Citations

Abstract Background Relapsed medulloblastoma remains a significant therapeutic challenge as it is near universally fatal. The tumor microenvironment of medulloblastoma plays a critical role in tumor progression, influencing tumor growth, immune evasion, and therapeutic resistance. We hypothesized that defining tumor-immune interactions in diagnostic and relapsed medulloblastoma may uncover mechanisms of immune evasion and identify novel therapeutic targets. Methods We analyzed paired primary and recurrent RNA-sequencing data from 140 medulloblastoma patients to profile immune cell composition and validate spatial relationships within the TME. To identify key tumor-immune interactions, we developed a novel algorithm to detect receptor-ligand pairs using single-cell RNA-sequencing data. These interactions were validated across RNA and proteomic datasets. Their functional significance was empirically demonstrated in newly developed immunocompetent models of recurrent medulloblastoma that closely recapitulate the human disease. Results We observed a shift toward a heightened immunosuppressive TME at relapse. Using our algorithm, we identified biologically significant receptor-ligand interactions, most notably MIF-CD74, constitutively expressed at RNA and protein levels across medulloblastoma subgroups, at diagnosis and relapse. Disrupting MIF-CD74 interactions led to significant alterations in the tumor microenvironment, highlighting its functional significance. Conclusions Our multifaceted approach identified key tumor-immune interactions in medulloblastoma. Among these, MIF-CD74 was validated as a targetable interaction, demonstrating the utility of our integrative approach for identifying novel therapeutic targets across multiple tumor types.

Abstract Background Right ventricular (RV) systolic function is an independent predictor of outcome, but a robust automated method of quantitation is lacking. Purpose To develop and validate a deep learning model for quantifying RV systolic function from 2D echo clips and assess its prognostic value in various loading states and left-heart disease. Methods A deep learning convolutional neural network (CNN) was developed to quantitate RV systolic function using all available apical 4 chamber (A4C) views from 13,039 patients (61,187 A4C video clips) in a US institution. Videos were converted to frames of 256x256 grayscale pixels, with graphics, including the ECG, removed. The model used the S3D architecture, a 3D-CNN with many of the spatial and temporal convolutions separated. RV free wall longitudinal strain (RVFWLS) was used to define RV function: normal (≤-25%); mild (-20% to –24%); moderate (-15% to –19%) and severe RV dysfunction (0% to –14%). The AI-estimate was the average of multiple 32-frame segments for each clip identified as an A4C, including both standard and RV-focused variations. The model was validated in four distinct clinical cohorts from independent data sources: 1) 1365 patients referred to an external diagnostic echocardiography lab in a different US state; 2) 569 patients recruited prospectively with known or suspected pulmonary hypertension (PH); 3) 416 patients with moderate or greater tricuspid valve regurgitation (TR); 4) 872 patients imaged at an Eastern European University with left-sided cardiac diseases (valvular disease, cardiomyopathies, etc.), athletes, or healthy volunteers. Results Model output was strongly correlated with the presence of RV dysfunction by manual measurement [AUC 0.907 (95% CI: 0.888-0.926)] in the internal validation set. Results were similar in an external validation US cohort [N=1365; AUC 0.919 (95% CI: 0.899-0.939)]. When the model was applied to 569 patients with known or suspected PH, presence and severity of the AI measures of RV dysfunction were strongly associated with functional class, 6 min walk distance, NT-proBNP levels and right heart failure (p<0.001). The presence and severity of RV dysfunction (as categorized by the AI model) was strongly associated with all-cause mortality in patients with PH (Figure 1A) and in patients with significant TR (Figure 1B). The European cohort was a geographically and institutionally distinct cohort with a low prevalence of >mild TR (10.8%) or PH (6.4%). In this cohort the AI model predicted a reduced RVEF (< 45%) with an AUC of 0.864 (95% CI: 0.831-0.898) and associated with both all-cause mortality (Figure 2A) and a composite endpoint of heart failure hospitalization or death (Figure 2B). Conclusions A fully automated, AI-based assessment of RV systolic function, using 2D apical 4 chamber echo views alone, is highly feasible and can accurately categorize disease severity and predict outcome across a wide spectrum of cardiovascular conditions.Figure 1 Figure 2

