Citations

Abstract Two recent studies suggested that the APOE ε4 haplotype was associated with increased α-synuclein pathology in cell and mouse models. Genetic variants in the SNCA region have strong association with Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and idiopathic REM sleep behaviour disorder (iRBD), while APOE is a genetic risk determinant for only DLB. To determine if genetic-level interactions between SNCA and APOE exists that can explain the protein-level association, we investigated the genotypic interaction of APOE and SNCA in cohorts of PD, DLB and iRBD. We analysed genome-wide association study (GWAS) data from 5229 PD patients and 5480 controls, 2610 DLB patients and 1920 controls, and 1055 iRBD patients and 3667 controls. We used logistic regression interaction models across all three cohorts independently between the (i) top GWAS signals of SNCA single nucleotide polymorphisms (SNPs) and APOE haplotypes and (ii) SNP×SNP and three-way SNP interaction across the entire coding region plus 200 kb flanking each gene. No significant interactions were found to be associated with any of the synucleinopathies after correction for multiple testing. Our results do not support a role for genetic interactions between APOE and SNCA across PD, DLB and iRBD. Since the tested genetic variants affect the expression and function of these proteins, it is likely that any interactions between them do not affect the risk of PD, DLB and iRBD.

ABSTRACT Background Critically ill patients may be overexposed to valproate because altered protein binding leads to a disproportionate free valproate fraction. The Fraser equation was derived and internally validated to estimate critically ill patients' free valproate concentrations, but it requires external validation. Methods Adult intensive care unit (ICU) patients at two academic centers with concurrently measured free and total valproate concentrations were included. Free valproate concentrations were estimated using the Fraser equation which includes total valproate, albumin and BUN concentration, and whether the patient received propofol or aspirin. The primary outcome was Fraser equation performance, assessed using Bland–Altman methods. Comparative performance against estimates from the Doré equation (an alternative predictive equation), therapeutic concordance using a target free valproate range of 5–15 mg/L, and equation improvements were explored. Results Overall, 315 patients and 556 free‐total valproate concentration pairs were included. The mean (±SD) age was 58 (±17) years and 90 (29%) patients were on valproate prior to hospital admission. The Fraser equation estimated free valproate concentrations were correlated with measured concentrations ( r = 0.728) with a negative bias (mean bias −2.77 mg/L, 95% LOA –18.9, 13.4). The Fraser equation increasingly underestimated measured concentrations as measured concentrations increased. 71% of Fraser equation estimates were therapeutically concordant (e.g., estimate and measured both within reference range) compared to 61.9% of Doré estimates ( p = 0.001). Fraser equation modifications led to minor performance improvements but did not overcome worsening underestimation with higher measured free valproate concentrations. Conclusion The Fraser equation was moderately accurate and corresponded with an appropriate interpretation for 71% of free valproate concentrations. Worse underestimation with higher measured free valproate concentrations suggests direct measurement of free valproate concentrations is warranted. While the Fraser equation could complement therapeutic decision making at centers where direct free valproate measurements are unavailable or slow to return, its accuracy is currently insufficient to replace direct measurement.

ABSTRACT Background Lung cancer (LC) and respiratory failure (RF) are leading causes of adult mortality worldwide. Analyzing long‐term mortality trends across demographic, racial, geographic, and socioeconomic groups is essential to address disparities and enhance outcomes. This study investigates US national mortality patterns for LC and RF from 1999 to 2023, focusing on changes in age‐adjusted mortality rates (AAMRs) and key disparities. Methods Mortality data from the CDC WONDER database (1999–2023) for adults aged 25+ with LC (ICD‐10: C34) or RF (ICD‐10: J96) were analyzed. AAMRs per 100,000 were calculated, stratified by gender, race/ethnicity, region, state, and urban–rural status. Temporal trends were assessed using Joinpoint regression to estimate annual percent changes (APCs) with 95% confidence intervals (CIs), with significance at p < 0.05. Results Over 1999–2023, 456,325 deaths from LC and RF were recorded. AAMRs declined from 1999 to 2010 (APC = −1.2, 95% CI: −1.6 to −0.9) but rose from 2010 to 2023 (APC = 1.4, 95% CI: 1.1–1.7). Men's AAMRs steadily decreased, whereas women's dropped initially, then increased from 2011 to 2023 (APC = 2.0, 95% CI: 1.7 to 2.5). Non‐Hispanic Whites saw a sharp AAMR rise from 2014 to 2017 (APC = 2.7, 95% CI: 0.9 to 3.3), with other racial/ethnic groups showing mixed trends. Regionally, the Northeast had the highest AAMRs (8.6, 95% CI: 8.5 to 8.7), and the Midwest the lowest (7.1, 95% CI: 7.0 to 7.1). Metropolitan areas saw increases post‐2006, whereas nonmetropolitan areas rose after 2009 (APC = 2.3, 95% CI: 1.8–3.1). Mississippi had the highest state AAMR (14.0, 95% CI: 13.7–14.4), Wisconsin the lowest (3.7, 95% CI: 3.5–3.8). Conclusion LC and RF mortality declined until 2010, then increased, revealing significant disparities. Targeted interventions are critical to address these trends and reduce inequities.

