Tag: nevin manimala

Front Vet Sci. 2026 Feb 23;13:1751034. doi: 10.3389/fvets.2026.1751034. eCollection 2026.

ABSTRACT

INTRODUCTION: Endothelial glycocalyx damage contributes to morbidity and mortality in critical illness. In this exploratory study in cats with trauma and non-traumatic illness, the endothelial glycocalyx thickness was estimated using sidestream dark field videomicroscopy and the Glycocheck™ software, with the primary aims of assessing feasibility, describing of Glycocheck™ microcirculatory parameters and exploring potential effects of illness severity and IV fluid administration.

METHODS: This was a prospective, single center, observational study. Recorded variables included age, weight, diagnosis, length of hospitalization (LOH), packed cell volume (PCV) and IV fluid administration. Each patient was assigned a fast Acute Patient Physiologic and Laboratory Evaluation score (APPLE_fast) and for cats with trauma – Animal Trauma Triage score (ATT). Within 24 h from admission, cats were anesthetized, and images from the sublingual mucosal vessels obtained for Glycocheck™ analysis. The perfused boundary region (PBR), an inverse estimate for endothelial glycocalyx thickness, was calculated for vessels with diameter of 5-25, 5-9, 10-19 and 20-25 μm, respectively. Normality was assessed using Shapiro-Wilk test and histograms. The effects of APPLE_fast, LOH, ATT, PCV, IV fluid administration, and illness group on PBR were analysed using generalised linear models. Distribution of vascular segment counts was assessed using Friedman’s test and Wilcoxon rank-signed test.

RESULTS: Nineteen cats were included, 11 with trauma. Success rate for measurements was 95%. Survival to discharge was 95%. Mean ± standard deviation for PBR 5-25 was 2.60 ± 0.22 μm, PBR 5-9: 1.38 ± 0.15 μm, PBR 10-19: 3.02 ± 0.22 μm and PBR 20-25: 3.03 ± 0.38 μm, within previously established tolerance intervals. There were no statistically significant effects of group, LOH, ATT, APPLE_fast, PCV and IV fluids on any PBR measurements. Vascular segment counts across the 5-25 μm range were not equally distributed (p < 0.001).

CONCLUSION: This exploratory study demonstrates the feasibility of assessing endothelial glycocalyx thickness in hospitalized sick cats. While no effects of clinical variables on PBR were identified, the study highlights important methodological considerations and provides valuable insights to guide future, larger-scale investigations.

PMID:41810410 | PMC:PMC12967996 | DOI:10.3389/fvets.2026.1751034

Gastro Hep Adv. 2025 Oct 12;5(4):100835. doi: 10.1016/j.gastha.2025.100835. eCollection 2026.

ABSTRACT

BACKGROUND AND AIMS: Crohn’s disease (CD) patients may experience anastomotic bleeding after lower gastrointestinal surgery, but its endoscopic management remains underexplored. We aimed to analyze the risk factors for anastomotic bleeding and the efficacy of endoscopic treatment.

METHODS: We retrospectively analyzed clinical characteristics, endoscopic treatments, and outcomes of CD patients with postoperative anastomotic bleeding from January 2021 to May 2025 at multiple centers. Anastomotic bleeding was defined as (i) direct bleeding (melena/hematochezia) or (ii) hemoglobin decrease ≥2 g/dL. Patients were followed up for 1 year, with rebleeding requiring endoscopic reintervention.

RESULTS: We included a total of 21 patients with 100% of patients having onsite bleeding controlled with initial endoscopic treatment and 9 patients (42.9%) having rebleeding. There was no statistical difference between the rebleeding group and nonrebleeding group in terms of age, gender, comorbidity, anticoagulation or antiplatelet therapy, clotting disorder, hemoglobin before or after procedure, bleeding type, the Rutgeert’s score, and endoscopic treatment. However, a greater number of patients in the rebleeding group required blood transfusion (88.9% vs 33.3%, P value = .011), and a greater volume of blood transfusion 2.0 (2.0-3.5 units) vs 0.0 (0.0-1.8 units) than those in nonrebleeding group (P value = .013). None of the 21 patients had no endoscopy-associated complications.

CONCLUSION: Endoscopic therapy appears to be safe and effective for the majority of CD patients with anastomotic bleeding following bowel surgery. The requirement for blood transfusion at the inception, in conjunction with a high volume of blood transfusion appear to be high risk factors for rebleeding.

