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Objective To determine the frequency and accuracy of diffusion restriction (DR) of the retina and/or optic nerve (ON) detection on standard brain magnetic resonance diffusion-weighted imaging (DWI-MRI) in patients presenting with acute non-arteritic central retinal artery occlusion (CRAO). Methods This is a retrospective case-control study that includes all consecutive patients presenting to our tertiary academic center from 2013-2021 with acute non-arteritic CRAO (cases) or acute ischemic stroke syndrome (controls, age and gender-matched) that had brain MRI performed within 14 days from symptom onset. Two neurology residents (junior and senior), a vascular neurologist, and two neuroradiologists, blinded to the site of CRAO, independently reviewed the brain MRIs to assess for the presence of retina and ON DR. The consensus agreement between the two neuroradiologists was used to perform sensitivity and specificity analyses and calculate inter-rater reliability (prevalence-adjusted bias-adjusted kappa coefficient). Results A total of 128 patients with acute non-arteritic CRAO (mean (SD) age 69 (14) years; 50% female; median time from CRAO to DW-MRI 2 days (IQR 1-5)) and 128 age and gender-matched controls with acute cerebral ischemia were included. After the neuroradiologist consensus, DR was correctly identified in the retina or ON in 51/128 (39.8%) CRAO cases, retina alone 27.3%, ON alone 24.2%, and both retina and ON 11.7%, with almost perfect neuroradiologists’ inter-rater reliability for retina (K = 0.91) and ON (K = 0.83). Among controls, the retina DR was identified in 1/128 (0.8%) and ON DR in 5/128 (3.9%). The sensitivity, specificity, positive predictive value, and negative predictive value were 28.1%, 99.2%, 97.3%, and 58.0% for retina DR, and 27.3%, 96.1%, 87.5%, and 56.9% for ON DR. Conclusions Though experienced neuroradiologists identified retina and ON DR with excellent inter-rater reliability, these are infrequent findings in real world CRAO practice, with excellent specificity but limited sensitivity. Prospective studies with larger cohort of patients, optimization of standardized orbit DWI-MRI protocols are needed to facilitate a more accurate and reliable identification of retina and ON DR in acute CRAO.

This chapter introduces human subjects research protections basics from a United States regulatory perspective. An introduction to the institutional review board (IRB) office provides descriptions of the types of research activities considered human subjects research (HSR) and not human subjects research (NHSR). Guidance is offered to new investigators for best practices in preparing for the ethical and responsible protection of human subjects in research and their data. Considerations for IRB policy and procedures, including suggestions for improving research protocol submissions for IRB review, are also offered.

Background Short-term outcomes after pancreatoduodenectomy (PD) are well-studied, but long-term reoperation rates and their indications remain poorly characterized. Methods A single-center retrospective chart review was performed on patients who underwent PD for pancreatic adenocarcinoma between 1/2011 and 12/2021. Reoperations occurring >90 days after PD were dichotomized to being related or unrelated to the index PD or pancreatic adenocarcinoma. The Kaplan-Meier analysis estimated the incidence of long-term reoperation at 1 and 5 years postoperatively. Results Six-hundred twenty-eight patients were included. The 5-year incidence of any additional operation >90 days after PD was 30.0% (95% CI 23.2-36.2%), and the 5-year incidence of any long-term related reoperation was 21.2% (95% CI 15.0-26.8%). The most common indications for reoperations by 5-year incidence were cancer recurrence (12.8%, 95% CI 7.6-17.7%), incisional hernia (6.2%, 95% CI 2.6-9.7%), small bowel obstruction (1.3%, 95% CI 0.2-2.4%), and leak, fistula, or infection (1.0%, 95% CI 0.1-2.0%). Of the examined risk factors, only 90-day reoperation was found to be predictive of long-term related reoperations ( P = 0.02). Additionally, the 5-year incidence of endoscopic or interventional radiology procedures was 20.2% (95% CI 14.5-25.4%). However, 40.9% (95% CI 33.6-47.3%) of patients required additional surgery or procedures of any kind between 90 days and 5 years after PD. Discussion Within 5 years of PD, one in three patients required additional surgery, and one in five had operations for related indications. Related reoperative indications included recurrence, hernia, PD-specific complications, and small bowel obstruction. However, the rates of each of these reoperations were relatively low.

Abstract Background The majority of missense variants in clinical genetic tests are classified as variants of uncertain significance. Prior research has shown that the deleterious effects and the subsequent molecular consequence of variants are often conserved among paralogous protein sequences within a gene family. Here, we systematically quantified on an exome-wide scale if the existence of pathogenic variants in paralogous genes at a conserved position could serve as evidence for the pathogenicity of a new variant. For the gene family of voltage-gated sodium channels where variants and expert-curated clinical phenotypes were available, we also assessed whether phenotype patterns of multiple disorders for each gene were also conserved across variant positions within the gene family. Methods We developed a framework that assesses the presence of pathogenic missense variants located in conserved residues across paralogous genes. We systematically mapped 2.5 million pathogenic and general population variants from the ClinVar, HGMD, and gnomAD databases onto a total of 9,990 genes and aligned them by gene families. We evaluated the quantity of classifiable amino acids by utilizing pathogenic variants identified in databases alone and then compared this assessment to the inclusion of paralogous pathogenic variants. We validated and quantified the evidence of conserved pathogenic paralogous variants in variant pathogenicity classification. Results Considering conserved pathogenic variants in paralogous genes, increased the number of classifiable variants 2.8-fold across the exome, compared to pathogenic variants in the gene of interest alone. The presence of a pathogenic variant in a paralogous gene is associated with a positive likelihood ratio of 8.32 for variant pathogenicity. The likelihood ratio was gene family-specific. Across ten genes encoding voltage-gated sodium channels and 22 expert-curated disorders, we identified cross-paralog correlated phenotypes based on 3D structure spatial position. For example, the established loss-of-function disorders SCN1A-associated Dravet syndrome, SCN2A-associated autism, SCN5A-associated Brugarda Syndrome, and SCN8A-associated neurodevelopmental disorder without seizures were correlated in their spatial variant position on structure. Finally, we show that phenotype integration in paralog variant selection improves variant classification. Conclusion Our results show that paralogous variants, in particular with phenotype information can enhance our understanding of variant effects.

