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Despite national efforts to improve research inclusion, people from underserved communities remain underrepresented in dementia trials. Barriers occur at the point of initial engagement and also within the participation pathway itself, as the structure and burden of early screening procedures can discourage continuation. ACCESS D (Advancing Community Collaboration and Engagement Strategies in Dementia) aims to address these challenges by testing a community-based model that combines co-produced engagement events, low-burden research participation, and real-time support from the South Central Ambulance Service (SCAS), a trusted, community-visible National Health Service (NHS) healthcare workforce serving the counties of Hampshire, Oxfordshire, Buckinghamshire and Berkshire in Southern England, UK. ACCESS D is a 12-month mixed-methods feasibility study recruiting 100 adults aged 50-90 years with either (1) a diagnosis of mild cognitive impairment or dementia or (2) a self- or proxy-reported memory concern affecting daily life. The study will deliver between 12-18 co-produced community outreach events in non-clinical settings, supported by SCAS research paramedics and nurses. Following written (paper or digital) informed consent, participants will complete a core questionnaire and may optionally take part in one or more low-burden research opportunities designed to provide supported, first-hand experience of dementia research. Feasibility outcomes, including pathway progression and opt-in to future dementia research contact, will be descriptively summarised and stratified using National Institute of Health and Care Research (NIHR) INCLUDE-aligned underserved characteristics. Qualitative interviews and focus groups with participants and staff will examine acceptability, perceived value, barriers and enablers and implementation learning, analysed using thematic analysis and integrated with quantitative findings. The study has received a favourable opinion from the Southwest-Frenchay Research Ethics Committee and Health Research Authority approval (IRAS 361074). Findings will be disseminated via peer-reviewed publications, conference presentations and co-produced lay outputs for community partners and participants. These outputs will be accompanied by an implementation toolkit for research teams and a visual summary for potential participants.

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder resulting from progressive degeneration and loss of motor neurones in the spinal cord. Current standards of care guidelines focus on a multidisciplinary approach and include recommendations for nine different aspects of care. Although intended for use in all patients with SMA, the guidelines are focused on paediatric best practices and evidence regarding care provision in adults with SMA remains limited. This cross-sectional analysis of a longitudinal registry cohort of adults with SMA study aimed to evaluate the clinical features and corresponding care provision to assess alignment with current care guidelines. Data from 426 patients with genetically confirmed SMA were analysed, including information on respiratory function, bulbar involvement, musculoskeletal complications and daily living support. Results demonstrated a high prevalence of respiratory impairment, bulbar dysfunction, contractures and significant limitations in activities of daily living. However, the care provision observed in this adult cohort did not consistently reflect the recommended standards outlined in the established SMA standards of care recommendations. In particular, gaps were noted in access to respiratory support, physiotherapy and nutritional management. These findings suggest that the application of current standards of care to the adult population is inconsistent. There is a need for improved translation of care provision into adult services to ensure comprehensive and equitable management of SMA across the lifespan.

Endovascular repair is an established option for symptomatic carotid artery dissection, particularly when hemodynamic compromise or embolic risk persists. In patients undergoing repair for acute type A aortic dissection (ATAAD), conventional transfemoral or transradial access may be prohibitive because of altered arch anatomy after graft reconstruction and stent-grafting. We report a postoperative left common carotid artery (CCA) dissection with focal aneurysmal dilatation and cerebral malperfusion following ATAAD repair. The lesion was treated using a hybrid strategy: direct cervical exposure for controlled retrograde transcarotid access and overlapping stent reconstruction. A 48-year-old man presented with acute chest and back pain and was diagnosed with ATAAD. He underwent composite aortic repair including aortic root reconstruction, ascending and arch replacement, and descending aortic stent-grafting. Twenty-six hours postoperatively, he developed severe right-sided hemiparesis in the intensive care unit. Computed tomography angiography (CTA) showed near-occlusion of the mid-left CCA and delayed distal opacification. Given unfavorable transfemoral catheterization, emergent surgical cervical exposure enabled retrograde transcarotid sheath placement and deployment of three overlapping self-expanding stents. Final angiography demonstrated complete reperfusion (modified Thrombolysis in Cerebral Infarction, mTICI, grade 3) without intracranial distal embolization. Neurological recovery was favorable, with sustained stent patency and functional independence at follow-up. Hybrid open retrograde transcarotid access may be considered a salvage option for postoperative CCA dissection after ATAAD repair when transfemoral access is prohibitive.