PMID:41810383 | PMC:PMC12969671 | DOI:10.1016/j.gastha.2025.100835

medRxiv [Preprint]. 2026 Feb 24:2026.02.23.26346831. doi: 10.64898/2026.02.23.26346831.

ABSTRACT

The daily cortisol cycle is a critical indicator of hypothalamic-pituitary-adrenal (HPA) axis function. The current analytical approaches produce several outputs difficult to integrate into simple statistical models, clinical workflows, and ML/AI pipelines requiring single-value inputs. We developed the Cortisol Sine Score (CSS), a model-free scalar metric that quantifies daily cortisol exposure by computing a weighted sum of cortisol measurements across the day, using sine-transformed time-of-day weights. The CSS produces positive values for morning-dominant patterns, negative values for evening-shifted profiles, and near-zero values for flattened rhythms characteristic of chronic stress and circadian disruption. We validated the CSS performance in 3,006 samples from 501 pregnant women enrolled in the March of Dimes program, with cortisol values measured at 6 time points per day collected during the second trimester of pregnancy. The CSS showed strong correlations with observed and model-estimated amplitude and acrophase from Cosinor regression and JTK_CYCLE approaches, with excellent classifying performance (AUC=0.89, high versus low). The CSS successfully captured established associations between social disadvantage and cortisol dysregulation, and demonstrated utility in predicting gut microbiome composition in metagenomic analyses. Importantly, the CSS maintains excellent fidelity to the full 6-sample protocol with as few as 3-4 daily measurements. The 4-sample protocol achieves great performance (r = 0.952, MAE = 0.087) while reducing participant burden. The 06:00 time point was identified as essential for accurate CSS quantification. The CSS bridges the gap between circadian analysis and practical implementation by providing a simple, interpretable, and robust assessment of cortisol daily cycle in large-scale epidemiological studies, clinical screening, and biomedical sensors.

HIGHLIGHTS: Current state-of-the-art approaches estimating the daily cortisol exposures produce multi-output information difficult to implement in simple statistical analyses or ML/AI multi-omics approachesCortisol Sine Score is a novel model-free scalar metric expressing cortisol daily exposure and rhythmicity (morning vs evening exposure)Cortisol Sine Score was validated using 3006 salivary samples from clinical data and golden standards in circadian analyses such as Cosinor and JTK_CYCLECortisol Sine Score was the top performer in our benchmarking approach predicting association with social disadvantage and gut microbiome compositionReliable with 3-4 daily samples, reducing participant burdenOpen-source R package CortSineScore democratizes cortisol cycle analysis.

PMID:41810379 | PMC:PMC12970380 | DOI:10.64898/2026.02.23.26346831

medRxiv [Preprint]. 2026 Feb 28:2026.02.23.26346364. doi: 10.64898/2026.02.23.26346364.

ABSTRACT

Cohesin is a fundamental genome-organizing complex that orchestrates three-dimensional chromosome folding and gene expression via DNA loop extrusion. Alterations to genes encoding cohesin subunits and cohesin loaders cause Mendelian disorders, including Cornelia de Lange syndrome (CdLS). By contrast, disruption of factors that remove cohesin from DNA, including WAPL and its binding partners PDS5A and PDS5B , have not yet been associated with human disease. Here, we explored the relevance of these cohesin release factors in Mendelian disease by establishing a rare disease cohort of deeply phenotyped individuals with heterozygous, predicted damaging variants in WAPL (n=27), PDS5A (n=8), and PDS5B (n=8), by modeling WAPL deficiency in human cell lines and mice, and by aggregating rare disease association statistics from consortia studies. We identified a WAPL -related disorder characterized by developmental delay, intellectual disability, and risk of other developmental anomalies including clubfoot. Similarities between individuals with damaging WAPL variants and those with large, recurrent 10q22.3q23.2 (10q) deletions (which encompass WAPL ) nominate WAPL as a driver gene within this genomic disorder region. While carriers of PDS5A or PDS5B variants exhibited features of developmental disorders, neither cohort-based statistics nor case phenotyping associated these genes with specific phenotypes. We used CRISPR engineering to generate truncating variants in WAPL , as well the 7.8 Mb 10q deletion or duplication in human iPSCs and induced neurons. Transcriptomic analyses identified differentially expressed genes in both models, with highly significant overlap between WAPL haploinsufficiency and 10q deletion signatures. Mice with 50% residual Wapl expression exhibited mild deficits of growth and learning/memory, whereas those with 25% residual Wapl expression displayed birth defects and postnatal lethality, revealing a dosage liability threshold below the level of heterozygosity. In summary, we delineated a novel genetic condition caused by cohesin release factor deficiency, nominated WAPL as a driver gene within a genomic disorder region, and further illuminated dosage sensitivity of human cohesin.

