Citations

Extracorporeal membrane oxygenation (ECMO) use during liver transplantation is a complex and evolving aspect of critical care. This retrospective analysis presents the largest North American case series to date, offering a detailed comparison of survival outcomes in liver transplant (LT) patients supported by ECMO. A total of 15 patients were supported with ECMO, eight were supported on venoarterial (VA) ECMO and the remaining seven on venovenous (VV) ECMO. The median duration of ECMO support was 10 days. Mean intensive care unit (ICU) and hospital stays were 34.8 (interquartile range [IQR]: 1–158) and 49.2 days (IQR: 1–121), respectively. Overall survival was 33.3%, comparable to published rates (20–30%). Survival was based on ECMO initiation timing: preoperative 33.3% (1/3); intraoperative 50% (3/6); postoperative, 16.6% (1/6). All the patients (five) discharged from hospital were alive at 1 year follow-up. Significant ECMO-related complications included acute kidney injury (AKI) requiring continuous renal replacement therapy (CRRT) (40%, n = 6/15), neurological complications (40%, n = 6/15), and bleeding requiring transfusion (26.6%, n = 4/15). Literature review suggests better outcomes with intraoperative or postoperative ECMO. While ECMO use is increasing in LT, outcomes remain poor. Improved survival may depend on careful patient selection, optimal timing of initiation, and distinguishing reversible pathology from irreversible one.

Background/Objectives: Erythromelalgia is a rare condition characterized by burning pain, redness, and warmth primarily in the extremities, usually worsened by heat and alleviated by cold. The objective of this study was to identify the top 10 priorities in pediatric erythromelalgia from multiple perspectives, including clinicians, people with lived experience of childhood-onset erythromelalgia, and their family members. Methods: A modified James Lind Alliance Priority-Setting Process was conducted. The top priorities were identified through four phases: (1) an international online survey to gather priorities, (2) data processing, (3) an interim prioritization online survey, and (4) a virtual workshop to set the final priorities. Results: In phase 1, 185 potential priorities were submitted by 74 respondents (53% patients, 24% family members, and 23% clinicians) that were developed into 68 unique research questions (phase 2). In phase 3, of the 68 questions, 50 were rated for importance by 58 participants (38% patients, 36% family members, and 26% clinicians), reducing the list to 25 questions. In phase 4, the top 10 was reached through consensus by 12 participants (33% patients, 25% family members, and 42% clinicians) across Canada, South Africa, the United States of America, and the United Kingdom. Conclusions: The final priorities focused on the treatment of erythromelalgia, understanding underlying mechanisms, the association of erythromelalgia with various body systems, and generating awareness. This list is the first international patient-centered research agenda for childhood-onset erythromelalgia and a call to action from key partners to improve future research and care.

Galactic cosmic ray (GCR) radiation is a major barrier to human space exploration beyond Earth’s magnetic field protection. Mesenchymal stem cells (MSCs) are found in all organs and play a critical role in repair and regeneration of tissue. We engineered bone marrow-derived MSCs and evaluated their response to ionizing radiation exposure. Epidermal growth factor receptor (EGFR) expression by certain types of cancers has been shown to induce radioresistance. In this study, we tested the feasibility of transfecting MSCs to overexpress EGFR (eMSC-EGFR) and their capacity to tolerate and recover from X-ray exposure. Quantitative real-time PCR (qRT-PCR) and immunoblotting results confirmed the efficient transfection of EGFR into MSCs and EGFR protein production. eMSC-EGFR maintained characteristics of human MSCs as outlined by the International Society for Cell & Gene Therapy. Then, engineered MSCs were exposed to various dose rates of X-ray (1–20 Gy) to assess the potential radioprotective role of EGFR overexpression in MSCs. Post-irradiation analysis included evaluation of morphology, cell proliferation, viability, tumorigenic potential, and DNA damage. eMSC-EGFR showed signs of radioresistance compared to naïve MSCs when assessing relative proliferation one week following exposure to 1–8 Gy X-rays, and significantly lower DNA damage content 24 h after exposure to 4 Gy. We establish for the first time the efficient generation of EGFR overexpressing MSCs as a model for enhancing the human body to tolerate and recover from moderate dose radiation injury in long-term manned space travel.

