95038 research outputs found
Sort by
WGX50 attenuates radiation enteritis by targeting ferroptosis and redox homeostasis via EGFR
Get PDFBackground Radiation enteritis (RE) is a common complication in patients undergoing abdominal and pelvic radiotherapy. Despite the advancements in radiotherapy, effective treatments remain limited. WGX50, a bioactive compound from Sichuan pepper, has shown anti-inflammatory and antioxidant properties. This study investigates the protective effects of WGX50 on RE, focusing on its potential to reduce radiation-induced damage in the intestine. Methods Network pharmacology and molecular docking were used to identify the molecular targets of WGX50. In vitro, human intestinal epithelial cells (HIEC6) and colon cells (NCM460) were exposed to radiation and treated with WGX50. In vivo, C57BL/6 mice were administered WGX50 prior to radiation exposure. Various assays, including CCK-8, colony formation, flow cytometry, histopathology, and 16S rRNA sequencing, were performed to evaluate cell proliferation, apoptosis, oxidative stress, intestinal damage, and gut microbiota composition. Tissue transcriptome sequencing was conducted to explore differentially expressed genes. Results In vitro, WGX50 significantly mitigated radiation-induced cell damage, enhanced cell proliferation, and reduced apoptosis at non-toxic concentrations. In vivo, WGX50 treatment preserved intestinal morphology and reduced inflammatory infiltration in irradiated mice. WGX50 also protected goblet cells, maintaining mucin production and epithelial barrier function critical for intestinal homeostasis. Molecular docking, dynamics simulations and surface plasmon resonance (SPR) revealed stable binding of WGX50 to Epidermal Growth Factor Receptor (EGFR), key targets involved in oxidative stress regulation and ferroptosis inhibition. Mechanistically, WGX50 upregulated the EGFR-SLC7A11-GPX4 axis, suppressing ferroptosis and protecting intestinal cells. Additionally, 16S rRNA sequencing showed that WGX50 mitigated radiation-induced gut microbiota dysbiosis, preserving microbial diversity and promoting beneficial bacterial populations. Conclusion WGX50 demonstrates potent radioprotective effects by reducing oxidative stress, suppressing ferroptosis, and maintaining intestinal homeostasis, including goblet cell function and gut microbiota composition. These findings support WGX50’s potential as a novel therapeutic agent for the prevention and treatment of radiation enteritis
Genomic and phenotypic correlates of mosaic loss of chromosome Y in blood
Get PDFMosaic loss of Y (mLOY) is the most common somatic chromosomal alteration detected in human blood. The presence of mLOY is associated with altered blood cell counts and increased risk of Alzheimer disease, solid tumors, and other age-related diseases. We sought to gain a better understanding of genetic drivers and associated phenotypes of mLOY through analyses of whole-genome sequencing (WGS) of a large set of genetically diverse males from the Trans-Omics for Precision Medicine (TOPMed) program. We show that haplotype-based calling methods can be used with WGS data to successfully identify mLOY events. This approach enabled us to identify differences in mLOY frequencies across populations defined by genetic similarity, revealing a higher frequency of mLOY in the European (EUR) ancestry group compared to other ancestries. We identify multiple loci associated with mLOY susceptibility and show that subsets of human hematopoietic stem cells are enriched for the activity of mLOY susceptibility variants. Finally, we found that certain alleles on chromosome Y are more likely to be lost than others in detectable mLOY clones
Criterion Validity, Scalability and Stability of Scoring on the Bayley‐III in Children With Angelman Syndrome
Get PDFBACKGROUND: The Bayley Scales of Infant Development is used in many studies and clinical trials in children with developmental disabilities, including children with Angelman syndrome (AS). METHOD: We assessed 142 children with AS in an international multicentre study with the Bayley Scales of Infant Development III, of which 52 children were tested more than once. We assessed criterion validity using proportion analysis, scalability using Mokken analyses and stability of scoring by counting pass-to-fail and fail-to-pass items. RESULTS: Results revealed good scalability in all scales but the expressive language scale, indicating that the items of these scales measured one underlying trait. In the expressive language scale, the AS-related speech difficulties invalidated scoring. Scoring within children across assessments was unstable for all scales except the gross motor scale, as more than half of the children made one or more errors in previously correct items. Loss or regression of skills does not fully explain this finding. Alternative explanations including motivation, concentration, on-task behaviour and anxiety should also be considered when scores decline. CONCLUSIONS: This study shows that caution should be taken when interpreting single and successive scores of children with AS on the Bayley-III and that other forms of assessment should complement assessment in children with AS
Consistent performance of large language models in rare disease diagnosis across ten languages and 4917 cases
