Nevin Manimala

bioRxiv [Preprint]. 2025 Jul 5:2025.07.01.662655. doi: 10.1101/2025.07.01.662655.

ABSTRACT

DNA methylation is a compulsory and fundamental epigenetic mechanism, and its significant changes (i.e., differential methylation) regulate gene expression, cell-type specification and disease progression without altering the underlying DNA sequence. Differential methylation biomarkers were widely used as inputs for various downstream investigations, and differential methylation could be detected via existing statistical tools by comparing two groups of methyomes (i.e. whole-genome methylation profiles). However, few toolboxes were available to integrate robust detection, annotation and visualization of differential methylation to efficiently streamline methylation investigation. Also, differential methylation detected via tools has poor reproducibility and no tools were tested on long-read methylomes. To address these issues, we introduced DiffMethylTools, an end-to-end solution to eliminate analytical and computational difficulties for differential methylation dissection. Comparison on six datasets including three long-read methylomes demonstrated that DiffMethylTools achieved overall better detection performance of differential methylation than existing tools like MethylKit, DSS, MethylSig, and bsseq. Besides, DiffMethylTools supported versatile input formats for seamless transition from upstream methylation detection tools, and offered diverse annotations and visualizations to facilitate downstream investigations. DiffMethylTools therefore offered a robust, interpretable, and user-friendly solution for differential methylation investigation, benefiting the dissection of methylation’s roles in human disease studies.

PMID:40631172 | PMC:PMC12236622 | DOI:10.1101/2025.07.01.662655

bioRxiv [Preprint]. 2025 Jul 1:2025.06.27.661814. doi: 10.1101/2025.06.27.661814.

ABSTRACT

Pooled single-cell perturbation screens represent powerful experimental platforms for functional genomics, yet interpreting these rich datasets for meaningful biological conclusions remains challenging. Most current methods fall at one of two extremes: either opaque deep learning models that obscure biological meaning, or simplified frameworks that treat genes as isolated units. As such, these approaches overlook a crucial insight: gene co-fluctuations in unperturbed cellular states can be harnessed to model perturbation responses. Here we present CIPHER (Covariance Inference for Perturbation and High-dimensional Expression Response), a conceptual framework leveraging linear response theory from statistical physics to predict transcriptome-wide perturbation outcomes using gene co-fluctuations in unperturbed cells. We validated CIPHER on synthetic regulatory networks before applying it to 11 large-scale single-cell perturbation datasets covering 4,234 perturbations and over 1.36M cells. CIPHER robustly recapitulated genome-wide responses to single and double perturbations by exploiting baseline gene covariance structure. Importantly, eliminating gene-gene covariances, while retaining gene-intrinsic variances, reduced model performance by 11-fold, demonstrating the rich information stored within baseline fluctuation structures. Moreover, gene-gene correlations transferred successfully across independent experiments of the same cell type, revealing stereotypic fluctuation structures. Furthermore, CIPHER outperformed conventional differential expression metrics in identifying true perturbations while providing uncertainty-aware effect size estimates through Bayesian inference. Finally, most genome-wide responses propagated through the covariance matrix along approximately three independent and global gene modules. CIPHER underscores the importance of theoretically-grounded models in capturing complex biological responses, highlighting fundamental design principles encoded in cellular fluctuation patterns.

PMID:40631127 | PMC:PMC12236818 | DOI:10.1101/2025.06.27.661814

bioRxiv [Preprint]. 2025 Jul 6:2024.11.23.624995. doi: 10.1101/2024.11.23.624995.

