Nevin Manimala

J Chem Theory Comput. 2025 Mar 13. doi: 10.1021/acs.jctc.4c01774. Online ahead of print.

ABSTRACT

Protein evolution has shaped enzymes that maintain stability and function across diverse thermal environments. While sequence variation, thermal stability and conformational dynamics are known to influence an enzyme’s thermal adaptation, how these factors collectively govern stability and function across diverse temperatures remains unresolved. Cytosolic malate dehydrogenase (cMDH), a citric acid cycle enzyme, is an ideal model for studying these mechanisms due to its temperature-sensitive flexibility and broad presence in species from diverse thermal environments. In this study, we employ techniques inspired by deep learning and statistical mechanics to uncover how sequence variation and conformational dynamics shape patterns of cMDH’s thermal adaptation. By integrating coevolutionary models with variational autoencoders (VAE), we generate a latent generative landscape (LGL) of the cMDH sequence space, enabling us to explore mutational pathways and predict fitness using direct coupling analysis (DCA). Structure predictions via AlphaFold and molecular dynamics simulations further illuminate how variations in hydrophobic interactions and conformational flexibility contribute to the thermal stability of warm- and cold-adapted cMDH orthologs. Notably, we identify the ratio of hydrophobic contacts between two regions as a predictive order parameter for thermal stability features, providing a quantitative metric for understanding cMDH dynamics across temperatures. The integrative computational framework employed in this study provides mechanistic insights into protein adaptation at both sequence and structural levels, offering unique perspectives on the evolution of thermal stability and creating avenues for the rational design of proteins with optimized thermal properties.

PMID:40079215 | DOI:10.1021/acs.jctc.4c01774

Infect Control Hosp Epidemiol. 2025 Mar 13:1-6. doi: 10.1017/ice.2025.9. Online ahead of print.

ABSTRACT

BACKGROUND: Concerns about penicillin-cephalosporin cross-reactivity have historically led to conservative prescribing and avoidance of cephalosporins in patients with penicillin allergy labels, potentially causing suboptimal outcomes. Recent evidence suggests a lower risk of cross-reactivity, prompting a reassessment of alert systems.

OBJECTIVE: To assess the impact of limited penicillin cross-reactivity alerts on outpatient cephalosporin use and the incidence of adverse reactions in a healthcare setting.

METHODS: This retrospective cohort study compared cephalosporin prescribing and adverse reactions in patients labeled as penicillin-allergic before and after limiting penicillin cross-reactivity alerts in the electronic medical record at a large academic medical center.

RESULTS: Among 17,174 patients (8,131 pre- and 9,043 post-implementation), there was a statistically significant increase in outpatient cephalosporin prescribing by 8% (P < .001). The use of alternative antibiotic classes decreased. There was no statistically significant increase in adverse events pre- and post-implementation (0.036%-0.058%, P = .547), and no severe events were attributable to cross-reactivity. The alert modification reduced alerts by 92% (P < .001).

CONCLUSION: The reduction of penicillin-cephalosporin cross-reactivity alerts was associated with increased cephalosporin use, without a significant increase in adverse reactions. This demonstrates that the practice is safe and decreases alert burden.

PMID:40079207 | DOI:10.1017/ice.2025.9

Birth Defects Res. 2025 Mar;117(3):e2463. doi: 10.1002/bdr2.2463.

ABSTRACT

BACKGROUND: Congenital heart defects (CHDs) are the most prevalent birth defects globally and the second leading cause of death in Mexican children under five. This study examines how industrial activity and social vulnerabilities independently and jointly influence CHD incidence across 2446 Mexican municipalities from 2008 to 2019.

METHODS: Using negative binomial regression models, we evaluated associations between polluting industries, healthcare access, and CHD incidence. We analyzed these factors independently, jointly, and through interaction terms to assess potential effect modification by healthcare access. Incidence rate ratios (IRRs) and 95% confidence intervals were estimated across healthcare access strata.

