Citations

Abstract Isolated/idiopathic rapid-eye-movement (REM)-Sleep Behavior Disorder (iRBD) is characterized by dream enactment behaviors associated with loss of REM atonia. iRBD is in most cases a prodromal synucleinopathy, and emerging evidence suggests associations between RBD and other neurological and psychiatric conditions. In this study, we performed pathway-based polygenic risk score (PRS) and rare variant burden analyses to examine these potential associations. Pathway-specific PRS were constructed from genome-wide association study summary statistics of five neurodegenerative and seven psychiatric traits across 10 biologically relevant pathway categories, including a total of 279 pathways, in 1,573 iRBD cases and 16,022 controls from the International RBD Study Group and UK Biobank. Rare variant burden tests were performed in 1,264 iRBD cases and 2,581 controls. We identified multiple potential pathways indicating shared polygenic risk between RBD and both neurodegenerative and psychiatric disorders. Lewy body diseases and post-traumatic stress disorder had the most shared polygenic risk pathways in neurological and psychiatric disorders, respectively. Two pathways, the serotonin transport pathway and the chaperone-mediated autophagy pathway, showed the strongest association with iRBD, and gene-based rare variants analyses revealed five genes associated with iRBD: GBA1 , PLEKHM1 , LRP2 , P2RX1 , and HAP1. Subsequent analysis of these genes in Parkinson’s disease and dementia with Lewy bodies replicated several associations. Together, these findings provide novel insights into the shared genetic architecture underlying iRBD, neurodegenerative disorders, and psychiatric traits, with implications for early identification and mechanistic understanding.

Abstract Background Our objective is to examine the generalizability of the relationships between four MRI markers of CVD: DTI‐derived free water (FW), fractional anisotropy (FA), perivascular space (PVS) and white matter hyperintensities (WMH) volume, with vascular risk factors (VRF) and cognition in the baseline POINTER Imaging and Framingham Heart Study (FHS) cohorts. Method We studied 907 U.S. POINTER and 797 FHS Offspring participants with available baseline demographic, clinical and imaging data (Table 1). Continuous FW, FA, WMH (log‐transformed) and PVS measurements were regressed against total cranial volume (TCV). Cognitive outcomes included a Global Cognitive Composite and executive function composite score for POINTER and FHS. For each MRI marker, we used linear and logistic regressions to assess the effect of age, sex, hypertension, diabetes and smoking status, adjusting for ethnicity. We then assessed, for each cognitive outcome, the individual effect of MRI markers using separate linear regressions adjusted for demographic and clinical factors, as well as TCV‐adjusted gray matter volume to control for atrophy. Result POINTER and FHS differed across most demographic and biomarker characteristics (Table 1). Despite these differences, there were similar associations between demographic and VRF and the 4 MRI vascular markers in POINTER and FHS (Figure 1): increased age was associated with worse outcomes for the 4 markers, hypertension was associated with increased FW, PVS and lower FA, diabetes was associated with increased FW only, smoking status did not impact any of the four markers. Only exception was that female had lower FW and increased WMH in POINTER and increased PVS in FHS. Associations between CVD measures and cognition were also similar across cohorts: reduced cognitive performance was significantly associated with both decreased FA and increased FW (Figure 2), but not with WMH nor PVS. Conclusion Our study explores four imaging markers representing diverse mechanisms by which CVD could impact brain structure and function in the POINTER and FHS studies. Despite differences in cohort characteristics, we found mostly consistent CVD relationships with demographic, VRF, and cognitive measures between cohorts which supports the generalizability of the relation of these markers with VRF and cognition identified in the POINTER cohort.

