Category: Nevin Manimala

Medicine (Baltimore). 2026 Apr 3;105(14):e48220. doi: 10.1097/MD.0000000000048220.

ABSTRACT

Although numerous studies have investigated the associations between micronutrients and peripheral artery disease (PAD), most existing evidence is observational and limited by confounding and lack of causal inference. To address these gaps, we combined Mendelian randomization (MR) analysis using genetic data with supportive epidemiologic evidence from National Health and Nutrition Examination Survey (NHANES) to examine the relationships between micronutrient status and PAD risk. This study was conducted in 2 phases. First, we used genome-wide association study summary statistics to assess the causal effects of 15 circulating micronutrients on PAD risk through 2-sample MR. A bidirectional MR was also performed to explore the possibility of a reverse causal effect between PAD and potential candidate micronutrients. In the second phase, we analyzed data from 3 cycles of the NHANES (1999-2004). Logistic regression and restricted cubic spline models were used to examine the association between dietary intake of potential candidate micronutrients and PAD risk, adjusting for relevant covariates. MR analysis showed that higher genetically predicted vitamin C levels were significantly associated with a reduced risk of PAD (inverse-variance-weighted odds ratio (OR) = 0.509, 95% confidence interval (CI): 0.356-0.727; P <.001), with no evidence of reverse causality. In the NHANES analysis, lower dietary vitamin C intake was independently and nonlinearly associated with higher PAD risk (overall prevalence 7.9%), showing an L-shaped relationship with a threshold at 225.82 mg/day. Compared to the lowest quartile, PAD risk was lower in the second quartile (adjusted OR = 0.79; 95% CI: 0.64-0.98) and third quartile (adjusted OR = 0.94; 95% CI: 0.63-1.38). No significant interactions were found in the subgroup analysis. Both genetic evidence from MR and supportive observational evidence from NHANES suggest that vitamin C may play a protective role in the development of PAD.

PMID:41931342 | DOI:10.1097/MD.0000000000048220

Medicine (Baltimore). 2026 Apr 3;105(14):e48241. doi: 10.1097/MD.0000000000048241.

ABSTRACT

Although estimated glomerular filtration rate (eGFR) is a key indicator of kidney function, its association with mortality in herpes simplex virus (HSV)-seropositive individuals remains unclear. We analyzed 17,848 HSV-1/HSV-2 seropositive participants from National Health and Nutrition Examination Survey (1999-2016). The eGFR was calculated using standard equations, and mortality data were linked to the National Death Index through December 31, 2019. Kaplan-Meier survival curves, Cox regression models, generalized additive models, and stratified analyses were used to assess the association between eGFR and all-cause and cardiovascular mortality. The mean age of participants was 33.85 years (standard deviation: 9.4), and the average eGFR was 110.4 mL/min/1.73 m2 (standard deviation: 18.7). During a median follow-up of 141 months, 598 participants (3.35%) died from all causes, and 139 (0.78%) died from cardiovascular causes. A U-shaped association was observed between eGFR and all-cause mortality. Below an inflection point of 85.22 mL/min/1.73 m2, each 10-unit increase in eGFR was associated with reduced risk of all-cause death (hazard ratio = 0.70; 95% confidence interval: 0.64-0.75; P < .0001). Above this threshold, higher eGFR was associated with increased mortality (hazard ratio = 1.12; 95% confidence interval: 1.05-1.20; P = .001). Similar trends were found for cardiovascular mortality, although the association with elevated eGFR was not statistically significant. These findings were consistent across stratified and sensitivity analyses. In HSV-infected individuals, eGFR showed a nonlinear relationship with mortality. Moderate eGFR levels were associated with the lowest mortality risk.

PMID:41931339 | DOI:10.1097/MD.0000000000048241

Medicine (Baltimore). 2026 Apr 3;105(14):e48210. doi: 10.1097/MD.0000000000048210.

