Citations

Abstract INTRODUCTION : Despite expanding use of plasma biomarkers for Alzheimer's disease (AD), minimal examination has been undertaken in early‐onset AD (EOAD). Prior analyses assessed criterion and convergent validity of common plasma biomarkers in a well‐characterized sample with sporadic EOAD. METHODS : Plasma amyloid beta (Aβ) 42/40, tau phosphorylated at threonine 231 (p‐tau231), glial fibrillary acidic protein (GFAP), and neurofilament light change (NfL) levels were obtained for 189 EOAD, 52 early‐onset non‐AD (EOnonAD), and 83 cognitively normal (CN) participants. Diagnostic group differences, convergence with imaging biomarkers, and the capacity to predict specific cognitive domains were investigated. RESULTS : After controlling for cognitive status, EOAD participants exhibited more pathologic levels of Aβ42/40, p‐tau231, and GFAP relative to EOnonAD participants. However, NfL displayed the greatest sensitivity to non‐amnestic cognitive impairment across the sample. DISCUSSION : These results establish criterion and convergent validity of plasma biomarkers in sporadic EOAD and highlight complementary roles that AD‐specific and non‐specific plasma markers may play across the course of AD care.

Background Large vessel occlusion (LVO) stroke is associated with a high risk of permanent disability. There are no reliable tools providing periprocedural information on clot characteristics, such as composition and length, that may impact first pass effect, which has been shown to improve functional outcomes. In the first study of a novel technology, we evaluated whether the Clotild Smart Guidewire System (Clotild), an impedance-based device, can provide in situ information on clot characteristics during a mechanical thrombectomy procedure. Methods This is the first-in-human, international, multicentric, single-arm trial involving LVO stroke patients. Of 45 enrolled subjects, 41 constituted the safety population; 39 was the per protocol population, of which 26 subjects with complete impedance data comprised the performance population. The latter was divided into development (11 subjects) and validation (15 subjects) populations for prediction model development and assessment. The safety endpoint assessed Clotild-related intracranial vessel perforation/dissection. Performance endpoints evaluated Clotild’s ability to perform classification of impedance measurements distinguishing substantial versus negligible local content in red blood cells (RBCs) and platelets, to detect the arterial wall and the distal end of the clot. Results The safety endpoint was met in all subjects. Performance analysis comparing the agreement between Clotild’s output and impedance experts’ readings showed an area under the receiver operating characteristic curve (AUC) of 0.97 (95% CI 0.93 to 0.99) for RBC, and 0.94 (95% CI 0.89 to 0.98) for platelet clot composition. Regarding detection, Clotild’s performance showed an AUC of 0.69 (95% CI 0.59 to 0.77) for the arterial wall, and 0.83 (95% CI 0.59 to 1.00) for the distal end of the clot. Conclusions Clotild was proven safe to acquire impedance data and to provide information on in situ clot characteristics in large vessel occlusions.

