Citations

AbstractBackgroundLate‐Onset Alzheimer’s Disease (LOAD) is characterized by genetic heterogeneity and there is no single model explaining the genetic mode of inheritance. To date, more than 70 genetic loci associated with AD have been identified but they explain only a small proportion of AD heritability. Structural variants (SVs) may explain some of the missing AD heritability, and specifically, their segregation in AD families has yet to be investigated.MethodWe analyzed WGS data from 197 NHW families (926 subjects, 58.5% affected) and 214 CH families (1,340 subjects, 59.17% affected). Manta, Absinthe, and MELT were used for large insertions/deletions calling from short‐read WGS, combined with Sniffles2 calls from 4 ONT‐sequenced genomes and an external SV call set from HGSVC on 32 PacBio‐sequenced genomes from the 1000 Genomes Project. Genotyping produced a unified project‐level VCF. We identified 45,251 insertions and 76,566 deletions genome‐wide. Variants were tested for segregation and pathogenicity using Annot‐SV, cadd‐SV, and Variant Effect Predictor. Segregation required SV presence in all affected family members and only in unaffected members five years younger than average disease onset.ResultWe identified 453 insertions and 598 deletions segregating in 78.68% and 87.31% of NHW families, respectively. In CH families, 432 insertions and 460 deletions were segregating in 75.23% and 72.90% of the families, respectively. Genes overlapping with the SVs exhibited high expression levels in brain tissues. Notably, around 93% of insertions and 76% of deletions segregating in NHW and CH families were less than 1 kilobase pair (1kbp) in length. A total of 79 insertions and 96 deletions were found to be segregating in both NHW and CH families. Interestingly, a segregating insertion was observed in CH families overlapping within the CACNA2D3 gene, which was previously reported in a CH GWAS for clinical AD. A deletion segregating in NHW overlapped with the PSEN1, and another in a CH family overlapped with the PTK2B gene.ConclusionOur findings suggested that there are several SVs associated with familial AD across CH and NHW families. Prioritizing the SVs based on their effects on gene function and expression will be helpful in understanding their contributions in AD.

Abstract Context Point-of-care ultrasound (POCUS) has diverse applications across various clinical specialties, serving as an adjunct to clinical findings and as a tool for increasing the quality of patient care. Owing to its multifunctionality, a growing number of medical schools are increasingly incorporating POCUS training into their curriculum, some offering hands-on training during the first 2 years of didactics and others utilizing a longitudinal exposure model integrated into all 4 years of medical school education. Midwestern University Arizona College of Osteopathic Medicine (MWU-AZCOM) adopted a 4-year longitudinal approach to include POCUS education in 2017. There is a small body of published research supporting this educational model, but there is not much data regarding how this approach with ultrasound curriculum translates to real-world changes in POCUS use by graduate student clinicians having received this model of education. Objectives The objectives of this study are to determine the frequency of POCUS use by MWU-AZCOM graduates and to assess how a 4-year longitudinal ultrasound curriculum may enhance the abilities of MWU-AZCOM graduates to perform and interpret ultrasound imaging in specific residency programs. Methods The study was approved by the MWU Institutional Review Board (#IRBAZ-5169, approval date October 3, 2022). An anonymous novel 12-question survey was conducted utilizing Research Electronic Data Capture (REDCap), a secure online platform, and distributed to MWU-AZCOM 2021 and 2022 graduates via email. Survey questions were aimed at assessing frequency of use, utilization of different imaging modalities, reasons for utilizing POCUS, barriers/enablers to utilizing POCUS, ultrasound training, and confidence in performing scans and interpreting POCUS imaging. All of the 104 surveys returned were included in the study. Statistical software R version 4.3 was utilized to conduct statistical analyses. Results Of the 484 surveys distributed, 104 were completed (21.5 % response rate). Responses came from residents working in 14 different specialties, 50 in primary care and 54 in nonprimary care. Of all respondents, 85.6 % currently utilize POCUS in their practice on at least a monthly basis and 77.0 % believe that their POCUS training in medical school enriches their current practice in residency. The top five modalities utilized by residents were procedures (89.9 %), cardiac (88.8 %), pulmonary (82.0 %), Focused Assessment with Sonography for Trauma (FAST, 73.0 %), and vascular (71.9 %). Respondents recognized POCUS as a beneficial diagnostic tool (97.8 %) and reported enhancements in physical examination skills (58.4 %) and professional growth (61.8 %). Facilitators for POCUS adoption included cost-effectiveness (82.0 %), diagnostic differentiation (78.7 %), and safety (79.8 %). Barriers included a lack of trained faculty (27.9 %), absence of necessary equipment (26.9 %), and cost of equipment (22.1 %). Participants demonstrated high confidence levels in performing (74.0 %) and interpreting (76.0 %) POCUS, with 43.3 % believing that their POCUS training enhanced their attractiveness as residency candidates. Conclusions This study supports the positive impact of a 4-year longitudinal POCUS curriculum on graduates’ practice. It emphasizes the link between MWU-AZCOM’s curriculum and real-world clinical needs. Addressing identified barriers and advancing hands-on training can further enhance POCUS understanding, ensuring that future physicians are well-prepared to leverage its diagnostic potential across medical specialties.