ABSTRACT

Valvular heart disease (VHD) is a common cardiovascular disorder with insidious early symptoms and can progress to heart failure or sudden death. Pharmacological options remain limited, and severe disease often requires surgical intervention. This study aimed to identify key molecular targets and potential therapeutic candidates for VHD using Mendelian randomization (MR) and integrative analyses. A 2-sample MR design was used to evaluate the association between genetically predicted exposures and VHD using publicly available genome-wide association study summary statistics. Downstream analyses included functional enrichment, drug repurposing with molecular docking, protein-protein interaction network construction with hub-gene identification, and single-cell RNA sequencing-based analysis to examine the cell-type distribution of candidate gene expression. MR analysis identified 76 genes associated with VHD, including stathmin 1, ribosomal protein S5, and mitogen-activated protein kinase 8. Enrichment analysis suggested that these genes were involved in multiple signaling pathways potentially related to disease progression. Drug prediction and molecular docking prioritized razoxane, reserpine, and bisindolylmaleimide I as candidate compounds targeting key molecules. Protein-protein interaction network analysis further identified 10 hub genes, such as DEAD-box helicase 6 and apolipoprotein E. Single-cell sequencing showed high expression of these genes in cardiomyocytes, fibroblasts, and smooth muscle cells. This study identified candidate genes and potential drug leads for VHD through an MR-based integrative analysis, providing targets for subsequent mechanistic and experimental validation.

PMID:41931316 | DOI:10.1097/MD.0000000000048210

Medicine (Baltimore). 2026 Apr 3;105(14):e48283. doi: 10.1097/MD.0000000000048283.

ABSTRACT

The causal interplay between thyroid dysfunction and gout remains controversial because of confounding and reverse causation in observational studies. Using Mendelian randomization (MR), this study investigated the causal effects of hyperthyroidism and hypothyroidism on the risk of gout. Summary statistics from the UK Biobank and FinnGen genome-wide association study databases were analyzed using 2-sample MR. Genetic instruments for thyroid dysfunction were selected under stringent criteria (P < 5 × 10-8, r2 < 0.001). Causal estimates were derived using inverse-variance weighted regression, supplemented by sensitivity analyses (MR-Egger, weighted median) and bidirectional MR. Genetically predicted hyperthyroidism exhibited a significant positive causal association with gout in both the UK Biobank (OR = 1.215, 95% confidence interval: 1.087-1.332, P = 3.12 × 10-5) and FinnGen cohorts (OR = 1.091, 95% confidence interval: 1.004-1.187, P = .041). No causal link was observed for the hypothyroidism. Bidirectional MR revealed no reverse causality, and sensitivity analyses confirmed robustness against pleiotropy and heterogeneity (P > .05). This study provides genetic evidence that hyperthyroidism is an independent risk factor of gout, indicating a possible unidirectional causal relationship. These findings underscore the necessity of closely monitoring uric acid levels in patients with hyperthyroidism and illuminating specific pathophysiological pathways that warrant further investigation of their underlying mechanisms.

PMID:41931314 | DOI:10.1097/MD.0000000000048283

Medicine (Baltimore). 2026 Apr 3;105(14):e48076. doi: 10.1097/MD.0000000000048076.

ABSTRACT

Omega-3 fatty acids, found in fish oil, flaxseed oil, and walnuts, are widely known for their anti-inflammatory properties and are used in the treatment of various inflammatory diseases. While their benefits in cardiovascular diseases and arthritis are well-documented, their role in musculoskeletal conditions, particularly Achilles tendinitis, remains unclear. This study investigates the causal relationship between Omega-3 fatty acids and the risk of Achilles tendinitis using a two-sample Mendelian randomization approach. Genetic variants associated with Omega-3 levels were selected from publicly available genome-wide association study data. Nineteen independent single nucleotide polymorphisms were used as instrumental variables to predict Omega-3 levels. The causal relationship between genetically predicted Omega-3 levels and Achilles tendinitis risk was evaluated using inverse variance weighting, MR-Egger regression, and weighted median methods. Sensitivity analyses, including leave-one-out analysis and funnel plots, were performed to assess robustness. The main analysis showed that for each 1 standard deviation increase in genetically predicted Omega-3 levels, the risk of Achilles tendinitis increased by 18% (odds ratio = 1.18, P = .020). Consistent results were observed across multiple robust methods, although only the inverse variance weighting method reached nominal significance. Sensitivity analyses confirmed that the results remained stable even when individual single nucleotide polymorphisms were excluded, and there was no significant evidence of horizontal pleiotropy or heterogeneity. This study suggests a potential causal relationship between Omega-3 fatty acids and the risk of Achilles tendinitis. Despite the small effect size and lack of statistical significance after multiple testing corrections, these findings warrant further investigation. Larger sample sizes and analyses of different Omega-3 subtypes are needed to confirm these results and explore their potential clinical implications in tendon diseases.

PMID:41931313 | DOI:10.1097/MD.0000000000048076

J Craniofac Surg. 2026 Apr 3. doi: 10.1097/SCS.0000000000012735. Online ahead of print.