Background α‐Klotho is a multifunctional protein implicated in vascular aging. Declining Klotho levels are associated with arterial stiffness, endothelial dysfunction, and vascular calcification. We investigated the associations between circulating klotho, aortoiliac calcification, endothelial progenitor cells, and 10‐year survival. Methods In this retrospective cohort, blinded clinicians scored calcification on computed tomography (0–10 scale: aorta 6 points, iliac 4 points). Plasma klotho was measured by ELISA; endothelial progenitor cell subsets were quantified via flow cytometry. Mortality data were obtained from the Minnesota Death Registry. Results This study included 148 participants (mean age 72.4±9.6 years; 41% female). Median calcification score was 3 (interquartile range, 1–5). Patients with low calcification had higher Klotho levels (669 [567–841] versus 556 [457–678] pg/mL; P <0.01), with Klotho inversely correlated with calcification (r=−0.315, P <0.01). Stratified by calcification location and severity, the highest Klotho levels were seen in patients without aortic or iliac calcification ( P =0.015). Over 10 years, low Klotho was independently associated with higher mortality (hazard ratio [HR], 3.056 [95% CI 1.288–7.878]; P =0.014). Klotho inversely correlated with mature osteocalcin‐positive EPCs; B=−0.16 (95% CI, −0.29 to −0.02; P =0.027). Immunohistochemistry and immunofluorescence confirmed endothelial Klotho expression in internal mammary artery. Conclusions Lower circulating Klotho levels are associated with increased aortoiliac calcification and higher 10‐year mortality, supporting a role for Klotho in vascular aging.

Study Design Retrospective cohort study using a nationally representative inpatient database. Objective To determine the incidence, timing, and predictors of new-onset psychiatric disorders following lumbar fusion surgery, and to propose a data-driven risk stratification model for early identification and intervention. Methods We queried the Nationwide Readmissions Database (2016-2019) to identify adults undergoing elective inpatient lumbar fusion. Patients with preexisting psychiatric diagnoses were excluded. Outcomes included new-onset depression, anxiety, suicidal ideation, and homicidal ideation within 12 months postoperatively. Predictors were assessed using odds ratios. Timing of onset was evaluated with density plots. Results Among 839,576 patients, 12,011 developed depression, 11,828 anxiety, 916 suicidal ideation, and 63 homicidal ideation. Most diagnoses occurred within 90 days postoperatively, with peak incidence around 3 weeks. Opioid use during the index admission significantly increased odds of suicidal ideation (OR 2.13, P = 0.001), anxiety (OR 1.26, P = 0.002), and showed a trend toward depression (OR 1.14, P = 0.087). Medicaid insurance was the strongest predictor of suicidal (OR 3.69) and homicidal ideation (OR 6.41). Female sex and younger age were associated with anxiety and depression; older age was protective against ideation. Conclusions New-onset psychiatric disorders are a frequent and early complication following lumbar fusion. Several modifiable and demographic factors - including perioperative opioid use and socioeconomic status - significantly predict risk. These findings underscore the need for structured mental health screening within the first 3 months post-surgery. Implementing a predictive risk stratification tool could enable earlier psychiatric referral, reduce long-term morbidity, and improve both recovery trajectories and overall quality of life.