Get PDFBACKGROUND: Large language models (LLMs) are increasingly used medicine for diverse applications including differential diagnostic support. The training data used to create LLMs such as the Generative Pretrained Transformer (GPT) predominantly consist of English-language texts, but LLMs could be used across the globe to support diagnostics if language barriers could be overcome. Initial pilot studies on the utility of LLMs for differential diagnosis in languages other than English have shown promise, but a large-scale assessment on the relative performance of these models in a variety of European and non-European languages on a comprehensive corpus of challenging rare-disease cases is lacking. METHODS: We created 4917 clinical vignettes using structured data captured with Human Phenotype Ontology (HPO) terms with the Global Alliance for Genomics and Health (GA4GH) Phenopacket Schema. These clinical vignettes span a total of 360 distinct genetic diseases with 2525 associated phenotypic features. We used translations of the Human Phenotype Ontology together with language-specific templates to generate prompts in English, Chinese, Czech, Dutch, French, German, Italian, Japanese, Spanish, and Turkish. We applied GPT-4o, version gpt-4o-2024-08-06, and the medically fine-tuned Meditron3-70B to the task of delivering a ranked differential diagnosis using a zero-shot prompt. An ontology-based approach with the Mondo disease ontology was used to map synonyms and to map disease subtypes to clinical diagnoses in order to automate evaluation of LLM responses. FINDINGS: For English, GPT-4o placed the correct diagnosis at the first rank 19.9% and within the top-3 ranks 27.0% of the time. In comparison, for the nine non-English languages tested here the correct diagnosis was placed at rank 1 between 16.9% and 20.6%, within top-3 between 25.4% and 28.6% of cases. The Meditron3 model placed the correct diagnosis within the first 3 ranks for 20.9% of cases in English and between 19.9% and 24.0% for the other nine languages. INTERPRETATION: The differential diagnostic performance of LLMs across a comprehensive corpus of rare-disease cases was largely consistent across the ten languages tested. This suggests that the utility of LLMs in clinical settings may extend to non-English clinical settings.
Fetal Personhood and Reproductive Criminalization - Implications for Patients, Clinicians, and Public Health.
Get PDFApregnant woman is declared brain-dead at 9 weeks’ gestation, but her body is kept on life support — not because of her previously expressed wishes or her family’s wishes, but so her body can serve as an incubator for the fetus. Other women are arrested and spend months in jail after having a miscarriage. Mothers are reported to child-welfare agencies for drug use, despite testing positive for only the routine pain medication given to them by the hospital during childbirth
Minimum Audible Angle and the Acoustic Change Complex Elicited by Azimuthal Shifts in Low-Frequency Sounds: Effects of Age
Get PDFThis study compared the behavioral minimum audible angle (MAA) and the electrophysiological acoustic change complex (ACC) elicited by an azimuthal shift in sound location. To examine age effects, 63 participants with normal or near-normal hearing were divided into three age groups (Young, Mid-Aged, and Older). The stimuli were narrow bands of noise centered at 500 Hz to facilitate reliance on primarily binaural temporal cues. Putative spatial location was manipulated by means of head-related transfer functions under headphones. MAA results showed that performance was dependent on the reference location, with performance becoming poorer as the reference location shifted away from midline. The Young group had smaller MAAs than the Older group, and performance of the Mid-Age group was intermediate. Measurement of the ACC was restricted to shifts away from midline, and results showed no ACC for shifts of 4.5° and 9° but present ACCs for shifts of 13.5°, 18°, and 36°. The robustness of the ACC, as measured with the intertrial phase coherence metric, grew with increasing azimuthal shift. For shifts of 13.5° and 18°, Young participants had more robust ACCs than Older participants. Although age-related deficits were found in both the MAA and in the robustness of the ACC, no associations were observed at the individual level between MAA and ACC measures. Further work is necessary to evaluate the ACC elicited by shifts from off-midline reference locations before a firm conclusion can be reached that the ACC is not a viable objective proxy for the MAA
Geopolitical Roots and Branches: Identity Label Preferences Among People of African Descent in the United States
Get PDFIn the United States, people of African descent have historically used different labels to express their collective racial identities. Scholars have traced these historical changes over time, which have shifted for various reasons, across different political and social movements, and with changing group dynamics. The purpose of this study was to examine contemporary racial identity label preferences among people of African descent living in the United States and explore the geopolitical roots and branches of those choices. In this study, an online sample of 451 people of African descent completed a survey about their racial identity label preferences and why they selected those labels. We hypothesized that selecting one's racial label for geopolitical reasons (vs. external or accuracy reasons) would predict how people of African descent see themselves (i.e., in terms of race and ancestry), how they perceive the world (i.e., perceptions of American racism), and how they act in the world (i.e., political activism). Overall, selecting one's racial identity label preference for geopolitical reasons was a consistent predictor of our outcomes
The relationship between psychological readiness to return to sport and kinesiophobia in teens and young adults after anterior cruciate ligament reconstruction