RELA-related disease is a rare, autosomal-dominant condition presenting with immune dysregulation and immunodeficiency. RELA encodes the p65 subunit, a component of the canonical NFκB pathway. The underlying pathogenesis, at least in part, involves impaired NFκB activation, increased susceptibility to TNFα-induced apoptosis, and hyperinflammation. To date, only a modest number of cases have been documented worldwide, and the full clinical and functional spectrum of disease remains incompletely defined. This study represents a large global cohort identified with RELA variants, comprising 40 patients from 30 institutions, expanding our previous report of a single large kindred (1). The clinical spectrum includes arthritis, mucocutaneous ulcers, uveitis, dermatitis, irritable bowel disease, recurrent infections, lymphopenia, hypogammaglobulinemia, recurrent fevers, and susceptibility to neoplasia. The patients represent 36 kindreds with 28 unique RELA variants, of which 15 are missense, 7 nonsense, and 6 frameshift variants. Fifteen are in the Rel homology domain, 7 in the transcriptional activation domain, and 6 in the C-terminal region proximal to TAD (Fig. 1). Functional studies assessed the canonical NFκB pathway in 27% of the cohort (n = 11; healthy controls = 40). Patient peripheral blood mononuclear cells (PBMCs) were used to quantify total and phosphorylated p65 (ph-p65, Ser529) by flow cytometry after stimulation with PMA (100 ng/ml) and ionomycin (1 uM). In 8 patients, we assessed the kinetics of IκBα degradation, required for p65 phosphorylation and nuclear translocation of p65/p50. All patients tested had decreased total p65, while 64% had decreased ph-p65 with altered phosphorylation kinetics. Nearly 45% had impaired IκBα degradation. One patient (P4) demonstrated increased IκBα degradation and ph-p65, while a related proband (P1) had decreased ph-p65. Additionally, P4 did not have the same mucocutaneous clinical phenotype as P1 despite sharing the same RELA variant. This could reflect the effect of other genetic modifiers, epigenetic, environmental, or stochastic variations, which could lead to variable expressivity and/or incomplete penetrance. All patients appeared to have haploinsufficiency, as none had normal levels of p65. This study expands the clinical and genetic spectrum of RELA-related disease and provides mechanistic insights into the impact of these variants on p65 phosphorylation and downstream function, resulting in variable expressivity. Figure 1. RelA protein structure. Represents unique variant locations and categories, key domains, and phosphorylation sites. Source: UniProt. Adapted from (2). BioRender.

Introduction Hyperuricemia, pulmonary hypertension, renal failure, alkalosis (HUPRA) syndrome is a mitochondrial disease caused by mutations in SARS2 (seryl-tRNA synthetase 2), which plays a role in protein synthesis. Limited case reports describe an association of HUPRA with immunodeficiency; however, no in-depth immune phenotyping has been described. We present a case of HUPRA with recurrent infections and lymphopenia, with clinical improvement on immunoglobulin replacement therapy (IgRT). Case Description An 11-month-old male born at 29 weeks’ gestational age with pulmonary hypertension (PH) and tracheostomy dependence was admitted with recurrent fevers and worsening PH. History revealed prior Enterococcus faecalis bacteremia as well as Staphylococcus aureus and Pseudomonas aeruginosa tracheitis. Laboratory evaluation revealed mildly low IgG with normal IgM and IgA. Lymphocyte subsets revealed T cell, B cell, and natural killer cell lymphopenias, with CD4+ T cell compartment skewing to a memory phenotype, normal total switched memory B cells, and normal T follicular helper cells. Vaccine titers were not obtained, given receipt of only one set of vaccines. T cell proliferations were reassuring. Genetic testing revealed compound heterozygous mutations in SARS2, confirming a diagnosis of HUPRA. He is being treated with IgRT with significant clinical improvement. Discussion In case series, up to half of patients with HUPRA can present with increased infections, often with leukopenia. Multiple studies have shown that aminoacyl-tRNA synthetases can play a role in immune cell development, regulation, and autoimmunity through interactions with innate and adaptive immune responses. Additionally, hyperuricemia is known to induce innate and adaptive immune responses. It is difficult to know how these findings relate to the function of SARS2 or patients with HUPRA. Our patient was found to have multilineage lymphopenia with mildly low IgG, with significant clinical improvement on IgRT. More in-depth evaluations are needed to better understand the pathophysiology of immune dysfunction with SARS2 deficiency. This case provides in-depth immune phenotyping and a potential treatment option for others with HUPRA. Tabular data are included as downloadable supplement files.