PMID:41810376 | PMC:PMC12970359 | DOI:10.64898/2026.02.23.26346364

medRxiv [Preprint]. 2026 Feb 25:2026.02.23.26346922. doi: 10.64898/2026.02.23.26346922.

ABSTRACT

Genome-wide association studies (GWAS) have implicated tens of thousands of genetic variants associated with complex traits and polygenic diseases. Colocalizing GWAS variants with variants that may regulate gene expression, via expression quantitative trait loci (eQTL) mapping, has successfully led to the identification of disease-critical genes and their cell types of action. Recent studies predominantly colocalize proximal cis -eQTLs, which are estimated to regulate ∼10% of variance in gene expression levels. However, trans -eQTLs have been hypothesized to account for an additional ∼20% of expression levels, although few studies have attempted to quantify the variance explained by empirically associated trans -eQTLs. Here, we introduce EGRET (Estimating Genome-wide Regulatory Effects on the Transcriptome), an ensemble framework that jointly models cis -eQTLs with three distinct trans -eQTL mapping approaches: standard pairwise association testing via Matrix eQTL, and two functionally-informed methods, trans-PCO and GBAT. In real data, EGRET produced 353,408 predictive gene expression models (cross-validation R ² > 0, p < 0.01) across 49 GTEx tissues, including 12,317 gene-tissue pairs with a significantly nonzero trans -heritable component. For this set of genes, EGRET models explain 33% more gene expression variance than cis -eQTL models (EGRET average R ² = 0.104, FUSION average R ² = 0.078). We found that putative trans-regulating variants of EGRET models are enriched for regulatory elements such as enhancers, histone marks, and cis -eQTLs of other genes. We then hypothesized that EGRET models could nominate new disease-critical genes via a transcriptome-wide association study (TWAS) framework that models genome-wide regulatory effects on gene expression. In simulations of theoretically representative gene expression architectures (∼30% heritability, where more than 70% is distal), EGRET increased the power to detect disease-critical genes by 1.2x-3.1x compared to cis -eQTL models. In real data analysis, we identified disease-associated genes via TWAS across GWAS summary statistics for 78 complex traits and polygenic diseases using gene expression prediction models from EGRET, cis -eQTL FUSION, and two state-of-the-art trans -eQTL TWAS methods, MOSTWAS and BGW-TWAS. EGRET identified 450,825 gene-disease associations that were not identified by FUSION models, 2,900 associations not identified by MOSTWAS, and 5,498 associations not identified by BGW-TWAS. Finally, we used EGRET models to construct gene regulatory networks, some of which harbored genes that were jointly associated with complex traits. For example, the gene members of the network defined by ARHGEF3 , whose cis -regulatory variants help predict expression of 10 genes in trans , were concordantly associated with platelet count using EGRET but not FUSION models. Overall, we find that modeling the genome-wide genetic component of gene expression greatly boosts the detection of disease-critical genes and helps define gene regulatory networks while improving the characterization of GWAS variants.

PMID:41810371 | PMC:PMC12970377 | DOI:10.64898/2026.02.23.26346922

medRxiv [Preprint]. 2026 Feb 27:2026.02.25.26347015. doi: 10.64898/2026.02.25.26347015.

ABSTRACT

Polygenic scores (PGS) have emerged as an important tool for genetic risk prediction in medicine to identify individuals at high-risk for disease. A major limitation in their implementation is the apparent disagreement among scores for the same individual decreasing their interpretability and utility in clinical settings. Here we show that the poor agreement across PGSes for type 2 diabetes (T2D) is fully explained by statistical uncertainty in PGS-based prediction; individual-level uncertainty estimates from a single PGS explain the variability across existing PGSes. We provide an approach for the selection of high-risk individuals that incorporates measures of uncertainty and show that individuals with high confidence based on their PGS uncertainty have higher risk agreement across existing PGS and are more likely to develop T2D than high-risk individuals based on only point estimates of PGS. Together, these findings shed light on the factors underlying a roadblock in PGS implementation and underscore the need to incorporate uncertainty in PGS-based predictions.