RESULTS: Municipalities without healthcare facilities were more likely to host polluting industries, highlighting structural inequities. The presence of polluting industries was associated with increased CHD incidence, even after adjusting for healthcare access. For instance, municipalities with poor healthcare access and two or more polluting industries exhibited a 42% higher CHD incidence (IRR = 1.42, 95% CI: 1.25-1.60) compared to a 26% increase in municipalities with better healthcare access (IRR = 1.26, 95% CI: 1.02-1.57).

CONCLUSIONS: These results show how environmental pollutant exposure and social vulnerabilities interact synergistically, disproportionately impacting socially vulnerable populations. Targeted policy interventions addressing both environmental pollution and healthcare inequities are crucial. Further research is also needed to clarify the mechanisms linking pollution to CHDs and to guide public health strategies aimed at reducing these disparities in Mexico.

PMID:40079194 | DOI:10.1002/bdr2.2463

BJOG. 2025 Mar 13. doi: 10.1111/1471-0528.18119. Online ahead of print.

ABSTRACT

BACKGROUND: Many studies have developed or validated prediction models to estimate the risk of stress urinary incontinence (SUI) in pregnant and postpartum women, but the quality of the model development and model applicability remains unknown.

OBJECTIVES: To systematically review and critically evaluate currently available prediction models for SUI in pregnant and postpartum women.

SEARCH STRATEGY: Cochrane Library, EBSCO, PubMed, Web of Science, EMBASE, Chinese CNKI, Wanfang and VIP databases were searched from inception until February 2024.

SELECTION CRITERIA: Prospective cohort or retrospective studies were considered eligible if they developed or validated prediction models for SUI in pregnant or postpartum women.

DATA COLLECTION AND ANALYSIS: Two reviewers independently screened the literature, extracted data and evaluated the quality of the included studies using PROBAST.

MAIN RESULTS: A total of 15 models were included. Eleven models were internally validated, including cross-validation and bootstrap and four models were externally validated. The most commonly used predictors were age, body mass index (BMI) and mode of delivery. The area under the curve or C-statistics reported by the modelling and validation groups ranged from 0.602 to 0.888. Only one study had a low risk of bias and 14 studies had a high risk of bias.

CONCLUSIONS: Fourteen models for predicting SUI in pregnant and postpartum women had a high risk of bias according to the PROBAST. Future research should focus on improving the methodological quality of the existing prediction models and developing new models.

PMID:40079163 | DOI:10.1111/1471-0528.18119

Arterioscler Thromb Vasc Biol. 2025 Mar 13. doi: 10.1161/ATVBAHA.124.320259. Online ahead of print.

ABSTRACT

There is a recent dramatic increase in research on thoracic aortic diseases that includes aneurysms, dissections, and rupture. Experimental studies predominantly use mice in which aortopathy is induced by chemical interventions, genetic manipulations, or both. Many parameters should be deliberated in experimental design in concert with multiple considerations when providing dimensional data and characterization of aortic tissues. The purpose of this review is to provide recommendations on guidance in (1) the selection of a mouse model and experimental conditions for the study, (2) parameters for standardizing detection and measurements of aortic diseases, (3) meaningful interpretation of characteristics of diseased aortic tissue, and (4) reporting standards that include rigor and transparency.

PMID:40079138 | DOI:10.1161/ATVBAHA.124.320259

J Biopharm Stat. 2025 Mar 13:1-22. doi: 10.1080/10543406.2024.2444242. Online ahead of print.

ABSTRACT

The restricted mean survival time has been widely used in the field of medical research because of its clear physical and simple clinical interpretation. In this paper, we propose an efficient estimation that incorporates the auxiliary restricted mean survival information into the estimation of the proportional hazard (PH) model. Compared to conventional models that do not incorporate available auxiliary information, the proposed method improves efficiency in estimating regression parameters by utilizing the double empirical likelihood method. We prove that the estimator asymptotically follows a multivariate normal distribution with a covariance matrix that can be consistently estimated. To address scenarios where the PH assumption is violated, we also extended the method to the stratified Cox model. In addition, simulation studies show that the proposed estimators are more efficient than those derived from the conventional partial likelihood approach. A type 2 diabetes dataset is then used to evaluate the risk of antidiabetic drugs and demonstrate the proposed method.

