Citations

Objective: To evaluate the associations between surgeon-patient sex concordance, long-term clinical outcomes and healthcare costs. Background Data: Emerging data suggest surgeon-patient sex concordance may improve short-term outcomes, especially for female patients, yet its long-term effects remain unknown. Methods: We conducted a population-based retrospective cohort study of adults undergoing common surgeries in Ontario, Canada (2007-2019). Patients were followed for 90 and 365 days. Surgeon-patient sex concordance was categorized into four dyads. Multivariate generalized estimating equations clustered by procedure type evaluated composite and individual (complications, readmission, mortality) clinical outcomes and healthcare costs. Results: A total of 1,165,711 patients were included. Female patients treated by male surgeons, compared with female surgeons, were more likely to experience an adverse composite event (90 d: aOR 1.12, 95% CI 1.08–1.17, P <0.001; 365 d: aOR 1.09, 95% CI 1.05–1.14, P <0.001), with no association among male patients (90 d: aOR 1.00, 95% CI 0.94–1.05, P =0.89; 365 d: 0.99, 95% CI 0.92–1.07, P =0.87). Long-term total healthcare costs were greater for patients treated by male surgeons - an effect seen in both male patients (90 d: aRR 1.08, 95% CI 1.03-1.14, P =0.002 and 365 d: aRR 1.08, 95% CI 1.02-1.14, P =0.007) and female patients (90 d: aRR 1.10, 95% CI 1.05-1.14, P <0.001, 365 d: aRR 1.09, 95% CI 1.05-1.14, P <0.001). Conclusions: Surgeon-patient sex concordance was associated with improved long-term outcomes for female, but not male, patients, and female surgeons’ patients had lower healthcare costs. Given these benefits, further investigation into the mechanisms driving these outcomes is warranted.

Extramedullary presentations of multiple myeloma (MM) involving the central nervous system (CNS) carry a dismal prognosis. Although historically rare, management of extramedullary disease—including CNS manifestations—has become increasingly clinically relevant as advances in systemic therapies have prolonged control of medullary disease. CNS manifestations may occur across a variety of clinical settings and at different time points throughout the disease course. Common symptoms include visual changes, headaches, loss of sensation, confusion, and seizures. MRI identifies leptomeningeal enhancement and/or parenchymal lesions in approximately 90% of cases, and lumbar puncture with cerebrospinal fluid testing for clonal plasma cell populations is confirmatory. Encouragingly, the incorporation of novel therapeutic agents has improved historically poor outcomes in CNS MM. Novel immunotherapeutic approaches using CAR T-cell therapy and bispecific T-cell–engaging antibodies have recently demonstrated significant efficacy in consolidating responses. Multimodality treatment strategies incorporating intrathecal chemotherapy, systemic novel agents, radiation therapy, and immunotherapy hold promise for achieving more durable responses in this devastating manifestation of MM.

Abstract INTRODUCTION The tau positron emission tomography (PET) overlap index (OI) has shown promise in maximizing signal‐to‐noise for longitudinal tau PET imaging, particularly for early tau pathology, but requires validation against neuropathology. METHODS Fifty‐seven participants who underwent serial tau PET imaging (flortaucipir) and subsequent autopsy were included. Tau PET OI and standardized uptake value ratios (SUVRs) were compared across neuropathological diagnoses. RESULTS Tau PET OI showed greater concordance with neurofibrillary tangle (NFT) severity in the entorhinal cortex (a key region for Alzheimer's disease [AD] tauopathy) than SUVR, particularly in early Braak tangle stages (positivity: 52.2% for OI vs. 13.0% for SUVR). OI detected overlapping tau voxels that exhibited spatial correspondence with immunohistochemical and autoradiography measures of tau deposition across both AD and non‐AD tauopathies. DISCUSSION These findings demonstrate the enhanced capacity of OI in serial tau PET to robustly detect early and spatially localized tau pathology, supporting its application as a sensitive imaging metric in AD and select non‐AD tauopathies.

