Nevin Manimala

Int J Legal Med. 2025 Jan 2. doi: 10.1007/s00414-024-03404-y. Online ahead of print.

ABSTRACT

This study aimed to test age-related changes in sternal fusion and sternal-rib cartilage ossification on multi-slice computed tomography (MSCT) images of the Croatian population. The additional aim was to develop models to estimate age and provide an interface for the model’s application and validation. This retrospective study was conducted on 144 MSCT images of the sternal region, and the developed models were tested on 36 MSCT images. We scored manubrium-mesosternal joint fusion (FM), xiphoid process and mesosternum fusion (FX), ossification of the first costal cartilage (OF), ossification of the second to seventh costal cartilages at the rib ends (OR), and ossification of the second to seventh costal cartilages at the sternal ends (OS). All sternal-rib cartilage ossification phases and sternal body and xiphoid process fusion scores showed statistically significant age differences (P < 0.001), except manubrium-mesosternal joint fusion. The final model that combined regression and classification using FM, FX, OR, OS, and sex obtained a 95% prediction interval (PI) coverage of 94.46% on the cross-validation (cv) and 91.67% on the test set with an average PI width of 42.29 and 42.95 years respectively. We also developed a Python Flask app called CroSterna: Age estimation from sternal fusion and rib ossification in the Croatian population ( https://crosterna.onrender.com/ ) to facilitate the estimation for professionals.

PMID:39745528 | DOI:10.1007/s00414-024-03404-y

J Neurophysiol. 2025 Jan 2. doi: 10.1152/jn.00490.2024. Online ahead of print.

ABSTRACT

Background: Despite a significant genetic component to insomnia (heritability: 22-25%), the genetic loci that modulate insomnia risk remain limited. Methods: We employed the Unified Test for Molecular Markers (UTMOST) for transcriptome-wide association studies (TWAS) across various tissues, integrating summary statistics from a Genome-Wide Association Study (GWAS) of 462,341 European participants with gene expression data from the Genotype-Tissue Expression (GTEx) project. Three validation methods (FUSION, FOCUS, and MAGMA) were used to confirm important genes. Tissue and functional enrichment analyses of insomnia-related single nucleotide polymorphisms (SNPs) were conducted with MAGMA. Conditional and joint analyses, along with fine mapping, were used to enhance our understanding of insomnia’s genetic architecture. Mendelian randomization was employed to assess causal associations between significant genes and insomnia. Results: Two novel susceptibility genes, VRK2 and MMRN1, were identified as linked to insomnia risk using four TWAS approaches. Mendelian randomization analysis suggests VRK2 increases the risk of insomnia. Tissue enrichment analyses indicated that insomnia-related SNPs were enriched in specific brain regions, including the cerebellum, frontal cortex (BA9), hypothalamus, and hippocampus. Conditional and joint analyses identified two genomic regions (2p16.1 and 4q22.1). Functional enrichment analyses showed that pathways related to insomnia involve the SMAD2/3 pathway, synaptic function, and oxidative stress. Conclusion: This study identifies two new candidate genes, VRK2 and MMRN1, that may contribute to insomnia risk through neurodevelopment, neuroinflammation, and synaptic function, suggesting potential therapeutic targets.

PMID:39745514 | DOI:10.1152/jn.00490.2024

Clin J Sport Med. 2025 Jan 1;35(1):67-74. doi: 10.1097/JSM.0000000000001245. Epub 2024 Jul 9.

ABSTRACT

OBJECTIVE: To determine if any gradual onset running-related injury (GORRI) was associated with any allergies, multiple allergies (allergies to animals, plants, medication), and allergy medication use.

DESIGN: Cross-sectional descriptive study.

SETTING: Two Oceans Marathons (56 km, 21.1 km), South Africa.

PARTICIPANTS: A total of 76 654 race entrants (2012-2015).

INDEPENDENT VARIABLES: The prevalence (%) and prevalence ratios (PR; 95% confidence intervals) for history of (1) any allergies, (2) multiple allergies to broad categories of allergens (animal material, plant material, allergies to medication, and other allergies), and (3) allergy medication use.

MAIN OUTCOME MEASURES: Using a compulsory online screening questionnaire, the outcome was a history of any GORRIs, and subcategories of GORRIs (muscle, tendon) in the past 12 months and history of GORRIs (and subtypes of GORRIs) were reported.