ABSTRACT

Quantifying the inheritance of protein regulation during asymmetric cell division remains a challenge due to the complexity of these systems and the lack of a formal mathematical definition. We introduce ODEinherit, a new statistical framework leveraging ordinary differential equations (ODEs) to measure how much a mother cell’s regulatory network is passed on to its daughters, addressing this gap. ODEinherit first estimates cell-specific regulatory networks through ODE systems, incorporating novel adjustments for non-oscillatory trajectories. Then, inheritance is quantified by evaluating how well a mother’s regulatory network explains its daughter’s trajectories. We demonstrate that precise quantification of this inheritance relies on pruning and adjustment for the network density. We benchmark ODEinherit on simulated data and apply it to live-cell, time-lapse microscopy data, where we track the expression dynamics of six proteins across 85 dividing S. cerevisiae cells over eight hours. Our results reveal substantial heterogeneity in inheritance rates among mother-daughter pairs, paving the way for applications in cellular stress response and cell-fate prediction studies across generations.

PMID:40631107 | PMC:PMC12236845 | DOI:10.1101/2024.11.23.624995

Front Psychol. 2025 Jun 24;16:1622757. doi: 10.3389/fpsyg.2025.1622757. eCollection 2025.

ABSTRACT

INTRODUCTION: Current research shows that there is no vitiligo quality-of-life measurement instrument suitable for Chinese patients. At present, the DLQI scale commonly used with vitiligo patients in China includes symptom dimensions or items that are not applicable to vitiligo patients. Therefore, it is necessary to develop a quality-of-life scale specific to vitiligo patients in China.

METHODS: In this study, the item pool was created through a comprehensive review of relevant literature, focus group discussions, and brainstorming. Two rounds of Delphi expert consultation and a semi-structured interview were conducted to modify the item pool and form the draft scale. Two rounds of questionnaire investigations were used to select items and form the final scale. The reliability, validity, and discriminative ability were evaluated based on the third round of questionnaire investigation.

RESULTS: The scale contains 3 dimensions and 25 items, and the total cumulative variance contribution rate was 64.54%. The Cronbach’s α coefficient was 0.972; the split-half reliability coefficient was 0.950, and the test-retest reliability coefficient was 0.776. The Spearman correlation coefficient with the Dermatology Life Quality Index (DLQI) was 0.650. The scores of the scale or each dimension were correlated with patient characteristics, including gender, disease course, disease stage, Body Surface Area (BSA), and white spot area.

CONCLUSION: This study developed the Chinese Vitiligo Quality of Life Scale (CVQLS) to measure the quality of life of vitiligo patients in China. Compared to the commonly used DLQI, the CVQLS removed items related to skin disease symptoms while incorporating concerns specific to Chinese patients, such as the economic burden. The scale is thus tailored to the needs of Chinese vitiligo patients. Preliminary results indicate that the CVQLS has good reliability, validity, and discriminative ability.

PMID:40631062 | PMC:PMC12236179 | DOI:10.3389/fpsyg.2025.1622757

JTCVS Open. 2025 Apr 15;25:264-274. doi: 10.1016/j.xjon.2025.03.021. eCollection 2025 Jun.

ABSTRACT

BACKGROUND: Cardiac surgery-associated acute kidney injury (CSA-AKI) is commonly observed after cardiac surgery and has been shown to be associated with increased morbidity and mortality. This study was conducted using the Kidney Disease Improving Global Outcomes (KDIGO) criteria to analyze potential perioperative biomarkers of CSA-AKI.

METHODS: Blood was collected from patients intraoperatively on entry into the pericardium and at 4, 12, 24, and 48 hours postoperatively. Repeated-measures, mixed-model analysis was conducted to determine which cytokines and/or chemokines were associated with postoperative CSA-AKI. LASSO regression and random forest modeling were used for variable selection and incorporation into a multivariable regression model.