This scoping review aims to identify, map, and synthesize evidence on the sexual and reproductive health (SRH) information needs of youth 15-24 years living with epilepsy, congenital heart disease (CHD), or systemic lupus erythematosus (SLE) in the USA and Canada, and identify barriers and facilitators to access to SRH information and services. Youth and young adults with chronic health conditions face elevated and condition-specific reproductive risks. Among youth with epilepsy, interactions between seizures, antiseizure medications, hormones, and hormonal contraceptives increase the risk of unintended pregnancy. For youth with congenital heart disease, a substantial proportion of pregnancies are associated with cardiac complications, and contraceptive counseling is often delayed or inconsistently delivered. In systemic lupus erythematosus, limited contraceptive options and teratogenic therapies further heighten reproductive risk, with active disease associated with significantly increased risks of preterm birth and pre-eclampsia. Despite these well-documented risks, youth with chronic conditions frequently report unmet SRH information needs related to contraception, medication safety, fertility, and pregnancy planning. Evidence remains fragmented across specialties and largely focused on pregnancy outcomes rather than youth-centered informational needs and access to services. Our preliminary search did not identify a comprehensive scoping review that maps sexual and reproductive health (SRH) information needs, barriers, and facilitators across these three chronic conditions among young people in North America. Given the anticipated heterogeneity in study designs, populations, and outcomes, a scoping review is appropriate for characterizing the breadth and nature of the evidence base. Eligible sources will include empirical studies from the USA and Canada involving youth aged 15-24 years diagnosed with epilepsy, CHD, or SLE. Studies must address SRH information needs and/or barriers and facilitators to accessing SRH information or services. Youth-reported needs will be distinguished from caregiver or provider perspectives, which will be included only when directly relevant to youth experiences. All primary qualitative, quantitative, and mixed-methods designs, as well as empirical grey literature, will be considered. This review will follow Joanna Briggs Institute (JBI) methodology for scoping reviews and will be reported in accordance with the PRISMA-ScR guidelines. A three-step search strategy will be implemented across MEDLINE, Embase, CINAHL, PsycINFO, Scopus, Web of Science, CENTRAL, and targeted grey literature sources from the inception of each database to the final search date. Two reviewers will independently screen records and extract data using a piloted standardized tool. Results will be synthesized descriptively and analyzed using manifest-level content analysis to categorize SRH information needs, barriers, and facilitators. Findings will be mapped across socio-ecological levels and developmental stages (15-19 and 20-24 years), where data permit. This protocol is registered with the Open Science Framework (https://doi.org/10.17605/OSF.IO/5SWTY).

Intraoperative intracranial electrophysiological recordings provide unique access to human cortical dynamics but remain difficult to translate across patients due to inconsistent localization of transient surface electrodes. Unlike chronic implantations, intraoperative electrodes are placed transiently, rarely visible on imaging, and often inconsistently documented. We present an open-source imaging pipeline, ALIGNER (Advanced Localization and Imaging Guidance for Neurosurgical Electrode Recording), designed to reconstruct intraoperative surface electrode array placements and quantitatively map neural activity to individualized anatomical and pathological substrates. By enabling anatomical localization of these electrodes, this framework supports systematic analysis of spatial gradients in neural activity relative to pathological tissue. We developed a multimodal reconstruction framework integrating pre- and postoperative MRI and CT, cortical surface modeling, semi-automated pathology segmentation, intraoperative photographs or videos when available, and physics-based electrode modeling. To improve robustness in cases with distorted anatomy, artificial intelligence tools such as SynthSR were used to enable reliable cortical surface reconstruction prior to FreeSurfer processing. A monocular depth-estimation network was incorporated to constrain electrode placement in conjunction with Blender cloth-physics simulation when photographic images were available, while atlas- and note-guided inference supported reconstruction otherwise. The pipeline was applied to 38 neurosurgical patients across drug-resistant epilepsy resection (n = 24), malformation (n = 1), brain tumor (n = 11), and deep brain stimulation (n = 2) cases, achieving some type of reconstruction and electrode localization in all participants. By exporting electrode coordinates for quantitative spatial analyses, including distance-based mapping relative to lesions and resection cavities, ALIGNER enables anatomically grounded and reproducible analysis of intraoperative electrophysiology. This open-source framework provides foundational infrastructure for cancer neuroscience studies of tumor-neuron interactions and establishes a scalable platform for future neurostimulation, implantable neurodevice, and brain-computer interface applications requiring precise anatomical localization.