PMID:40079137 | DOI:10.1080/10543406.2024.2444242

Psychol Med. 2025 Mar 13;55:e85. doi: 10.1017/S0033291725000455.

ABSTRACT

BACKGROUND: Population-level preventive interventions are urgently needed and may be effective for psychosis due to social determinants. We tested three syndemic models along pathways from childhood adversity (CA) to psychotic spectrum disorder (PSD) and their implications for prevention.

METHODS: Cross-sectional data from 7461 British men surveyed in 5 population subgroups. We tested interactions on both additive and multiplicative scales for a syndemic of violence/criminality (VC), sexual behavior (SH), and substance misuse (SM) according to the presence of CA and adult traumatic life events; mediation analysis of path models; and partial least squares path modeling, with PSD as outcome.

RESULTS: Multiplicative synergistic interactions were found between VC, SH, and SM among men, who experienced CA and traumatic adult life events. However, when disaggregated, only SM mediated the pathway from CA to PSD. Path modeling showed traumatic life events acted on PSD through the syndemic and had no direct effect on PSD. Higher syndemic scores and living in areas of deprivation characterized men with PSD and CA.

CONCLUSIONS: Our findings support a broad division of PSD into cases due to (i) biological/inherent causes, and (ii) social determinants, the latter including a syndemic pathway determined by CA. Preventive strategies should focus primarily on preventing adverse effects of CA on developmental pathways which result in PSD. Single component prevention strategies may prevent triggering effects of SM on PSD during adolescence/early adulthood among vulnerable individuals due to CA. Future research should determine applicability and transferability of interventions based on these findings to different populations, specifically those experiencing syndemics.

PMID:40079091 | DOI:10.1017/S0033291725000455

Curr Med Res Opin. 2025 Mar 13:1-17. doi: 10.1080/03007995.2025.2478160. Online ahead of print.

ABSTRACT

BACKGROUND: Systemic lupus erythematosus (SLE) is a multifaceted autoimmune disorder that significantly impacts renal function. Despite conventional treatments, morbidity and mortality remain high, necessitating the exploration of safer and more effective therapies, including the potential benefits of Traditional Chinese Medicine (TCM) for improving kidney health and survival rates.

METHODS: Patients with newly diagnosed with SLE with catastrophic illness certificate were retrospectively enrolled from CGRD between 2005 and 2020. Patients were stratified into groups based on TCM treatment post-diagnosis. Outcomes measured included end-stage renal disease (ESRD) incidence and all-cause mortality, using Cox proportional hazard models and Kaplan-Meier analysis for statistical evaluation.Results Among 10462 newly diagnosed SLE patients, 1831 had received at least 28 days of TCM treatment, while 7966 had not received TCM treatment. After propensity score matching, there were equally 1831 individuals in each group, with no significant baseline differences in age, sex, biochemical profiles and comorbidities. TCM usage was associated with a significantly reduced rate of ESRD over a 0.5-year follow-up (adjusted hazard ratio (aHR): 0.24; 95% confidence interval (CI): 0.07-0.80, p = 0.02), with a trend that persisted over five years. TCM group’s proteinuria was significantly lower than that of the non-TCM group at various time points post-index date, including 6 months (174.98 mg vs. 248.09 mg, p < 0.001), 1 year (161.05 mg vs. 303.03 mg, p < 0.001), 3 years (150.26 mg vs. 250 mg, p = 0.03), and 10 years (147.06 mg vs. 190.75 mg, p = 0.03). After adjusting for confounding covariates, TCM users had a significantly decreased risk of mortality (aHR 0.70, 95% CI 0.58-0.83).