RESULTS: There were no demographic or preoperative differences between patients with CSA-AKI and patients without CSA-AKI except for preoperative diabetes status, hemoglobin concentration, and CKD status. Additionally, there were no significant differences in preoperative medications between the 2 groups. Ten of the 40 biomarkers were statistically significant (P < .05) for the between-group main effect after repeated measures analysis: myoglobin, growth/differentiation factor 15 (GDF-15), neutrophil gelatinase-associated lipocalin (NGAL), haptoglobin, tumor necrosis factor alpha (TNFα), monocyte chemoattractant protein 1 (MCP-1), interleukin (IL)-1RA, IL-8, IL-6, and C-reactive protein. Multivariable stepwise regression showed the earliest independent predictors of postoperative AKI were 4-hour myoglobin (adjusted odds ratio [aOR], 1.61; 95% confidence interval [CI], 1.12-3.12; P = .036), 4-hour IL-1RA (aOR, 1.001; 95% CI, 1.000-1.001; P = .48), and 4-hour haptoglobin (aOR, 1.07; 95% CI, 1.03-1.18; P = .001).

CONCLUSIONS: Multiple cytokines were significantly elevated between the CSA-AKI group and the CSA-non-AKI group. Myoglobin, haptoglobin, and IL-1RA are potential blood biomarkers for AKI after cardiac surgery. Further research is needed to investigate the roles of these biomarkers and their associations with CSA-AKI.

PMID:40631034 | PMC:PMC12230585 | DOI:10.1016/j.xjon.2025.03.021

JTCVS Open. 2025 Apr 1;25:143-153. doi: 10.1016/j.xjon.2025.03.018. eCollection 2025 Jun.

ABSTRACT

BACKGROUND: Valvular heart disease (VHD)-associated heart failure (HF) remains an important and growing cause of morbidity and mortality. There are no contemporary data on the efficacy and safety of SGLT2 inhibitors in patients with a history of VHD.

METHODS: The EMPEROR-Pooled trial analyzed 9718 patients with HF who were enrolled in the randomized trials of empagliflozin versus placebo in HF with reduced left ventricular ejection fraction (HfrEF; EMPEROR-Reduced) and HF with preserved left ventricular ejection fraction (HFpEF; EMPEROR-Preserved). These trials evaluated a primary outcome of time to first HF hospitalization or cardiovascular death. Here we analyze outcomes of the EMPEROR-Pooled patients according to the presence and etiology of VHD history.

RESULTS: Of the 9717 patients enrolled in EMPEROR-Pooled with available data, 1484 (15.3%) had a history of VHD. Of the patients with VHD history, a history of isolated mitral disease (39.2%) was the most common subtype. In patients randomized to placebo, the risk of the primary outcome was higher among patients with VHD history (hazard ratio [HR], 1.30; 95% confidence interval [CI], 1.10-1.53; P < .01), and particularly those with a history of multivalvular disease (HR, 1.51; 95% CI, 1.13-2.04; P < .01) compared with no valvular disease. No heterogeneity was introduced by VHD history with respect to the efficacy of empagliflozin on all major clinical outcomes evaluated in EMPEROR-Pooled (P _interaction > .05).

CONCLUSIONS: We present the first large analysis of SGLT2i (empagliflozin) use in HF patients by history of VHD. Although VHD history was associated with worse outcomes in HF patients, empagliflozin demonstrated consistent safety, efficacy, and patient-reported outcomes across all categories of VHD history.

PMID:40631012 | PMC:PMC12230564 | DOI:10.1016/j.xjon.2025.03.018

J Innov Card Rhythm Manag. 2025 Jun 15;16(6):6307-6328. doi: 10.19102/icrm.2025.16065. eCollection 2025 Jun.