Automated analysis of peripheral nerve ultrastructure is bottlenecked by heterogeneous electron microscopy (EM) datasets, where varying staining protocols and resolutions create domain shifts that confound deep learning. To address this, we developed a generalized segmentation pipeline. Using a custom pre-processing workflow (CLAHE and noise suppression) integrated into ZEISS Arivis Pro, we standardized inputs across three disparate domains: traditional osmium-based Palade, lanthanide-based "green" Uranyl-free method, and low-resolution Ellisman preparations. A U-Net trained on a highly constrained 15-image composite dataset achieved peak internal Intersection over Union (IoU) scores >0.95 for myelin and Schwann cells. Crucially, during open-world, zero-shot inference on an expanded independent testing cohort (N = 40), the model sustained robust Dice Similarity Coefficients of 0.854 for myelin and 0.597 for mitochondria. This demonstrates that integrating classical image standardization with deep learning effectively mitigates EM domain gaps, enabling comprehensive 3D multi-organelle reconstructions from challenging data. To ensure transparency and community utility, the pre-trained models and standardization scripts are provided in a public, open-access repository. Ultimately, this pipeline supports the transition to sustainable, non-toxic EM protocols and provides a robust pathway for unlocking historical clinical archives for automated organellomics.

This debate addresses the choice of placebo versus active comparator in randomized controlled trials (RCTs) for chronic migraine (CM), a disabling condition with high global burden. Placebo-controlled designs have traditionally been considered the gold standard for new treatments, allowing quantification of placebo and pharmacological effects, ensuring internal validity, smaller sample sizes, and regulatory acceptance. Yet, ethical concerns arise from the possibility that participants may be denied effective treatments. The emergence of migraine-specific therapies targeting the calcitonin gene-related peptide (CGRP) pathway has prompted calls for active comparator designs. Such trials may enhance clinical relevance, support recruitment, and better mirror clinical practice compared with placebo-controlled RCTs. However, defining a universal standard of care may be challenging given global disparities in access, cost, and treatment preferences, limiting the feasibility of RCTs with active comparators. Placebo-controlled trials remain valuable, but alternative strategies, including short placebo phases with open-label extensions, add-on designs, or three-arm trials (investigational treatment, placebo, active comparator) may reconcile scientific rigor with ethical considerations. Ultimately, the optimal trial design depends on the research question, regulatory requirements, and evolving definitions of standard care in CM prevention.

Autoantibody testing supports the diagnosis of systemic autoimmune diseases, but indiscriminate use in low pre-test probability settings can reduce test positivity and inflate direct laboratory costs. Hospital-wide audits of real-world ordering practices across specialties remain scarce and, to our knowledge, have not been reported in the Gulf region. To describe the test positivity rate, direct laboratory cost, and departmental variation of hospital-wide autoantibody testing in a tertiary center in the Eastern Province of Saudi Arabia. We conducted a retrospective hospital-wide audit of all autoantibody tests ordered across 15 clinical departments at King Fahd University Hospital between 1 January and 30 April 2024. Test volumes, positivity rates, and direct laboratory costs were summarized at departmental and subspecialty levels. Rheumatology was compared with all non-rheumatology services as a pre-specified inferential contrast using chi-square or Fisher exact tests with 95% Wilson confidence intervals and Benjamini-Hochberg adjustment across per-marker comparisons; the unit of analysis was the test order. A total of 5973 autoantibody tests were performed in 1059 patients, with an overall test positivity rate of 16.3% (95% CI 15.4-17.2). Total direct laboratory expenditure was USD 509,136, of which 87% was attributable to negative results. Test positivity ranged from 26% in Pediatrics to &#x2264;7% in Neurology and Neurosurgery. Rheumatology had a higher positivity rate (24.4%, 95% CI 22.2-26.8) than non-rheumatology services combined (13.9%, 95% CI 12.9-14.9; p<0.001), with the largest absolute differences for antinuclear antibodies (88.7% vs 35.7%; p<0.001) and SSA antibodies (27.9% vs 5.9%; p<0.001). Direct cost per positive result was USD 364 in Rheumatology versus USD 606 in non-rheumatology services. In this single-center audit, autoantibody ordering practices clustered into two descriptive patterns: hypothesis-driven, higher-positivity testing within specialist care and broader, lower-positivity panel use in several non-specialist services. These differences were statistically significant and most plausibly reflect more disciplined application of pre-test probability by specialists, although referral filtering and case-mix differences contribute and cannot be fully separated from clinician-level reasoning in this dataset. These patterns suggest that targeted diagnostic stewardship-reflex-cascade algorithms, order-menu redesign, and indication-based gating-could concentrate autoantibody testing where pre-test probability is highest, improving positivity and reducing avoidable cost without restricting clinical access.