ABSTRACT

BACKGROUND: Sex estimation is a fundamental component of skeletal identification in forensic and medicolegal contexts. Although cranial metrics are widely used, their accuracy and reproducibility are influenced by population specificity and landmark reliability. Within the modern Greek population, craniometric reference data remain limited.

METHODS: This pilot study analyzed 100 dried adult crania (51 males and 49 females) from Greece using 13 craniometric measurements obtained by 2 independent raters. Measurements were recorded manually using digital calipers, with a computed tomography (CT) subset (n=30) used for intermethod comparison. A novel cranial base metric, the Prosthion-Opisthion chord (PO chord), was introduced as a reproducible alternative to conventional cranial length. Landmarks were classified using Bookstein typology, and a Composite Bookstein Classification (CBC) was applied to estimate expected measurement reliability. Sex estimation models were developed using logistic regression with internal validation via 10-fold cross-validation.

RESULTS: Inter-rater reliability was high (ICC=0.864), with greater reproducibility observed for CBC Type I and II measurements. Significant sexual dimorphism was identified for the PO chord, facial height, nasal height, and foramen magnum length. The final multivariable model retained a quadratic term for the PO chord, along with cranial breadth, facial height, and nasal breadth. Cross-validated model performance was moderate, with a mean area under the receiver operating characteristic curve (AUROC) of 0.78 and an overall accuracy of 68.0%. Apparent (in-sample) accuracy was higher (77.7%), underscoring the importance of internal validation. Computed tomography-based measurements demonstrated acceptable concordance with manual measurements, particularly for CBC Type I and II traits.

CONCLUSIONS: This study provides population-specific pilot data on cranial sex estimation in a modern Greek sample. The PO chord represents a reproducible alternative to conventional cranial length, and the CBC offers a transparent framework for interpreting measurement reliability. Although classification accuracy was moderate, the findings emphasize the importance of reproducibility, internal validation, and population specificity in cranial sex estimation. Larger multicenter studies incorporating expanded data sets and 3-dimensional morphometric approaches are warranted.

PMID:41931311 | DOI:10.1097/SCS.0000000000012735

JAMA Netw Open. 2026 Apr 1;9(4):e262574. doi: 10.1001/jamanetworkopen.2026.2574.

ABSTRACT

IMPORTANCE: Long-term follow-up studies regarding the safety of risk-reducing mastectomy (RRM) in terms of cancer risk and surgical complications among women with germline pathogenic variants (gPVs) in BRCA1 or BRCA2 (BRCA1/2) are scarce.

OBJECTIVE: To analyze cancer risk and surgical complications after RRM.

DESIGN, SETTING, AND PARTICIPANTS: This nationwide cohort study investigated 1208 Swedish women with a confirmed gPV in BRCA1/2 without previous breast cancer identified through the Swedish Cancer Genetic Units between March 31, 1994, and January 2, 2019. Data were extracted from the National Patient Care Register, the Cancer Register, and the Cause of Death Register. Women were followed up from the date of RRM (RRM group) or genetic testing (no RRM group) until breast cancer diagnosis, death, emigration, or end of follow-up (December 31, 2023).

MAIN OUTCOMES AND MEASURES: Breast cancer incidence was calculated per 10 000 person-years, with women undergoing RRM contributing person-years to the no RRM group until RRM, and women with occult breast cancer contributing breast cancer cases to the no RRM group.

RESULTS: In the RRM group (507 women; median age at RRM, 39.7 years [range, 19.6-72.1 years]), 1 woman developed breast cancer, corresponding to a breast cancer incidence of 2 cases per 10 000 person-years. In the no RRM group (701 women; median age at genetic testing, 50.6 years [range, 4.3-93.6 years]), 112 women developed breast cancer, corresponding to a breast cancer incidence of 162 cases per 10 000 person-years. At RRM, 17 of 507 women (3.4%) received a diagnosis of occult breast cancer. In the RRM group, 296 of 507 women (58.4%) underwent simple mastectomy, 143 of 507 (28.2%) underwent nipple-sparing mastectomy, and 68 of 507 (13.4%) underwent skin-sparing mastectomy. Most women (382 of 507 [75.3%]) underwent implant-based breast reconstruction, with only 73 of 507 (14.4%) undergoing autologous tissue reconstruction with or without implants. Early major surgical postoperative complications associated with reoperation occurred in 19 of 507 women (3.7%).

