Significant Covariates Research Articles

Survival Analysis of Ovarian Cancer Patients in Yazd City, Central part of Iran, 1999-2018

Background: Ovarian Cancer (OC) as a common gynecologic cancer according to mortality rate has the seventh rank among women in the world. This study aimed to identify risk factors associated with OC survival in Yazd, Iran. Methods: In this observational retrospective cohort study, the medical records of 150 patients who were definitively diagnosed with OC from 1999 to 2018 were investigated. The Kaplan–Meier estimator and the Cox proportional hazard model with hazard ratio and the log-rank test were used for data analysis. All statistical analyses were done in R 4.0.5, package survival. Results: 60.77% (91 people) of patients were under 60 years old. 32.7% (49 people) were in stage III of the disease. 62% (93 people) did not have ascites, 67.3% (101 people) had disease-free survival more than 65 months. 45 (30%) of 150 patients were dead. Median survival time was 96 months (95% CI∶57.20 to 134.79), one, three, five-, and ten-year survival rates were 83,73,55 and 33 months; respectively. Log-rank test results showed there was a significant difference between age, stage, ascites, disease-free survival, and Treatment method, CA125 after and before treatment (p < 0.05). Cox proportional hazard model result showed ascites (HRadj = 3.89, 95% CI: 1.35 to 11.15, P = 0.01) and DFS (HRadj = 23.52, 95 % CI: 4.21to128.33, p = < 0.001) as significant covariates. Conclusion: The results of our study showed that disease-free survival and ascites are the main risk factors for OC and paying attention to them will be effective in increasing patient survival.

Reduced rates of substance use disorder in patients with alopecia: An all of us case-control study.

Alopecia areata (AA), depression, anxiety, and decreased quality of life are highly associated in the literature. It has been noted that there is an increased risk of substance use in those with AA to help cope with the psychological burdens and perceived stigmatization. This study aims to explore the relationship between substance use disorder (SUD) and scarring/non-scarring alopecia using the All of Us database. Of the 9,385 patients with alopecia, 8.4% had SUD of any kind. Multivariable regression revealed that alopecia is a potential protective factor against SUD when controlling for other covariates of significance, with a decreased odds of 0.73. Substance use disorder prevalence was not different between scarring and non-scarring alopecia. This may be the result of patients fearing exacerbation of hair loss, or due to increased mental health and community support in patients with alopecia. Dermatologists and primary care providers should continue to promote psychotherapy and community support to patients whose diagnosis of alopecia has a negative psychosocial impact.

Impact of breaks in therapy on survival for pediatric patients with relapsed or refractory solid tumors: A single-center study.

10021 Background: Relapsed or refractory (R/R) solid tumors remain a significant cause of mortality for children. While upfront therapies have been well-studied, the cumulative effects of multiple relapses and salvage regimens is unknown. We describe the disease trajectory in these patients, from the time of first R/R event (on-therapy progression/refractoriness or off-therapy relapse) to time of death or last follow-up. We also analyze whether breaks ( > 30 days) between diagnosis of events and initiation of subsequent therapies have an impact on survival. Methods: We reviewed data from electronic medical records for patients with primary, malignant R/R extracranial solid tumors treated at Texas Children’s Hospital between 2005-2023. Descriptive analysis was performed along with univariate chi-square, one-way ANOVA, and independent sample t-tests. Cox regression analysis was used to evaluate time from first event to death or last known follow-up for each variable described. Analysis was performed with SPSS v29. Results: We reviewed data for 466 patients with R/R solid tumors (female: 47%; median age: 8.66 years; median follow-up after first event: 12.9 months). Most common diagnoses were neuroblastoma (21.5%), rhabdomyosarcoma (19.1%), and osteosarcoma (16.1%). Patients had a median of 3 (interquartile range [IQR]: 1-4) R/R events with a median of 93 (IQR 52-200) days between each event. The most common post-event therapy regimens were intravenous chemotherapy alone (21.4%) or in combination with surgery and/or radiotherapy (19.9%). Deceased patients (n = 339) had a median of 291 (IQR: 127-549) days from first event to death. Increased time from first R/R event to death was associated with a break in disease-directed therapy; type of diagnosis; non-metastatic stage at original diagnosis; type of first event; type of first salvage regimen; and receiving phase 1 therapy. Of 438 patients who received ≥1 salvage therapy regimen, 116 (26.5%) took ≥1 break between an R/R event and subsequent therapy. Reasons for breaks varied relatively evenly between intentional/goal-concordant (e.g., to seek second opinion, to focus on quality of life), and unintentional (e.g., care coordination, care access issues). In a multivariable Cox regression model, taking a > 30 day break in disease-directed therapy was associated with prolonged survival, even after adjusting for number of events and significant covariates (p < 0.05). Conclusions: The prognosis for children with R/R solid tumors is poor. Most children experience multiple R/R events and therapy regimens without a break in therapy. Presence of a > 30 day break between an R/R event and subsequent therapy did not negatively impact survival, implying that time between therapy regimens can safely be offered to some patients to promote quality of life, exploration of goals of care, and thoughtful decision-making, without compromising survival.

