194341 research outputs found
Sort by
Genetic Determinants of Multiple Sclerosis Susceptibility in People From Diverse Ancestral Backgrounds
No full textThe genetic basis of multiple sclerosis (MS) susceptibility has been studied extensively in European (EUR) ancestry populations. The aim of our study was to determine the genetic architecture of MS susceptibility in people of South Asian (SAS) and African (AFR) genetic ancestral backgrounds.
We recruited and genotyped a cohort of ancestrally diverse people with MS (pwMS) from across the United Kingdom. Cases were combined with controls from the UK Biobank (UKB). After genetic ancestry inference, we performed within-ancestry case-control genetic association studies of MS susceptibility, exploring single nucleotide variants and imputed classical human leukocyte antigen alleles.
We analyzed genetic data from 676 pwMS from our cohort (median age = 45.7 years, 71.7% female genetic sex), 2,426 pwMS from the UKB (median age = 55.0 years, 72.3% female), and 27,640 UKB controls (median age = 54.0 years, 52.5% female). Genetic variants within the Major Histocompatibility Complex were associated with MS susceptibility across all ancestries (SAS: lead SNP chr6:32635095:G:C, odds ratio [OR] = 1.7,
= 4.2 × 10
, nearest gene
; AFR: lead SNP chr6:32593550:T:C, OR = 1.7,
= 1.2 × 10
, nearest gene
). EUR ancestry susceptibility alleles were over-represented in cases from both ancestries, with the degree of concordance stronger for the SAS (ρ = 0.46,
= 8.3 × 10
) than the AFR (ρ = 0.35, Spearman
= 2.5 × 10
) ancestry cohort. EUR-derived genetic risk scores performed better than chance but less well than in EUR ancestry cohorts, explaining 3.9% (SAS,
= 1.0 × 10
) and 1.9% (AFR,
= 2.0 × 10
) of the liability to MS, contrasting with 9.6% (empirical
= 1.0 × 10
) in the EUR cohort. Several classical human leukocyte antigen (HLA) alleles associated with MS in EUR ancestry populations show similar effects in SAS and AFR ancestry cohorts, including
; however, the population-level risk explained by this allele is lower in SAS (8.8%) and AFR (2.9%) cohorts than in EUR cohorts due to allele frequency. We found some evidence for a protective role for the SAS-enriched
allele in the SAS cohort, which has not been previously described.
The genetic architecture of MS susceptibility shows strong concordance across ancestral groups suggesting shared disease mechanisms. Larger studies in diverse populations are likely to enhance our understanding of how genetic variation contributes to MS susceptibility in people of all ancestral backgrounds
Vascular Destabilization and Pericyte Detachment are Mediated by hIAPP Aggregation in Transgenic Mice
Get PDFAims/hypothesis: Human islet amyloid polypeptide (hIAPP) deposition is a common feature of type-2 diabetes (T2D). Previous studies have demonstrated hIAPP-mediated endothelial cell (EC) dysfunction and inflammation, but little is known about islet microvascular stability or pericyte function in hIAPP-containing islets. This study investigates how islet endothelial cells and pericytes are influenced by hIAPP aggregation. Methods: Bulk RNAseq and qPCR were conducted on hIAPP or vehicle treated MS-1 cells and bead-purified human islet CD31+ cells from donors with or without T2D to determine how islet ECs respond to hIAPP exposure. Confocal imaging of living pancreatic slices obtained from hIAPP transgenic mice was conducted to evaluate the effect of hIAPP deposition on islet pericyte function and vasomotor responses. Results: hIAPP-treated MS-1 cells and ECs purified from T2D islets demonstrate downregulation of leading-edge genes associated with extracellular matrix and cell adhesion pathways. Pericytes from hIAPP-expressing mouse islets appear detached from underlying endothelial cells, which was associated with impaired vasomotor responses to constrictive or dilatory stimuli. Conclusions/interpretation: hIAPP induces vascular destabilization by downregulating mRNA of key extracellular matrix and cell adhesion molecules in ECs, likely promoting the breakdown of EC-EC and EC-pericyte coupling. hIAPP disrupts EC-pericyte connections, and pericyte detachment ultimately impairs pericytes' ability to modulate capillary diameter without impairing intracellular Ca2+ dynamics. Our data suggest that amyloid deposition compromises EC health and survival by altering islet microvascular morphology, stability, and function. This, in turn, may disrupt islet microvascular stability and exacerbate endocrine cell dysfunction in T2D.Competing Interest StatementThe authors have declared no competing interest.Funder Information DeclaredDepartment of Veterans Affairs, VA Puget Sound Health Care System, I01-BX004063Canada Excellence Research Chairs, https://ror.org/02tvrwm90, CERC-22-0023NIH Common Fund, https://ror.org/001d55x84, NIH T32 HL00702
Telehealth education for patients with cancer: a standalone solution for symptom relief?