Objectives: In the United States, training for physicians who manage critically ill adult patients (intensivists) evolved through parallel subspecialty critical care medicine (CCM) pathways with significant commonality. The Society of Critical Care Medicine Adult Critical Care Physician Core Knowledge and Skills Task Force aimed to delineate the common core knowledge and skills required of all intensivists. Design: A master list of content areas and procedural skills was compiled from all CCM subspecialty program requirements and blueprints of the certification examinations. Using a modified Delphi approach, participants were asked to categorize the knowledge items as “advanced knowledge is essential,” “general, but not advanced, knowledge is essential,” or “knowledge is not essential.” Procedures were categorized as “intensivist performs routinely,” “intensivist only performs in an emergency,” or “intensivist knows” about the procedure. Setting: Representatives from CCM stakeholder organizations, including accreditation and certification organizations, critical care societies, and program directors’ societies, were invited to participate. SUBJECTS: Members of the Adult Critical Care Physician Core Knowledge and Skills Task Force of the Society of Critical Care Medicine. Interventions: For the first two rounds of the modified Delphi process, Research Electronic Data Capture was used. For the third and fourth rounds, the process was completed through online meetings with Zoom (Zoom Video Corporations, San Jose, CA) utilizing Zoom’s polling feature. Measurements and Main Results: A total of 541 items were determined to be essential, with 145 requiring advanced knowledge and 323 requiring general knowledge. For 73 items, consensus regarding advanced vs. general could not be achieved, but they remained essential. Only eight items were felt to be nonessential. Of the 16 procedures, most were categorized as “intensivist performs.” Conclusions: The large number of items included in the list of essential knowledge and skills demonstrates the complexity of modern CCM. Utilization of a common framework across the subspecialties of CCM could lead to greater harmonization among the fellowship program requirements and certification examinations.

ABSTRACT Background Proton beam therapy (PBT) offers dosimetric advantages in pediatric radiotherapy by reducing radiation exposure to healthy tissues. However, broad implementation raises important ethical, logistical, and equity considerations, especially in settings with limited access to advanced technologies. Procedure This position paper by the Paediatric Radiation Oncology Society (PROS) reviews the clinical rationale for selecting radiotherapy modalities in children, with a specific focus on ethical utilization of PBT. The document synthesizes evidence on the benefits and limitations of modern photon and proton therapies, explores disparities in access, outlines the role of local pediatric radiation oncologists, and addresses the impact of industry‐driven messaging on family decision‐making. Results While PBT offers clinical benefit in selecting pediatric cancers, high‐quality photon‐based treatments such as IMRT and VMAT remain effective and widely accessible alternatives. The referral and evaluation process for PBT is complex and may introduce treatment delays. Travel and financial burdens can exacerbate disparities. PROS underscores the critical role of local pediatric radiation oncologists in counseling families, and calls for balanced, evidence‐based communication from providers and industry stakeholders. Conclusions PROS advocates for an ethical, equitable, and evidence‐informed approach to radiotherapy modality selection in children, reflecting holistic considerations beyond dosimetry. Proton therapy should be pursued when clinically indicated and accessible without compromising timely care. Investment in a comprehensive radiation therapy infrastructure, including professional education, collaborative research, and responsible public messaging, is essential to optimize pediatric cancer outcomes globally.

Background: Sudden cardiac death (SCD) is a leading cause of mortality in the U.S., with emerging evidence pointing to racial disparities and the impact of social vulnerability. Yet, geographic patterns integrating race and county-level vulnerability remain underexplored. Objective: To identify U.S. counties where socially vulnerable communities, stratified by race/ethnicity, experience disproportionate burdens of SCD-related mortality. Methods: We analyzed county-level data (1999-2020), integrating age-adjusted mortality rates (AAMR) for SCD with the 2020 CDC Social Vulnerability Index (SVI). Counties were categorized into SVI quartiles (Q1: Low to Q4: High Social Vulnerability). Analyses were stratified by race/ethnicity: Black or African American, Hispanic/Latino, White, American Indian/Alaska Native (AI/AN), and Asian/Pacific Islander (API). We used RStudio (v2023.06.1) for data cleaning, ANOVA testing, and descriptive analysis. “Unreliable” mortality values were handled as missing or set to zero, with only valid AAMR > 0 included. Hotspot counties were identified by selecting the top decile of AAMR SCD within Q4 SVI counties. Results: Significant disparities emerged across SVI quartiles for Black (p = 0.0003), Hispanic (p < 0.0001), and White (p < 0.0001) groups. Mean AAMR more than doubled from low to high SVI counties in Black communities (17.0 to 39.4 per 100,000). White and Hispanic groups showed smaller but consistent increases. API (p = 0.60) or AI/AN (p = 0.63) groups showed no significant trends. Madison Parish, LA appeared in the top-10 highest-burden counties across all groups. Black populations faced extreme rates in some SVI counties (e.g., Madison Parish, LA: 351.4 per 100,000), while API groups had low AAMR even in vulnerable areas. Data misclassification limited interpretation in the Hispanic group. Conclusions: Black, Hispanic, and White populations showed significant differences in SCD mortality tied to social vulnerability. Black populations in the most vulnerable areas experienced more than twice the rate of mortality compared to those in less vulnerable areas, suggesting a strong correlation between social vulnerability and SCD mortality in Black communities. API and AI/AN groups showed no significant associations, likely due to small sample sizes. Madison Parish, LA reflects the compounded impact of structural disadvantage. Findings support targeted interventions in socially and racially vulnerable counties to reduce preventable cardiac deaths.