Glioblastoma (GBM) is the most frequent and aggressive malignant primary tumor of the central nervous system in adults, with an incidence of 3.23 per 100,000 people. Despite the existence of various therapeutic approaches, the absence of a cure and the unfavorable prognosis persist for this neoplasm, with a median survival of approximately 8-15 months and a 5-year survival rate of 6.9%. In this review, we address the epidemiology, histopathology, molecular characteristics, and treatment of GBM. We highlight the relationship of GBM with the microenvironment in the lateral ventricle wall and the cerebrospinal fluid. The location of GBM in this region results in more aggressive tumors and shorter life expectancy for patients. Understanding the malignancy mechanisms that hinder remission, treatment, and positive prognosis opens the possibility of improving diagnostic and therapeutic interventions against GBM.

Background: Tibiotalar arthrodesis (TTA) is a common operation for end-stage ankle arthritis. Elevated body mass index (BMI) is believed to contribute to complications following TTA. Previous studies involved national registries or small, underpowered cohorts. This study aimed to determine the effects of elevated BMI on nonunion and complication rates following TTA with a large cohort from a single academic institution. Methods: A retrospective study identified 514 patients (527 ankles) who underwent primary TTA from 2005-2017. Mean age was 60 years. Patients were stratified by BMI according to the World Health Organization classification. A reference group of 203 patients (208 ankles) included normal weight or mildly overweight patients (BMI 18.5 to <30). Ankle radiographs were evaluated to determine union or nonunion. Other outcomes included revision TTA, reoperations, subsequent adjacent joint arthrodesis, infection, and readmission. Data were analyzed using Pearson χ 2 and odds ratios for categorical variables. Analysis of variance and Kaplan-Meier estimation assessed continuous variables and time-to-event outcomes, respectively. Mean follow-up was 34.3 months. Results: Obesity class III patients had elevated risk of complications compared with normal weight patients including nonunion (odds ratio [OR] 3.96, P = .002), revision (OR 3.69, P = .03), superficial infection (OR 9.36, P = .002), and readmission (OR 10.90, P = .01). Superficial infection rates were elevated in class I (OR 6.36, P = .007) and readmissions in class II (OR 9.98, P = .01). No differences were found in reoperation ( P = .448), symptomatic implant removal ( P = .805), adjacent joint arthrodesis ( P = .353), or deep infection ( P = .507) rates. Discussion: In this retrospective review after TTA, increased rates of nonunion, revision, superficial infection, and readmission were found in obesity class III patients, compared with the reference group of normal weight or mildly overweight patients. Superficial infection rates were likewise relatively elevated in class I and readmission rates in class II patients.

Abstract Extracellular vesicles (EVs) are small membrane‐bound structures that originate from various cell types and carry molecular cargos to influence the behaviour of recipient cells. The use of EVs as biomarkers for diagnosis and as delivery vehicles for treatment in a wide range of human disease is a rapidly growing field in research and clinical practice. We hypothesized that electric fields (EFs) could influence the release and content of EVs. To examine this hypothesis, we developed a specialized bioreactor enabling cells to thrive in a three‐dimensional setting, replicating in‐vivo conditions amidst programmable EF environments. We established a three‐step EV purification protocol to achieve high‐density production of EVs. We also performed mass spectrometry‐based proteomics analysis on EV‐carrying proteins and used high‐resolution nanoparticle flowcytometry for single‐vesicle analysis. Findings from this report suggest that electrical stimulation, employing physiologically relevant amplitudes typical in therapeutic deep brain stimulation, influences the release of EVs and their cargo content in a frequency‐dependent fashion. This conclusion could carry significant implications for both fundamental biological understanding and medical advancements. First, it raises an intriguing question about how the endogenous electrical activity of neuronal and other cellular assemblies influence the production and composition of EVs. Second, it reveals a novel underlying mechanism of how therapeutic electrical stimulations can modulate EVs and treat human brain disorders. Third, it provides a novel approach to utilize electrical stimulation for generating desired EV cargos in a programmable setting.

Introduction: Delirium is a common, severe neuropsychiatric syndrome in hospitalised older adults. We evaluated use of validated delirium assessment tools, adherence to national guidelines and prevalence and management of delirium across Scotland, identifying barriers to effective care. Methods: Secondary analysis of national survey data, collected by participating clinicians on World Delirium Awareness Day (15 March 2023). Results: Among 120 responses (3,257 patients), the 4AT was the most frequently used assessment tool (75%), while 14% of units reported using clinical judgement alone. The delirium assessment rate was 74%, with a prevalence of 22% at 8 am. Management protocols varied, with frequent routine non-pharmacological interventions including pain management (88%), hydration (87%) and open family visiting (80%). Barriers to delirium care included insufficient staffing and training. Conclusion: While many hospital settings follow national delirium guidelines, some still rely on clinical judgement for assessment, with variability in management protocols and practices. We have highlighted key barriers to effective delirium care in Scotland.