Nevin Manimala

Crit Rev Eukaryot Gene Expr. 2026;36(1):1-17. doi: 10.1615/CritRevEukaryotGeneExpr.2025062255.

ABSTRACT

BACKGROUND: Colorectal cancer (CRC) remains a major global health burden, and genetic factors such as vitamin D receptor (VDR) polymorphisms have been implicated in its pathogenesis. However, the translational relevance of these variants in clinical risk stratification remains unclear.

METHODS: We conducted a comprehensive meta-analysis of case-control studies assessing the association between four common VDR single-nucleotide polymorphisms (Fok1, Apa1, Bsm1, and Taq1) and CRC risk, integrating data from PubMed, Embase, Google Scholar, and other sources through 2024. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated under multiple genetic models. Heterogeneity, publication bias, and sensitivity analyses were performed. Statistical power was evaluated using G*Power 3.1.

RESULTS: Across 24 datasets from diverse ethnic populations, no significant associations were observed for any of the four VDR variants in allelic, dominant, recessive, or overdominant models. Statistical power exceeded 0.99 for all variants, indicating that the null results were unlikely due to sample size limitations.

CONCLUSION: This study provides robust evidence that these common VDR polymorphisms are not clinically functional as biomarkers for CRC susceptibility. Eliminating these variants from biomarker panels can help redirect resources toward more promising genetic or molecular predictors. These findings also reinforce the need for integrative studies exploring gene-environment interactions, particularly vitamin D status, diet, and lifestyle, to clarify the role of vitamin D pathways in CRC prevention and treatment.

PMID:41824933 | DOI:10.1615/CritRevEukaryotGeneExpr.2025062255

Medicine (Baltimore). 2026 Mar 13;105(11):e47975. doi: 10.1097/MD.0000000000047975.

ABSTRACT

Prostate cancer is one of the most common and serious cancers among Iranian men. Given the high prevalence of opium use in Iran and its classification as a group 1 carcinogen, understanding its potential association with prostate cancer is of clinical and public health importance. This study aimed to evaluate the relationship between opium consumption and pathological findings of prostate biopsy among men referred to Shahid Bahonar Hospital in Kerman. This retrospective cross-sectional study included 441 men who underwent prostate biopsy between 2014 and 2019 due to elevated prostate-specific antigen (PSA > 4 ng/mL) or abnormal digital rectal examination. Patients with a previous diagnosis of prostate cancer, history of pelvic radiotherapy, or a family history of prostate cancer were excluded. Participants were categorized into opium users (n = 143) and non-users (n = 298) based on self-reported opium consumption. Demographic characteristics, PSA levels, prostate volume, Gleason score, clinical and pathological stage, and risk group were extracted from medical records. Statistical analyses were performed using independent t-test and chi-square test with a significance level of .05. There were no significant differences in age or body mass index between the 2 groups (P > .05). The proportion of biopsy-confirmed prostate cancer was significantly higher in non-users (63.8%) compared with opium users (53.1%; P = .033). Mean PSA level was also significantly higher in non-users (54.22 ± 1.64) than in opium users (52.28 ± 2.64; P = .046). No significant differences were observed between the groups regarding prostate volume, Gleason score, clinical stage, pathological stage, or risk group classification (P > .05). Opium consumption was not associated with more advanced clinical or pathological features of prostate cancer. However, opium users showed lower PSA levels and a lower rate of cancer detection compared with non-users, suggesting that opium may influence PSA levels and potentially affect prostate cancer detection. Further studies are recommended to clarify the biological effects of opium on PSA and diagnostic accuracy.

PMID:41824892 | DOI:10.1097/MD.0000000000047975

Medicine (Baltimore). 2026 Mar 13;105(11):e47986. doi: 10.1097/MD.0000000000047986.