CONCLUSIONS AND RELEVANCE: In this cohort study of 1208 women with a gPV in BRCA1/2, the risk of developing breast cancer or early major surgical complications after RRM was very low. The low occurrence of primary breast cancer precluded meaningful statistical comparisons between different RRM techniques.

PMID:41931296 | DOI:10.1001/jamanetworkopen.2026.2574

JAMA Netw Open. 2026 Apr 1;9(4):e263764. doi: 10.1001/jamanetworkopen.2026.3764.

ABSTRACT

IMPORTANCE: Out-of-hospital cardiac arrest (OHCA) survival is lower in neighborhoods with low (vs high) socioeconomic status. While emergency medical services (EMS) practices of intra-arrest transport (IAT) vary, it is unknown whether neighborhood-level factors are associated with these transport patterns.

OBJECTIVE: To determine the association between greater neighborhood socioeconomic vulnerability and odds of IAT among adults with OHCA.

DESIGN, SETTING, AND PARTICIPANTS: This cohort study used a large national database of deidentified EMS electronic health record data. The cohort comprised US adults (aged ≥18 years) with attempted EMS resuscitations for nontraumatic OHCA between January 1, 2022, and December 31, 2022. Data were analyzed between December 2023 and December 2024.

EXPOSURES: The exposure was the Social Vulnerability Index (SVI) of the EMS encounter within a US Census tract. Neighborhoods were stratified into quartiles based on SVI percentile. Higher SVI percentiles indicated greater socioeconomic vulnerability.

MAIN OUTCOME AND MEASURE: The primary outcome was the odds of IAT. The association between SVI quartile and EMS transport pattern was assessed using marginal logistic regression modeling.

RESULTS: A total of 61 524 patient encounters were included. Patients had a median (IQR) age of 65 (52-76) years and included 38 546 males (62.6%). Bystander resuscitation was administered in 23 124 encounters (37.6%), while 23 492 patients (38.2%) received IAT and 38 032 patients (61.8%) received continued on-scene resuscitation. Adults in neighborhoods in the highest SVI quartile had a higher occurrence of IAT than those in the lowest SVI quartile (7052 [41.1%] vs 4000 [32.8%]; P < .001). After adjustment, patients in the highest SVI quartile had greater odds of receiving IAT than those in the lowest SVI quartile (adjusted odds ratio, 1.35; 95% CI, 1.15-1.57).

CONCLUSIONS AND RELEVANCE: In this cohort study of EMS resuscitations of adults for nontraumatic OHCA, greater neighborhood socioeconomic vulnerability was associated with increased odds of IAT. This association may contribute to socioeconomic disparities in OHCA outcomes and warrant further investigations into factors in EMS transport decisions for OHCA, particularly in marginalized communities.

PMID:41931295 | DOI:10.1001/jamanetworkopen.2026.3764

JAMA Netw Open. 2026 Apr 1;9(4):e264801. doi: 10.1001/jamanetworkopen.2026.4801.

ABSTRACT

IMPORTANCE: Few studies, mostly from the era before the Dobbs v. Jackson Women’s Health Organization US Supreme Court decision, have projected increases in pregnancy-related and maternal mortality in states with restrictive abortion laws. However, the association between post-Dobbs abortion bans and pregnancy-associated mortality remains unclear.

OBJECTIVE: To examine the associations of complete and 6-week abortion bans with pregnancy-associated mortality in the US.

DESIGN, SETTING, AND PARTICIPANTS: This retrospective, population-based cohort study included 14 states with abortion bans and 37 control states, including the District of Columbia, without abortion bans. US National Center for Health Statistics birth and mortality data from 2018 to 2023 were analyzed using synthetic control methods with staggered adoption, comparing ban states to their synthetic controls. Data were analyzed from July to December 2025.

EXPOSURE: State-level implementation of complete or 6-week abortion bans.

MAIN OUTCOMES AND MEASURES: The primary outcome was pregnancy-associated mortality. Secondary outcomes included pregnancy-related, maternal, and nonobstetric causes of death. Mortality ratios were examined quarterly and between preban and postban periods.