Background/Objectives: Muscle aging is a complex, dynamic process that impairs overall metabolism and physiological function. The molecular mechanisms underlying declines in muscle performance and metabolic efficiency remain poorly understood, largely due to the time and resource demands of traditional model organisms. The hawk moth Manduca sexta offers a promising alternative, with a short adult lifespan (~10 days) and notable similarities to vertebrate muscle systems, making it well-suited for time-course molecular dissection of muscle aging. Methods: In this study, we performed high-resolution temporal analysis of muscle tissues from aging M. sexta, spanning the physiomuscular aging process from middle age to advanced age. Results: We observed decreased expression of genes involved in fatty acid β-oxidation, ATP synthase subunits, superoxide dismutase, glutathione S-transferases, and heat shock proteins. In contrast, genes associated with proteolysis, catabolic processes, insulin signaling, akirin, titin, high-affinity choline transporters, and vesicular acetylcholine transporters were increased in expression. Conclusions: These changes suggest a shift toward increased proteolysis and protein catabolism with age. Our findings support the use of M. sexta as a complementary model for muscle aging research. However, it remains unclear whether the observed gene expression changes are driven by intrinsic, sex-specific age-related muscle aging or confounded by potential starvation effects in older males.

Retrieval-augmented generation (RAG) quality depends on how source documents are segmented before indexing; fixed-length chunks can split concepts or add noise, reducing precision. We evaluated whether proposition, semantic, and adaptive chunking improve accuracy and relevance for safer clinical decision support. Using a curated domain knowledge base with Gemini 1.0 Pro, we built four otherwise identical RAG pipelines that differed only in the chunking strategy: adaptive length, proposition, semantic, and a fixed token-dependent baseline. Thirty common postoperative rhinoplasty questions were submitted to each pipeline. Outcomes included medical accuracy and clinical relevance (3-point Likert scale) and retrieval precision, recall, and F1; group differences were tested with ANOVA and Tukey post hoc analyses. Adaptive chunking achieved the highest accuracy—87% (Likert 2.37 ± 0.72) versus baseline 50% (1.63 ± 0.72; p = 0.001)—and the highest relevance (93%, 2.90 ± 0.40). Retrieval metrics were strongest with adaptive (precision 0.50, recall 0.88, F1 0.64) versus baseline (0.17, 0.40, 0.24). Proposition and semantic strategies improved all metrics relative to baseline, though less than adaptive. Aligning chunks to logical topic boundaries yielded more accurate, relevant answers without modifying the language model, offering a model-agnostic, data-source-neutral lever to enhance the safety and utility of LLM-based clinical decision support.

Background Admixture mapping can be leveraged to identify genomic loci associated with disease traits in admixed individuals such as Hispanic Americans. Methods and Results We characterized fine‐scale population structure of participants (n=105 108) in the multiethnic eMERGE‐III (electronic Medical Records and Genomics) cohort, using reference panels from the 1000 Genomes Project and a Native American cohort. We defined “genetically admixed Hispanic Americans” as those having ≥10% Native American genetic ancestry (n=5025), in addition to European (specifically, Iberian) and African genetic ancestry. This population descriptor was subsequently applied to 3 other cohorts: the MESA (Multi‐Ethnic Study of Atherosclerosis; n=1176), WHI (Women’s Health Initiative; n=2873), and the HCHS/SOL (Hispanic Community Health Study/Study of Latinos; n=7804). We inferred local ancestry along the genome in genetically admixed Hispanic Americans in each cohort using RFMix2 with phased haplotypes from SHAPEIT2. Local ancestry proportions were used for admixture mapping of lipid traits (low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol, total cholesterol, and triglycerides) using extended linear mixed models that incorporated multiple or single ancestries. After accounting for fixed‐effect covariates and random effects, ancestry proportions at the following loci were associated with lipid traits in the HCHS/SOL cohort: 11q12.2 ( P =6.8×10 −7 ) with low‐density lipoprotein cholesterol, 2p23.3 ( P =5.2×10 −7 ) with total cholesterol, and 11q23.3 ( P =7.3×10 −12 ) with triglycerides. The LDL cholesterol and triglyceride loci replicated in at least one independent cohort, whereas the total cholesterol locus showed suggestive evidence for replication in the eMERGE cohort ( P =0.073). Native American (NAMR) ancestry appeared to drive the LDL‐C association, whereas both NAMR and Iberian population in Spain (IBS) ancestries contributed to the triglyceride signal. Conclusions Admixture mapping in genetically admixed Hispanic Americans identified genomic loci influencing lipid traits and the different ancestral origins driving these associations.