No full textBackground
Telehealth-delivered education offers a practical approach to chemotherapy teaching and symptom self-management support. Advanced practice providers (APPs) play an increasingly vital role in guiding oncology patients through treatment, particularly in managing symptoms and reducing preventable emergency department (ED) use. This study evaluated whether an APP-led telehealth symptom education and monitoring (TSEM) intervention improved symptom self-management engagement and reduced ED utilization in patients with cancer.
Methods
This retrospective study included 120 patients with gastrointestinal (GI), lung, or sarcoma cancers treated at a single academic institution. The intervention group (
n
= 61) received a tailored telehealth education session from specialized oncology APPs within seven days of treatment initiation. The control group (
n
= 59) received standard patient education. Outcomes included ED visits and symptom self-management engagement, measured via medical record-documented patient-initiated symptom support calls. Data were analyzed using multivariable binary logistic, linear, and negative-binomial regression models adjusted for demographic, clinical covariates.
Results
The intervention did not significantly reduce ED utilization overall. Patients with GI cancer in the TSEM group had increased odds of ED visits. However, patients in the TSEM group made significantly more symptom self-management calls (74% higher rate;
p
< 0.05), especially those with GI cancer, suggesting increased patient engagement in managing treatment-related symptoms.
Conclusions
APP-led telehealth education enhanced patient engagement in symptom self-management but did not reduce ED visits. Tailored, cancer-specific education delivered by APPs may empower patients to manage symptoms earlier. Further prospective, multi-site research is needed to assess the long-term impact on acute care utilization and quality outcomes in broader, diverse oncology populations
Multiomic characterization of small cell lung cancer: Real‐world insights into therapeutic opportunities
No full textNK, natural killer; STING, Stimulator of Interferon Genes; TCI, T‐cell inflamed
Reducing Preschool Exclusionary Discipline Practices Through Infant and Early Childhood Mental Health Consultation: Findings from the Jump Start Program
No full textBackground/Objectives: National data show that about 250 preschoolers are suspended or expelled daily in the United States. Jump Start is a multi-tiered infant and early childhood mental health consultation program that strengthens early care and education centers’ capacity to support children’s social–emotional development and prevent school suspension and expulsion. This retrospective study examined center-level exclusionary discipline practices, Jump Start participation, and related changes in discipline and expulsion policies. Methods: Data from 270 early care and education centers across Miami-Dade County that received Jump Start services during one of three academic years (2022–2023, 2023–2024, or 2024–2025) were included. Analyses examined associations between baseline exclusionary discipline practices, program duration, discipline and expulsion policy changes, and post-Jump Start exclusionary discipline practices. Results: Statistically significant reductions were observed in the frequency of traditional suspensions/expulsions and soft expulsions following Jump Start participation. The association between the Jump Start duration and post-Jump Start soft expulsions was significantly moderated by changes in center discipline policies, such that Jump Start was effective at reducing soft expulsions only when discipline policies showed meaningful improvement. Conclusions: Infant and early childhood consultation models, such as Jump Start, show promise in reducing exclusionary discipline practices, especially when implementation improves discipline policies
Metabolic assessments of neurostimulation therapy to reduce apnea (MANTRA) trial: rationale and methods
No full textTo investigate the effects of hypoglossal nerve stimulation (HGNS) therapy on energy balance and insulin resistance among patients stabilized on HGNS.