AbstractBackgroundTauopathies are a group of neurodegenerative disorders which are characterized by the accumulation of abnormal tau protein in the brain. However, the mechanistic understanding of pathogenic tau formation and spread within the brain remains elusive. Astrocytes are major immune reactive cells in the brain and have been implicated in exacerbating tau pathology by releasing extracellular vesicles (AEVs) containing pro‐inflammatory cytokines and chemokines upon activation. Our prior investigation revealed a significant association between AEVs and tau pathology development, as well as cognitive function, by analyzing brain‐derived EV proteins from AD patients. In this study, we explore the potential roles of AEVs in tau pathogenesis using a human induced pluripotent stem cell (iPSC) model.MethodWe obtained two male P301L tau mutant iPSC lines from a Polish family with frontotemporal dementia. By including two male control lines, these iPSCs were differentiated into astrocytes (iAs) and characterized by immunocytochemistry and subjected for bulk RNAseq. Bioinformatics analysis was conducted to compare the transcriptome profile between wild‐type (WT) and P301L iAs. EVs from WT and P301L iAs were isolated by ultracentrifugation combined with size exclusion chromatography. Characterization of WT and P301L iAEVs involved nanoparticle tracking analysis, nano‐flow cytometry and super‐resolution microscopy.ResultWe successfully differentiated WT and P301L mutant iPSC lines into astrocytes with >99% purity. P301L iAs displayed distinctive astrocyte reactivity compared to WT cells, with elevated levels of pan‐reactive astrocyte genes (e.g., GFAP, CD44) and decreased expression of neuroprotective A2 astrocyte‐specific genes (e.g., TM4SF1, PTGS2). Additionally, gene enrichment set analysis of RNAseq data revealed dysregulation in the endo‐lysosomal pathway and extracellular matrix in P301L iAs compared to WT iAs. The count of intraluminal vesicles marked by CD9+ were reduced in P301L iAs compared to WT cells. Moreover, we observed a significant increase in the internalization of Tau by P301L iAs compared to WT iAs following incubation with preformed Tau fibrils, resulting in an augmented release of tau‐containing EVs from P301L iAs.ConclusionOur findings suggest a potential alteration in EV biogenesis in P301L iAs, potentially contributing to astrocyte‐mediated tau pathology. Future investigations will focus on understanding how AEVs contribute to tau propagation and accumulation.

Abstract Aging is associated with intestinal dysbiosis, a condition characterized by diminished microbial biodiversity and inflammation. This leads to increased vulnerability to extraintestinal manifestations such as autoimmune, metabolic, and neurodegenerative conditions and accelerates mortality. As such, modulation of the gut microbiome is a promising way to extend healthspan. In this study, we explore the effects of fecal microbiota transplant (FMT) from long-living Ames dwarf donors to their normal littermates, and vice versa, on the recipient gut microbiota and liver transcriptome. Importantly, our previous studies highlight differences between the microbiomes of Ames dwarf relative to their normal siblings, potentially contributing to their extended lifespan and healthspan. Our findings demonstrate that FMT from Ames dwarf mice to normal mice significantly alters the recipient’s gut microbiota, reprograms bacterial metabolic functions related to healthy aging, and changes the liver transcriptome, indicating improved metabolic health. Our liver mRNA sequencing and RT-PCR validation reveals that FMT in normal recipient animals administered dwarf donor stool may contribute to the significant downregulation of p21, Elovl3, and Insig2, genes involved with cellular senescence and liver metabolic pathways. Our data suggest a regulatory axis exists between the gut and liver, highlighting the potential of microbiome-targeted therapies in promoting healthy aging. Future research should validate these findings and study the underlying mechanisms that confer geroprotection.

