaction. Together, these findings reveal a compartment-specific mismatch, as SE augments epithelial and embryonic metabolic activity but compromises stromal support for implantation, with potential consequences for implantation due to stromal dysfunction.

Background Artificial intelligence (AI) is increasingly being integrated into healthcare systems, with growing applications in clinical decision support, workflow optimization, and population health management. While substantial investments have been made in digital infrastructure, the successful adoption of AI in primary care depends critically on the readiness, awareness, and educational preparedness of healthcare professionals. Global health authorities emphasize the need for ethically grounded and workforce-focused approaches to AI integration; however, evidence on clinicians readiness for AI, particularly in primary care settings and in the Middle East region, remains limited. Objectives This study aims to assess the level of awareness, perceptions, attitudes, and educational needs related to AI among healthcare professionals working within Qatars Primary Health Care Corporation (PHCC). In addition, it seeks to examine organizational factors influencing the integration of AI-focused education in primary care and to develop an AI readiness framework that can inform targeted training strategies and policy planning. Methods This study will adopt a mixed-methods design guided by the Organizational Readiness for Change (ORC) framework, adapted for AI integration in primary care. The quantitative component will consist of an anonymous, census-style online survey distributed to all healthcare professionals across PHCC health centers and headquarters, assessing AI awareness, attitudes, training needs, and perceived infrastructure readiness. Composite AI awareness and attitude scores will be calculated, and regression analyses will be used to explore factors associated with AI readiness. The qualitative component will include semi-structured interviews and focus group discussions using maximum variation sampling to capture diverse professional perspectives. Qualitative data will be analyzed thematically, following COREQ and SRQR reporting standards. Quantitative and qualitative findings will be integrated to generate an AI readiness profile and an actionable education roadmap aligned with national digital health priorities. Discussion This study will provide the first comprehensive assessment of AI readiness among primary care healthcare professionals in Qatar. By identifying knowledge gaps, training priorities, and organizational enablers and barriers, the findings are expected to inform the development of evidence-based AI education strategies within continuing professional development frameworks. The proposed AI readiness framework may also offer a transferable model for other health systems seeking to align workforce development with responsible AI implementation in primary care.

Objectives: Compare Anterior Cruciate Ligament (ACL) Return to Sport after Injury (ACL-RSI) scores over time following ACL reconstruction (ACLR) between male and female patients aged 15 to 25 years with primary ACL injuries and ACL reinjuries. Design: Retrospective cohort design. Setting: Sports physical therapy clinics. Participants: 332 patients aged 15-25 years who underwent ACLR following either primary ACL injury or ACL reinjury, either contralateral or ipsilateral graft reinjury, and had at least one observation of the ACL-RSI. Main Outcome Measures: ACL-RSI score. Results: ACL-RSI scores significantly increased over time post- ACLR (p < .001), males reported significantly higher scores compared to females (p < .001), and patients with contralateral ACL reinjury demonstrated higher scores than those with ipsilateral ACL graft reinjury (p = .006), though there was no difference in scores between patients with primary ACL injury and ACL reinjury. A significant interaction effect of sex and injury status was also observed (p = .009), generally demonstrating that females had lower psychological readiness compared to males across injury statuses. Conclusions: ACL-RSI following ACLR varies based on biological sex and time post-ACLR, though ACL reinjury, independent of the reinjured leg, does not appear to effect scores compared to primary ACL injury.

Background: In low- and middle-income countries, the burden of hypertension is increasing. Medication adherence is a critical component of reducing hypertension-related cardiovascular disease (CVD) risk and death. There are many barriers to hypertension medication adherence, including challenges with access to and possession of medication. To address these challenges, we aim to implement a strategy in rural western Kenya that combines peer delivery of medications and health information technology to improve hypertension medication possession and adherence. Recognizing that stakeholder experience and knowledge can be useful to optimize successful implementation, we sought to assess micro- and macro-level stakeholder perceptions of the planned implementation strategy. Methods: Focus group discussions in both English and Kiswahili were conducted among people living with hypertension, community members, and health workers. In addition, key informant interviews were conducted with public sector health administrators including the program/policy planners for non-communicable diseases at the national and county levels. Content analysis of all transcripts was conducted. A codebook containing deductive codes was generated based on a priori themes identified from the interview guide. These included the perceptions of peers being involved in health service provision, medication delivery, psychosocial support, and the use of health information technology. Emerging themes were also identified and integrated into the results. The investigator team pooled codes according to conceptual alignment and integrated them into common themes after joint review and discussion. NVIVO 12 was used for the data analysis. Results:The PT4A implementation strategy was perceived to have both benefits and potential challenges. Major themes included the importance of trust resulting from a safe space to share experiences with peers, increased access to medications, improved hypertension management at the facility and community levels, and anticipated improved health outcomes for people living with hypertension. The success of the program was felt to rely heavily on the peers competency and how well they communicated, which was viewed as a potential challenge by some stakeholders. Areas of consensus expressed across all participant groups were mostly focused on patient psychosocial support and access to medications. Conclusion: This study was able to identify key perceptions elicited for an implementation strategy that combines peer medication delivery and health information technology to improve hypertension medication adherence. Pre-implementation stakeholder engagement can unearth unique perspectives around perceived benefits and challenges that can be used to refine strategies to increase the success of implementing evidence-based interventions in new contexts.