PMID:41810369 | PMC:PMC12970363 | DOI:10.64898/2026.02.25.26347015

Risk Manag Healthc Policy. 2026 Mar 4;19:572604. doi: 10.2147/RMHP.S572604. eCollection 2026.

ABSTRACT

PURPOSE: Climate extremes are a catastrophic manifestation of climate change. Motorcycle ambulances are an emerging sort of vehicle that is intended to offer quick access in large cities. This study evaluated the effect of extreme weather events on the accessibility of emergency motorcycle ambulance services.

PATIENTS AND METHODS: We conducted a retrospective analysis of motorcycle ambulance operation data from January 2020 to December 2024. Data on motorcycle ambulance operating times, rainfall levels in the operational area, and ground temperatures at the Emergency medical services (EMS) unit were collected. Continuous data were presented as means and standard deviations (SD), while categorical data were reported as frequencies and percentages. Associations between categorical variables were evaluated using the chi-square test. A two-tailed p-value of less than 0.05 was considered statistically significant.

RESULTS: With a total of 569 operations documented over the five years, services were postponed during rainy weather and when ground temperatures exceeded 40°C. The availability of operational motorcycle ambulances declined from 81.28% to 34.03%. Increased rainfall (hours lost increased from 1065.1 to 2711.7; p<0.001) and rising temperatures exceeding 40°C (hours lost increased from 574.9 to 3067.3; p<0.001) were the main causes of service interruptions. This occurred despite increased utilization of motorcycle ambulances for emergency responses (65 to 165 operations annually; p=0.022) and a growing use of AED-equipped units for cardiac emergencies (4.6% to 23.6% of operations; p=0.014).

CONCLUSION: This quantitative evidence of the impact of climate extremes on emergency healthcare access due to reduced motorcycle ambulance availability. The gradual reduction in operational hours was caused by rising rainfall and elevated temperatures.

PMID:41810354 | PMC:PMC12968811 | DOI:10.2147/RMHP.S572604

World J Clin Oncol. 2026 Feb 24;17(2):113428. doi: 10.5306/wjco.v17.i2.113428.

ABSTRACT

BACKGROUND: Colorectal cancer (CRC), encompassing both colon and rectal carcinogenesis, is a major health concern. Metastatic CRC (mCRC) is the third most common cancer and the second leading cause of cancer-related death in United States adults. Despite advances in therapy, the 5-year survival rate remains low at 15%. KRAS mutations contribute to treatment resistance by altering the tumor microenvironment, necessitating novel therapeutic approaches.

AIM: To evaluate immunomodulatory and cytotoxic potential of reovirus as an adjuvant therapy in KRAS-mutant-mCRC patients by analyzing gene and cytokine expression.

METHODS: Five KRAS-mutant mCRC patients were treated with reovirus. Serum samples were collected at five time points over 15 days. Cytokine levels were measured using enzyme-linked immunosorbent assay, and transcriptomic profiling was performed to assess gene expression. Data were analyzed using the 2^-ΔΔCt method, and statistical significance was determined via two-tailed t-tests (P < 0.05).

RESULTS: Out of 271 genes associated with Janus kinase/signal transducer and activator of transcription, Ras, Wnt, and phosphoinositide 3-kinase- alpha serine/threonine-protein kinase pathways, 85 showed significant modulation. Additionally, 17 of 25 cytokines were significantly altered. Reovirus induced changes in both gene and cytokine expression, suggesting activation of a complex intracellular signaling network.

CONCLUSION: Reovirus demonstrates potential as an immunomodulatory and cytotoxic adjuvant in KRAS-mutant mCRC by altering key signaling pathways and cytokine profiles. These findings support further investigation into its potential therapeutic contributions.

PMID:41810348 | PMC:PMC12968548 | DOI:10.5306/wjco.v17.i2.113428

World J Clin Oncol. 2026 Feb 24;17(2):115245. doi: 10.5306/wjco.v17.i2.115245.