ABSTRACT Background Sunlight has profound impacts on physical and mental health, beyond vision, including effects on circadian rhythms, alertness, mood, and sleep. A family history of any mood disorders is strongly associated with psychiatric disorders including bipolar disorder. The purpose of this study was to evaluate the association between a family history of any mood disorder in patients with bipolar I disorder and solar insolation at varied international onset locations. Methods Data for this analysis were available from 5842 patients with a diagnosis of bipolar I disorder obtained at 83 collection sites in both hemispheres. This included 4752 patients from 71 collection sites in the northern hemisphere and 1090 patients from 12 collection sites in the southern hemisphere. Patient data variables were obtained from records or interviews. Solar insolation data were obtained from The National Aeronautics and Space Administration (NASA) Power database for each onset location, and the ratio of the mean monthly minimum/mean monthly maximum solar insolation was calculated. Typically, the ratio is largest near the equator (little yearly change in solar insolation) and smallest near the poles (large yearly change in solar insolation). Results A significant relationship was found between a family history of any mood disorder, the ratio of the mean monthly minimum/mean monthly maximum solar insolation, and gender. The odds of a family history of mood disorder increased as patient location nears the poles and decreased near the equator. Female gender also increased the odds of having a family history of a mood disorder. Conclusions This study highlighted the association between family history, solar insolation, and gender in international patients with bipolar I disorder. Given the profound effects of sunlight on human health, the family of patients with bipolar disorder who live in the same location with the same solar insolation, and especially females, may be at increased risk for a mood disorder.

Abstract Objectives Traditional laboratory regulatory frameworks provide robust guidance for conventional clinical testing but lack requirements for data documentation for artificial intelligence and machine learning (AI/ML) solutions. This gap creates significant risks since AI solutions directly inherit patterns, biases, and limitations from their training data. Here, we describe the development and implementation of a comprehensive data documentation checklist with accompanying data lineage for use within an AI lifecycle framework for clinical laboratories. Methods Building on the previously established Clinical AI Readiness Evaluator (CARE) framework, we developed a comprehensive data checklist and data lineage methodology through a multiphase process, including (1) comprehensive review of existing AI/ML data documentation frameworks, (2) focused meetings with 3 institutional AI operations teams, and (3) 3 rounds of iterative refinement by our multidisciplinary team. The checklist’s effectiveness was then assessed using 3 diverse AI/ML projects moving through the CARE framework. Results The CARE Data Checklist and Data Lineage provide a structured approach to documenting critical aspects of datasets used in AI/ML projects, including data composition, demographics, collection methods, labeling processes, usage constraints, maintenance requirements, and a data readiness assessment. The checklist addresses unique data-centric challenges of AI/ML applications, facilitating transparency, reproducibility, and regulatory compliance. Conclusions The CARE Data Checklist and Data Lineage serve as both a technical guide and a communication tool bridging gaps between technical and clinical stakeholders. By working on these documents early in the AI lifecycle, laboratories can anticipate and address data-related challenges, ultimately saving time, optimizing resources, and improving the reliability of AI-augmented laboratory solutions.

Abstract Chromosome 5p15.33 harbors several independent association signals which demonstrate antagonistic pleiotropy across cancer types, with causal mechanisms largely unresolved. To identify functional variants and enhancer elements at this locus, we performed statistical fine-mapping followed by massively parallel reporter assays (MPRA) and proliferation based CRISPRi screens. This approach identified eight multi-cancer functional variants (MCFVs) across three GWAS signals. Targeting rs421629 (part of the CLPTM1L signal marked by rs465498) with CRISPRi revealed opposing effects on TERT expression in pancreatic versus lung cancer cells, consistent with the antagonistic pleiotropy observed for this signal. Furthermore, CRISPRi nominated an intronic CLPTM1L variable number tandem repeat (VNTR) as a potent enhancer. Long-read sequencing established VNTR polymorphisms as potential causal variants for the rs465498 signal. We showed that Hippo-pathway transcription factors mediate VNTR enhancer activity in lung and pancreatic cancer cells. Together, these findings indicate that cancer susceptibility at 5p15.33 may be mediated by both SNPs and VNTRs and provide an integrated framework for resolving complex pleiotropic loci.