In this randomized, within-subject crossover trial, we compare energy balance and insulin resistance during active HGNS ("HGNS-on") versus HGNS withdrawal ("HGNS-off") among 30 patients with OSA who have been stabilized on HGNS for ≥3 months. Participants will undergo between 2-4 weeks of each study phase (HGNS-on and HGNS-off), with the duration of HGNS-on and HGNS-off standardized within participants. Between the two study phases (HGNS-on and HGNS-off), patients resume HGNS for 1 week. At the end of each study phase, participants undergo fasting anthropometric measurements, blood sample collection, and home sleep testing. A subset of participants undergo additional assessments of energy expenditure (via doubly labeled water technique) and energy intake.
The primary outcome is energy balance, as calculated from the difference between energy expenditure and energy intake. The secondary outcome is insulin resistance, as assessed by the homeostatic model assessment for insulin resistance.
There is a dearth of mechanistic data examining the metabolic effects of HGNS. We present methods of the Metabolic Assessments of Neurostimulation Therapy to Reduce Apnea (MANTRA) trial, the first randomized crossover study designed to examine the metabolic effects of HGNS
A Novel Multi-Agent Architecture to Reduce Hallucinations of Large Language Models in Multi-Step Structural Modeling
No full textLarge language models (LLMs) such as GPT and Gemini have demonstrated remarkable capabilities in contextual understanding and reasoning. The strong performance of LLMs has sparked growing interest in leveraging them to automate tasks traditionally dependent on human expertise. Recently, LLMs have been integrated into intelligent agents capable of operating structural analysis software (e.g., OpenSees) to construct structural models and perform analyses. However, existing LLMs are limited in handling multi-step structural modeling due to frequent hallucinations and error accumulation during long-sequence operations. To this end, this study presents a novel multi-agent architecture to automate the structural modeling and analysis using OpenSeesPy. First, problem analysis and construction planning agents extract key parameters from user descriptions and formulate a stepwise modeling plan. Node and element agents then operate in parallel to assemble the frame geometry, followed by a load assignment agent. The resulting geometric and load information is translated into executable OpenSeesPy scripts by code translation agents. The proposed architecture is evaluated on a benchmark of 20 frame problems over ten repeated trials, achieving 100% accuracy in 18 cases and 90% in the remaining two. The architecture also significantly improves computational efficiency and demonstrates scalability to larger structural systems
Prevalence of treatment-acquired homozygous losses (homozygous deletions) of PTEN from androgen receptor pathway inhibitors (ARPI) in metastatic prostate cancer
No full text27Background: Validated homozygous loss detection is becoming increasingly important in clinical practice, with prostate NCCN guideline inclusion of BRCA1/2 loss (often portending durable PARP inhibitor benefit) and multi-tumor trials of PRMT5 and MAT2A inhibitors ongoing (biomarker: MTAP loss). Homozygous losses are challenging to detect and require intentional NGS assay design and validations. Using an FDA-approved NGS assay, we evaluated the most frequent losses identified in metastatic prostate cancer, evaluated prognostic associations on ARPI, and prevalence before and after ARPI treatments. Methods: This study used the nationwide (US-based) de-identified Flatiron Health-Foundation Medicine Prostate Cancer clinico-genomic database (FH-FMI CGDB), originating from approximately 280 US cancer clinics (~800 sites of care). Patients with metastatic prostate cancer and tissue tumor genomic testing by FoundationOne CDx were eligible for analysis. Alteration prevalence was compared between non-sequential groups of specimens obtained from patients naïve to ADT and ARPI, naïve to ARPI but not ADT, or exposed to any ARPI. Outcome analyses adjusted for: ECOG performance score, age, baseline PSA, and socioeconomic status. To limit immortal time confounding, outcome analyses were restricted to patients with specimens tested prior to initiation of ARPI. Results: 1990 specimens from 1984 unique patients met criteria for assessment. The most common losses and respective ADT & ARPI naïve vs ADT exposed & ARPI-naïve vs ARPI-exposed prevalence were PTEN (17.1% vs 24.8% vs. 33.5%, p < 0.001), FAS (2.4% vs 5.0% vs 5.8%, p = 0.003), BRCA2 (4.2% vs 3.2% vs. 2.8%, p = 0.36), RB1 (1.6% vs 3.0% vs 3.5%, p = 0.062), and TP53 (2.3% vs 2.3% vs 4.4%, p = 0.064). 