Medication Risks and Their Association with Patient-Reported Outcomes in Inpatients with Cancer.

We aimed to assess medication risks and determine factors influencing the health-related quality of life (HRQOL) in cancer inpatients. A retrospective analysis was conducted to identify drug-related problems (DRPs) based on medication reviews, including patient-reported outcomes (PROs). Multiple linear regression analyses were performed to identify sociodemographic, disease-related, and drug therapy-related factors influencing changes from hospital admission to discharge in the scales of the EORTC QLQ-C30 questionnaire. A total of 162 inpatients with various hematological and solid cancer diseases was analyzed. Patients received a mean of 11.6 drugs and 92.6% of patients exhibited polymedication resulting in a mean of 4.0 DRPs per patient. Based on PRO data, 21.5% of DRPs were identified. Multiple linear regression models described the variance of the changes in global HRQOL and physical function in a weak-to-moderate way. While drug therapy-related factors had no influence, relapse status and duration of hospital stay were identified as significant covariates for global HRQOL and physical function, respectively. This analysis describes underlying DRPs in a German cancer inpatient population. PROs provided valuable information for performing medication reviews. The multiple linear regression models for global HRQOL and physical function provided explanations for changes during hospital stay.

Population pharmacokinetic, pharmacodynamic and efficacy modeling of SB12 (proposed eculizumab biosimilar) and reference eculizumab

PurposeTo describe, compare similarity of pharmacokinetic (PK), pharmacodynamic (PD) and efficacy of SB12 and reference eculizumab (ECU) and find clinically significant covariate relationships.MethodsThe PK, PD (terminal complement activity) and efficacy (LDH) data of SB12 and ECU were obtained from 289 subjects from phase I and phase III studies. One- and two-compartment PK models with first-order elimination were evaluated for SB12 and ECU. For PD and efficacy, both direct and indirect models were tested. The impact of covariates on PK, PD and efficacy parameters was assessed. Relationship between PK/PD and PD/efficacy was characterized. This modeling was performed using NONMEM version 7.4 (Icon Development Solutions, Ellicott City, MD, USA).ResultsThe two-compartment model adequately described the PK of SB12 and ECU, and the subject’s weight was chosen as a clinically significant covariate affecting drugs’ clearance and central volume of distribution. Treatment group was not a significant covariate affecting clearance. The direct response model using inhibitory sigmoid Emax and sigmoid Emax relationship well described the PK/PD relationship and PD/efficacy relationship of SB12 and ECU, respectively. Through this modeling, the relationships between PK, PD and efficacy were characterized. There were no differences in PK, PD and efficacy parameters between SB12 and ECU in pooled populations of healthy subjects and paroxysmal nocturnal haemoglobinuria (PNH) patients.ConclusionThe population modeling showed PK, PD and efficacy similarities between SB12 and ECU in pooled population of healthy subjects and PNH patients, supporting the totality of evidence on biosimilarity for SB12.

A Semi-Mechanistic Population Pharmacokinetic Model of Noscapine in Healthy Subjects Considering Hepatic First-Pass Extraction and CYP2C9 Genotypes.