Background: Macromastia causes significant physical and psychological distress in adolescents. Although reduction mammaplasty alleviates these symptoms, the mental health impact of macromastia in younger populations remains underexplored. This systematic review and meta-analysis aimed to evaluate mental health and quality of life outcomes in adolescents/young women undergoing reduction mammaplasty. Methods: A systematic search of PubMed, Embase, and the Cochrane Central Register of Controlled Trials was conducted from inception to September 2024. Studies reporting mental health or quality of life outcomes through the BREAST-Q, Short Form-36, Rosenberg Self-Esteem Scale, and Eating Attitudes Test were included. Odds ratios and mean difference with 95% confidence intervals were pooled using a random-effects model. Heterogeneity was assessed with I 2 statistics. The Risk of Bias in Nonrandomized Studies of Interventions tool was used to assess study quality. Meta-analysis was performed on 4 BREAST-Q domains. Results: Of 701 articles identified, 8 observational studies involving 660 patients were included. Pooled BREAST-Q scores postsurgery showed significant improvements across all 4 domains. Improvement in Short Form-36, Rosenberg Self-Esteem Scale, and Eating Attitudes Test scores was noted in individual studies, though meta-analysis was limited by incomplete data. Conclusions: These results indicate that reduction mammaplasty significantly improves the physical, psychosocial, and sexual well-being of adolescents/young women with macromastia.

Background: Paroxysmal atrial fibrillation (AF) is a common arrhythmogenic complication in the intensive care unit (ICU) associated with significant costs and morbidity. AF detection models in the literature have utilized entropic analyses of telemetry to diagnose AF, but they have not been utilized to forecast its onset. Hypothesis: Deep learning techniques applied to high-frequency telemetry data can be utilized to forecast AF with clinically significant lead time. Methods: Telemetry data were collected from 72 ICU monitored beds in a tertiary care center from 4/2018-12/2023. Coefficient of sample entropy (COSEn), a metric of heart rate variability complexity, was calculated on successive 1-minute windows and utilized to identify areas of AF initiation as well as control windows without AF. ECG lead II (256Hz) and beat-to-beat (B2B) measurements were analyzed by the MOMENT time-series foundational model to generate representation embeddings. A binary classification multilayer perceptron (MLP) was trained on these embeddings to forecast AF onset 5m in advance. All results were reported on separate test sets. Group-based trajectory modelling (GBTM) was performed on risk score trajectories from the 20m before AF onset or absence. Results: Over 230,000 hours of B2B data from 2263 patients was analyzed using COSEn to identify 287 transitions to AF from 136 patients. The same number of AF-absent windows were randomly selected. COSEn alone as a forecaster produced an area under the receiver operating characteristic curve (AUC) of 0.65 (95% CI: 0.61-0.69). The MOMENT + MLP model (MMM) achieved an AUC of 0.81 (0.78-0.83) (Fig. 1). COSEn and MMM were subsequently applied to the two hours preceding AF onset or absence. For COSEn, the mean risk trajectory dipped in the baseline period whereas the MMM risk trajectory sustained a high level through the baseline, highlighting its capacity to forecast AF (Fig. 2). For AF patients, GBMT yielded two types of trajectories: one with elevated risk throughout, and another with a rising trend 5 minutes prior to AF onset (Fig. 3). Conclusions: Deep learning techniques can forecast the onset of AF with up to 5 minutes of lead-time and GBTM allowed for the identification of different pre-AF risk trajectory phenotypes.The ability to forecast AF onset has potential to clinically prevent poor outcomes in the ICU, though further refinements to augment the amount of lead time are warranted.