ABSTRACT

BACKGROUND: Despite widespread mammographic screening, a substantial proportion of breast cancers are still diagnosed as palpable lesions, frequently self-detected by the patient. Prior studies have investigated palpability as a prognostic factor, but few have incorporated contemporary staging systems or focused on clinically homogeneous, screening-eligible populations. In high-resource settings with equal access to screening, it remains unclear whether palpability reflects intrinsic tumor aggressiveness rather than delayed detection. This study evaluates whether palpable tumors exhibit distinct clinicopathological characteristics and worse outcomes in a screening-eligible population, hypothesizing that palpability may reflect aggressive tumor biology and potentially influence prognosis even when screening programs are accessible.

AIM: To compare clinicopathological features and survival outcomes of palpable vs non-palpable breast cancers in a screened population.

METHODS: We retrospectively analyzed 2110 women with clinically node-negative, localized breast cancer treated surgically between 2004 and 2024. Palpability at diagnosis was used to classify tumors as palpable (n = 1234) or non-palpable (n = 876). Endpoints included tumor size, grade, subtype, Ki-67 index, nodal status, overall survival, and breast cancer-specific survival. Statistical analyses included χ ² and t-tests and Kaplan-Meier estimates, with significance set at P < 0.05.

RESULTS: Palpable tumors were significantly larger (17.5 mm ± 8.6 vs 11.0 ± 6.7 mm, P < 0.001), more often high-grade (G3: 33% vs 16.3%, P < 0.001), and more frequently of luminal B or triple-negative subtype (37.1% vs 20.6%, P < 0.001). Ki-67 proliferation index was markedly higher in palpable tumors (24.7% ± 11.9% vs 15.1% ± 9.4%, P < 0.001). Sentinel lymph node positivity was increased (27.6% vs 16.7%, P < 0.001). While 10-year overall survival was similar (92% palpable vs 95% non-palpable, P = 0.56), breast cancer-specific survival showed a trend toward worse survival in palpable cases (96% vs 99%, P = 0.1).

CONCLUSION: Palpable tumors display faster growth kinetics and aggressive features, potentially shortening the preclinical window. Palpability may indicate biologically aggressive disease, warranting individualized management despite access to routine screening.

PMID:41810341 | PMC:PMC12968550 | DOI:10.5306/wjco.v17.i2.115245

Res Pract Thromb Haemost. 2026 Feb 13;10(2):103397. doi: 10.1016/j.rpth.2026.103397. eCollection 2026 Feb.

ABSTRACT

BACKGROUND: Sickle cell disease (SCD) is associated with an increased risk of thrombosis and often leads to mortality.

OBJECTIVES: This study aimed to compare the clinical outcomes of direct oral anticoagulants (DOACs) with warfarin in the management of patients with SCD and first venous thrombosis.

METHODS: This retrospective study included adult patients aged ≥ 18 years with SCD who developed their first episode of venous thrombotic event. Recurrent thrombosis and bleeding were compared between patients treated with DOACs and warfarin. Data were analyzed using IBM Statistical Package for the Social Sciences version 21.

RESULTS: We included 99 patients, of whom 67 (67.7%) were treated with DOACs and 32 (32.3%) with warfarin. The median follow-up time was 44 (1-130) months. Pulmonary embolism was the most common type of thrombosis observed in 64 patients (64.6 %). Three patients developed recurrent venous thromboembolism within 6 months of the first episode, whereas 6 patients developed recurrent thrombosis after 1 year. No significant difference was noted among patients on either type of anticoagulation in terms of major bleeding episodes (OR = 1.1; 95% CI: 1.1-1.8; P: 1.00), recurrence of thrombosis (OR = 0.68; 95% CI: 0.03-11.2; P: .68), or mortality (OR = 0.46; 95% CI: 0.06-3.4; P: .59). Clinically relevant nonmajor bleeding was significantly lower in patients on DOACs than those on warfarin (OR = 0.06; 95% CI: 0.01-0.52; P: .01).

CONCLUSION: DOACs are associated with similar clinical outcomes and fewer bleeding complications as compared to warfarin in the management of patients with SCD and thrombosis. Randomized controlled trials are required to further confirm our findings.

PMID:41810336 | PMC:PMC12969728 | DOI:10.1016/j.rpth.2026.103397