Noscapine is a commonly used cough suppressant, with ongoing research on its anti-inflammatory and anti-tumor properties. The drug has a pronounced pharmacokinetic variability. This evaluation aims to describe the pharmacokinetics of noscapine using a semi-mechanistic population pharmacokinetic model and to identify covariates that could explain inter-individual pharmacokinetic variability. Forty-eight healthy volunteers (30 men and 18 women, mean age 33 years) were enrolled in a randomized, two-period, two-stage, crossover bioequivalence study of noscapine in two different liquid formulations. Noscapine plasma concentrations following oral administration of noscapine 50 mg were evaluated by a non-compartmental analysis and by a population pharmacokinetic model separately. Compared to the reference formulation, the test formulation exhibited ratios (with 94.12% confidence intervals) of 0.784 (0.662-0.929) and 0.827 (0.762-0.925) for peak plasma concentrations and area under the plasma concentration-time curve, respectively. Significant differences in p values (<0.01) were both observed when comparing peak plasma concentrations and area under the plasma concentration-time curve between CYP2C9 genotype-predicted phenotypes. A three-compartmental model with zero-order absorption and first-order elimination process best described the plasma data. The introduction of a liver compartment was able to describe the profound first-pass effect of noscapine. Total body weight and the CYP2C9 genotype-predicted phenotype were both identified as significant covariates on apparent clearance, which was estimated as 958 ± 548 L/h for extensive metabolizers (CYP2C9*1/*1 and *1/*9), 531 ± 304 L/h for intermediate metabolizers with an activity score of 1.5 (CYP2C9*1/*2), and 343 ± 197 L/h for poor metabolizers and intermediate metabolizers with an activity score of 1.0 (CYP2C9*1/*3, *2/*3, and*3/*3). The current work is expected to facilitate the future pharmacokinetic/pharmacodynamic development of noscapine. This study was registered prior to starting at "Deutsches Register Klinischer Studien" under registration no. DRKS00017760.

Population pharmacokinetics and dosage optimization of linezolid in Chinese older patients.

To assess the pharmacokinetics and pharmacodynamics of linezolid in a retrospective cohort of hospitalized Chinese older patients. Patients > 60years of age, who received intravenous linezolid (600mg), were included. A population pharmacokinetics (PPK) model was established using nonlinear mixed-effects modeling. The predictive performance of the final model was assessed using goodness-of-fit plots, bootstrap analyses, and visual predictive checks. Monte Carlo simulations were used to evaluate the achievement of a pharmacodynamics target for the area under the serum concentration-time curve/minimum inhibitory concentration (AUC0-24/MIC). A total of 210 samples were collected from 120 patients. A one-compartment PPK model with linear elimination best predicted the linezolid plasma concentrations. Linezolid clearance (CL) was 4.22 L h-1 and volume of distribution (Vd) was 45.80 L; serum uric acid (SUA) was a significant covariate of CL. The results of this study indicated that the standard dose was associated with a risk of overexposure in older patients, particularly those with high SUA values; these patients would benefit from a lower dose (300mg every 12h).

Long-term outcomes of titanium-nitride-oxide coated stents and drug-eluting stents in acute coronary syndrome: A systematic review and meta-analysis.

In severe cases of coronary artery disease, percutaneous coronary intervention provide promising results. The stent used could be a drug-eluting stent (DES) or a titanium-nitride-oxide coated stent (TiNOS). To compare the 5-year effectiveness and safety of the two stent types. The following systematic review and meta-analysis was conducted in accordance with the preferred reporting items for systematic reviews and meta-analysis guidelines, and PubMed/MEDLINE, Scopus, and Cochrane Central were searched from inception till August 2023. Primary outcomes were major adverse cardiac events (MACE), cardiac death, myocardial infarction (MI), cardiac death or MI, and ischemia-driven total lesion revascularization (ID-TLR). Four randomized controlled trials (RCT), which analyzed a sum total of 3045 patients with acute coronary syndrome (ACS) after a median follow-up time of 5 years were included. Though statistically insignificant, an increase in the ID-TLR was observed in patients receiving TiNOSs vs DESs. In addition, MI, cardiac death and MI, and definite stent thrombosis (DST) were significantly decreased in the TiNOS arm. Baseline analysis revealed no significant results with meta-regression presenting non-ST elevated MI (NSTEMI) as a statistically significant covariate in the outcome of MACE. TiNOS was found to be superior to DES in terms of MI, cardiac death or MI, and DST outcomes, however, the effect of the two stent types on ID-TLR and MACE was not significant. A greater number of studies are required to establish an accurate comparison of patient outcomes in TiNOS and DES.