Background Strengthening emergency care systems could reduce death and disability in low- and middle-income countries (LMICs), yet many struggle to provide timely, high-quality care. LMICs also face growing risks from climate-related shocks and mass casualty events. This study identifies unmet emergency care needs in Nepal—one of the world’s most climate-vulnerable countries—using high-resolution geospatial data to estimate socioeconomic and climate-related inequalities. Methods We conducted a cross-sectional geospatial analysis using data from the 2022 Nepal Demographic and Health Survey (DHS), the 2021 DHS Service Provision Assessment and publicly available climate vulnerability data. Government hospitals were classified into three emergency care levels using World Health Organzation criteria: A (basic 24-hour services), B (A plus resuscitative capabilities) and C (B plus ≥50 beds and a surgeon). Household location and injury data were obtained from the DHS. Accessibility was defined as the proportion of the population within 1-hour and 2-hour travel times, estimated using AccessMod 5.8, incorporating road networks, rivers, land cover and elevation. Findings Most public hospitals (77.7%) met Level A criteria but only 49.3% met Level B and 10.8% met Level C. Nationally, 78.7% of households had 1-hour access to Level A care, 71.8% to Level B and 44.6% to Level C. Adjusted logistic regression showed rural, poorer and climate-vulnerable households had significantly lower 1-hour access compared with urban households, rural households had lower odds of access: Level A OR: 0.33 (95%CI 0.30 to 0.37), Level B OR: 0.33 (95%CI 0.30 to 0.36), Level C OR: 0.56 (95%CI 0.51 to 0.61). Households in high climate vulnerability areas had reduced access across all levels. Conclusions Substantial gaps and inequities in timely access to high-quality emergency care exist in Nepal. Rural, poorer and climate-vulnerable populations experience markedly lower access. Targeted, decentralised strengthening of emergency care capacity is essential both in Nepal and in other LMICs facing similar constraints.

Introduction: Abnormal sleep has been linked to increased dementia risk, but the pathophysiological processes driving this connection are unclear. To provide insight into the biological pathways underlying the relationship between sleep and brain health, we tested the hypothesis that increased obstructive sleep apnea (OSA) severity and shorter habitual sleep duration are associated with a higher burden of Alzheimer’s disease (AD) pathology, neurodegeneration, and neuroinflammation measured through plasma biomarkers. Methods: ARIC participants who took part in the Sleep Heart Health Study at Visit 4 (1996-98) with stored plasma samples at Visit 3 (1993-95) and Visit 5 (2011-13) were examined (n=261; mean age 61.3 years; 43.3% male). OSA severity, categorized based on the number of apneas and hypopneas per hour of sleep (<5 events/hour [Normal], 5 to <15 events/hour [Mild OSA], or ≥15 events/hour [Moderate/Severe OSA]) was assessed via in-home polysomnography, and average habitual sleep duration (<7 hours, 7 to <8 hours, or ≥8 hours) was self-reported. Plasma biomarkers of amyloid beta (Aβ) 42 and 40, phosphorylated Tau 181 (p-Tau181), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were measured using Quanterix Simoa immunoassays. Covariate-adjusted linear regression models estimated associations of sleep indices in 1996-98 with standardized plasma biomarker measurements in 1993-95 (3 years earlier) and in 2011-13 (15 years later). Covariate-adjusted linear mixed effects models quantified associations of sleep measures with the 5-year rates of change in standardized biomarker levels (1993-2013). Results: Compared to a habitual sleep duration of 8 hours or more, sleeping less than 7 hours per night was associated with higher NfL, a biomarker of neurodegeneration, 15 years later (β = 0.252; 95% confidence interval [CI]: 0.003, 0.501). Sleep indices were not associated with biomarker levels 3 years earlier. Counter to our hypothesis, Moderate/Severe OSA was associated with slower increases in p-Tau181 (β = -0.102; 95% CI: -0.198, -0.006), a biomarker of AD pathology, over a median of 17.9 years. Conclusions: Short habitual sleep duration may impact dementia outcomes through neurodegenerative and other processes rather than through pathways specific to AD pathology or neuroinflammation. Longitudinal studies with sleep measurements in larger, more diverse samples are needed to further distinguish the pathways linking sleep to dementia.