Background Tumors with mismatch repair deficiency (MMRd) classically display concomitant loss of MLH1/PMS2 or MSH2/MSH6 on immunohistochemistry (IHC) with microsatellite instability-high (MSI-High) status on molecular testing. Nevertheless, a different phenotype can occur in up to 15% of MMRd tumors (unusual phenotype). Data on the efficacy of immunotherapy in this population remain scarce. Methods We conducted a retrospective study within the IMMUNODIG MSI cohort including patients with advanced gastrointestinal MMRd tumors treated with immune checkpoint blockade in the real-world setting. We selected patients with both IHC and MSI assays data available. Unusual MMRd tumors were classified into four distinct groups: (1) isolated loss of PMS2 or MSH6 with MSI-H (isolated/MSI-H), (2) complex loss of MMR proteins with MSI-H (complex/MSI-H), (3) loss of one or more MMR proteins without MSI-H (MMRd-IHC/microsatellite stability (MSS) or MSI-low (MSI-L)), and (4) four MMR proteins retained with MSI-H (retained IHC/MSI-H). Results Out of 759 patients in the IMMUNODIG-MSI cohort, 571 patients met inclusion criteria. Of these, 90 (15.8%) had an unusual phenotype (47 isolated/MSI-H, 19 complex/MSI-H, 16 MMRd-IHC/MSS or MSI-L and 8 retained IHC/MSI-H). Compared with classical phenotypes, patients with a tumor harboring an unusual phenotype had a younger age at treatment (p=0.005), increased RAS mutation (p=0.005), reduced BRAF p.V600E mutation rates (p<0.001), a higher proportion of Lynch syndrome (p<0.001) and a higher prevalence of non-colorectal cancers (p=0.021). After a median follow-up of 28.1 months (mo), there was a significant difference in progression-free survival, with median values of not reached, 66.4 mo, 37.2 mo, 18.3 mo and 5.5 mo for complex/MSI-H, isolated/MSI-H, classical, retained IHC/MSI-H and MMRd-IHC/MSS or MSI-L subgroups, respectively (p<0.001). Notably, objective response rates were 59.1%, 58.7%, and 63.2% for complex/MSI-H, isolated/MSI-H and classical contrasting with 50% and 25% for retained IHC/MSI-H and MMRd-IHC/MSS or MSI-L, with no complete response observed in the latter two. Conclusion Our findings underscore the need for dual testing and advocate for the presence of both MMRd-IHC and MSI-H for optimal immunotherapy response. Of note, complex MMR aberrations and isolated PMS2/MSH6 losses with MSI-H may represent promising candidates for enhanced immunotherapy efficacy.

Immune checkpoint inhibitors (ICIs) are an important class of cancer treatment. Endocrine immune-related adverse events (E-irAEs) account for a significant proportion of irAEs in ICI-treated patients. Diagnosing E-irAEs accurately and timely can be challenging in the absence of clear categorization and standardization across oncology, endocrinology and other specialties. While existing guidelines provide some broad directions to diagnosis and management, they lack clarity on irAE-specific symptom evaluation and work-up, as well as assessment of severity. These limitations can then impact triage, time-sensitive management and care escalation to specialists such as oncoendocrinologists. The objective of this study was to develop consensus-based statements on disease definitions for E-irAEs. A core working group of endocrinologists with expertise in the oncoendocrinology field drafted a survey with statements outlining the general approach to E-irAEs, disease definition and management approach of six specific diagnoses: ir-thyroiditis thyrotoxic phase, ir-thyroiditis hypothyroidism, ir-Graves’ disease, ir-hypophysitis, ir-adrenalitis and ir-type 1 diabetes mellitus. Severity grading tables were drafted for three disease categories—“thyroid”, “pituitary and adrenal”, and “diabetes mellitus”. A two-round modified Delphi process, using the RAND/University of California Los Angeles (RAND/UCLA) Appropriateness Method, was employed. In this process, a 25-member voting panel consisting of endocrinologists, oncologists and other specialists and healthcare providers with experience in management of ICI-treated patients and irAEs was recruited. The panel rated anonymously on usability, accuracy, appropriateness or agreement of 41 items on a 9-point scale in Survey 1, after which a meeting was convened. Statements were modified based on voting results from Survey 1 and Meeting 1, and the process was repeated in Survey 2 and Meeting 2. At the end of this process, consensus was achieved for all statements. Our study findings address the gap in standardized nomenclature, clinical, laboratory and radiological evaluations, and management principles of E-irAEs. With consensus achieved from a panel of experts from a variety of disciplines, we anticipate that the statements can form the basis for standardization of the diagnostic process and improvement of patient care.