Population Pharmacokinetics of Dasatinib in Healthy Subjects.

Dasatinib is one of the tyrosine kinase inhibitors. The main use of these agents is inhibition of cancerous cell proliferation. The therapeutic importance of tyrosine kinase inhibitors raises the necessity of many types of investigations, especially the pharmacokinetic analysis of these drugs in humans. This analysis, along with other investigations and clinical research, will contribute to the overall knowledge of the drug. This study focused on the population pharmacokinetics of dasatinib. The objective of the study was to investigate the sources of the variability of dasatinib in a population pharmacokinetics study in healthy participants. We utilized 4180 plasma observations from 110 subjects who were administered SPRYCEL® on two separate occasions under fasting conditions; data from 20% of the subjects (22 subjects) were extracted for the purpose of internal model evaluation and data from 88 subjects were used in modeling. The model was evaluated by visual predictive check of three different datasets. A two-compartmental model with first order absorption and transit compartment was considered the simplest base model to describe the data based on the corrected Bayesian information criterion evaluation. Covariates were tested through conditional sampling for the stepwise approach-screening procedure in Monolix 2020R1 version. Conditional sampling for the stepwise approach was used to include the correlated covariates within the base model in the forward inclusion step and then to eliminate them backwardly to ensure that the key covariates were kept in the model at the final stage. The effect of body mass index on the absorption rate constant was considered as significant covariate in the final established model. Visual predictive check for simulations, 20% of the original dataset (internal dataset) and an external dataset demonstrated the appropriateness of the final model. Population pharmacokinetic modeling was performed to describe dasatinib pharmacokinetics in healthy subjects. Body mass index was considered as a factor that might be used in the future along with studies on patients to adjust the dosing regimens. Dasatinib is classified as a highly variable drug; this variability was demonstrated in the study by the effect of body mass index on the absorption rate constant.

Population Pharmacokinetic Analysis and Simulation of Alternative Dosing Regimens for Biosimilars to Adalimumab and Etanercept in Patients with Rheumatoid Arthritis.

Efficacy to biologics in rheumatoid arthritis (RA) patients is variable and is likely influenced by each patient's circulating drug levels. Using modelling and simulation, the aim of this study was to investigate whether adalimumab and etanercept biosimilar dosing intervals can be altered to achieve therapeutic drug levels at a faster/similar time compared to the recommended interval. RA patients starting subcutaneous Amgevita or Benepali (adalimumab and etanercept biosimilars, respectively) were recruited and underwent sparse serum sampling for drug concentrations. Drug levels were measured using commercially available kits. Pharmacokinetic data were analysed using a population approach (popPK) and potential covariates were investigated in models. Models were compared using goodness-of-fit criteria. Final models were selected and used to simulate alternative dosing intervals. Ten RA patients starting the adalimumab biosimilar and six patients starting the etanercept biosimilar were recruited. One-compartment PK models were used to describe the popPK models for both drugs; no significant covariates were found. Typical individual parameter estimates were used to simulate altered dosing intervals for both drugs. A simulation of dosing the etanercept biosimilar at a lower rate of every 10 days reached steady-state concentrations earlier than the usual dosing rate of every 7 days. Simulations of altered dosing intervals could form the basis for future personalised dosing studies, potentially saving costs whilst increasing efficacy.

Transactional Linkages Between Parenting Behaviors and Child Executive Functions and Self-Regulation from Early Childhood to Adolescence.