LRRK2 variants are major contributors to Parkinson's disease (PD). Many pathogenic variants increase kinase activity, underscoring the value of functional assays in nominating therapeutic targets and kinase inhibitors as potential disease-modifying therapies. To develop an interactive resource that provides functional context and ancestry-specific variant frequencies. Genotyping and short-read sequencing data were analyzed for 101,678 individuals (61,709 PD, 39,969 controls) from the Global Parkinson's Genetics Program (GP2) and integrated with clinical and in-vitro biochemical kinase activity information. The LRRK2 Browser (http://gp2.org/lrrk2browser) displays ancestry-specific genetic data for 19,596 LRRK2 variants (968 exonic, 14 disease-associated) across 11 populations, and functional data for 171 variants. Clinical annotations include age, age at onset, and family history of PD. The publicly available LRRK2 Browser represents an open-access, multi-ancestry resource to support LRRK2 variant interpretation. It aims to enhance the translational potential of genetic and functional data for precision medicine and the implementation of gene-targeted therapies in diverse populations.

Schwannomas are benign neurogenic tumors commonly arising in the posterior mediastinum. Although typically asymptomatic, lesions with intraspinal extension may lead to neurological compromise.&#xa0;We report a 47-year-old male who presented with symptoms suggestive of a lower respiratory tract infection and was incidentally found to have a thoracic mass on chest radiography. Further imaging revealed a large, left paravertebral&#xa0;tumor with intrathoracic and intraspinal components extending through the left T7-T8 intervertebral foramina, consistent with a dumbbell schwannoma causing spinal cord compression. Options for surgery include thorax-first, spine-first, combined thoracic-neurosurgical open approaches, thoracoscopic-assisted approaches, and selected minimally invasive paraspinal or transforaminal techniques. Complete macroscopic excision was performed through a coordinated thoracic and spinal surgical approach involving open thoracotomy and foraminotomy. The patient's postoperative period was complicated by a lower respiratory tract infection requiring intravenous antibiotics. However, the patient was neurologically intact at post-op and at one-month follow-up. This case report highlights that large, thoracic dumbbell schwannomas may remain neurologically silent despite significant intraspinal extension and are best managed&#xa0;with a multidisciplinary approach to achieve the best outcomes.

Blood metabolites are critical biomarkers linking genetic variation to diverse health outcomes, exhibiting significant variability across individuals. Here, we analyze and integrate whole-genome sequencing with plasma metabolomics to investigate the genetic architecture of 313 metabolic biomarkers in up to 199,138 UK Biobank participants. Through single-variant analyses, we identify 36,105 independent signals, with 22.20% being novel. Furthermore, we pinpoint 12,361 putative causal variant-trait associations, demonstrating enhanced causal signal discovery and improved fine-mapping resolution compared with imputed array-based approaches. Rare-variant aggregate testing reveals 1,527 conditionally independent protein-coding gene-trait pairs, with 32.9% being unique to non-coding regions. We estimate the heritability at a median of h2&#x2009;=&#x2009;0.31, nearly tripling the heritability estimates obtained from array-based approaches. Integrating our findings with disease genetics reveals 245 potential causal associations, such as that between omega-3 fatty acids and cholelithiasis risk. Prioritizing proteins with concordant effects on metabolites and clinical outcomes revealed 410 potential targets, offering opportunities for therapeutic strategies and drug repurposing. Our open-access resource (https://metabolome-whole-genome-landscape.com/) provides a foundation for future research into metabolic pathways, disease mechanisms, and therapeutic development.