Background While delivery of supplemental oxygen is a life-saving therapy, exposure to high oxygen, called hyperoxia, leads to increased intensive care unit mortality. Hyperoxia induces oxidant-mediated acute lung injury (ALI) and pulmonary cell death, called hyperoxic ALI (HALI). Elucidating molecular mechanisms in HALI could identify therapeutic targets in ALI. Methods In the current study, we examined in vivo effects of HALI on Beclin-1 (BCN1), which regulates autophagy, and modulation of BCN1 by epidermal growth factor receptor (EGFR). Effects of HALI on BCN1 and autophagy were examined in mice with genetically decreased EGFR (EGFR Wa5/+ ). Wildtype (WT) and EGFR Wa5/+ mice were exposed to 100% oxygen for 24–72 hours along with normoxia controls (eight groups; n=4–6/group), and analysis of pulmonary BCN1 and autophagy was completed. Results In WT, HALI led to increased BCN1 (59% increased total BCN1/β-Actin; p<0.01) in lung and alveolar epithelium (484% increased H-score; p<0.001). HALI led to decreased microtubule-associated protein 1B-light chain (LC3B)-II/-I ratios (43% decrease; p<0.05) and increased p62 (93% increase; p<0.05), suggesting reduced autophagic flux. In human alveolar type-II cells derived from induced pluripotent stem cells (AT2s iPSC ), HALI caused increased LDH release (130% increase; p<0.0001) and decreased LC3B-II/-I ratios (32% decrease; p<0.05). We previously showed that EGFR Wa5/+ mice are protected in HALI. In the current study, EGFR Wa5/+ mice showed increased pulmonary BCN1 (122% increase; p<0.05), reduced phosphorylated-(p-)/total BCN1 (47% decrease; p<0.05) and decreased LC3B-II/-I ratios (70% decrease; p<0.01) in HALI compared with WT. In addition, wortmannin (1 mg/kg), which decreases BCN1-mediated autophagy, increased mortality in HALI compared with vehicle control (n=10/group; 18% decreased hours survived; p<0.001). Conclusions These data delineate a novel cell death pathway in HALI involving BCN1 and EGFR with therapeutic potential.

Background: Simultaneous carpal tunnel release (sCTR) with emergent forearm fasciotomy in the setting of acute compartment syndrome (ACS) has been reported, but the national incidence and cost of delayed carpal tunnel release (CTR) remain unknown. This large database study aims to evaluate how often sCTR is performed, the frequency of delayed CTR when not performed simultaneously, and the associated costs. Methods: The PearlDiver Mariner database was queried for patients who underwent forearm fasciotomies between January 1, 2015, and October 31, 2022. Patients were grouped based on CTR timing: simultaneous, within 2 weeks, 2 weeks to 1 year, 1 to 5 years, or no CTR. Reimbursement data were collected, and patient numbers and costs were analyzed across cohorts. Results: More than half of patients undergoing emergent forearm fasciotomy received sCTR. Among those who did not, 31% required CTR within 1 year and 35% within 5 years. The total cost was highest when CTR was performed within 1 year but not on the same day as fasciotomy. After 1 year, the additional cost of CTR was similar to that of patients who never underwent fasciotomy. Conclusions: This large database study shows that over one-third of patients who did not undergo sCTR at the time of emergent forearm fasciotomy required it within 1 year, incurring significantly higher costs. Including sCTR during initial fasciotomy may reduce delayed care and associated expenses. While these findings suggest that including sCTR during initial fasciotomy may reduce delayed care and expenses, the retrospective design precludes definitive recommendations, and clinical judgment remains essential Level of Evidence: 4