Research on the development of executive functions (EFs) and self-regulation (SR) has focused heavily on the early childhood years, when these abilities first emerge. Less is known in comparison about how these abilities develop through adolescence, and how contextual factors, such as parenting, influence their development in later years. Using longitudinal data from the Study of Early Child Care and Youth Development (SECCYD), we used random intercept cross-lagged panel modeling (RI-CLPM) to examine the bidirectional linkages between three parenting behaviors (i.e., autonomy support, supportive presence, hostility), child EFs (i.e., working memory, inhibitory control) and child SR outcomes, from early childhood to adolescence. Parenting in early childhood was significantly associated with change in child EFs from early to middle childhood, but not from middle childhood to adolescence. Specifically, greater autonomy support in early childhood was associated with stronger child working memory and inhibitory control in middle childhood; greater supportive presence in early childhood was associated with stronger child working memory in middle childhood; and higher rates of hostility in early childhood were associated with weaker child inhibitory skills in middle childhood. Reciprocal effects of child EF and SR on parenting were also observed. Specifically, stronger child inhibitory control in early childhood was associated with less hostility in middle childhood, and stronger child self-regulation in middle childhood was associated with greater supportive presence in adolescence. Accounting for lagged and stability effects, there was significant residual covariance between parenting behaviors and child SR in adolescence, suggesting that parenting continues to be associated with the development of SR skills through adolescence. Understanding reciprocal linkages between parenting and child EF/SR through adolescence is critical in developing targeted parenting interventions beyond early childhood to improve children's outcomes.

Software and equations using segmental measures to estimate height in children and adolescents with cerebral palsy considering the level of gross motor function

In children with Cerebral palsy (CP) bone deformities create a difficulty in the collection of height measures by direct methods. Body segments are an alternative to study for anthropometric evaluation in children with CP. Motor compromise affects growth in these children. To our knowledge, no equations have been developed to estimate height that consider the level of involvement of children with CP. The aim was to develop equations to estimate height using segmental measures for children with cerebral palsy (CP). This was a cross-sectional study. The sample consisted of children and adolescents with CP of both sexes from 2 to 19 years old from five cities in Argentina. Children whose height and knee-heel height (KH) could be measured were included. Height, KH, and clinical covariables were collected. Linear regression models with height as the dependent variable and KH as predictors adjusted for significant covariates were developed and compared for R2, adjusted R2, and the root mean square of the error. 242 children and adolescents (mean age 9±4 years) with a confirmed diagnosis of CP were included. The interaction between height and other variables such KH, sex, GMFCS, and age was analyzed. Two equations were developed to estimate height according to GMFCS level (GMFCS Level I-III: H =1.5 × KH(cm)+2.28 × age(years)+ 51; GMFCS Level IV-V: H =2.13 × KH (cm)+ 0.91 × age(years)+37). The concordance correlation coefficient between estimated and observed height was 0.95 (95%CI [0.94; 0.96]). Height in children and adolescents with CP can be predicted using KH, GMFCS, and age. The equations and software can estimate height when this cannot be obtained directly.

Population pharmacokinetics and dose rationale for aciclovir in term and pre-term neonates with herpes.

Aciclovir is considered the first-line treatment against Herpes simplex virus (HSV) infections in new-borns and infants. As renal excretion is the major route of elimination, in renally-impaired patients, aciclovir doses are adjusted according to the degree of impairment. However, limited attention has been given to the implications of immature renal function or dysfunction due to the viral disease itself. The aim of this investigation was to characterize the pharmacokinetics of aciclovir taking into account maturation and disease processes in the neonatal population. Pharmacokinetic data obtained from 2 previously published clinical trials (n = 28) were analyzed using a nonlinear mixed effects modeling approach. Post-menstrual age (PMA) and creatinine clearance (CLCR) were assessed as descriptors of maturation and renal function. Simulation scenarios were also implemented to illustrate the use of pharmacokinetic data to extrapolate efficacy from adults. Aciclovir pharmacokinetics was described by a one-compartment model with first-order elimination. Body weight and diagnosis (systemic infection) were statistically significant covariates on the volume of distribution, whereas body weight, CLCR and PMA had a significant effect on clearance. Median clearance varied from 0.2 to 1.0 L/h in subjects with PMA <34 or ≥34 weeks, respectively. Population estimate for volume of distribution was 1.93 L with systemic infection increasing this value by almost 3-fold (2.67 times higher). A suitable model parameterization was identified, which discriminates the effects of developmental growth, maturation, and organ function. Exposure to aciclovir was found to increase with decreasing PMA and renal function (CLCR), suggesting different dosing requirement for pre-term neonates.

Exploring Differences in Intraoperative Medication Use Between African American and Non-Hispanic White Patients During General Anesthesia: Retrospective Observational Cohort Study.