Many individuals with epilepsy often develop major depressive disorder (MDD), creating a complex interplay that exacerbates outcomes for affected individuals. The relationship between these disorders may be mediated by overlapping neurobiological mechanisms, including disturbances in the limbic system, neurotransmitter imbalances, and the psychosocial stressors of chronic illness. While the co-occurrence typically leads to a worsening of symptoms, rare instances have been reported in which seizure activity appears to ameliorate psychiatric symptomatology. We present the case of a 23-year-old pregnant Hispanic female with a longstanding history of treatment-resistant depression with psychotic features and epilepsy, who demonstrated full remission of depressive and psychotic symptoms following a generalized tonic-clonic seizure. The patient, previously admitted to a psychiatric state center due to severe depressive symptoms and self-injurious behaviors, was transferred to our institution following seizure onset for medical stabilization. Remarkably, psychiatric evaluation revealed no evidence of current psychopathology. This case emphasizes the potential neuromodulatory effects of ictal activity and draws parallels to the therapeutic mechanisms of electroconvulsive therapy (ECT), raising important considerations for the intersection of neurology and psychiatry. Further investigation into the antidepressant effects of seizure activity may offer insights into novel treatment avenues for refractory psychiatric disorders.

Cognitive impairment is common in long COVID and severely affects daily life, with no proven treatments to date. To evaluate the ability of cognitive rehabilitation (CR) to improve goal attainment, cognitive, and clinical outcomes in individuals with cognitive impairment as part of long COVID. This multicenter, single-blind, 2-arm, parallel-group randomized clinical trial was conducted at 3 sites in England between February 2023 and March 2024. Participants were adults aged 30 to 60 years with prior COVID-19 infection and objective cognitive impairment (&#x2265;1 SD below age norm in &#x2265;2 cognitive domains). A sample size of 88 participants (44:44) was required to detect a conservative effect of 0.7 on the goal attainment score at 3 months. Participants were randomized (1:1) to CR or treatment as usual (TAU). CR consisted of 10 individual 1-hour sessions conducted once per week with a trained researcher, applying evidence-based strategies to 3 individually selected, personally meaningful functional goals. TAU was variable, with most participants having access to specialist memory clinics. The primary outcome consisted of participant-reported goal-attainment scores at 3 months after randomization measured by the Bangor Goal-Setting Interview. Analysis was conducted on an intention-to-treat basis using multilevel mixed-effects models with 2-sided 95% CIs and 5% significance. A total of 78 participants (24 male [30.8%] and 54 female [69.2%]; mean [SD] age, 47.3 [7.2] years) were randomized, including 38 individuals in CR and 40 individuals in TAU groups. At 3 months after randomization, goal attainment was significantly greater in the CR compared with the TAU group (adjusted mean difference, 2.88 [95% CI, 2.03-3.73]; P&#x2009;<&#x2009;.001; Cohen d&#x2009;=&#x2009;1.57), with CR providing a large and clinically meaningful treatment effect. This was sustained at 6 months, with a lower effect size (adjusted mean difference, 1.72 [95% CI, 0.86-2.57]; P&#x2009;<&#x2009;.001; Cohen d&#x2009;=&#x2009;0.91). In this study, individualized, goal-oriented CR led to significant and sustained improvements in goal attainment in people with long COVID-related cognitive impairment. These findings may guide and inform the provision of CR treatments and services for people living with long COVID. ClinicalTrials.gov Identifier: NCT05731570.

Polypharmacy is common in epilepsy, particularly in patients with psychiatric comorbidities requiring concomitant pharmacological treatment. Long-term treatment often increases the risk of adverse drug reactions and pharmacological interactions. Stem cell therapy has emerged as a topic of growing interest in neurology because of its immunomodulatory and neuromodulatory properties. We report the case of a 15-year-old female patient with mesial temporal sclerosis characterized by marked cognitive and psychiatric comorbidities requiring a complex five-drug pharmacological regimen. The patient underwent treatment with autologous stem cells harvested from the superficial abdominal fascia and was followed clinically for one year. During follow-up, the patient also continued to receive antiepileptic treatment, psychopharmacological management, psychotherapy, and multidisciplinary clinical care. Throughout follow-up, individualized pharmacological optimization was performed under close clinical monitoring. This case highlights the importance of individualized pharmacological management during longitudinal multidisciplinary care. The report describes the longitudinal clinical course and pharmacological optimization of a patient with mesial temporal sclerosis undergoing stem cell therapy within a broader multidisciplinary treatment framework.

