Citations

Abstract Parkinson’s disease (PD) is the fastest growing neurodegenerative disease in the world1. Gastrointestinal (GI) dysfunction can occur decades before motor impairments and in up to 80% of individuals living with PD2,3,4. We investigated peripheral relationships that may underlie environmental contributions to mechanisms along the gut-blood axis that contribute to PD pathogenesis. Single-cell multiomic spatial molecular imaging (SMI) of colonic tissue localized inflammatory injury within epithelial cells that appear to be associated with iron mishandling in both inflammatory bowel disease (IBD) and PD biosamples. We found that both the single-cell SMI of RNA and protein revealed parallel cross-modal dysregulation in the gut epithelium, in both IBD and PD biosamples. These data are accompanied by plasma (PD) and stool (IBD) protein depletion of CCL22. Our findings suggest iron mishandling along the gut barrier likely contributes to systemic inflammation, which may be the catalyst that primes circulating immune cells to body-first PD pathogenesis.

Empirical evidence suggests direct thrombin inhibitors (DTIs) produce more favorable hemostatic outcomes than heparin in patients supported by extracorporeal membrane oxygenation (ECMO), yet the exact mechanisms responsible are unknown. We systematically searched databases and registers for studies comparing DTIs to heparin in humans receiving ECMO. A total of 28 studies were identified, most of which (n = 25) used bivalirudin, while the rest (n = 3) used argatroban. In random-effects meta-analysis, DTIs achieved the therapeutic anticoagulation range faster (mean difference = −6.96 hours, 95% confidence interval [CI] = −11.98 to −1.95, p = 0.006) and maintained the therapeutic range for a greater proportion of time (mean difference = 18.6%, 95% CI = 8.78–28.42, p < 0.001) than heparin. Subgroup analysis revealed these effects were similarly significant in adult patients and when bivalirudin was the DTI; however, they were not significant in pediatric patients or when argatroban was the DTI. Sensitivity analysis confirmed robustness of the primary findings in only low-risk of bias studies and in only studies published as full papers. In summary, DTIs—specifically bivalirudin—were associated with faster time to therapeutic anticoagulation and maintained the goal range for a greater percentage of time than heparin during ECMO support.

Abstract Alcohol misuse among women has risen compared to men. Women experience barriers to engaging in patient-centered comparative effectiveness research (CER) that, in turn, limits the evidence base for addressing alcohol misuse in this population. In this manuscript, we describe WomenWise, a community-partnered project and outline how we co-developed community focused CER training curriculum and collaboratively planned future partnered learning sessions (PLSs) with Community Advisory Board (CAB) feedback. Through this approach we aim to empower women to contribute to future patient-centered CER and enhance the stakeholder capacity for future patient-centered research.

ABSTRACT 3‐hydroxy acylcarnitines (3‐OH‐ACs) are key biomarkers for screening of long‐chain 3‐hydroxyacyl‐CoA dehydrogenase and trifunctional protein deficiencies (LCHADD/TFPD). The utility of this biomarker for disease monitoring in identified patients remains debated, and recent suggestions have highlighted the potential use of lipidomics for diagnosis, monitoring, prognosis, and/or identification of new biomarkers. We evaluated the use of omics in LCHADD/TFPD patients by analyzing plasma acylcarnitine profiles, metabolomics, and lipidomics, combined with genotype, visual assessments, and dietary records. Fasting plasma from 39 participants with LCHADD/TFPD and 32 control subjects were analyzed through untargeted metabolomic and lipidomic analyses. In LCHADD/TFPD participants, acylcarnitine profiling, visual and retinal function assessments were performed, and 3‐day diet records were collected. Relationships between acylcarnitines, metabolomics, lipidomics, along with visual outcomes and dietary intake were investigated. Plasma of LCHADD/TFPD participants exhibited elevated 3‐OH‐ACs, which correlated with genotype and visual outcomes. Metabolomics successfully distinguished LCHADD/TFPD from controls, and the biggest divergence was observed in lipid pathways. Metabolomic profiles tightly correlated with 3‐OH‐ACs, genotype, and visual outcomes. Lower concentrations of total lipids and some individual lipid species such as phosphoethanolamines (PE) were detected in LCHADD/TFPD, except for elevations in several certain triglycerides. LCHADD/TFPD participants followed a diet low in long‐chain fat (LCFA) as recommended. LCFA intake did not correlate with either plasma 3‐OH‐ACs or metabolomics. 3‐OH‐ACs are strong consistent biomarkers of LCHADD/TFPD that are associated with clinical parameters of vision and genotype. We did not observe a relationship between dietary LCFA intake and 3‐OH‐ACs.