This study aimed to explore whether differences exist in anesthesia care providers' use of intraoperative medication between African American and non-Hispanic White patients in adult surgical patients who underwent noncardiothoracic nonobstetric surgeries with general anesthesia. A retrospective observational cohort study used electronic health records between January 1, 2018 and August 31, 2019 at a large academic health system in the southeastern United States. To evaluate the isolated impact of race on intraoperative medication use, inverse probability of treatment weighting using the propensity scores was used to balance the covariates between African American and non-Hispanic White patients. Regression analyses were then performed to evaluate the impact of race on the total dose of opioid analgesia administered, and the use of midazolam, sugammadex, antihypotensive drugs, and antihypertensive drugs. Of the 31,790 patients included in the sample, 58.9% were non-Hispanic Whites and 13.6% were African American patients. After adjusting for significant covariates, African American patients were more likely to receive midazolam premedication (p < .0001; adjusted odds ratio [aOR] = 1.17, 99.9% CI [1.06, 1.30]), and antihypertensive drugs (p = .0002; aOR = 1.15, 99.9% CI [1.02, 1.30]), and less likely to receive antihypotensive drugs (p < .0001; aOR = 0.85, 99.9% CI [0.76, 0.95]) than non-Hispanic White patients. However, we did not find significant differences in the total dose of opioid analgesia administered, or sugammadex. This study identified differences in intraoperative anesthesia care delivery between African American and non-Hispanic White patients; however, future research is needed to understand mechanisms that contribute to these differences and whether these differences are associated with patient outcomes.

Population pharmacokinetics, dosing optimization and clinical outcomes of biapenem in patients with sepsis.

Introduction: Biapenem is a carbapenem antibiotic widely used in Asia, can be used for the treatment of adults and children with infections due to susceptible bacteria. Although biapenem is utilized in the treatment of a diverse range of bacterial infections, current pharmacokinetic data in the context of septic populations remain limited. Consequently, our research aims to evaluate the pharmacokinetics and efficacy of biapenem within a septic population to optimize biapenem therapy. Methods: In this study, we characterized the pharmacokinetics of biapenem in septic patients using a population pharmacokinetic (PPK) approach. The clinical PK data to develop the PPK model were obtained from 317 septic patients admitted to Nanjing Drum Tower Hospital between 2018 and 2022. All patients were randomized to the modeling and validation cohorts at a 3:1 ratio, with PPK modeling and validation performed utilizing the NONMEM software. Results: The model found to best describe the available data was a two-compartment PPK model with first-order elimination characterized by the parameters clearance (CL), central volume (V1), peripheral volume (V2), and intercompartmental clearance (Q). A covariate analysis identified that creatinine clearance (CLCR) was a significant covariate influencing biapenem CL, while blood urea nitrogen (BUN) was a significant covariate influencing biapenem Q. Accoding to the clinical outcome analyses, 70% of the time that the free antimicrobial drug concentration exceeds the MIC (fT >MIC) is associated with favourable clinical outcomes. The PPK model was then used to perform Monte Carlo simulations to evaluate the probability of attaining 70% fT >MIC. Conclusions: A final PPK model of biapenem was established for patients with sepsis. The current daily dosage regimen of 1.2g may insufficient to achieve 70% fT >MIC in septic patients. The dosage regimen of 600mg every 6h appears to be the optimal choice.

Integrating Genome-Wide Polygenic Risk Scores With Nongenetic Models to Predict Surgical Site Infection After Total Knee Arthroplasty Using United Kingdom Biobank Data