ABSTRACT

Examining pediatric hospitalization profile is important for healthcare planning and provision. The aim of this study was to identify the most common causes of hospitalization for the pediatric population in Australia between 1998 and 2019. This was an ecological study that examined the hospitalization profile for pediatric population in Australia using the National Hospital Morbidity Database. Between 1998 and 2019, there were 16,966,610 reported hospital admission episodes among the pediatric population in Australia. The number of annual admissions increased by 23.0%. Children who were admitted to the hospital for overnight-stay admissions comprised 55.9% of all admissions. Rates of same-day hospital admission among pediatrics increased by 22.1% [from 5596.7 (95% confidence interval [CI]: 5577.0-5616.4) in 1998 to 6832.1 (95% CI: 6812.3-6851.9) in 2019 per 100,000 persons, P ≤ .05]. Rates of overnight-stay hospital admission among pediatrics declined by 9.7%. Diseases of the respiratory system accounted for 15.1% of all hospital admissions. Hospital admission rates among females rose by 6.1% [from 13294.5 (95% CI: 13,252.8-13,336.2) in 1998 to 14,105.5 (95% CI: 14,066.2-14,144.7) in 2019 per 100,000 persons], compared to a 0.1% increase among males. While pediatric hospital admission counts increased substantially, the overall hospitalization rate remained largely stable. Important shifts were observed, including a rise in same-day admissions and higher admission rates among females. The predominance of respiratory conditions in young children and increasing hospitalizations in adolescents, particularly females, highlights the need for targeted strategies such as improved respiratory infection prevention, early parental guidance for acute illness, injury prevention programs, and expanded youth mental health services.

PMID:41824890 | DOI:10.1097/MD.0000000000047986

Medicine (Baltimore). 2026 Mar 13;105(11):e47990. doi: 10.1097/MD.0000000000047990.

ABSTRACT

BACKGROUND: The adaptogenic effects of Ashwagandha root extract are evident. An earlier study showed the therapeutic effects of a once-daily sustained-release (SR) formulation (300 mg) of Ashwagandha root extract over an extended period. This study aimed to evaluate the efficacy and safety of Ashwagandha root extract sustained-release (AshwaSR) 150 and 300 mg capsules in reducing stress in healthy adult, stressed subjects.

METHODS: In this double-blind, randomized, placebo-controlled trial, healthy subjects with Perceived Stress Scale score 14 to 26 were randomized (1:1:1) to AshwaSR 150 mg (group A) or 300 mg (group B) or placebo (group C). Change from baseline to day 60 was evaluated for stress levels, sleep quality, psychological well-being, eating behavior, and serum cortisol levels in all groups.

RESULTS: Of 135 subjects randomized, 126 completed the trial (mean age, 34.79 ± 8.16 years). Mean Perceived Stress Scale scores significantly reduced from baseline to day 60 in group A and B (mean change, 38.6% and 41.6% respectively; P < .001). Sleep quality, psychological well-being, and eating behavior significantly improved from baseline to day 60 in groups A and B (P < .001). Serum cortisol levels in group B were significantly reduced on day 60 (P < .05). Both group A and B showed significant improvements in stress levels, sleep quality, psychological well-being, and eating behavior at day 60 (P < .05) compared to group C. No safety concerns were reported.

CONCLUSION: AshwaSR 150 and 300 mg capsules reduced perceived stress and improved sleep quality, eating behavior, and psychological well-being and were safe in healthy adult, stressed subjects over 60 days of administration.

PMID:41824889 | DOI:10.1097/MD.0000000000047990

Medicine (Baltimore). 2026 Mar 13;105(11):e48006. doi: 10.1097/MD.0000000000048006.

ABSTRACT

Caregivers of individuals with rare genetic diseases experience substantial and persistent challenges that negatively affect their quality of life (QoL) and increase their burden. This study explored factors associated with caregiver QoL and burden in South Korea, focusing on patient characteristics, treatment availability, and genetic counseling experience. A cross-sectional survey was conducted with 159 caregivers of patients with rare genetic diseases at a tertiary general hospital. Caregiver QoL and burden were measured using the Caregiver QoL Scale and the Korean version of the Burden Assessment Scale. Demographic and clinical characteristics were also collected. Statistical analyses were performed using R software. Group differences were evaluated using Welch t tests, Wilcoxon rank-sum tests, and one-way analysis of variance with post hoc tests. Correlation analyses examined associations between QoL and caregiver burden. Caregiver QoL was significantly higher among those caring for minors, whereas caregiver burden was significantly higher among those caring for patients with registered disabilities. Treatment availability was associated with higher caregiver QoL and lower burden. Disease category also influenced outcomes: caregivers of patients with progressive conditions and localized impairments reported significantly lower QoL than those caring for patients with chronic conditions with effective treatment or symptomatic care or stable conditions with disabilities. Conversely, caregivers of patients with fatal diseases lacking effective treatment reported significantly higher burden than those caring for patients with chronic conditions with effective treatment. Caregiver QoL and burden were strongly and negatively correlated. Most caregivers (68.6%) had no prior genetic counseling experience, although those with counseling experience reported higher family openness scores, a QoL subdomain. Caregiver QoL and burden are closely linked to patient characteristics, treatment availability, and contextual caregiving demands. Expanding access to effective treatments, improving service accessibility, and integrating genetic counseling into caregiver support systems may improve the well-being of families affected by rare genetic diseases.