227 patients had tissue specimens obtained and NGS results reported prior to initiation of ARPI. Sufficient patients with PTEN loss were present for nominal outcome associations, observing less favorable time to next treatment (HR: 1.81, 95%CI: 1.24 – 2.65, p = 0.002) and overall survival (HR: 1.65, 95%CI: 1.02 – 2.65, p = 0.040) from the initiation of ARPI. In the mHSPC (ADT and ARPI naïve) setting, 17.1% had PTEN loss, 32.8% had an HRR gene alteration, and 2.8% had both. Conclusions: Our results are consistent with homozygous losses of certain genes, notably PTEN, potentially being acquired resistance alterations to ARPI. Prostate cancer trials often do not specify timing of specimen acquisition relative to treatment initiation. For trials like IPATential-150 or CAPItello-280 that evaluate AKT inhibitors in post-ARPI setting, patients with PTEN status determined by archival tissue could be false negatives and reduce power of analysis in biomarker(+) group. Our results underscore the importance of clinical context, especially prior treatment exposures, when interpreting biomarker prevalence
Knowledge-based planning for intensity-modulated proton therapy of the breast and chest wall with regional lymph nodes: development, validation, and comparative evaluation of two models
Get PDFPurpose: Knowledge-based planning (KBP) can improve efficiency and consistency in radiotherapy. In intensity-modulated proton therapy (IMPT) for breast cancer, particularly with regional lymph nodes, treatment planning remains complex. This study developed, validated, and compared two KBP models for IMPT of the breast and chest wall (CW) to enhance plan quality, reduce inter-planner variability, and streamline workflows.Materials and methods: Fifty patients (25 left-sided, 25 right-sided) previously treated with IMPT to the breast or CW including regional lymph nodes were used for model development. A combined model was trained on all patients, while side-specific models were developed separately for left- and right-sided treatments. Planning objectives were refined via iterative replanning of 20 training cases. For validation, 20 additional patients (10 left, 10 right) were evaluated using the respective models. Dosimetric metrics for target volumes and organs at risk (OARs) were compared among model-generated and clinical plans using paired t-tests (p < 0.05). An expert physician ranked each plan for clinical preference.Results: All KBP-generated plans met clinical constraints. Both models achieved target coverage comparable to clinical plans. The combined model produced cooler hot spots in axillary, supraclavicular, and internal mammary nodes, with modest improvements in OAR sparing (heart, esophagus, trachea, thyroid). The side-specific model showed similar benefits, particularly for esophagus and thyroid sparing. Between models, side-specific plans had cooler hot spots, while the combined model offered slightly better OAR sparing. Physician review deemed all KBP plans clinically acceptable, preferring the KBP plan in 11 of 20 cases.Conclusions: KBP models can generate clinically acceptable IMPT plans for breast and CW with regional lymph nodes, achieving comparable target coverage to clinical plans with modest improvements in OAR sparing and hot spot reduction, supporting their potential to streamline treatment planning
Future Shoaling of the AMOC and Its Impact on Oceanic Heat Transport to the Subpolar North Atlantic
No full textThe Atlantic Meridional Overturning Circulation (AMOC) carries oceanic heat northward to the subpolar North Atlantic (SPNA), where the surface water cools and sinks to the deep ocean. According to a large-ensemble simulation under a medium-to-high emission scenario, the surface cooling and oceanic heat convergence in the SPNA may decrease to similar to 20% of their historical levels by 2100. We show here that the projected weakening of the AMOC volume transport alone cannot explain such a large decrease in the heat convergence rate. Our analysis indicates that, due to the suppression of deep-water formation in the SPNA, the AMOC's lower limb becomes shallower, carrying relatively warm water southward away from the SPNA. This in turn accelerates the decrease in oceanic heat transport to the SPNA per unit AMOC weakening. These results are supported in other multi-ensemble models analyzed, despite large inter-model spreads