Diabetes and the social, biologic, and behavioral determinants of endometrial cancer in the United States.

BACKGROUND: Endometrial cancer is one of the most common types of cancer that affects women's reproductive system. The risk of endometrial cancer is associated with biologic, behavioral and social determinants of health (SDOH). The focus of the work is to investigate the cumulative effect of this cluster of covariates on the odds of endometrial cancer that heretofore have only been considered individually. METHODS: We conducted a quantitative study using the Behavioral Risk Factor Surveillance System (BRFSS) national data collected in 2020. Data analysis using weighted Chi-square test and weighted logistic regression were carried out on 84,118 female study participants from the United States. RESULTS: Women with diabetes mellitus were approximately twice as likely to have endometrial cancer compared to women without diabetes (OR 1.54; 95%CI: 1.01-2.34). Biologic factors that included obesity (OR 3.10; 95% CI: 1.96-4.90) and older age (with ORs ranging from 2.75 to 7.21) had a significant increase in the odds of endometrial cancer compared to women of normal weight and younger age group of 18 to 44. Among the SDOH, attending college (OR 1.83; 95% CI: 1.12-3.00) was associated with increased odds of endometrial cancer, while renting a home (OR 0.50; 95% CI: 0.28-0.88), having other arrangements (OR 0.05; 95% CI: 0.02-0.16), being divorced (OR 0.55; 95% CI: 0.30-0.99), and having higher incomes ranging from $35,000 to $50,000 (OR 0.35; 95% CI: 0.16-0.78), and above $50,000 (OR 0.29; 95% CI: 0.14-0.62), were all associated with decreased odds of endometrial cancer. As for race, Black women (OR 0.24; 95% CI: 0.07-0.84) and women of other races (OR 0.37; 95% CI: 0.15-0.88) were shown to have lower odds of endometrial cancer compared to White women. CONCLUSION: Our results revealed the importance of adopting a comprehensive approach to the study of the associated factors of endometrial cancer by including social, biologic, and behavioral determinants of health. The observed social inequity in endometrial cancer among women needs to be addressed through effective policies and changes in social structures to advocate for a standardized healthcare system that ensures equitable access to preventive measures and quality of care.

Role of Insulin Use and Social Determinants of Health on Non-melanoma Skin Cancer: Results From the Behavioral Risk Factor Surveillance System.

BACKGROUND: Non-melanoma skin cancer (NMSC) is a frequent type of malignancy with a steadily increasing incidence rate worldwide. Although NMSC was shown to be associated with diabetes, no studies have addressed the extent to which insulin use influences the risk of NMSC in light of social determinants of health (SDOH). We conducted a quantitative study that examined the interplay between insulin use, SDOH, additional covariates, and NMSC among individuals with diabetes. METHODS: We based our analysis on the 2020 Behavioral Risk Factor Surveillance System (BRFSS), a national survey conducted yearly in the US. We performed weighted chi-squared test, logistic regression, and survival analyses on 8685 eligible participants with diabetes enrolled in the BRFSS. RESULTS: Kaplan Meier survival curves showed higher probability of NMSC event-free survival for participants with diabetes using insulin compared to participants with diabetes not using insulin (log-rank test P < .001). Significant associations were detected between insulin use and reduced odds of NMSC (OR .56; 95% CI: .38-.82), and decreased hazard (HR .36; 95% CI: .21-.62), along with indices of SDOH. CONCLUSIONS: Our findings suggest that socioeconomic differences related to the healthcare system and behavioral patterns are linked to discrepancies in the use of insulin and the development of NMSC.

Population under Stress: The Coping Mechanisms of Lebanese Adults in Times of Intermingling Crises and Their Relationship with Stress.

The Lebanese population has faced numerous stressors due to multiple crises in the past four years. This study aims to measure the perceived stress of the Lebanese population, identify the coping mechanisms being used, and determine whether they are associated with their stress levels. A cross-sectional study of 205 individuals randomly selected from Beirut was conducted. Frequency distribution, descriptive analysis, and multivariable cumulative logit models were used to determine the associations between coping mechanisms and perceived stress. Our results indicated that 95.4% of our population had moderate to high perceived stress levels. Problem-focused coping was the most adopted mechanism and was associated with a statistically significant lower stress level, whereas avoidant coping was associated with a statistically significant higher stress level. Our study can pave the way for raising awareness on the importance of managing stress with adaptive coping mechanisms.