Study Design Retrospective cohort analysis. Objective (1) Develop a novel computed tomography (CT)-based assessment of endplate bone density (EP-HU), (2) Determine if EP-HU was a stronger predictor than trabecular HU for subsidence after transforaminal lumbar interbody fusion (TLIF). Methods All adult patients who underwent single-level TLIF for lumbar degenerative conditions at an academic center between 2017-2022 were retrospectively identified. EP-HU was calculated from a 2 mm superior and inferior endplate region on the preoperative mid sagittal CT scans, accounting for surface undulations. Lumbar vertebral HUs (trabecular region) were determined in a standard fashion on axial CT. EP-HU + vertebral HU served as an aggregate bone quality metric. Interbody subsidence (≥2 mm threshold) was directly measured on the endplate-facing surface of 1 year CT scans. Univariate and multivariate analysis compared subsidence based on CT bone metrics. Results A total of 114 patients met the inclusion/exclusion criteria. There was no significant difference in fusion or reoperation rate based on subsidence occurrence. Both vertebral HU ( P = .012) and EP-HU ( P < .001) were associated with subsidence. In receiver operating curves, EP-HU was more optimal for subsidence prediction than vertebral HU, but the aggregate metric further optimized the specificity and total area under the curve. In a predictive logistic regression model EP-HU + vertebral HU (aggregate HU < 515 odds ratio: 7.82, P < .001) was a strong independent predictor of subsidence. Conclusion Preoperative calculation of EP-HUs in addition to vertebral HUs may enhance prediction of TLIF subsidence where aggregate endplate and vertebral HU < 515 can be used to identify high risk patients.

Abstract Overall response (OR) that combines complete (CR) and partial responses (PR) is the conventional end point for acute graft-versus-host disease (GVHD) trials. Because PR includes heterogeneous clinical presentations, reclassifying PR could produce a better end point. Patients in the primary treatment cohort from the Japanese Society for Transplantation and Cellular Therapy (JSTCT) were randomly divided into training and validation sets. In the training set, a classification and regression tree algorithm generated day 28 refined response (RR) criteria based on symptoms at treatment and day 28. We then evaluated RR for primary and second-line treatments, using the area under the receiver operating characteristic curve (AUC) and negative predictive value (NPV) for 6-month nonrelapse mortality as performance measures. RR considered patients with grade 0/1 at day 28 without additional treatment as responders. RR for primary treatment produced higher AUCs than OR with small improvement of NPVs in both validation sets: JSTCT (AUC, 0.73 vs 0.69 [P &lt; .001]; NPV, 92.0% vs 89.6% [P &lt; .001]) and the Mount Sinai Acute GVHD International Consortium (MAGIC; AUC, 0.71 vs 0.68 [P = .032]; NPV, 90.9% vs 89.8% [P = .009]). RR for second-line treatment produced similar AUCs but much higher NPVs than OR in both validation sets of JSTCT (AUC, 0.64 vs 0.63 [P = .775]; NPV, 74.5% vs 66.0% [P &lt; .001]) and MAGIC (AUC, 0.67 vs 0.64 [P = .105]; NPV, 86.8% vs 76.1% [P = .004]). Classifying persistent but mild skin symptoms as responses and residual lower gastrointestinal GVHD as nonresponses were major drivers in improving the prognostic performance of RR. Our externally validated day 28 RR would serve as a better end point than conventional criteria in future first- and second-line treatment trials.

Pediatric central nervous system tumors are the leading cause of cancer-related deaths in children. The five-year survival rate for high-grade glioma in children is less than 20%. The development of new treatments is dependent upon multi-institutional collaborative clinical trials requiring reproducible and accurate centralized response assessment. We present the results of the BraTS-PEDs 2023 challenge, the first Brain Tumor Segmentation (BraTS) challenge focused on pediatric brain tumors. This challenge utilized data acquired from multiple international consortia dedicated to pediatric neuro-oncology and clinical trials. BraTS-PEDs 2023 aimed to evaluate volumetric segmentation algorithms for pediatric brain gliomas from magnetic resonance imaging using standardized quantitative performance evaluation metrics employed across the BraTS 2023 challenges. The top-performing AI approaches for pediatric tumor analysis included ensembles of nnU-Net and Swin UNETR, Auto3DSeg, or nnU-Net with a self-supervised framework. The BraTS-PEDs 2023 challenge fostered collaboration between clinicians (neuro-oncologists, neuroradiologists) and AI/imaging scientists, promoting faster data sharing and the development of automated volumetric analysis techniques. These advancements could significantly benefit clinical trials and improve the care of children with brain tumors.

Background Family participation in the delivery of nonpharmacological measures has shown in past studies to prevent 17-75% of incident delirium. A scalable and sustainable method to partner with family (i.e., care partners) and support their delivery of nonpharmacologic measures is needed. Objectives To test the feasibility, acceptability, and usability of iPREPARED in a pilot randomized controlled clinical trial (RCT). iPREPARED is a mobile health technology co-designed with patients and care partners containing resources on nonpharmacological interventions to prevent delirium. Methods Hospitalized adults ( > 65 years) with > 1 delirium risk factor and a care partner (family or friend > 18yo) willing to participate were enrolled. The primary outcomes were feasibility, acceptability, and usability. Descriptive statistics are reported. Results In total, 23 dyads completed the study (median age 72 years (IQR 64, 79), 60% male, and 100% Caucasian). Dyads reported that iPREPARED was acceptable, with moderate usability. Recruitment in the emergency department was feasible whereas recruitment once hospitalized and admitted was more difficult. Conclusion The study design was feasible. iPREPARED was acceptable and usable as an intervention.