Citations

ABSTRACT Objectives Systematic evidence reviews (SERs) produced by the U.S. Agency for Healthcare Research and Quality (AHRQ) Evidence‐based Practice Center (EPC) Program use contextual questions to provide context and background information on the topic. There is currently no standardized approach to address contextual questions in systematic reviews. This study explored the use of publicly available large language models (LLMs) in addressing contextual questions. Study Design Using a set of 20 published and 5 yet to be published SERs, we selected one contextual question per report and used it as a prompt to elicit answers from an LLM (ChatGPT, Bard, Claude, or Perplexity). Two independent reviewers rated the results using a priori established evaluation criteria ( https://osf.io/4k3cu/ ), comparing the response in the SER to LLM‐generated responses. The study was guided by six research questions addressing feasibility, validity of content, validity of structure, mistakes, congruence between responses, and incremental validity of using LLMs to address contextual questions. Results Using minimal prompt engineering produced relevant responses and documented the feasibility of LLM‐generated answers to contextual questions. Responses differed in content and format and are not reproducible (e.g., LLMs update regularly), but LLMs were able to produce articulate, clinically plausible, and well‐structured responses. We detected few factual errors, contradictions, and no instance of suspected bias, but citations supporting LLM‐generated responses could often not be produced or could not be verified (‘confabulations’). Congruence with human generated responses varied, with LLM‐generated responses providing more background on the topic and SERs providing more nuanced answers in response to the contextual question. Results regarding incremental validity were mixed and may depend on the tool. Conclusion LLMs are potentially helpful in addressing contextual questions in systematic reviews but human expertise remains essential for using the generated information in a meaningful way.

ABSTRACT The COVID‐19 pandemic underscored the critical need to strengthen healthcare systems and optimize resource allocation planning during times of disruption and crisis. This retrospective, single‐center, cross‐sectional study included 33,158 admissions for patients ≤ 17 years old admitted to the Children's Hospital (CH) between January 1, 2017, and December 31, 2021. Data was abstracted using Vizient Clinical Data Base and the internal data warehouse. A Poisson regression model was implemented to compare admission diagnosis patterns during the pre‐ and intra‐pandemic phases. CH SARS‐CoV‐2 prevalence rate was 0.1% in 2020 and 0.5% in 2021. There was a decrease in overall admissions to the CH ( p < 0.01) and PICU ( p < 0.01) at the onset of the pandemic. There were significant and variable differences in admission patterns for certain infectious and seizure‐related diagnoses. The CH experienced an increase in certain specific mental health diagnoses. Seasonality was noted for viral bronchiolitis during the pre‐pandemic phase, but was disrupted during the intra‐pandemic phase. The COVID‐19 pandemic had a significant impact on the number and pattern of admissions, despite low prevalence of SARS‐CoV‐2 in our hospital. These changes may be secondary to COVID‐19 community mitigation strategies. Results can inform anticipated patterns during future pandemics.

ABSTRACT Background Monoclonal gammopathy‐associated myopathies (MGAMs) include light chain (AL) amyloid myopathy, sporadic late‐onset nemaline myopathy (SLONM), and vacuolar myopathy with monoclonal gammopathy and stiffness (VAMMGAS). These subtypes usually occur separately, although rare overlap has been described. We report a patient with monoclonal gammopathy and concurrent SLONM and excessive glycogen accumulation, resembling VAMMGAS but with distinct features. Methods Case report with clinical, electrophysiological, pathological, and therapeutic characterization of a patient with IgG‐kappa monoclonal gammopathy and coexisting SLONM and glycogen accumulation within muscle fibers. Results A 69‐year‐old man developed subacute progressive axial and limb weakness, head drop, dysphagia, and weight loss. Examination showed proximal/distal weakness, neck extensor weakness, and lumbar hyperlordosis. EMG revealed myopathic motor unit potentials without electrical myotonia or complex repetitive discharges. Serum studies identified IgG‐kappa monoclonal protein with elevated kappa light chain and ratio. Muscle biopsy demonstrated nemaline rods (1% of fibers) and scattered fibers with non‐rimmed vacuoles (0.3% of fibers) containing PAS‐positive, diastase‐labile material consistent with concurrent SLONM and glycogen storage myopathy‐like pathology. Genetic testing for congenital nemaline and glycogen storage myopathies was negative. Plasma‐cell directed therapy with daratumumab, lenalidomide, and dexamethasone led to rapid functional improvement and M‐protein reduction. Further gains followed autologous stem cell transplantation. Conclusion This case expands the MGAM spectrum, highlighting co‐occurrence of SLONM and an excessive glycogen accumulation responsive to immunotherapy and transplantation. These findings suggest a spectrum of related disease processes. Recognition of this combined pathology is clinically important, as affected patients may benefit from targeted immunotherapy or stem cell transplantation.