Dietary High Salt Intake Exacerbates SGK1-Mediated T Cell Pathogenicity in L-NAME/High Salt-Induced Hypertension.

Sodium chloride (NaCl) activates Th17 and dendritic cells in hypertension by stimulating serum/glucocorticoid kinase 1 (SGK1), a sodium sensor. Memory T cells also play a role in hypertension by infiltrating target organs and releasing proinflammatory cytokines. We tested the hypothesis that the role of T cell SGK1 extends to memory T cells. We employed mice with a T cell deletion of SGK1, SGK1fl/fl × tgCD4cre mice, and used SGK1fl/fl mice as controls. We treated the mice with L-NAME (0.5 mg/mL) for 2 weeks and allowed a 2-week washout interval, followed by a 3-week high-salt (HS) diet (4% NaCl). L-NAME/HS significantly increased blood pressure and memory T cell accumulation in the kidneys and bone marrow of SGK1fl/fl mice compared to knockout mice on L-NAME/HS or groups on a normal diet (ND). SGK1fl/fl mice exhibited increased albuminuria, renal fibrosis, and interferon-γ levels after L-NAME/HS treatment. Myography demonstrated endothelial dysfunction in the mesenteric arterioles of SGK1fl/fl mice. Bone marrow memory T cells were adoptively transferred from either mouse strain after L-NAME/HS administration to recipient CD45.1 mice fed the HS diet for 3 weeks. Only the mice that received cells from SGK1fl/fl donors exhibited increased blood pressure and renal memory T cell infiltration. Our data suggest a new therapeutic target for decreasing hypertension-specific memory T cells and protecting against hypertension.

General Versus Locoregional Anesthesia in TEVAR: An NSQIP Analysis.

BACKGROUND: Thoracic Endovascular Aortic Repair (TEVAR) is a minimally invasive surgery for repairing thoracic aneurysms and dissections. This study aims to compare postoperative outcomes of TEVAR performed under general versus locoregional anesthesia. METHODS: Utilizing the 2008-2019 American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database, patients older than the age of 18 years who received TEVAR, were identified using the following current procedural terminology codes: 33,880, 33,881, 33,883, 33,884, or 33,886. Patients who underwent concomitant procedures, those with both thoracoabdominal and abdominal aortic pathologies, and trauma cases were excluded. Standard descriptive statistics, in addition to χ2, Fisher's exact test, and Mann-Whitney U-tests were used to compare patient baseline characteristics and postoperative outcomes between general and locoregional anesthesia groups as appropriate. Univariable and multivariable logistic regression analyses were performed to assess independent predictors of hospital length of stay (LOS) greater than 7 days. RESULTS: Of the 1,028 patients included in the study, 86.5% received general anesthesia, and 13.5% received locoregional anesthesia, such as local anesthesia with monitored anesthesia care or regional anesthesia. No significant differences were found between patients receiving locoregional versus general anesthesia in mortality (3.6% vs. 7.9%, respectively, P = 0.071) and morbidity (18.7% and 24.8%, respectively, P = 0.121) within 30 days post-TEVAR, including any wound, pulmonary, thromboembolic, renal, septic, and cardiac arrest complications. Patients who received general anesthesia had significantly higher median LOS compared to those who received locoregional anesthesia [5 days (interquartile range (IQR): 3-10) versus 4 days (IQR: 2-7), P = 0.002], with 34.3% of the general anesthesia group having an LOS greater than 7 days compared to 21.6% of locoregional anesthesia group, P = 0.003. On multivariable logistic regression analysis, general anesthesia was found to be an independent predictor of prolonged LOS greater than 7 days (odds ratio (OR): 1.72, 95% confidence interval (CI): 1.05-2.81, P = 0.031). CONCLUSIONS: Locoregional anesthesia results in significantly lower postoperative hospital LOS with similar postoperative mortality and morbidity compared to general anesthesia in patients undergoing TEVAR.