Background Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disorder caused by pathogenic variants in TSC1 or TSC2. Despite established clinical diagnostic criteria, a subset of patients remains molecularly unsolved after conventional genetic screening, often due to deep intronic variants, structural anomalies, or low-level somatic mosaicism. Methods A retrospective cohort study was performed. Patients without an identified pathogenic variant after conventional Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) were selected for targeted high-depth next-generation sequencing (NGS), achieving a median sequencing depth of at least 800&#xd7;. Clinical data were collected for phenotypic characterization. Results High-depth targeted sequencing identified pathogenic or likely pathogenic variants in the TSC2 gene in four out of seven previously unresolved patients, resulting in an incremental diagnostic yield of 57.1% (4/7). The identified variants were deep intronic structural alterations or splice-modifying changes (c.2838-122G>A, c.848+281C>T, and c.2640-16_2640-8del). Two unrelated patients carried the identical c.848+281C>T deep intronic variant. Patients with identified TSC2 variants exhibited a high prevalence of structural central nervous system anomalies, epilepsy, and multi-system tumor involvement compared to the molecularly unconfirmed subgroup. Discussion High-depth targeted sequencing using hybrid-capture enrichment provides a substantial diagnostic advantage for detecting deep intronic variants in previously unsolved TSC cases. These findings advocate for integrating deep sequencing into clinical practice. Although TSC remains mainly a clinical diagnosis, identifying pathogenic variants has an important role in diagnosing patients who do not meet complete clinical criteria, in providing genetic counseling, as well as access to potential targeted therapies.

Tuberous sclerosis complex (TSC)-associated neuropsychiatric disorders (TAND) affect most patients with TSC and encompass a range of psychiatric, intellectual, neuropsychological, and behavioral manifestations of the disease. Epilepsy Comorbidities (EpiCom), an ongoing, phase 3b/4, open-label study, is assessing the effects of adjunctive therapy with a plant-derived, highly purified pharmaceutical formulation of cannabidiol (Epidiolex&#xae; [US]/Epidyolex&#xae; [EU], 100 mg/mL oral solution) on TAND, including behavioral outcomes, in participants with TSC-associated seizures. EpiCom was designed in collaboration with the TSC community including patients, caregivers, and healthcare professionals (HCPs), to incorporate stakeholder perspectives into study design and execution. To describe how collaboration among patient advocacy groups (PAGs), HCPs, and the clinical trial sponsor helped optimize the co-creation and execution of the EpiCom study. HCPs and PAG advisors, including caregivers of individuals with TSC, were identified across the USA and Europe and invited to participate in an advisory board meeting to discuss the challenges faced by the TSC community. Surveys collected PAG and HCP input on topics, including study objectives, outcome assessments, study design, eligibility criteria, and recruitment. PAG and HCP advisory board meetings were then conducted to capture patient/caregiver and HCP perspectives on the EpiCom study design, including the objectives, feasibility, resources needed for successful execution, and strategies to engage the patient community throughout the study. A joint PAG-HCP Steering Committee comprising 5 PAG representatives and 15 HCPs from the USA, Canada, and Europe was formed to guide study objectives and PAG engagement, and to provide study oversight. Advisory board meetings (9 PAG advisors; 14 HCPs) provided insight into the needs of the TSC community and ways to enhance collaboration with patients and caregivers. Feedback from the advisory boards and steering committee meetings refined the EpiCom study objectives and informed recruitment strategies, study duration, patient- and HCP-friendly study design considerations, preferred data collection methods, and communication plans. These insights supported the development of a decentralized clinical trial framework aimed at reducing participant burden and barriers. PAG input guided the decision to broaden study eligibility criteria by removing seizure severity and intelligence quotient requirements and include remote assessments to facilitate capturing data in everyday settings. HCP input guided inclusion of clinical outcome measures, including the use of the novel TAND Self-Report Quantified Checklist to assess behavioral changes. Proactively involving PAGs, caregivers, and HCPs enabled the co-creation of a study that explicitly addresses outcomes important to the broader TSC community. This patient- and caregiver-informed approach of EpiCom also highlights the need for stronger collaboration between industry and PAGs in clinical trials, including the opportunities and challenges of trial implementation. NCT05864846 (May 9, 2023).