BackgroundPrediction of the risk of developing surgical site infection (SSI) in patients following total knee arthroplasty (TKA) is of clinical importance. Genetic susceptibility is involved in developing TKA-related SSI. Previously reported models for predicting SSI were constructed using nongenetic risk factors without incorporating genetic risk factors. To address this issue, we performed a genome-wide association study (GWAS) using the UK Biobank database. MethodsAdult patients who underwent primary TKA (n = 19,767) were analyzed and divided into SSI (n = 269) and non-SSI (n = 19,498) cohorts. Nongenetic covariates, including demographic data and preoperative comorbidities, were recorded. Genetic variants associated with SSI were identified by GWAS and included to obtain standardized polygenic risk scores (zPRS, an estimate of genetic risk). Prediction models were established through analyses of multivariable logistic regression and the receiver operating characteristic curve. ResultsThere were 4 variants (rs117896641, rs111686424, rs8101598, and rs74648298) achieving genome-wide significance that were identified. The logistic regression analysis revealed 7 significant risk factors: increasing zPRS, decreasing age, men, chronic obstructive pulmonary disease, diabetes mellitus, rheumatoid arthritis, and peripheral vascular disease. The areas under the receiver operating characteristic curve were 0.628 and 0.708 when zPRS (model 1) and nongenetic covariates (model 2) were used as predictors, respectively. The areas under the receiver operating characteristic curve increased to 0.76 when both zPRS and nongenetic covariates (model 3) were used as predictors. A risk-prediction nomogram was constructed based on model 3 to visualize the relative effect of statistically significant covariates on the risk of SSI and predict the probability of developing SSI. Age and zPRS were the top 2 covariates that contributed to the risk, with younger age and higher zPRS associated with higher risks. ConclusionsOur GWAS identified 4 novel variants that were significantly associated with susceptibility to SSI following TKA. Integrating genome-wide zPRS with nongenetic risk factors improved the performance of the model in predicting SSI.

Cumulative lifetime violence, social determinants of health, and cannabis use disorder post-cannabis legalization in a community sample of men: An intersectional perspective.

Despite Canada having the highest disease burden globally for cannabis use disorder (CUD) and violence being ubiquitous in men's lives, little is known about how intersections among social determinants of health (SDOH) and cumulative lifetime violence severity (CLVS) influence CUD in men post-cannabis legalization. Using data collected in a survey with a national community sample of 597 men who self-identified as having experienced violence, we conducted a latent profile analysis using 11 subscales of the CLVS-44 scale and explored differential associations between CLVS profiles and CUD considering SDOH covariates. Four profiles were distinguished by intersections among CLVS-44 subscale severity and roles as target and perpetrator. CLVS profiles were significantly associated with CUD in the unadjusted model and in the adjusted model where age, adverse housing, and education were significant covariate controls. In the adjusted model, CUD was differentially associated with CLVS profiles and significantly higher in Profile 4 (highest severity target and perpetrator) than in Profile 1 (lowest severity target, no perpetration). Chi-square tests showed significant intersection between adverse housing, younger age, Profile 4 CLVS, and moderate to severe CUD among cannabis users. These results reveal the importance of understanding simultaneous intersections among indicators of CLVS in determining profiles of lifetime violence. Also critical are intersections among CLVS profiles and significant covariates as a basis for trauma- and violence-informed care for CUD that prioritizes men most disadvantaged by this convergence and attends to individual and structural health disparities at practice and policy levels.

The reflective measurement model of adherence to non-pharmaceutical interventions (NPIs) in accordance with normalization process theory (NPT) in coherent and convenient social subgroups: PLS-SEM analysis.

Non-pharmaceutical interventions (NPIs) decrease COVID-19 transmission. Reliability and validity of adherence to NPIs in accordance with normalization process theory (NPT) in coherent and convenient social subgroups using reflective measurement model assessment has not been evaluated. In February 2021, a sample of medical students and people with substance use disorders in treatment as coherent (based on continuous probability distribution) vs. convenient groups (based on convenience, not equal probability) composed of travellers and COVID-19 suspected persons from Split-Dalmatia County (SDC) (n = 656) in the Mediterranean completed self-administered surveys. Partial least squares structural equation modelling (PLS-SEM) was used to measure reflective model assessment of adherence to NPIs according to NPT. PLS-SEM reflective model assessment provided two-group specific factors in inverse relationships which determined adherence to NPIs with excellent goodness-of-fit [χ2 = 1.292, df = 1; P = 0.297, CFI = 1, TLI = 0.997, RMSEA = 0.011 (90% CI 0-0.105), RMSEA P = 0.604, SRMR = 0.008, Hoelter CN (α = 0.05) = 2322.757]. Significant negative factors covariance estimate (-0.716) revealed an inverse relationship between first (adherence to NPIs and internal locus of control (LoC) (0.640)) and second factor; young adulthood age (≤25) and highest level of education (1362). As the first factor increased the second tended to decrease. LoC is expected potential mechanism by which sex (MLsex = -0.017, SE = 0.007, P < 0.016) and belonging to coherent subgroups (MLgroup = -0.008, SE = 0.003, P = 0.015) can produce indirect effect of adherence to NPIs. Coherent subgroups had a more pronounced tendency toward integration of NPIs in everyday life. Group factors that facilitate the normalization were higher educated younger adults with a tendency toward external LoC.