Objective To establish a framework for validating candidate biomarkers of cerebral small vessel diseases (SVD) associated with cognitive impairment and characterize individuals enrolled by the MarkVCID2 consortium under this framework. Methods Participants age 60 to 90 years were enrolled across 17 MarkVCID2 sites. Recruitment was targeted to enrich in cognitive symptoms (mild dementia, mild cognitive impairment, subjective cognitive decline), defined risk factors (diabetes mellitus, advanced hypertension), and Black/African American, White, and Hispanic/Latino subgroups. Enrolled participants underwent baseline visits that included cognitive testing, multimodal magnetic resonance imaging (MRI), and biofluid collection. Provisional risk for SVD‐related cognitive decline was estimated primarily by baseline cognitive symptoms plus SVD risk factors. Adjudicated risk status was estimated by cognitive symptoms plus presence of moderate‐to‐severe white matter hyperintensities, microbleeds, or lacunes on baseline MRI. Results MarkVCID2 enrolled 1883 individuals age 73.4 ± 7.5 years, 65.0% female, 24.2% Hispanic, and 27.1% non‐Hispanic Black. Among enrollees, 44.8% were provisionally designated high‐risk. After baseline MRI, 48.5% were categorized as adjudicated high‐risk status, with substantial recategorization both from low‐ to high‐risk (primarily because of MRI lesions without SVD risk factors) and high‐ to low‐risk (primarily suspected cognitive impairment at screening not confirmed by baseline testing). Interpretation MarkVCID2 baseline data indicate successful enrollment of diverse individuals enriched in factors associated with SVD‐related cognitive decline. Changes over 3 years of longitudinal follow‐up will be analyzed to validate the candidate biomarkers for 2 projected contexts of use: subject selection (identifying likelihood of future SVD progression) and study outcome (efficiently measuring SVD progression). ANN NEUROL 2026;99:449–458

Objectives: A framework of high-reliability principles was used to identify, investigate, and mitigate infusion pump safety concerns at a large, multisite health care system. We developed a systematic approach to address challenges associated with overinfusions, underinfusions, and the inability to clear upstream occlusion alarms. We identified 112,875 upstream occlusion events for 389,604 infusion starts (failure rate, 29%) within 6 months. Methods: Five high-reliability principles were applied to infusion pump management. Preoccupation with failure emphasized reporting safety concerns and performing appropriate clinical and bench tests. Deference to expertise prompted the development of a multidisciplinary team with internal and external partners. Sensitivity to operations prompted assessment of human factors design, with simulations and analysis of medication-specific factors (e.g., viscosity; infusion rates). Reluctance to simplify prompted assessment of tubing characteristics (e.g., concentricity; wall thickness) with micro–computed tomography and process development for removing faulty equipment. Practice of resilience ensured ongoing engagement and commitment to a culture of safety and patient advocacy. Results: The multidisciplinary oversight team prompted a national recall, removal of malfunctioning pumps, and development of system-wide training and mitigation protocols. Despite ongoing pump challenges, our team optimized internal patient safety systems and processes. The cause of these malfunctions remains under investigation, but serious patient harm has been prevented. Conclusions: Key strategies for enhancing patient safety were continuous vigilance, interdisciplinary collaboration, and embracing complexity in a large health care organization. Future directions involve deeply integrating these high-reliability principles across all aspects of health care delivery to continue improving safety and quality outcomes.