Citations

Abstract Tau pathology emerges early in Alzheimer’s disease within entorhinal cortex layer II (ECII) and reaches hippocampal CA1, but how this circuit-level spread translates into sex-dependent vulnerability remains unclear. Using a circuit-defined model in which P301L human tau is expressed selectively in Wolframin-1 (Wfs1 + ) ECII neurons and propagates to CA1, we found that the extent and proximal–distal distribution of tau-positive CA1 neurons were comparable in males and females. Despite similar propagation, females exhibited broad hippocampal-dependent cognitive impairment (working memory, object recognition, fear acquisition, trace associative memory, and contextual fear memory), whereas males showed a selective deficit in trace associative memory. Consistent with these behavioral outcomes, CA1 pyramidal neurons in tau-propagated females displayed reduced excitability (slower action potential kinetics, reduced firing during depolarizing steps) and reduced spontaneous excitatory postsynaptic current (EPSC) amplitude, while males showed subtler intrinsic changes with altered EPSC kinetics. Bulk RNA sequencing of entorhinal cortex and CA1 revealed robust immune pathway engagement after tau propagation, with males showing a stronger Th1/Th2 and neuroinflammatory signature and CTLA4-associated signaling changes, whereas females showed prominent complement–phagosome pathway enrichment and a female-specific increase in Clec7a + microglia density in CA1. CD4 + T-cell infiltration into CA1 was detected in both sexes. Together, these results indicate that sex-specific neuroimmune programs, rather than differences in tau propagation load, shape CA1 electrophysiological dysfunction and the breadth of memory impairment following early entorhinal-to-hippocampal tau spread.

FRACTURE MRI demonstrated strong agreement with conventional radiography and CT in evaluating key bone tumor characteristics, including lesion type, location, and matrix content.

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.

Importance Treatment for cognitive dysfunction due to postacute sequelae of long COVID (ie, symptoms of fatigue, malaise, weakness, confusion that persist beyond 12 weeks after an initial COVID infection) remains a significant unmet need. Objective To test evidence-based rehabilitation strategies for improving cognitive symptoms in persons with long COVID. Design, Setting, and Participants This was a 5-arm, multicenter, randomized clinical trial of 3 remotely delivered interventions conducted between August 17, 2023, and June 10, 2024. The study took place at 22 trial sites and included the screening of individuals with cognitive long COVID. Interventions Participants were randomized to 1 of 5 arms: adaptive computerized cognitive training (BrainHQ [Posit Science]), cognitive-behavioral rehabilitation involving both group and individual counseling sessions (PASC-Cognitive Recovery [PASC-CoRE]) paired with BrainHQ, and transcranial direct current stimulation (tDCS) paired with BrainHQ. Two comparator arms were included as follows: unstructured computer puzzles and games (active comparator) and sham tDCS paired with BrainHQ. The interventions occurred 5 times per week over 10 weeks. Main Outcomes and Measures Cognitive and behavioral in-person assessments were performed at baseline, midintervention, at the end of intervention, and 3 months after the end of the intervention. The primary outcome measure was the modified Everyday Cognition Scale 2 (ECog2) completed at the end of the intervention compared to the baseline visit based on participant self-report looking back over the prior 7 days. Results A total of 378 individuals were screened, from which there were 328 participants (median [IQR] age, 48.0 [37.0-58.0] years; 241 female [73.5%]; race: 15 Asian [4.6%], 47 Black [14.3%], and 235 White [71.6%]; ethnicity: 52 Hispanic [15.9%]). None of the 3 active interventions demonstrated benefits on the modified ECog2 in the intention-to-treat population by the end of the intervention period. The adjusted differences in mean change were 0.0 (95% CI, −0.2 to 0.2) for BrainHQ vs active comparator, 0.1 (95% CI, −0.1 to 0.3) for PASC-CoRE + BrainHQ vs active comparator, 0.0 (95% CI, −0.2 to 0.2) for tDCS-active + BrainHQ vs tDCS-sham + BrainHQ, and 0.1 (95% CI, −0.1 to 0.3) for PASC-CoRE + BrainHQ vs BrainHQ alone. Secondary participant-reported outcomes and neuropsychological tests showed no differential benefits for any treatment arm. All 5 arms demonstrated some improvements over time on the modified ECog2 and on secondary outcomes. There were no serious adverse events attributable to the interventions. Conclusions and Relevance This phase 2 randomized clinical trial failed to demonstrate differential benefits for online cognitive training, a structured cognitive rehabilitation program, and tDCS for cognitive long COVID. Trial Registration ClinicalTrials.gov Identifier: NCT05965739 .