Estimation of linezolid exposure in patients with hepatic impairment using machine learning based on a population pharmacokinetic model.

To investigate the pharmacokinetic changes of linezolid in patients with hepatic impairment and to explore a method to predict linezolid exposure. Patients withhepatic impairment who received linezolid were recruited. A population pharmacokinetic model (PPK) was then built using NONMEM software. And based on the final model, virtual patients with rich concentration values was constructed through Monte Carlo simulations (MCS), which were used to build machine learning (ML) models to predict linezolid exposure levels. Finally, we investigated the risk factors for thrombocytopenia in patients included. A PPK model with population typical values of 3.83 L/h and 34.1 L for clearance and volume of distribution was established, and the severe hepatic impairment was identified as a significant covariate of clearance. Then, we built a series of ML models to predict the area under 0-24h concentration-time curve (AUC0-24) of linezolid based on virtual patients from MCS. The results showed that the Xgboost models showed the best predictive performance and were superior to the methods for estimating linezolid AUC0-24 based on though concentration or daily dose. Finally, we found that baseline platelet count, linezolid AUC0-24, and combination with fluoroquinolones were independent risk factors for thrombocytopenia, and based on this, we proposed a method for calculating the toxicity threshold of linezolid. In this study, we successfully constructed a PPK model for patients with hepatic impairment and used ML algorithm to estimate linezolid AUC0-24 based on limited data. Finally, we provided a method to determine the toxicity threshold of linezolid.

Racial and Ethnic Differences in Mortality and Functional Outcomes Following Aneurysmal Subarachnoid Hemorrhage.

Ischemic and hemorrhagic stroke incidence tends to be higher among minority racial and ethnic groups. The effect of race and ethnicity following an aneurysmal subarachnoid hemorrhage (aSAH) remains poorly understood. Thus, we aimed to explore the association between race and ethnicity and aSAH outcomes. Single-center retrospective review of patients with aSAH from January 2009 to March 2023. Primary outcome was in-hospital mortality. Secondary outcomes included delayed cerebral ischemia, cerebral infarction, radiographic and symptomatic vasospasm, pulmonary complications, epileptic seizures, external ventricular drain placement, and modified Rankin Scale score at discharge and 3-month follow-up. Associations between race and ethnicity and outcomes were assessed using binary and ordinal regression models, with multivariable models adjusted for significant covariates. A total of 1325 patients with subarachnoid hemorrhage presented to our center. Among them, 443 cases were excluded, and data from 882 patients with radiographically confirmed aSAH were analyzed. Distribution by race and ethnicity was 40.8% (n=360) White, 31.4% (n=277) Hispanic, 22.1% (n=195) Black, and 5.7% (n=50) Asian. Based on Hunt-Hess and modified Fisher grade, aSAH severity was similar among groups (P=0.269 and P=0.469, respectively). In-hospital mortality rates were highest for Asian (14.0%) and Hispanic (11.2%) patients; however, after adjusting for patient sex, age, health insurance, smoking history, alcohol and substance abuse, and aneurysm treatment, the overall likelihood was comparable to White patients. Hispanic patients had higher risks of developing cerebral infarction (adjusted odds ratio, 2.17 [1.20-3.91]) and symptomatic vasospasm (adjusted odds ratio, 1.64 [1.05-2.56]) than White patients and significantly worse discharge modified Rankin Scale scores (adjusted odds ratio, 1.44 [1.05-1.99]). Non-White patients also demonstrated a lower likelihood of 0 to 2 discharge modified Rankin Scale scores (adjusted odds ratio, 0.71 [0.50-0.98]). No significant interactions between race and ethnicity and age or sex were found for in-hospital mortality and functional outcomes. Our study identified significant differences in cerebral infarction and symptomatic vasospasm risk between Hispanic and White patients following aSAH. A higher likelihood of worse functional outcomes at discharge was found among non-White patients. These findings emphasize the need to better understand predisposing risk factors that may influence aSAH outcomes. Efforts toward risk stratification and patient-centered management should be pursued.