CONCLUSION: Integrating TCM with conventional treatment could lower risk of ESRD and mortality, highlighting the potential for a more holistic approach to patient care for SLE.

PMID:40079084 | DOI:10.1080/03007995.2025.2478160

J Biopharm Stat. 2025 Mar 13:1-6. doi: 10.1080/10543406.2025.2473612. Online ahead of print.

ABSTRACT

Conventionally, the product quality specification and control chart limits are determined as the mean plus and minus 3 sample standard deviations with the assumption that the quality data is normally distributed. These limits correspond to an interval centered at the mean, covering approximately 97.3% of the population. The estimate of such an interval is called the $\beta$-content tolerance interval. It has been proposed to use a two one-sided $\beta$-content tolerance interval approach for determining drug product quality specifications. For a given confidence level, $1–\alpha ,$ and a coverage percentage p, the $\beta$-content tolerance interval is not precise when the sample size is small. For the derivation of a precise $\beta$-content tolerance interval, Faulkenberry and Daly proposed a “goodness” criterion for sample size determination. In order to avoid overestimating the $\beta$-content tolerance interval when p is large, we propose to define the precision requirement as the probability of the tolerance interval covering more than $\frac{\left(1+p\right)}{2}$ is restricted to a pre-specified significance level ${\alpha }^{‘}$. Quality specification studies are often not planned with proper sample sizes. To obtain precise $\beta$-content tolerance intervals for quality specification studies, the proper coverage p satisfying the “goodness” criterion and the minimum sample sizes were also determined with the pre-specified significance level ${\alpha }^{‘}$. With this approach, one may properly set the product specificationwhile avoiding over-specifying the quality limits.

PMID:40079049 | DOI:10.1080/10543406.2025.2473612

Front Pediatr. 2025 Feb 26;13:1444471. doi: 10.3389/fped.2025.1444471. eCollection 2025.

ABSTRACT

BACKGROUND: With advances in perinatal medicine, there has been a rise in the preterm birth rate, especially the rate of very low birth weight (VLBW) and extremely low birth weight infants. Studies have shown that maternal age during pregnancy and at the time of delivery is associated with pregnancy complications and poor neonatal outcomes. Little is known about the effect of maternal age on the outcome of very low birth weight infants.

OBJECTIVES: To investigate the effects of maternal age on the adverse outcomes of singleton very low birth weight neonates.

METHODS: We used data of VLBW infants from the neonatal database of our hospital. Maternal age was categorized as 20-24, 25-34 (reference group), 35-39 and ≥40 years. Statistical analyses included univariate and multivariate logistic regression analysis.

RESULTS: The study ultimately included 603 singleton, very low birth weight infants. After adjustment, neonatal outcomes in the group of older mothers were similar to those of the reference group for bronchopulmonary dysplasia, necrotizing enterocolitis, respiratory distress syndrome, severe asphyxia, retinopathy of prematurity and intraventricular hemorrhage grades 3-4. In the 20-24 year age group higher odds were present for sepsis [Odds ratio (OR) = 6.021; 95% confidence interval (CI), 1.741-20.818, p < 0.05] and for mortality (OR = 7.784; 95% CI, 2.198-27.568, p < 0.05). Higher odds for asphyxia (OR = 1.891; 95% CI, 1.238-2.890, p < 0.05) and death (OR = 2.101, 95% CI, 1.004-4.395, p < 0.05) were observed in infants of mothers in the 35-39 year age group. The incidence of sepsis was significantly higher in the age group of ≥40 years (OR = 2.873; 95% CI, 1.186-6.958, p < 0.05).

CONCLUSIONS: In singleton very low birth weight neonates, neonatal outcomes were associated with maternal age, and adverse outcomes were more pronounced in infants of advanced maternal age (AMA) mothers.

PMID:40079033 | PMC:PMC11897033 | DOI:10.3389/fped.2025.1444471