Abstract INTRODUCTION Determining apolipoprotein E ( APOE ) ε4 allele status, a key genetic risk factor for Alzheimer's disease (AD), requires molecular genotyping infrastructure not widely accessible beyond specialized centers. METHODS A fully automated high‐throughput apoE E4 proteotyping immunoassay was evaluated for clinical performance (460 participants across three cohorts) and analytical validity. Concordance with polymerase chain reaction (PCR)‐based genotyping and measures of analytical validity were reported. RESULTS The apoE E4 immunoassay demonstrated 99.6% (95% confidence interval [CI]: 98.4% to 99.9%) concordance with PCR‐based APOE ε4 genotype results across the pooled clinical cohort; 100.0% (95% CI: 97.1% to 100.0%) in those with AD ( N = 127) and 99.4% (95% CI: 97.8% to 99.8%) in those without AD (333). The assay met analytical validity criteria for E4 isoform specificity, interference, precision, and stability. DISCUSSION The apoE E4 immunoassay demonstrated high concordance with PCR‐based genotyping and robust analytical validity, offering an accessible alternative for APOE ε4 zygosity assessment. Highlights A novel high‐throughput plasma‐based proteotyping immunoassay for APOE ε4 zygosity classification was developed and evaluated for clinical performance and analytical validity. The apoE E4 immunoassay demonstrated high concordance (99.6%) with PCR‐based APOE ε4 genotyping across a diverse international cohort, and a robust analytical profile. An apoE E4 immunoassay may offer a more cost‐effective and accessible alternative to DNA genotyping approaches currently used for AD risk evaluation and anti‐amyloid treatment decisions.

Abstract Current assessments of brain permeability rely predominantly on drug delivery to contrast-enhancing tumor regions. However, substantial portions of central nervous system (CNS) tumors reside within non-enhancing brain (NEB), where drug concentrations frequently remain subtherapeutic. This collaborative Adult Brain Tumor Consortium and Food and Drug Administration workshop aimed to identify criteria for defining NEB permeability to accomplish 2 critical objectives: (1) allocate clinical trial resources toward agents achieving therapeutic NEB concentrations and (2) minimize systemic toxicity when CNS benefit is improbable. The workshop systematically evaluated permeability assessment modalities, including drug physicochemical properties, in vitro blood-brain barrier models, and penetration into cerebrospinal fluid and normal rodent brain. Methodological approaches to determine requisite NEB drug concentrations and approaches to measuring NEB pharmacokinetics and pharmacodynamics were examined. This culminated in developing the Non-Enhancing Brain Permeability Index (NEBPI), which assigns therapeutic agents to 3 categories: sufficiently permeable, insufficiently permeable, or impermeable. The NEBPI provides a standardized framework to assist investigators and regulatory agencies to evaluate NEB penetration before human efficacy studies are initiated for agents that require direct tumor contact. Assessing NEB drug penetration is critical to improving outcomes in CNS tumors and reducing the incidence of brain metastases in systemic malignancies.

Abstract Insulinoma is the most prevalent neuroendocrine tumor of the pancreas, presenting with a spectrum of neuroglycopenic symptoms. This case report describes a 64-year-old woman with primarily postprandial hypoglycemia, resulting in altered consciousness and confusion occurring several hours after meals. Continuous glucose monitoring (CGM) was used to establish the postprandial pattern of the patient's hypoglycemia, and this facilitated the confirmatory biochemical evaluation by a single blood draw done at the time of symptoms, without performing a 72-hour fast. Imaging demonstrated an 11-mm tumor in the pancreas, which was removed and confirmed to be a well-differentiated neuroendocrine tumor on histopathology. While awaiting pancreatic surgery, the patient began taking melatonin for sleep and reported an improvement in the frequency and severity of hypoglycemia symptoms, which was supported by CGM data and a robust expression of melatonin receptors on the excised tumor. This case raises interest in the role of melatonin receptor signaling in counteracting hyperinsulinemia and corresponding hypoglycemia in patients with insulinoma.

Abstract Objectives Diagnosing adult T-cell leukemia/lymphoma (ATLL) remains challenging due to its clinical and histopathologic heterogeneity. While HTLV-1 serology is a key diagnostic criterion, it is often unavailable at the time of diagnosis and does not confirm viral integration in tumor cells. The HTLV-1–encoded HBZ RNA is a reliable diagnostic biomarker for ATLL. We evaluated the diagnostic performance of RNAscope in situ hybridization (ISH) for HBZ RNA in formalin-fixed, paraffin-embedded (FFPE) tissues to distinguish ATLL from other T-cell lymphomas. Methods HBZ ISH was evaluated in 72 cases, including 52 ATLLs and 20 non-ATLL T-cell lymphomas, to determine diagnostic sensitivity and specificity, interobserver agreement, interlaboratory reproducibility, and comparison with digital gene expression. Results This assay demonstrated 86.5% sensitivity and 100% specificity, with sensitivity improving to 97% when excluding bone marrow clot sections and FFPE blocks older than 5 years. Interobserver agreement among 3 pathologists was excellent (κ = 0.92, percent agreement: 94%). Interlaboratory reproducibility of HBZ ISH was high, with 93% to 95% concordance across these Clinical Laboratory Improvement Amendments–certified laboratories. HBZ RNA ISH–positive cases demonstrated significantly higher HBZ gene expression levels by digital gene expression profiling. Conclusions We established HBZ ISH as a reliable tissue-based surrogate for HTLV-1 infection in ATLL. This assay will enhance diagnostic accuracy, expedite definitive diagnosis, and improve patient selection for targeted therapies and clinical trials, particularly in regions with a high prevalence of HTLV-1.