Background Acute ischemic stroke (AIS) is a primary cause of death and disability globally, imposing a significant burden in Bangladesh. Preliminary prognostic evaluation continues to be difficult, especially in resource-constrained environments. The triglyceride-glucose (TyG) index, an indicator of insulin resistance (IR), has surfaced as a possible predictor of poor outcomes in stroke. This study aimed to evaluate the association and predictive performance of the TyG index for short-term outcomes among patients with AIS. The primary objective was to assess its association and predictive ability for in-hospital mortality, while the secondary objective was to evaluate its association with 90-day functional outcome. Methods This prospective observational study was carried out in the Department of Neurology, National Institute of Neurosciences and Hospital (NINS), Dhaka, from January 2024 to June 2025. A total of 120 patients with radiologically confirmed first-ever AIS were included, of whom 118 completed the 90-day follow-up. Demographic data, clinical status, comorbidities, admission stroke severity, and laboratory values were gathered. Patients were observed for in-hospital mortality, and 90-day functional outcomes were evaluated using the modified Rankin Scale (mRS). The TyG index was calculated from fasting triglyceride and fasting plasma glucose levels measured within 24 hours of admission. Results The average age of participants was 63.38 &#xb1; 14.49 years, with 61.9% (n=73) being male. The in-hospital mortality rate was 28.8% (n=34). A higher TyG index was strongly linked with in-hospital&#xa0;mortality (median 9.49 vs. 8.85, p-value: 0.001). In multivariate logistic regression analysis, the TyG index remained an independent predictor of death (OR: 2.84; 95% CI: 1.43-5.64; p-value: 0.003). The ROC analysis showed moderate&#xa0;predictive performance (AUC: 0.680, p-value: 0.002), with an appropriate cutoff value of &#x2265;8.87 (sensitivity 79.41%, specificity 51.19%). At 90 days, poor functional outcome was observed in 105 (89.0%) patients, which may reflect the tertiary-care hospital setting and inclusion of clinically more severe admitted stroke cases. A higher TyG index was significantly associated with poor functional outcome (OR: 2.21, 95% CI: 1.023-4.798; p=0.044). Patients with a higher TyG index had significantly lower survival rates, according to Kaplan-Meier analysis (log-rank p-value: <0.001). Conclusion A higher TyG index was significantly associated with increased mortality and poor functional outcomes among patients with AIS. However, its discriminative ability was moderate; therefore, the TyG index may be considered only as a simple, low-cost adjunct marker for early risk assessment rather than a standalone prognostic tool, particularly in resource-limited settings.

Mutations in MAPT, the tau gene, give rise to forms of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17&#xa0;T), with abundant filamentous tau inclusions in brain cells. Some mutations that encode missense and deletion variants can give rise to a clinical picture of Pick's disease and filaments made of three-repeat tau in nerve cells. Here we report the electron cryo-microscopy (cryo-EM) structures of tau filaments from the brains of individuals with MAPT mutations D252V, G272V, S320F and &#x394;G389-I392. The two-layered Pick fold was present in the brains of individuals with mutations D252V and &#x394;G389-I392 who had also abundant tau inclusions in glial cells. By contrast, mutations G272V and S320F gave rise to a more open variant of the Pick fold, with residues 272-341 rotated by 20-25&#xb0; with respect to the rest of the structure. These findings show that missense mutations within the filament core can modify the Pick fold, generating closely related structural variants. In addition, we were able to reconstitute the Pick fold and some of its variants using seeded assembly with recombinant 0N3R tau carrying 12 serine or threonine to aspartate substitutions (PAD12) and missense mutations D252V, G272V and S320F. This work provides a foundation for the development of structure-based diagnostic and therapeutic approaches.

Diabetic cardiovascular autonomic neuropathy (DCAN) is a common, but underdiagnosed, complication of diabetes. The condition arises due to damage to the autonomic nerve fibres innervating the heart and vasculature. This can manifest clinically in a variety of ways, including coexisting orthostatic hypotension and supine hypertension. We present a case of DCAN in a middle-aged patient, which highlights how debilitating this condition can be and the therapeutic challenge posed to clinicians by its management. This female patient had severe orthostatic hypotension, causing recurrent collapses and limited mobility, alongside refractory hypertension, which progressed to cause target organ damage. Her management required a multidisciplinary approach including medical (cardiology, renal, neurology, endocrinology), physiotherapy, and occupational therapy teams. Her medication regimen was frequently titrated and modified to try to find a balance in blood pressure that maintained safety and functional status. Ultimately, she required a combination of five antihypertensive medications, and the orthostatic hypotension could only be managed supportively. This did not provide a satisfactory functional outcome for the patient, whose mobility and independence were severely restricted by haemodynamic fluctuations. This calls attention to the need for further research into management strategies for this condition.