Objective: To retrospectively analyze publicly available elbow ulnar collateral ligament reconstruction (UCLR) injury data for professional baseball players. Design: Descriptive epidemiology study. Setting: A retrospective analysis using an open-source database was performed. The database contained all known UCLR surgeries among Major League Baseball (MLB) and Minor League Baseball (MiLB) players. Participants: In total, 1801 professional male professional baseball pitchers (age: 24.5 ± 3.9 years) who have undergone UCLR between 1974 and 2024. Main Outcome Measures: The number of UCLR procedures each year. Independent Variables: Change-point analysis was used to identify changes in the number of UCLR surgeries over time among MLB and MiLB players. For MLB players, number of UCLR surgeries from 1974 to 2023 was analyzed, while for MiLB players, data starting from 1981 to 2024 were analyzed. Results: For MLB players, 3 change points were identified, occurring around 1989 (95% confidence interval [CI], 1988–1990), 2000 (95% CI, 2000–2000), and 2012 (95% CI, 2011–2017). For MiLB players, 3 change points were identified occurring around 2001 (95% CI, 2001–2001), 2009 (95% CI, 2008–2010), and 2013 (95% CI, 2013–2015). Conclusions: Overall, there has been a rise in the number of UCLR surgeries per year for the past 50 years in professional baseball, with distinct time points identified, representing increases in the number of UCLR surgeries each year. A higher number of UCLR surgeries are performed per year in the MiLB than in the MLB.

Since the dawn of humanity, human beings have inherently sought a state of security, trying to make their existence as comfortable as possible. Accordingly, among the many factors affecting human health, comfort and well-being, the quality of the micro-environment and ecology, as well as the health care system and health-saving resources, are important. In this regard, environmental security, with its systemic nature, brings a significant contribution to the PPM model by optimizing the state of balance in the interrelationship of natural, anthropogenic, physiological and social processes. Accordingly, individualized nutrition and pharmacointervention for preventive and prophylactic purposes, being important tools for health preservation, represent an integrative approach aimed at understanding the interaction between nutrition and the environment within the formed or formed lifestyle. This review will consider the main components of human health protection, as well as their impact on the preservation of ecobiocenosis stability.

Everyone has the right to the highest attainable standard of health, and modern preventive, preventive and rehabilitative manipulations promote health and well-being. Thanks to a number of fundamental projects on the study of human health at various levels (genomic, proteomic, and metabolomic), and molecular mechanisms of the development of pathological conditions, there has been a great leap in the field of applied sectors of industrial biotechnology, including segments of the pharmaceutical and food industries, significantly replenished health-saving resources and improved the quality of life of the population. This article will review the advanced achievements of fundamental and applied research, as well as promising areas of the bioindustry.

PURPOSE SWOG S1815 was a randomized, open label phase III trial, evaluating gemcitabine, nab-paclitaxel, and cisplatin (GAP) versus gemcitabine and cisplatin (GC) in patients with newly diagnosed advanced biliary tract cancers (BTCs). METHODS Patients with newly diagnosed locally advanced unresectable or metastatic BTC, including intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC) and gallbladder carcinoma (GBC), were randomly assigned 2:1 to either GAP (gemcitabine 800 mg/m 2 , cisplatin 25 mg/m 2 , and nab-paclitaxel 100 mg/m 2 intravenously once per day on days 1 and 8 of a 21-day cycle) or GC (gemcitabine 1,000 mg/m 2 and cisplatin 25 mg/m 2 intravenously once per day on days 1 and 8 of a 21-day cycle). RESULTS Among 452 randomly assigned participants, 441 were eligible and analyzable, 67% with ICC, 16% with GBC, and 17% with ECC. There was no significant difference in overall survival (OS) between GAP versus GC. Median OS with GAP was 14.0 months (95% CI, 12.4 to 16.1) and 13.6 months with GC (95% CI, 9.7 to 16.6); hazard ratio (HR), 0.91 (95% CI, 0.72 to 1.14); P = .41. Median progression-free survival (PFS) was similar between groups with median PFS for GAP being 7.5 months (95% CI, 6.4 to 8.5) versus 6.3 months for GC (95% CI, 4.4 to 8.2); HR, 0.89 (95% CI, 0.71 to 1.12); P = .32. In exploratory subset analyses, the OS and PFS benefits of GAP versus GC treatment were greater in locally advanced disease compared with metastatic disease, although not statistically significant (interaction P = .14 for OS and P = .17 for PFS). Moreover, GAP versus GC showed greater improvement in PFS among participants with GBC than those with ICC or ECC (interaction P = .01), but not OS (interaction P = .28). CONCLUSION The addition of a taxane in the GAP regimen to the standard gemcitabine-cisplatin regimen did not improve OS in newly diagnosed BTC. More toxicity was encountered with GAP versus GC.