Background: Inclisiran, a small interfering RNA (siRNA), inhibits hepatic PCSK9 synthesis, leading to significant LDL-C reduction. Previous meta-analyses have addressed short-term efficacy; however, recent long-term data warranted an updated systematic review and meta-analysis to evaluate inclisiran’s lipid-lowering efficacy and safety in hyperlipidemic patients. Methods: A systematic search of PubMed, Embase, Cochrane Library, and ClinicalTrials.gov was conducted from inception to April 2025 to identify randomized controlled trials (RCTs) comparing inclisiran with placebo or standard care in adults with hypercholesterolemia. Primary efficacy outcomes included percentage change in LDL-C, PCSK9, total cholesterol, apolipoprotein B (apo-B), and non-HDL-C. Safety outcomes included adverse events, cardiovascular events, and all-cause mortality. Data were analyzed using a random-effects model following PRISMA guidelines. Risk ratios (RR) and weighted mean differences (WMD) were calculated with 95% confidence intervals. The protocol was registered on PROSPERO (CRD420251059229). Results: Eleven RCTs with 5,601 patients were included; 3,135 received inclisiran and 2,466 received placebo. Inclisiran significantly reduced: LDL-C (WMD –48.99%, 95% CI: –54.29 to –43.69) PCSK9 (WMD –78.52%, 95% CI: –81.52 to –75.51) Total cholesterol (WMD –31.21%, 95% CI: –33.47 to –28.56) Apo-B (WMD –40.09%, 95% CI: –43.43 to –36.75) Non-HDL-C (WMD –35.22%, 95% CI: –41.25 to –29.20) Inclisiran showed no significant impact on all-cause mortality (RR 0.94; p=0.83), cardiovascular mortality (RR 1.19; p=0.60), myocardial infarction (RR 0.85; p=0.60), stroke (RR 0.89; p=0.86), or major adverse cardiovascular events (RR 0.80; p=0.07). Total adverse events were slightly higher with inclisiran (RR 1.06; p=0.02), but serious adverse events were not significantly different (RR 0.90; p=0.36). Injection site reactions were more common with inclisiran (RR 6.45; p<0.001). Conclusion: Inclisiran significantly reduces LDL-C, PCSK9, total cholesterol, apo-B, and non-HDL-C, confirming strong lipid-lowering efficacy. It is generally well tolerated, with a slightly higher incidence of mild injection site reactions but no increase in serious adverse events. Longer-term studies are needed to assess its effect on cardiovascular outcomes.

Background: The arteriovenous fistula (AVF) is a requirement for hemodialysis therapy in end-stage kidney disease (ESKD) patients. A consequence of AVF creation is compensatory cardiovascular hemodynamics, which are subsequently associated with cardiac remodeling. Relatedly, cardiovascular mortality and morbidity are elevated in ESKD patients, which worsens in dialysis patients. Currently, no suitable uremic large animal models exist to investigate the underlying mechanisms of AVF-induced cardiac remodeling. Research Question: This study aims to characterize cardiovascular changes secondary to AVF creation, supported by percutaneous transluminal angioplasty (PTA), in a uremic pig model. Methods: Chronic kidney disease (CKD) was induced via renal embolization, followed by AVF creation 28 days later. The AVF was created by anastomosis of the left common carotid artery to the left external jugular vein. AVF stenosis was alleviated 28 days thereafter via PTA, and cardiac MRI was performed at 14-, 28-, and 42-days post-PTA. Results: Increased end-diastolic volumes were observed in the left and right ventricles at day 42 vs 14 (200.8ml to 249.5ml, p=0.0457, and 204.6ml to 260.0ml, p=0.0268 respectively), while systolic function was preserved. Left ventricle (LV) stroke volume and blood flow through the aorta, pulmonary artery, and vena cava were also increased. In perivascular areas of the free wall of the LV at day 42 vs control, senescence markers showed increased p16 expression (fold change 10.21, p=0.0086) and decreased p21 expression (fold change 0.07, p=0.0357). The LV showed perivascular fibrosis (0.2% to 0.59%, p=0.021), via picrosirius red, reduced collagen-type IV expression (fold change 0.81, p=0.0089), and increased MMP2 levels (fold change 14.33, p=0.0213). Cardiomyocyte cross-sectional area was increased (from 800.9 µm 2 to 1250.0 µm 2 , p=0.0296), without CD4+ or CD68+ cell LV infiltration. Conclusion: In conclusion, AVF creation leads to modified left and right ventricular function and increased peripheral flow, potentially mediated by cellular senescence and fibrosis, resulting in progressive cardiac remodeling. This model of uremic kidney disease can now be used to evaluate mechanisms of AVF induced cardiac disease and test the efficacy of therapeutics like senolytics and anti-fibrotic agents.