ABSTRACT

Atrial fibrillation (AF) ablation is a common treatment for symptomatic AF. Remote magnetic navigation (RMN) and manual catheter navigation (MCN) are two predominant techniques employed in this procedure, each with advantages and limitations. This meta-analysis compares the efficacy, safety, and procedural outcomes of RMN versus MCN for AF ablation. A comprehensive search was conducted across PubMed, Google Scholar, and Embase to identify relevant studies comparing RMN and MCN for AF ablation. Statistical pooling was done using Review Manager 5.4.1 (Cochrane Collaboration, London, UK). The Newcastle-Ottawa scale was used for the evaluation of bias in observational studies. We evaluated the robustness of the evidence following the guidelines outlined by the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) working group. The primary outcomes of the study included freedom from AF, procedure time, fluoroscopy time, and total complication rate in patients undergoing AF ablation either using the RMN or MCN technique. A total of 22 studies involving 5361 patients were included in the meta-analysis. The pooled analysis demonstrated comparable freedom from AF between RMN and MCN (relative risk [RR], 0.94; 95% confidence interval [CI], 0.84-1.04; P = .23). However, RMN was associated with a significantly prolonged procedure duration (mean difference [MD], 48.58; 95% CI, 31.49-65.66; P < .00001) and reduced fluoroscopy time (MD, -12.52; 95% CI, -17.84 to -7.20; P < .00001) compared to MCN. Additionally, RMN showed a trend toward lower total complication rates (RR, 0.63; 95% CI, 0.45-0.88; P = .007). In AF ablation, RMN and MCN exhibit comparable efficacy in achieving freedom from AF. However, RMN is associated with a prolonged procedure duration compared to MCN. Nonetheless, RMN offers advantages in terms of reduced fluoroscopy times and lower total complication rates, highlighting its potential for improving procedural safety. The choice between RMN and MCN should be made considering individual patient factors and procedural objectives.

PMID:40630984 | PMC:PMC12233321 | DOI:10.19102/icrm.2025.16065

BMC Sports Sci Med Rehabil. 2025 Jul 8;17(1):186. doi: 10.1186/s13102-024-01046-6.

ABSTRACT

OBJECTIVES: Video-based decision-making training is considered a promising intervention to enhance the decision-making skills of football referees. This study conducted a systematic review and meta-analysis to validate the effectiveness of video-based training and evaluate its overall impact on improving referees’ decision-making skills, providing a scientific basis for the optimization and innovation of referee training methods.

METHOD: A systematic search was performed across four electronic databases (EBSCO, PubMed, Scopus, and Web of Science). Inclusion and exclusion criteria were defined using the PICOS framework. Relevant literature was independently screened, and key information was extracted. The revised Cochrane risk-of-bias tool (RoB 2) was employed to assess the risk of bias in the included studies, and statistical analyses were conducted using CMA 3.0 software.

RESULT: Six randomized controlled trials (RCTs) involving a total of 163 participants were included. The meta-analysis revealed that video-based training significantly improved referees’ decision-making skills (Hedges’ s g = 1.718, 95% CI [1.058, 2.377], P < 0.001, τ² = 0.464). The overall risk of bias across the included studies was assessed as low to moderate, indicating a generally reliable methodological quality. Sensitivity analysis confirmed the robustness of the overall effect size.

CONCLUSION: This meta-analysis demonstrates that video-based decision-making training is an effective and practical intervention for significantly enhancing the decision-making skills of football referees. Its convenience and cost-effectiveness make it an essential supplementary training tool for referees. However, the findings are limited by factors such as the small sample size of included studies, incomplete descriptions of participant characteristics, and insufficient gender representation. Future high-quality research is needed to comprehensively evaluate the effectiveness of video-based training across referees of different levels and genders.

PMID:40629454 | DOI:10.1186/s13102-024-01046-6

Parasit Vectors. 2025 Jul 8;18(1):269. doi: 10.1186/s13071-025-06836-6.

ABSTRACT

BACKGROUND: Bed bugs (Cimex spp.) are obligate ectoparasites that have long been associated with human dwellings, causing discomfort and psychosocial distress. Conventional control strategies relying on insecticides are increasingly challenged by resistance, necessitating alternative interventions. Ivermectin, an endectocide known to impact various neglected tropical diseases and hematophagous arthropods, is currently being assessed for malaria vector control. This study aimed to evaluate the toxicity of ivermectin on Cimex hemipterus, the predominant bed bug species in Africa, within the framework of the Broad One Health Endectocide-based Malaria Intervention in Africa (BOHEMIA) project in Kwale, Kenya.