Digital thermography and vascular involvement in ß-thalassemia intermedia.

Beta-thalassemia intermedia (ß-TI) is associated with vascular dysfunction. We used digital thermal monitoring (DTM), a non-invasive tool that evaluates vascular function based on changes in fingertip temperature during and after cuff occlusion on ß-TI patients. Thirty-three patients (18 years and older) were recruited in this study and divided into 3 groups: thalassemia, anemic controls, and healthy controls. Exclusion criteria included factors that are known to be associated with vascular damage. Patients underwent DTM and results were extracted as vascular reactivity index (VRI), a measure of how well the circulatory system responds to stimuli that require adjustments of blood flow. One-way analysis of variance (ANOVA) was used to test the mean difference in VRI between the 3 groups. A multiple linear regression was also carried out with VRI as the outcome of interest and a function of covariates that were thought to be of clinical relevance to VRI. The frequency, mean VRI ± standard error (SE) for the thalassemic group were (N = 16), mean = 2.243 ± 0.111; for anemic controls (N = 9), mean = 2.374 ± 0.162; and for the controls (N = 8), mean = 2.338 ± 0.092. ANOVA test indicated a non-significant difference in mean VRI between the three groups (P value = 0.731). Multiple linear regression couldn't detect any significant association between VRI and any of the predictors including the groups. Our study did not show a significant difference in VRI between the 3 study groups. Prospective studies of larger sample size are warranted to establish DTM as a possible non-invasive tool used to evaluate vascular function in ß-TI patients.

Knowledge and attitudes towards E-cigarette use in Lebanon and their associated factors.

BACKGROUND: Despite the misconceptions regarding E-cigarettes (ECs), only a few studies have been conducted in the Middle East that focused on this topic. This study assesses the knowledge of and attitudes towards ECs in Lebanon, determines how these two measures are associated, and identifies the variables that explain each of these measures. METHODS: A cross sectional study was conducted on a convenience sample of Lebanese pedestrians aged between 18 and 64 inclusive. A structured self-administered questionnaire comprising of knowledge and attitude scales, and questions on demographical, health and smoking characteristics was used. RESULTS: Scores for attitudes and knowledge of ECs were summed and dichotomized using a 75% cutoff, above which the participant was considered to have a positive attitude and good knowledge. Among the 352 participants (56.6% males, 43.3% females, mean age 30.3, 46.2% smokers), 63.3% exhibited a lower level of EC knowledge. More than 50% erroneously thought that ECs are not associated with lung and bladder cancer or impair lung and heart function. 65% falsely thought that it is harmless and not addictive. As for attitude, 43.3, 53.9, and 44.3% thought that it is socially acceptable, helps in smoking cessation, and is a good replacement for cigarettes and an enjoyable recreational device respectively. Our results revealed an inverse correlation between attitude and knowledge scores (Spearman's correlation = -.30, p < .001). Predictors of knowledge included health-related occupation (p = .010), regular exercise (p = .016), healthy diet (p = .026), EC use (p = .026), perception that ECs are not harmful (p = .001), and help in smoking cessation (p = .017). Predictors of attitude included EC use (p = .008), sex (p = .010), and knowledge that most ECs are addictive (p = .006), harmful (p = .014), and impair heart and lung function (p = .047). CONCLUSIONS: Our study revealed a gap in EC knowledge, especially among participants who displayed a positive attitude towards ECs. Hence, measures should be undertaken to regulate its use by instituting more stringent laws and holding nationwide awareness campaigns.

Analysis of longitudinal semicontinuous data using marginalized two-part model.