RESULTS: In 68 258 records with injury and allergy data, the following were significantly associated with reporting any GORRIs: a history of any allergy (PR = 2.2; P < 0.0001), a history of allergies to broad categories of allergens (animal, plant, medication allergy, other) ( P < 0.0001), and the use of allergy medication ( P < 0.0001). A history of any allergies (PR = 2.4; P < 0.0001), all broad categories of allergies, and allergy medication use were significantly associated with muscle ( P < 0.0001) and tendon injuries ( P < 0.0001). The risk of reporting a GORRI increased as the number of reported categories of allergies increased ( P < 0.0001).

CONCLUSIONS: A novel finding was the cumulative risk effect with a history of multiple allergies. Further studies should aim to determine the underlying mechanism relating allergies and GORRIs.

PMID:39745513 | DOI:10.1097/JSM.0000000000001245

Clin Trials. 2025 Jan 2:17407745241304059. doi: 10.1177/17407745241304059. Online ahead of print.

ABSTRACT

BACKGROUND: Clinical trials handle a huge amount of data which can be used during the trial to improve the ongoing study conduct. It is suggested by regulators to implement the remote approach to evaluate clinical trials by analysing collected data. Central statistical monitoring helps to achieve that by employing quantitative methods, the results of which are a basis for decision-making on quality issues.

METHODS: This article presents a scoping review which is based on a systematic and iterative approach to identify and synthesise literature on central statistical monitoring methodology. In particular, we investigated the decision-making processes (with emphasis on quality issues) of central statistical monitoring methodology and its place in the clinical trial workflow. We reviewed papers published over the last 10 years in two databases (Scopus and Web of Science) with a focus on data mining algorithms of central statistical monitoring and its benefit to the quality of trials.

RESULTS: As a result, 24 scientific papers were selected for this review, and they consider central statistical monitoring at two levels. First, the perspective of the central statistical monitoring process and its location in the study conduct in terms of quality issues. Second, central statistical monitoring methods categorised into practices applied in the industry, and innovative methods in development. The established methods are discussed through the prism of categories of their usage. In turn, the innovations refer to either research on new methods or extensions to existing ones.

DISCUSSION: Our review suggests directions for further research into central statistical monitoring methodology – including increased application of multivariate analysis and using advanced distance metrics – and guidance on how central statistical monitoring operates in response to regulators’ requirements.

PMID:39744904 | DOI:10.1177/17407745241304059

Environ Sci Process Impacts. 2025 Jan 2. doi: 10.1039/d4em00376d. Online ahead of print.

ABSTRACT

Background: Exposure to particulate matter <2.5 μm (PM_2.5) is linked to chronic obstructive pulmonary disease (COPD), but most studies lack individual PM_2.5 measurements. Seasonal variation and their impact on clinical outcomes remain understudied. Objective: This study investigated the impact of PM_2.5 concentrations on COPD-related clinical outcomes and their seasonal changes. Methods: A multicentre panel study enrolled 105 COPD patients (age range: 46-82) from July 2019 to August 2020. Their mean forced expiratory volume in 1 second after bronchodilation was 53.9%. Individual PM_2.5 levels were monitored continuously with indoor measurements at residences and outdoor data from the National Ambient Air Quality Monitoring Information System. Clinical parameters, including pulmonary function tests, symptom questionnaires (CAT and SGRQ-C), and impulse oscillometry (IOS), were assessed every three months over the course of one year. Statistical analysis was conducted using a linear mixed-effect model to account for repeated measurements and control for confounding variables, including age, sex, smoking status and socioeconomic status. Results: The mean indoor and outdoor PM_2.5 concentrations were 16.2 ± 8.4 μg m^-3 and 17.2 ± 5.0 μg m^-3, respectively. Winter had the highest PM_2.5 concentrations (indoor, 18.8 ± 11.7 μg m³; outdoor, 22.5 ± 5.0 μg m^-3). Higher PM_2.5 concentrations significantly correlated with poorer St. George’s Respiratory Questionnaire for COPD (SGRQ-C) scores and increased acute exacerbations, particularly in winter. Patients of lower socioeconomic status were more vulnerable. Increased PM_2.5 concentrations were also associated with amplified small airway resistance (R5-R20). Conclusions: PM_2.5 concentration changes are positively correlated with poorer SGRQ-C scores and increased acute exacerbations in COPD patients with significant seasonal variations, especially in winter.