PMID:41824885 | DOI:10.1097/MD.0000000000048006

Eur J Endocrinol. 2026 Mar 13:lvag050. doi: 10.1093/ejendo/lvag050. Online ahead of print.

ABSTRACT

OBJECTIVE: Adiposity rebound is the first rise in BMI that occurs after the initial decrease during infancy. Early adiposity rebound, before age 5, is a risk factor for later obesity and metabolic problems. We investigated adiposity rebound in children with Congenital Adrenal Hyperplasia due to 21-hydroxylase deficiency (CAH).

DESIGN: Longitudinal observational registry study.

METHODS: Height, weight and BMI from patients younger than 20 years in the I-CAH Registry was described by non-linear mixed-effects models. Covariates of glucocorticoid dose, mineralocorticoid dose, 17-Hydroxyprogesterone were assessed on growth and bone age.

RESULTS: A total of 10,261 visits within 573 patients (43.6% male) showed significant variation in age at latest peak height velocity (8.4 years (SD = 3.0) in boys; 9.0 years (SD = 1.6) in girls). Peak height velocity was more blunted in boys (7.7 cm/year (SD = 1.4)) than girls (7.4 cm/year (SD = 1.3)) in comparison to normative values. Adiposity rebound occurred earlier than age 5 years in 82% of the cohort, mean age 3.7 years (SD = 1.3) in boys and 3.9 years (SD = 0.9) in girls. Girls prescribed higher doses of glucocorticoid were associated with heavier weight in adolescence and earlier adiposity rebound. Bone age was increasingly advanced in those prescribed higher doses in both sexes.

CONCLUSIONS: There is a large variation in the timing of adiposity rebound and SITAR-estimated latest peak height velocity in children with CAH. In addition to identifying individuals with CAH who may be at risk of adverse cardiometabolic outcomes these metrics may serve as early surrogate outcomes in future research investigating early-life treatment strategies.

PMID:41823987 | DOI:10.1093/ejendo/lvag050

JAMA Netw Open. 2026 Mar 2;9(3):e260692. doi: 10.1001/jamanetworkopen.2026.0692.

ABSTRACT

IMPORTANCE: An increasing number of older adults living with frailty are undergoing surgery, yet scarce data on postoperative functional recovery, care needs after surgery, and extent of caregiver supports exist.

OBJECTIVE: To characterize older adults’ and caregivers’ recovery experiences in the first 6 months after surgery.

DESIGN, SETTING, AND PARTICIPANTS: This mixed-methods, multicenter, prospective nested cohort study included 17 hospitals in Canada. Participants included adults aged 65 years or older with a Clinical Frailty Scale score of 4 or more, who were recovering after major elective noncardiac surgery between March 16, 2021, and June 13, 2023, and their caregivers.

MAIN OUTCOMES AND MEASURES: Surveys included functional status via basic and instrumental activities of daily living, care needs, and care received or provided. A subset of patients and caregivers were invited to participate in semistructured interviews about their experiences and were analyzed using interpretive descriptive qualitative analysis.

RESULTS: There were 289 individuals, including 204 older adults (mean [SD] age, 72.8 [5.6] years; 108 males [52.9%]) and 85 caregivers (mean [SD] age, 68.2 [12.2] years; 50 females [59.5%]), who participated in surveys, and 63 individuals (43 older adults and 20 caregivers) who participated in interviews. Older adults had a median (range) Clinical Frailty Score of 4 (3-6), indicating mild frailty, and 190 (93.1%) had 1 or more chronic diseases. Caregivers had a median (range) of 2 (0-8) chronic diseases, and 69 (82%) were spouses. Two months postoperatively, 129 of 203 older adults (64%) had more than 1 instrumental activities of daily living impairment, decreasing to 84 of 198 (42%) at 6 months after surgery; 68 of 203 (33%) had more than 1 activities of daily living impairment 2 months postoperatively, and this decreased to 38 of 198 (19%) at 6 months after surgery. Themes related to the recovery experiences were: (1) inadequate patient and caregiver education, preparation for surgery, and discharge; (2) the association of reduced independence with patient and caregivers; (3) the association of surgery with mental health; and (4) postoperative support from the health care team. All participants indicated that they wanted to be better prepared for surgery and discharge.