Importance Sex differences are increasingly recognized as modifiers of Alzheimer disease and related dementias, with women exhibiting greater tau burden and faster cognitive decline than men. Even though α-synuclein copathology frequently occurs in Alzheimer disease, its contribution to sex differences in disease progression is unclear. Objective To test whether α-synuclein positivity, measured using cerebrospinal fluid seed amplification assay (SAA), is differentially associated with tau accumulation in women vs men across the Alzheimer disease continuum. Design, Setting, and Participants This cohort study used longitudinal tau positron emission tomography from the Alzheimer’s Disease Neuroimaging Initiative collected between 2015 and 2023, with a median (IQR) follow-up of 1.23 (0.00-3.84) years. Participants were stratified by cerebrospinal fluid α-synuclein seed amplification assay status and sex. Participants were cognitively unimpaired or cognitively impaired (mild cognitive impairment or dementia) at baseline. Exposure Cerebrospinal fluid α-synuclein status determined by SAA and dichotomized as SAA negative or SAA positive. Main Outcomes and Measures Tau burden was quantified as standardized uptake value ratio (SUVr) in the medial temporal composite region of interest. Linear mixed-effects models tested SAA by sex by time interactions on longitudinal tau accumulation, adjusting for baseline age, baseline cognitive status, apolipoprotein E ε4 carrier status, and site. Sample size estimates were calculated to detect 25% and 50% treatment effects with 80% power in those with cognitive impairment. Results Among 415 participants (mean [SD] age, 72.3 [7.6] years; 220 women [53%]; 69 SAA positive [17%] and 346 SAA negative [83%]), there was a significant interaction between SAA status, sex, and time on tau accumulation (β, 0.061; 95% CI, 0.030-0.093; P &amp;lt; .001). Women with positive SAA results exhibited the fastest tau accumulation compared with other groups (0.066 SUVr per year; 95% CI, 0.043 to 0.089 SUVr per year; P &amp;lt; .001). Clinical trials targeting tau pathology in cognitively impaired individuals with 18-month follow-up would require 129 SAA-positive women to detect a 25% treatment effect with 80% power, compared with 518 SAA-negative women. Conclusions and Relevance In this cohort study of participants across the Alzheimer disease continuum, α-synuclein copathology was associated with faster tau accumulation in women than men. These findings may inform sex-specific interpretation of α-synuclein biomarkers and trial design.

Background The primary objective of this analysis was to assess the association between non-invasive biomarker results within the first 2-years post-kidney transplant and 10-year All Cause Graft Loss (ACGL). Methods CTOT-08 was linked with the Scientific Registry of Transplant Recipients (SRTR) to assess 10-year ACGL. Cox Regression was used to determine the association between gene expression profile (GEP) and donor-derived cell-free DNA (dd-cfDNA) results and ACGL. A Cox Regression with time-varying covariates was used to test associations with ACGL with simultaneous and repeated biomarker results. Results The final landmarked Cox model included clinical acute rejection (aHR 2.58 (1,30,5.13) for 1 rejection, aHR 3.41 (1.07,10.85) for 2 rejections), diabetes (aHR 1.71 (0.99,2.96)), recipient age (aHR 1.02 (1.00,1.04)), the highest quartile of positive GEP (aHR 2.44 (1.45,4.10)) and the highest quartile of positive dd-cfDNA (aHR 2.91 (1.77,4.78)). In the time-varying model, having both biomarkers positive at the same time carried the greatest association with ACGL (aHR 4.29 (2.10,8.76)). Conclusions In this multicenter, prospective analysis of GEP and dd-cfDNA on patient and graft outcomes, an independent association with long-term ACGL was demonstrated. Further, a time-varying analysis demonstrated that two biomarkers with independent methodologies tested at the same time can provide more information than either one alone.

Rationale: Neuromuscular blocking agents (NMBAs) show potential benefits on mortality and other complications of acute respiratory distress syndrome (ARDS) in adult patients. Evidence-based decisions and processes ensure appropriate use of neuromuscular blockade in adult patients with ARDS. Objectives: The objective of these guidelines was to develop evidence-based recommendations for the administration of NMBAs in critically ill adult patients with ARDS. Design: The American College of Critical Care Medicine Board convened a 21-member multidisciplinary panel of experts in critical care medicine, nursing, respiratory therapy, pharmacology, surgery, neurology, and anesthesiology. The panel included two expert methodologists specialized in developing evidence-based recommendations in alignment with the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. Conflict-of-interest policies were strictly followed during all phases of guidelines development including task force selection and voting. Methods: The panel members identified and formulated five Population, Intervention, Comparison, and Outcome questions. We conducted a systematic review for each question to identify the best available evidence, statistically analyzed the evidence, and assessed the certainty of the evidence using the GRADE methodology. We used the GRADE evidence-to-decision framework to formulate the recommendations. Results: The panel generated two conditional recommendations. One recommendation is to use NMBAs in adults with ARDS with Pa o 2 /F io 2 less than 150. For the other recommendations, there was equipoise in the recommendation for and against using titratable vs. fixed-dose NMBA dosing, a monitoring-based strategy for assessing depth of sedation and analgesia in adults with ARDS before initiating or while receiving neuromuscular blockade, and administration of NMBAs for patients who are proned, due to overall lack of evidence in critically ill patients and due to considerations of patient safety and experience concerns. Conclusions: These guidelines provide additional perspectives on the use of NMBA in patients with ARDS, recognizing that institutional and patient-specific considerations must help to guide the decision-making process.