Abstract INTRODUCTION Alzheimer's disease (AD) is a progressive neurodegenerative disorder that needs better predictive tools. Using the National Alzheimer's Coordinating Center Uniform Data Set, this study developed machine learning (ML) models and a practical clinical tool for AD prediction. METHODS Data from 52,537 individuals (22,371 with AD) and more than 200 variables were processed with MissForest imputation and genetic algorithm‐based selection. Multiple ML models were trained, and interpretability was performed using SHAP and permutation importance. A LightGBM model was refined through iterative backward feature elimination (IBFE) followed by manual refinement. RESULTS LightGBM performed best (receiver operating characteristic‐area under the curve [ROC‐AUC] 0.91, accuracy 82.0%). Key predictors included arthritis, age, body mass index, and heart rate. A 19‐feature model retained accuracy (81.2%) and ROC‐AUC (0.90). DISCUSSION This lightweight tool predicts AD using mostly routine variables. Limitations include its cross‐sectional nature, and would need external validation. An interactive web app and GitHub resource are available. Highlights Developed a lightweight ML based tool using 19 routinely available features. The lightweight model achieved an ROC-AUC of 0.90 for Alzheimer's disease prediction on NACC multicenter data. Genetic algorithm, IBFE, and manual refinement enabled optimal feature selection. Tool hosted on an open‐access platform for clinical and research use. SHAP analysis provided model interpretability and feature‐level insights.

Abstract This review explores smart catheters as an emerging class of medical devices that combine embedded sensors, robotics, and communication systems with increasing functionality and complexity to enable real‐time health monitoring, diagnostics, and treatment. Evolving from traditional catheters used as drains or entry ports, smart systems are now able to track blood pressure, temperature, biochemical signals, and mechanical forces within the body with a high degree of accuracy. Advances in materials, wireless communication, and robotic navigation have helped reduce common risks like infection and catheter blockage while also improving precision catheter placement for minimally invasive procedures. This review highlights recent developments across a variety of different types of smart catheters, ranging from sensing and imaging tools to therapeutic and multimodal systems. Additionally, it discusses the challenges that remain, including biocompatibility, long‐term performance, and clinical translation. The incorporation of new capabilities is changing how catheters are used, and these new uses promise to enable more personalized and responsive healthcare.

Background Spontaneous intracranial hypotension (SIH) results from cerebrospinal fluid (CSF) leakage due to spinal dural tears or CSF–venous fistulas. Orthostatic headache is the hallmark presentation, though severe downward displacement of the brainstem may lead to altered consciousness or coma. Definitive treatments include targeted epidural blood patches, venous embolization, or surgical repair. Methods This article reviews the role of the Trendelenburg position as a temporizing measure in the acute management of SIH. We describe the correct technique, physiologic rationale, and practical considerations for its application, with attention to both therapeutic and diagnostic utility. Discussion Positioning the patient with the feet elevated above the head can reduce brain sag and provide short-term symptomatic relief while awaiting definitive treatment. Although the Trendelenburg position is widely used in practice, supporting evidence remains limited, and clinicians must be aware of its benefits, indications, and inherent limitations. Its appropriate application may assist in stabilizing patients with acute or severe SIH, particularly those with impaired consciousness, until more definitive interventions are pursued.

Feeding children is part of family caregiving. Children with Down syndrome have increased risks for feeding problems, but there is limited literature on caregiving specific to feeding children with Down syndrome. The purpose of this study is to understand mothers’ experiences related to feeding their 3- to 10-year-old children with Down syndrome within family and sociocultural contexts. This was a qualitative study using interviews and photo-elicitation. Twenty-nine mothers of children with Down syndrome in the United States participated. Three themes were identified: (a) Feeding Challenges and Foodwork Related to the Child’s Feeding Attributes, (b) Family Dynamics and Routines that Impact Foodwork, and (c) Influence of Family and Sociocultural Norms on Feeding Experiences. Mothers engage in complex family caregiving work to feed their children with Down syndrome. Feeding can be influenced by child and family characteristics and by sociocultural contexts. Findings have implications for clinical practice and research.