Get PDFPsychological readiness and kinesiophobia are important variables to consider for return to sport clearance after anterior cruciate ligament (ACL) reconstruction. Both have been associated in adult populations; however, it is unknown if they are associated in teens after ACL reconstruction. Therefore, the purpose of this study was to assess the relationship between psychological readiness and kinesiophobia in teens and young adults after ACL reconstruction. A retrospective cohort design was used. Participants aged 13–30 years, who were 6–12 months post-ACL reconstruction, who completed the Tampa Scale of Kinesiophobia and the ACL Return-to-Sport after Injury Scale were included from a multi-site registry. Two age groups were established (teen: <19 years, adult: ≥19 years), and psychological readiness was categorized using an ACL Return-to-Sport after Injury Scale cutoff of 77 (<77 = unacceptable). Independent samples t-tests, Pearson correlations, and binary logistic regression were performed to examine associations between kinesiophobia and psychological readiness, and the influences of age, sex, and months since surgery. 315 participants (54.3% female; 18.3 ± 3.3 years; 8.2 ± 1.9 months post-surgery) were analyzed. ACL Return-to-Sport after Injury Scale and Tampa Scale of Kinesiophobia scores were significantly correlated in both groups (teen: r = −0.59, p < 0.001; adult: r = −0.45, p < 0.001), with no significant difference in the correlation coefficients (z = −1.49). Overall, 47.9% scored below the ACL Return-to-Sport after Injury pass threshold. Each one-point increase in kinesiophobia was associated with a 28% higher likelihood of reporting unacceptable psychological readiness. Adults were twice as likely as teens to report unacceptable psychological readiness. Greater psychological readiness was associated with lower kinesiophobia in both teens and young adults. Additionally, nearly half reported poor psychological readiness, highlighting the need for interventions aimed at improving psychological readiness during ACL rehabilitation
Efficacy and Feasibility of OptraDam® Plus Versus Conventional Rubber Dams in Preclinical Simulation Training: A Randomized Crossover Trial
Get PDFBackground/Objectives: Despite clear benefits, conventional rubber dam use remains low due to barriers that often originate during undergraduate training. To examine a potential approach to mitigating these barriers, this study evaluated the efficacy and feasibility of OptraDam® Plus, a user-friendly alternative to the conventional rubber dam, in preclinical simulation training. Methods: In this 2 × 2 crossover trial, preclinical undergraduate students were randomly assigned to two groups to perform two types of dental isolation, conventional rubber dam and OptraDam® Plus, in alternating sequences on a dental simulator. The efficacy and feasibility of both systems were evaluated based on application time, isolation quality, and students’ perceptions. Results: Data from 94 randomized students were collected and analyzed. Although students’ performance was suboptimal with both systems, there were significant differences in efficacy and feasibility between them. Application time was shorter with the conventional rubber dam (mean reduction 77 s; 95% CI 4–151; p = 0.039), whereas using OptraDam® Plus was associated with 51% lower odds of achieving a higher isolation quality category (OR 0.49; p = 0.011). In addition, students perceived the conventional rubber dam to be superior to the OptraDam® Plus in achieving higher-quality dental isolation and in their confidence in using it. Conclusions: OptraDam® Plus cannot be considered a suitable alternative to the conventional rubber dam in preclinical simulation training due to its inferior efficacy and feasibility. The findings of this study challenge the assumption that utilization of newer marketed “user-friendly” rubber dam systems necessarily overcome the core technical barriers faced by undergraduate students
Vitamin B12 Protects the Exacerbated Ischemia–Reperfusion Injury-Induced Chronic Kidney Disease in Mice with Genetically Increased Elmo1
Get PDFIschemia–reperfusion injury (IRI) is a leading cause of acute kidney injury (AKI) and a major driver of progression to chronic kidney disease (CKD). Oxidative stress is recognized as a central mediator of this transition. Engulfment and Cell Motility 1 (ELMO1) regulates cytoskeletal remodeling and reactive oxygen species generation through Rac1 activation, but its contribution to CKD progression remains poorly defined. To investigate this, we established a unilateral renal IRI model in wild-type (WT) and Elmo1-overexpressing (Elmo1H/H) mice and evaluated kidney function one and four months post-IRI. Compared with WT, Elmo1H/H mice developed more severe kidney dysfunction, including an elevated plasma cystatin C and urinary albumin-to-creatinine ratio, reduced estimated glomerular filtration rate (eGFR), and pronounced fibrosis and glomerular injury observed by light and electron microscopy. Molecular analysis confirmed the dysregulation of redox-related pathways by RT-qPCR, with RNA sequencing showing enrichment of oxidative stress signatures. A subset of mice received chronic vitamin B12 (B12) supplementation following IRI to evaluate its therapeutic potential. Vitamin B12 supplementation improved kidney function, reduced fibrosis, preserved glomerular structure, and normalized the expression of antioxidant genes in both groups. These findings identify Elmo1 as a driver of redox-mediated kidney injury and support vitamin B12 as a promising antioxidant therapy for AKI-to-CKD progression