CONCLUSION AND RELEVANCE: In this mixed-methods cohort study, functional recovery in the first 6 months after noncardiac major elective surgery was associated with daily living impairment for older adults and their caregivers. Targeted interventions including preoperative education, caregiver-inclusive discharge planning (eg, wound-care teaching, how to recognize complications and what to do for support, and more rehabilitation), and early follow-up after discharge may optimize recovery experiences.

PMID:41823967 | DOI:10.1001/jamanetworkopen.2026.0692

JAMA Netw Open. 2026 Mar 2;9(3):e261641. doi: 10.1001/jamanetworkopen.2026.1641.

ABSTRACT

IMPORTANCE: Inappropriate antimicrobial use is a major but modifiable contributor to antimicrobial costs and harms. To address this global threat, many countries have implemented national stewardship programs. However, the cost-effectiveness of such programs targeting primary care physicians remains unknown.

OBJECTIVE: To determine the economic value of an antibiotic audit and feedback (A&F) program from a Canadian public payer perspective.

DESIGN, SETTING, AND PARTICIPANTS: This economic evaluation used data from a randomized clinical trial of primary care physicians in Ontario, Canada, in which a mailed A&F intervention reduced antibiotic prescribing among patients 65 years and older. Trial data were linked with administrative databases to estimate the program costs and savings from reduced antibiotic use, adverse events, and undertreatment harms. A decision model was developed to calculate monetary costs and benefits. Data were collected from January 1 to July 1, 2022, and were analyzed from March 1 to April 1, 2025. All costs are reported in 2024 Canadian dollars.

INTERVENTION: A mailed A&F letter sent to primary care physicians with their antibiotic prescribing rate compared with their peers, with additional messaging about the harms of unnecessary antibiotics.

MAIN OUTCOMES AND MEASURES: Net costs and benefits, return on investment (ROI), and probability of achieving a positive ROI (>1). Uncertainty was explored using probabilistic analysis with 5000 simulations and deterministic sensitivity analyses.

RESULTS: The study included 4879 primary care physicians, of whom 2711 (55.6%) were male, with a mean (SD) of 25.0 (13.3) years since medical school graduation. The program cost was $5.50 per physician and generated $43.03 in savings. The ROI was $8.82 (95% uncertainty interval, $1.32-$22.56) per dollar invested. The probability that the antibiotic A&F program provided an ROI greater than 1 was 93.2%. Scaling the program to all primary care physicians in Ontario would further improve the estimated ROI. Results were robust across sensitivity analyses.

CONCLUSIONS AND RELEVANCE: In this economic evaluation of a mailed antibiotic A&F intervention, the intervention was associated with substantial economic and clinical value. These findings support A&F as a scalable, low-cost component of antimicrobial stewardship programs and highlight its potential to optimize prescribing and reduce antimicrobial resistance.

PMID:41823966 | DOI:10.1001/jamanetworkopen.2026.1641

JAMA Netw Open. 2026 Mar 2;9(3):e261703. doi: 10.1001/jamanetworkopen.2026.1703.

ABSTRACT

IMPORTANCE: Transfers of deceased organ donors from acute care hospitals to specialized donor care units (DCUs) offer operational and outcome advantages; however, current access to DCUs is limited and geographically uneven. Expanding access to DCUs may improve donation system efficiency.

OBJECTIVE: To evaluate the geographic distribution of operating DCUs relative to acute care hospitals and explore how to most efficiently operationalize recommendations that a DCU operate in every donation region.

DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study analyzed deceased organ donor and hospital data captured in the Organ Procurement and Transplantation Network and American Hospital Association survey databases from January 1, 2018, to December 31, 2023. Acute-care hospitals and DCUs operating in the continental US and adult (aged ≥18 years) organ donors with brain death managed in acute care hospitals located in 2203 zip codes were included. The data analysis was performed between October 1, 2024, and December 1, 2025.

EXPOSURES: Geographic location of organ donor hospitals.