Abstract Objective: Electronic Health Record (EHR) data are critical for advancing translational research and AI technologies. The ENACT network offers access to structured EHR data across 57 CTSA hubs. However, substantial information is contained in clinical narratives, requiring natural language processing (NLP) for research. The ENACT NLP Working Group was formed to make NLP-derived clinical information accessible and queryable across the network. Methods: We established the ENACT NLP Working Group with 13 sites selected based on criteria including clinical notes access, IT infrastructure, NLP expertise, and institutional support. We divided sites into five focus groups targeting clinical tasks within disease contexts. Each focus group consisted of two development sites and two validation sites. We extended the ENACT ontology to standardize NLP-derived data and conducted multisite evaluations using the Open Health Natural Language Processing (OHNLP) Toolkit. Results: The working group achieved 100% site retention and deployed NLP infrastructure across all sites. We developed and validated NLP algorithms for rare disease phenotyping, social determinants of health, opioid use disorder, sleep phenotyping, and delirium phenotyping. Performance varied across sites (F1 scores 0.53–0.96), highlighting data heterogeneity impacts. We extended the ENACT common data model and ontology to incorporate NLP-derived data while maintaining Shared Health Research Informatics NEtwork (SHRINE) compatibility. Conclusion: This demonstrates feasibility of deploying NLP infrastructure across large, federated networks. The focus group approach proved more practical than general-purpose approaches. Key lessons include the challenge of data heterogeneity and importance of collaborative governance. This work also provides a foundation that other networks can build on to implement NLP capabilities for translational research.

Introduction: Robot-assisted radical prostatectomy (RARP) with extended pelvic lymph node dissection (PLND) represents the gold standard surgical treatment for high-risk localized prostate cancer. PLND carries the risk of lymphocele formation, which can lead to complications such as deep vein thrombosis (DVT), infection, and voiding dysfunction. Many techniques have been described to minimize lymphocele formation, yet no method has seen widespread use or been described as sutureless. The objective of this study is to describe the novel, sutureless peritoneal window (PWIN) technique and assess its efficacy in lymphocele prophylaxis for extended PLND. Methods: This was a retrospective review of patients with high-risk prostate cancer undergoing RARP with extended PLND by a single surgeon from 2018 to 2024. PLND was carried out in the usual manner with bipolar cautery. PWIN technique is performed by excising a 3 × 5 cm PWIN over the lymphadenectomy bed to maintain lymphatic communication with the abdominal cavity. The primary outcome was a comparison between the incidence of symptomatic lymphoceles (SLs) with PWIN vs standard technique. SLs were defined as lymphoceles presenting with pain, DVT, voiding dysfunction, or infectious symptoms. Patients with asymptomatic lymphoceles were excluded. Results: Our study included 199 patients who underwent RARP with extended PLND. There were 46 patients (23.1%) in the standard approach group and 153 patients (76.9%) in the PWIN group. We identified 5/46 (10.9%) SLs in the standard technique, which were significantly higher than the 3/153 (2.0%) observed in the PWIN group (p = 0.017). There was no difference between the standard and PWIN cohorts regarding symptomology or treatment of their lymphocele. Conclusion: This study describes a novel, sutureless PWIN technique that significantly decreases SL after extended PLND. This technique offers a practical, time-efficient, and cost-effective alternative for lymphocele prevention. Future prospective studies are warranted to validate these findings.