RESULTS: From 2018 to 2023, there were 22 011 131 live births and 12 993 pregnancy-associated deaths. Pregnancy-associated mortality declined by 9.8% in nonban states (54.5 [95% CI, 53.3 to 55.8] to 49.2 [95% CI, 46.5 to 52.0] deaths per 100 000 live births). In states with bans, smaller declines were observed: 2.4% in states excluding Texas (83.2 [95% CI, 80.1 to 86.3] to 81.2 [95% CI, 74.5 to 88.4] deaths per 100 000 live births) and 3.3% in Texas (54.2 [95% CI, 50.5 to 58.1] to 52.4 [95% CI, 47.4 to 57.7] deaths per 100 000 live births). Increases were largest among non-Hispanic Asian (41.0%; from 39.5 [95% CI, 27.7 to 54.7] to 55.7 [95% CI, 26.7 to 102.4] deaths per 100 000 live births) and non-Hispanic Black or African American (17.8%; from 140.2 [95% CI, 131.7 to 149.1] to 165.2 [95% CI, 144.2 to 188.3] deaths per 100 000 live births) individuals in ban states excluding Texas. Synthetic control analyses yielded an estimated difference of 5.1 (95% CI, -7.9 to 18.2) pregnancy-associated deaths per 100 000 live births, which was not statistically significant. Overall estimates for pregnancy-related mortality (-2.0; 95% CI, -11.5 to 7.5), maternal mortality (-3.0; 95% CI, -10.2 to 4.2), and nonobstetric causes (1.2; 95% CI, -7.3 to 9.7) were likewise not statistically significant. State-specific estimates were heterogeneous, but none reached statistical significance. Covariate-adjusted models yielded similar results.

CONCLUSIONS AND RELEVANCE: This cohort study found that abortion bans were not associated with statistically significant overall or state-specific increases in pregnancy-associated mortality. The short postban observation window and wide CIs highlight the need for continued surveillance as more post-Dobbs data become available.

PMID:41931294 | DOI:10.1001/jamanetworkopen.2026.4801

JAMA Netw Open. 2026 Apr 1;9(4):e264812. doi: 10.1001/jamanetworkopen.2026.4812.

ABSTRACT

IMPORTANCE: The Salton Sea, a drying saline lake in southeastern California, is a growing source of wind-blown dust. Its long-term impact on children’s lung function growth remains unclear.

OBJECTIVE: To investigate the association of proximity to the Salton Sea and dust exposure with children’s lung function growth trajectories.

DESIGN, SETTING, AND PARTICIPANTS: For this longitudinal cohort study, community-engaged research was conducted in Imperial Valley, California, in partnership with Comité Civico del Valle, a long-standing local community organization. Children in first to third grades from 5 elementary schools near the Salton Sea were invited to participate between May 1, 2017, and May 27, 2019. Participants with missing data on core variables or with only 1 spirometry measure were excluded from analysis. Lung function assessment was conducted from March 22, 2019, to July 25, 2022; data analyses were conducted from July 2024 to July 2025.

EXPOSURES: The primary exposure was the distance from each child’s home to the edge of the Salton Sea, with residence near the sea defined as less than 11 km. Secondary exposures included particulate matter (PM) and dust storm hours (PM10 > 150 µg/m3), estimated using data from regulatory monitors.

MAIN OUTCOMES AND MEASURES: Lung function was assessed via spirometry (forced expiratory volume in 1 second [FEV1] and forced vital capacity [FVC]). Covariates included age, sex, ethnicity, socioeconomic status, height, body mass index, baseline respiratory health, and asthma status.

RESULTS: Of 499 children enrolled, 369 were included in the final analysis (205 [55.6%] female and 164 [44.4%] male), with a mean (SD) baseline age of 10.1 (0.6) years and mean (SD) follow-up of 2.0 (1.0) years, contributing a total of 1146 spirometry measurements (approximately 3 per participant). In fully adjusted mixed effects models, living near the sea (<11 km) was associated with 52.18 mL/y lower FVC growth (95% CI, -100.96 to -3.40 mL/y; P = .04), compared with living farther from the sea. The association with FEV1 did not reach statistical significance. More hours of dust event exposure were associated with lower FVC (β = -4.10 mL/y; 95% CI, -7.55 to -0.75 mL/y) and FEV1 growth (β = -2.26 mL/y; 95% CI, -4.22 to -0.29 mL/y), with a stronger association between dust event and FVC observed among children living near the sea (P for interaction = .04).

CONCLUSIONS AND RELEVANCE: In this cohort study of school-aged children, closer residential proximity to the Salton Sea was associated with reduced lung function growth. These findings underscore the need to address environmental degradation in the region to protect children’s respiratory health.

PMID:41931293 | DOI:10.1001/jamanetworkopen.2026.4812