METHODS: A cross-sectional survey was conducted in 352 households to obtain information on self-reported bed bug infestations, socioeconomic status, and household characteristics. Bed bugs were collected from 40 infested households. After collection, bed bugs were acclimatized and exposed to blood meals spiked with ivermectin at five concentrations (85 ng/ml, 64 ng/ml, 43 ng/ml, 21 ng/ml, and 11 ng/ml), corresponding to expected serum levels 4 h to 6-7 days following a 400 µg/kg oral dose. Mortality and fecundity were monitored over a 14-day period. Statistical analyses, including Cox proportional hazard models and probit regression, were applied to assess dose-response relationships.

RESULTS: Bed bug infestation was common, with 75% of participating households reporting their presence, with infestations being strongly associated with the number of people residing in a household. Ivermectin exposure resulted in significant dose-dependent mortality in Cimex hemipterus, with the higher concentrations (43, 64, and 85 ng/ml) inducing over 90% mortality within 3 days postfeeding. Bed bugs that ingested blood meals containing sublethal doses of ivermectin did not lay eggs. Kaplan-Meier survival analyses demonstrated a clear inverse relationship between ivermectin concentration and bed bug survival.

CONCLUSIONS: These findings provide evidence that ivermectin, administered as part of a mass drug administration campaign, could contribute to bed bug control alongside its intended impact on other diseases or vectors. The results underscore the potential for integrated public health approaches leveraging endectocide interventions. Further field evaluations in diverse locations are needed to determine the optimal number of administrations and treatment intervals required for complete infestation elimination.

PMID:40629452 | DOI:10.1186/s13071-025-06836-6

Ital J Pediatr. 2025 Jul 8;51(1):213. doi: 10.1186/s13052-025-01927-7.

ABSTRACT

BACKGROUND: Intraventricular hemorrhage (IVH) is a serious complication of prematurity with a potential impact on morbidity and mortality particularly in very low birth weight neonates. Despite advances in neonatal care over recent years, there is no recent data regarding IVH in our setting. This study aimed to determine the proportion of IVH, its associated factors, and mortality at Muhimbili National Hospital (MNH).

METHODS: A hospital-based prospective cohort study was conducted among preterm very low birth weight neonates admitted at MNH. Data was obtained from interviews, physical examination, review of maternal antenatal cards, and neonatal records. Cranial ultrasound was done on day 3 and day 7 of life to determine the presence and severity of IVH. Mortality of neonates was determined on day 7. Data were summarised using frequencies, percentages, median, and interquartile range. Chi-square and Fisher’s exact were used to measure the association between categorical variables. Variables found to be significantly associated with IVH were analysed by Poisson regression. A p-value of 0.05 or less was considered statistically significant.

RESULTS: The proportion of VLBW neonates with IVH was 22.9% with grade 1 being the most prevalent. The majority of IVH (74.7%) occurred within the first 3 days of life. Factors found to increase the risk of IVH in the univariate analysis were gestational age, mode of delivery, respiratory distress syndrome, hypothermia, early-onset sepsis, use of inotropes, thrombocytopenia and mechanical ventilation. However, none of these factors were independent predictors of IVH in multivariate Poisson regression analysis. Mortality of VLBW neonates with IVH was significantly higher than their counterparts without IVH (RR = 2,95% CI (1.25-3.34).

CONCLUSIONS: IVH is common among VLBW neonates most of which occurred by day 3 of life. The risk of Mortality was two times higher among VLBW neonates with IVH compared to those without IVH. Further research should be conducted to explore predictors of mortality and long-term outcome of VLBW neonates with IVH.

PMID:40629448 | DOI:10.1186/s13052-025-01927-7