OBJECTIVE: Volatile anesthetics (VAs) are gaining renewed interest as a sedation strategy in the intensive care, offering an alternative to traditional IV agents. VAs provide several pharmacologic advantages, including rapid onset and offset, minimal systemic metabolism, and favorable recovery profiles. Advances in delivery systems enabled the safe and practical administration of volatile agents in the ICU. Thus, we aimed to describe the pharmacology and safety aspects of inhaled agents as well as the systems designed to deliver VAs in the ICU. DATA SOURCES: Relevant literature was identified through PubMed and MEDLINE databases. STUDY SELECTION: Original research, review articles, commentaries, and guidelines addressing safety, efficacy, and use of VAs in adult ICU patients were included. DATA EXTRACTION: Studies were reviewed by the authors, with key findings summarized and organized by pharmacologic properties, delivery systems, and safety domains. DATA SYNTHESIS: VAs are halogenated hydrocarbons whose mechanism of action is not fully understood. Although the CNS is the primary site of action, the end-tidal concentration of exhaled anesthetic is used to monitor clinical effects such as immobility to a noxious stimulus. Inhaled agents have unique pharmacokinetics, minimal metabolisms, and distinct recovery. The side effect profile is also unique, with malignant hyperthermia being the most feared, yet rare complication. Two systems for inhalational sedation delivery are available internationally, with one currently under evaluation in the United States. The systems are composed of a miniature vaporizer, delivery controller, and a monitor. The systems have distinct safety considerations, such as tidal volume limits. CONCLUSIONS: VAs can be used as sedative agents in the ICU. This article comprehensively reviews the pharmacology of VAs along with their safety profile and describes the structure and function of miniature vaporizers currently available on the world market.

ABSTRACT Background The COVID‐19 pandemic presented unprecedented challenges to hospital system and critical care resources, leading to significant changes to operations and patient care. There are limited national data on these changes and instances of unsanctioned deviations from patient care, yet understanding the COVID response is key to future preparedness efforts. We sought to understand how hospitals and states navigated scarcity during COVID‐19, particularly in the absence of a declaration of crisis standards of care. Methods Between February 2022 and September 2022 we conducted 34 interviews with 36 leaders of U.S. states' COVID‐19 planning and response efforts. Interviews were transcribed verbatim and verified. We analyzed interviews using iterative inductive thematic analysis for descriptions of resource scarcity and changes to policies and procedures to prevent rationing lifesaving care. Results Nearly all participants described equipment and personnel scarcity in their home institution or state during COVID‐19. Hospitals across regions and states developed formal and informal coordination processes for load and resource sharing in response to influxes of high‐acuity patients, avoiding formal rationing of lifesaving resources in many regions. Participants also described unsanctioned patient triage, early discharge, and patients counseled to accept less aggressive care (e.g., premature transition to hospice) in states that had not declared crisis standards of care. Conclusions Extending limited resources and inter‐institutional collaboration helped avoid formal rationing. Yet, patient care was unquestionably impacted due to scarcity, both real and perceived. Reports of using hospital triage protocols to deny patients lifesaving care outside of formally recognized crisis conditions and attempts to nudge patients to accept less‐resource‐intensive care are concerning. This may have had disproportionate effects on older adults, individuals with disabilities, and racial and ethnic minoritized groups. To avoid unsanctioned deviations from standard practice in future health emergencies, we recommend that transparent and equitable triage protocols are implemented with robust oversight.

Individuals with congenital heart disease are living well into adulthood, resulting in a growing population at risk for neurocognitive and psychosocial challenges. Numerous studies have described these risks in childhood, but significant gaps remain in our understanding of how those challenges evolve across stages of adulthood and how to optimally integrate neurocognitive and psychosocial care for adults with congenital heart disease. A multidisciplinary group of experts and patient partners assembled in April 2024 in Atlanta, GA, forming 3 working groups: (1) Genetics and Brain Health, (2) Characterizing Neuropsychological and Psychological Outcomes, and (3) Neuropsychological and Psychosocial Interventions. Current knowledge was reviewed, knowledge gaps were identified, and recommendations to address these gaps were formulated. Five critical questions regarding the characterization of neuropsychological and psychological outcomes of adults with congenital heart disease were prioritized for discussion: which neurocognitive and psychosocial domains should be prioritized in research and clinical care, what are the trajectories of neurocognitive and psychosocial functioning over the lifespan, how should neurocognitive and psychosocial screening be deployed, what should neurocognitive and psychosocial assessments include, and how do we make comprehensive neurocognitive and psychosocial care a reality. Although many gaps in knowledge were identified, particularly around characterizing neurocognitive trajectories throughout adulthood, there is substantial evidence of increased risk for poor psychosocial outcomes among adults with with congenital heart disease. Clinical and research advances must progress in tandem to address these risks. Specific recommendations for advancing this field over the next decade are offered.