PMID:39744880 | DOI:10.1039/d4em00376d

Eur J Breast Health. 2025 Jan 1;21(1):1-8. doi: 10.4274/ejbh.galenos.2024.2024-8-1.

ABSTRACT

We investigate the evidence for adverse effects of intraparenchymal and peritumoral application of isosulfan blue dye in sentinel lymph node (SLN) mapping in breast cancer patients. A meta-analysis on the adverse effects of intraparenchymal and peritumoral application of isosulfan application in SLN mapping was conducted using Medline and Embase databases up to 2023. Procedure-based adverse reactions were divided into three grades: Grade I (allergic skin reactions), Grade II (hypotension) and Grade III (requiring vasopressor support). Heterogeneity was expressed with I-squared and tau statistics. Subgroup analysis was conducted for administrative route. Univariable meta-regression was performed to assess dose-response effect on adverse reactions. Sensitivity analysis was conducted using fixed effect modelling. A total of 19,183 patients were identified from eight studies. The pooled total adverse event rate after isosulfan administration was 11.65 events per 1,000 patients [95% confidence interval (CI) 7.44-18.19]. The rate of Grade I reactions was 7.96 per 1,000 (95% CI 4.08-15.46); Grade II 0.08 per 1,000 (95% CI 0.00-1.31), Grade III 1.86 per 1,000 (95% CI 0.94-3.66), with no reported mortalities. Intraparenchymal administration was associated with 15.16 events per 1,000 (95% 8.64-26.45), versus 7.04 events per 1,000 (95% CI 5.24-9.45) in peritumoral administration (p=0.02). Univariable meta-regression did not show a significant association between volume of dye infused and total adverse events (-0.164 events per mL, 95% CI -0.864 to 0.534, p=0.645). Isosulfan has low adverse event rates regardless of injection technique or volume administered. Clinicians should have a high level of confidence in its use as an agent for SLN mapping, especially when administering it peritumorally.

PMID:39744877 | DOI:10.4274/ejbh.galenos.2024.2024-8-1

Urogynecology (Phila). 2024 Dec 31. doi: 10.1097/SPV.0000000000001642. Online ahead of print.

ABSTRACT

IMPORTANCE: Wound complications after obstetric anal sphincter injury (OASI) can amplify morbidity and affect quality of life.

OBJECTIVE: The objective of this study was to evaluate for characteristics associated with wound complications after OASI.

STUDY DESIGN: This was a retrospective cohort study of patients with an OASI who were evaluated in a postpartum pelvic floor healing clinic between November 1, 2020, and May 16, 2023. Our primary outcome was to identify factors associated with wound complications (wound infection or breakdown, antibiotic treatment, or surgical intervention). We hypothesized that operative vaginal delivery would be associated with wound complications and that peripartum antibiotics would be protective. Statistical analyses included t tests, chi-square test, Fisher exact test, and multivariable logistic regression.

RESULTS: Of 332 patients with an OASI, 74 (22.3%) experienced a wound complication. There were 31 (9.3%) wound infections and 62 (18.7%) wound breakdowns; 50 (15.1%) patients received additional antibiotics, and 20 (6.0%) underwent additional surgical intervention. On univariate analysis, those with wound complications were older (31.9 vs 30.6 years, P = 0.01) and more likely to have had an episiotomy (23.0% vs 12.5%, P = 0.03). On multivariable logistic regression, older maternal age was associated with wound complication (odds ratio, 1.1, 95% CI, 1.01-1.13, P = 0.03), and peripartum antibiotics were associated with decreased odds of wound complication (odds ratio, 0.57, 95% CI, 0.33-0.97, P = 0.04). Patients with wound complications were more likely to undergo in-office procedures (P < 0.001) and report postpartum pain (P < 0.001), urinary incontinence (P = 0.02), fecal urgency (P = 0.02), and other symptoms (P = 0.04).

CONCLUSIONS: Older maternal age was associated with wound complications after OASI, while peripartum antibiotics were protective. Patients with wound complications were more likely to report symptoms of pelvic floor disorders.

PMID:39744876 | DOI:10.1097/SPV.0000000000001642

Stroke. 2025 Jan 2. doi: 10.1161/STROKEAHA.124.048024. Online ahead of print.