MAIN OUTCOMES AND MEASURES: The main outcome was the optimal number of DCUs required to enable transportation of all cohort donors from acute care hospitals to DCUs via ambulance (within a 180-minute drive). The number of additional DCUs needed to operationalize recommendations of a DCU in every donation region was quantified with and without consideration for donation service area boundaries using location-allocation modeling.

RESULTS: Between 2018 and 2023, 53 093 deceased donors met the inclusion criteria (mean [SD] age, 44.3 years [15.0]; 60.0% male). Among the cohort, 61.9% of donors were managed in acute care hospitals within driving distance of 34 operating DCUs. In the current system with distinct donation service area boundaries, an additional 38 DCUs were estimated to provide plausible access to 92.7% of donors. If donation service area boundaries were ignored, 22 new DCUs were estimated to provide a referral facility for a larger proportion of donors (96.5%).

CONCLUSIONS AND RELEVANCE: This cohort study found that despite their reported advantages and consensus endorsement, heterogeneous adoption of DCUs has left a substantial proportion of deceased donors after brain death more than a 180-minute drive from a DCU. Given inefficiencies introduced by donation service area boundaries, opening additional DCUs in acute care hospitals and donor transport across these existing boundaries may be 2 potential approaches to improve system efficiency and donation outcomes.

PMID:41823965 | DOI:10.1001/jamanetworkopen.2026.1703

JAMA Netw Open. 2026 Mar 2;9(3):e261741. doi: 10.1001/jamanetworkopen.2026.1741.

ABSTRACT

IMPORTANCE: Diagnosing urinary tract infection (UTI) in preverbal, pre-toilet trained children is challenging and may lead to unnecessary testing and treatment. UTICalc estimates UTI risk using clinical and laboratory data but has not been prospectively validated.

OBJECTIVES: To prospectively validate UTICalc version 3.0 for predicting UTI and to evaluate its utility in guiding clinical decisions.

DESIGN, SETTING, AND PARTICIPANTS: This prospective diagnostic study was conducted at 2 tertiary care pediatric emergency departments (EDs) in Canada from November 2022 to January 2025. Children aged 2 to 24 months presenting with measured fever (≥38.0 °C) were enrolled. Exclusions included congenital urinary tract abnormalities, immunosuppression, current antimicrobials, or prior enrollment. Participants were followed up to identify UTIs; urine culture results were reviewed within 48 hours, and phone or email follow-up was completed within 2 weeks for those without testing at the index visit.

EXPOSURE: UTICalc-predicted probability of UTI.

MAIN OUTCOMES AND MEASURES: The primary outcome was UTI, defined as positive urinalysis and significant uropathogen culture growth. The primary analysis examined discriminative performance using area under receiver operating characteristic curve (AUROC). Secondary analyses included calibration (calibration plots, slope, Brier score) and clinical utility (net benefit analysis, comparison with clinician practice).

RESULTS: Among 2561 included participants (1212 [47%] female; 1326 [64%] younger than 12 months), 111 children (4%) were classified as having a UTI. In the full sample, 2256 (88.1%) had urine testing and/or provided follow-up data. The clinical model AUROC was 84.1% (95% CI, 80.4%-87.9%). At a 2% UTI risk threshold, sensitivity was 96.4%, and specificity was 34.1%; at a 5% risk threshold, sensitivity was 82.0%, and specificity was 73.8%. The clinical and dipstick model AUROC was 95.3% (95% CI, 93.3%-97.4%), with 94.0% sensitivity and 86.9% specificity at 5% risk. The sensitivity and specificity for clinicians were 98.2% and 57.3%, respectively. Calibration slopes were 0.11 (95% CI, 0.09-0.13) and 0.06 (95% CI, 0.05-0.07) and Brier scores were 0.04 (95% CI, 0.03-0.05) and 0.05 (95% CI, 0.04-0.06) for the clinical and clinical and dipstick models, respectively. Decision curve analysis showed both models were associated with positive net benefit across a range of risk thresholds.

CONCLUSIONS AND RELEVANCE: In this cohort study of 2561 febrile children aged 2 to 24 months presenting to the ED, UTICalc showed strong diagnostic performance, especially with dipstick results. While it did not outperform experienced clinicians, it offered a useful, evidence-based adjunct for guiding urine testing decisions, supporting efficient care in the pediatric ED.

PMID:41823964 | DOI:10.1001/jamanetworkopen.2026.1741