Abstract INTRODUCTION The genetic basis of sporadic early‐onset Alzheimer's disease (EOAD) remains largely unknown, prompting evaluation of late‐onset Alzheimer's disease (LOAD) polygenic risk in EOAD. METHODS A LOAD polygenic score (PGS) was calculated in the Longitudinal Early‐onset Alzheimer's Disease Study (LEADS) and Alzheimer's Disease Neuroimaging Initiative (ADNI) study and tested for associations with AD risk, cognitive performance, and imaging and fluid biomarkers. RESULTS Though PGS was elevated in LOAD and EOAD, it was not a significant predictor of EOAD adjusting for APOE ε4 carrier status and was not associated with age of EOAD onset ( p = 0.106) or with cognitive performance ( p = 0.417). In LEADS, greater LOAD PGS was associated with differences in neuroimaging and fluid biomarkers, including elevated synaptosomal‐associated protein 25 (SNAP‐25) ( p = 2.3 × 10 −5 ). DISCUSSION While LOAD polygenic risk contributed minimally to EOAD onset and cognitive dysfunction, PGS association with fluid biomarkers in LEADS suggests a role for LOAD polygenic risk in EOAD pathophysiology. Highlights LOAD PGSs were elevated in both LOAD and EOAD compared to controls; however, LOAD PGS did not significantly predict EOAD risk, age at onset, or cognitive performance independent of APOE ε4 in the LEADS. Higher LOAD PGS was associated with lower amyloid PET Centiloids (less brain amyloid deposition) as well as lower CSF biomarker Aβ42 in LEADS (proxy marker suggesting higher brain amyloid deposition) in LEADS; these contradictory findings support the need for larger studies to further investigate whether LOAD PGS is associated with increased amyloid deposition in EOAD. Higher LOAD PGS was also associated with higher levels of CSF synaptosomal‐associated protein 25 (SNAP‐25), a key component of the SNARE complex, suggesting that LOAD genetic factors may contribute to dysregulation of synaptic transmission and/or pathological protein aggregation in EOAD.

ABSTRACT This study investigated the association between induction type and long‐term outcomes in kidney retransplant recipients who experienced graft loss due to BK virus–associated nephropathy (BKVAN). Using Scientific Registry of Transplant Recipients data (2003–2021), we identified 277 adult kidney‐alone retransplant recipients with BKVAN‐related graft loss and categorized them by induction regimen: depletional ( n = 217) and nondepletional ( n = 60). The groups were similar overall, except the nondepletional cohort had lower panel‐reactive antibodies, a shorter time between transplants, and more live donor kidneys. Kaplan–Meier curves assessed 10‐year recipient and graft survival, and Cox proportional hazards models, adjusted for key donor and recipient factors, evaluated associations between induction type and outcomes. Rates of delayed graft function, one‐year rejection, and estimated glomerular filtration rate were comparable between groups. Ten‐year recipient and death‐censored graft survival did not differ by induction type (recipient survival: HR 1.09; 95% CI 0.43–2.77; p = 0.85; graft survival: HR 0.85; 95% CI 0.24–2.97; p = 0.79). Recurrent BKVAN‐related graft failure occurred only in the depletional group (5 of 217; 2.3%), while rejection‐related graft failure was more common in the nondepletional group (5 of 60; 8.3% vs. 6 of 217; 2.8%). Although these differences did not translate into long‐term graft survival disparities, they highlight the competing risks of viral recurrence and rejection. Thus, clinicians should interpret these results with caution and weigh the risks and benefits of induction choice in retransplant recipients with prior BKVAN, recognizing that this observational study cannot establish causality.