ABSTRACT

Noninferiority trials aim to prove that the efficacy, defined in terms of a key clinical outcome, of a new treatment is not meaningfully worse than that of an established active control. Noninferiority trials are important when other aspects of care can be improved, such as convenience, toxicity, costs, and safety (nonefficacy benefits). While the motivation for a noninferiority trial is straightforward, the design, execution, and interpretation of these trials is not a trivial task. Several safeguards that protect superiority trials from incorrect conclusions do not apply or even work in reverse for noninferiority trials. This review aims to provide stroke clinicians and researchers with a general overview of noninferiority trials and a deeper understanding of 10 pitfalls they should consider when designing and interpreting such trials.

PMID:39744847 | DOI:10.1161/STROKEAHA.124.048024

Am J Med Genet B Neuropsychiatr Genet. 2025 Jan 2:e33020. doi: 10.1002/ajmg.b.33020. Online ahead of print.

ABSTRACT

Externalizing traits and behaviors are broadly defined by impairments in self-regulation and impulse control that typically begin in childhood and adolescence. Externalizing behaviors, traits, and symptoms span a range of traditional psychiatric diagnostic categories. In this study, we sought to generate an algorithm that could reliably identify transdiagnostic childhood-onset externalizing cases and controls within a university hospital electronic health record (EHR) database. Within the Vanderbilt University Medical Center (VUMC) EHR, our algorithm identified cases with a clinician-validated positive predictive value of 90% and controls with a negative predictive value of 88%. In individuals of genetically defined European ancestry (CEU-clustered; N_case = 487, N_control = 5638), case status was significantly associated with psychiatric comorbidity and with elevated externalizing polygenic scores (OR: 1.20; 95% CI: 1.09-1.33; p = 1.14 × 10^-3; based on published genome-wide association data). To test whether our cohort definitions could be applied to generate novel genetic insights, we examined rare (allele frequency < 0.5%) copy number variation. An association (OR: 9.70; CI: 3.24-29.0) was identified in the CEU-clustered cohort on chromosome 2 (chr2: 45,408,678-45,551,530; duplication), although the statistical strength of this association was modest (p = 0.052). We also examined the role of an externalizing burden score based on the number of externalizing diagnoses present in cases and found similar results to our case-control analysis. This analysis identified several other statistically significant CNV region associations. This study provides a framework for identifying childhood externalizing case-control cohorts within an EHR. Future work should validate this framework within other health systems. A broadly applicable algorithm, like this one, may allow for detection of rare outcomes or outcomes in populations historically excluded from genomic research through meta-analysis of data across health care systems.

PMID:39744833 | DOI:10.1002/ajmg.b.33020

Acta Obstet Gynecol Scand. 2025 Jan 2. doi: 10.1111/aogs.15022. Online ahead of print.

ABSTRACT

INTRODUCTION: Evidence suggests that gestational diabetes mellitus (GDM) is associated with subsequent cardiovascular disease; however, it is unclear what impact changes in screening and diagnostic criteria have had on the association of GDM with long-term outcomes such as cardiovascular disease. The purpose of this study was to determine the association between GDM and subsequent cardiovascular disease during a period of rising gestational diabetes diagnosis in England. Specifically, associations were compared before and after 2008, when national guidelines supporting risk factor-based screening were introduced.

MATERIAL AND METHODS: We conducted a cohort study using routinely collected data from the Clinical Practice Research Datalink linked to the Hospital Episode Statistics and Office for National Statistics databases. The study consisted of persons aged 15-45 years with a livebirth or stillbirth between 1998 and 2017 and without a history of cardiovascular disease or pre-pregnancy diabetes mellitus. Cox proportional hazards models, with propensity score weighting using matching weights, were used to estimate adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) for the association of GDM diagnosis in the first recorded pregnancy with subsequent cardiovascular disease.

RESULTS: Among 232 315 individuals, the incidence of cardiovascular disease was 6.6 per 1000 person-years among those with GDM and 2.2 per 1000 person-years among those without GDM over a mean follow-up duration of 5.8 years. The overall aHR, 95% CI was 1.91 (1.41, 2.60). Diagnosis of GDM increased over the study period, from 0.7% in 1998-99 to 5.3% in 2017. The effect size was not markedly different in the years before (1998-2007: adjusted HR 2.05, 95% CI 2.05 1.35, 3.12) and after 2008 (2008-2017: adjusted HR 1.79, 95% CI 1.15, 2.80).

CONCLUSIONS: There was a strong association of GDM with cardiovascular disease after accounting for social and demographic factors and multiple comorbidities, and this association was present both before and after 2008, when national gestational diabetes screening criteria were established.

PMID:39744821 | DOI:10.1111/aogs.15022