Purpose To assess the ability of artificial intelligence (AI) to identify common sports‐related pathologies using radiologic imaging and to compare ChatGPT 4.0 with 2 competitors, Grok 2 and Claude 3.5 Sonnet. Methods ChatGPT 4.0, Grok 2, and Claude 3.5 Sonnet were used. Five common orthopaedic sports pathologies were chosen: anterior cruciate ligament tears, posterior cruciate ligament tears, meniscal tears, chondral pathologies, and rotator cuff tears. Fifty images representing each pathology were collected from a radiologic imaging database when possible, which included radiographic images, computed tomography, and magnetic resonance imaging. Normal images were collected that corresponded to each diagnostic category. Receiver operator characteristic curves and area under the curve values were calculated to assess the accuracy of each AI platform. Results ChatGPT 4.0, Grok 2, and Claude 3.5 Sonnet accurately identified the pathology in 23.6%, 15.7%, and 17.1% of diseased images, respectively. ChatGPT and Grok were most accurate at identifying meniscus pathologies (ChatGPT: 48%, Grok: 42%), whereas Claude Sonnet was most accurate at identifying anterior cruciate ligament pathologies (30%). The area under the curve for ChatGPT, Grok, and Claude Sonnet was 0.21, 0.16, and 0.15, respectively (ChatGPT 4.0 vs Grok 2, P = .30; ChatGPT 4.0 vs Claude 3.5 Sonnet, P = .24; Grok 2 vs Claude 3.5 Sonnet, P > .99). There were no differences in performance between the 3 platforms overall or within any of the diagnostic categories. Conclusions ChatGPT 4.0, Grok 2, and Claude 3.5 Sonnet correctly identified the pathology in less than 25% of images of common sports‐related pathologies and showed area under the curve values well below 0.5, indicating poor accuracy. Based on these findings, we do not recommend the current use of these generative AI models for image‐based diagnosis in orthopaedics. Clinical Relevance As the use of AI becomes more popular within the general public, it becomes increasingly important to make aware the capabilities and limitations of popular AI platforms in regard to their current image‐based diagnostic capabilities.

ABSTRACT Background Cytomegalovirus (CMV) infection remains one of the most prevalent and consequential post solid organ transplant (SOT) infections. Treatment is often challenging, especially when dealing with refractory and resistant CMV infections. Methods We performed a retrospective multicenter cohort study of SOT recipients with clinically significant CMV infection (csCMVi) during 2010–2016. The primary outcome was early refractory CMV infection and secondary outcomes were drug resistance, CMV recurrence, and mortality. Analysis was done with Kaplan‐Meier, univariable logistic regression analysis, and multivariable Cox regression. Results We included 145 SOT recipients with csCMVi, majority were liver transplant (49%). Most common induction was an anti‐IL‐2 antibody (43.9%). The majority ( n = 82; 56.5%) were CMV D+/R‐ mismatch and presented asymptomatic infection (50.3%). After the initial 3 weeks of antiviral therapy, 13 (8.9%) patients had probable refractory csCMVi; most of them (10 [76.9%]) were CMV D+/R‐ mismatch. Longer time after transplant had lower risk (OR 0.68; CI 0.48–0.95, p = 0.029) while lower absolute lymphocyte count (ALC) had a higher risk of early refractory csCMVi (OR 1.54; CI 1.01–2.44, p = 0.048). Drug‐resistant csCMVi occurred in 7 patients (4.8%); a high initial CMV DNA level was associated with resistant csCMVi (OR 2.00; CI 1.08–3.93, p = 0.031). 25 patients (17.2%) experienced recurrent csCMVi within 6 months. 30 patients (20.7%) died; refractory, resistant or recurrent CMV infections were not associated with mortality. Conclusion Refractory csCMVi is associated with a low ALC and an earlier onset after transplant. Resistant csCMVi is associated with high initial CMV DNA levels. Recurrence of csCMVi is common and potentially associated with low ALC at the end of antiviral treatment.