BACKGROUND: Connective tissue growth factor (CTGF), is a secreted matricellular factor that has been linked to increased risk of cardiovascular disease in diabetic subjects. Despite the biological role of CTGF in diabetes, it still remains unclear how CTGF expression is regulated. In this study, we aim to identify the clinical parameters that modulate plasma CTGF levels measured longitudinally in type 1 diabetic patients over a period of 10 years. A number of patients had negligible measured values of plasma CTGF that formed a point mass at zero, whereas others had high positive values of CTGF that were measured on a continuous scale. The observed combination of excessive zero and continuous positively distributed non-zero values in the CTGF outcome is referred to as semicontinuous data. METHODS: We propose a novel application of a marginalized two-part model (mTP) extended to accommodate longitudinal semicontinuous data in which the marginal mean is expressed in terms of the covariates and estimates of their effect on the mean responses are generated. The continuous component is assumed to follow distributions that stem from the generalized gamma family whereas the binary measure is analyzed using logistic model and both have correlated random effects. Other approaches including the one- and two-part with uncorrelated and correlated random effects models were also applied and their estimates were all compared. RESULTS: Our results using the mTP model identified intensive glucose control treatment and smoking as clinical factors that were associated with decreased and increased odds of observing non-zero CTGF values respectively. In addition, hemoglobin A1c, systolic blood pressure, and high density lipoprotein were all shown to be significant risk factors that contribute to increasing CTGF levels. These findings were consistently observed under the mTP model but varied with the distributions for the other models. Accuracy and precision of the mTP model was further validated using simulation studies. CONCLUSION: The mTP model identified new clinical determinants that modulate the levels of CTGF in diabetic subjects. Applicability of this approach can be extended to other biomarkers measured in patient populations that display a combination of negligible zero and non-zero values.

Joint Modeling of Covariates and Censoring Process Assuming Non-Constant Dropout Hazard.

In this manuscript we propose a novel approach for the analysis of longitudinal data that have informative dropout. We jointly model the slopes of covariates of interest and the censoring process for which we assume a survival model with logistic non-constant dropout hazard in a likelihood function that is integrated over the random effects. Maximization of the marginal likelihood function results in acquiring maximum likelihood estimates for the population slopes and empirical Bayes estimates for the individual slopes that are predicted using Gaussian quadrature. Our simulation study results indicated that the performance of this model is superior in terms of accuracy and validity of the estimates compared to other models such as logistic non-constant hazard censoring model that does not include covariates, logistic constant censoring model with covariates, bootstrapping approach as well as mixed models. Sensitivity analyses for the dropout hazard and non-Gaussian errors were also undertaken to assess robustness of the proposed approach to such violations. Our model was illustrated using a cohort of renal transplant patients with estimated glomerular filtration rate as the outcome of interest.

Analysis of multivariate longitudinal kidney function outcomes using generalized linear mixed models.

BACKGROUND: Renal transplant patients are mandated to have continuous assessment of their kidney function over time to monitor disease progression determined by changes in blood urea nitrogen (BUN), serum creatinine (Cr), and estimated glomerular filtration rate (eGFR). Multivariate analysis of these outcomes that aims at identifying the differential factors that affect disease progression is of great clinical significance. Thus our study aims at demonstrating the application of different joint modeling approaches with random coefficients on a cohort of renal transplant patients and presenting a comparison of their performance through a pseudo-simulation study. The objective of this comparison is to identify the model with best performance and to determine whether accuracy compensates for complexity in the different multivariate joint models. METHODS AND RESULTS: We propose a novel application of multivariate Generalized Linear Mixed Models (mGLMM) to analyze multiple longitudinal kidney function outcomes collected over 3 years on a cohort of 110 renal transplantation patients. The correlated outcomes BUN, Cr, and eGFR and the effect of various covariates such patient's gender, age and race on these markers was determined holistically using different mGLMMs. The performance of the various mGLMMs that encompass shared random intercept (SHRI), shared random intercept and slope (SHRIS), separate random intercept (SPRI) and separate random intercept and slope (SPRIS) was assessed to identify the one that has the best fit and most accurate estimates. A bootstrap pseudo-simulation study was conducted to gauge the tradeoff between the complexity and accuracy of the models. Accuracy was determined using two measures; the mean of the differences between the estimates of the bootstrapped datasets and the true beta obtained from the application of each model on the renal dataset, and the mean of the square of these differences. The results showed that SPRI provided most accurate estimates and did not exhibit any computational or convergence problem. CONCLUSION: Higher accuracy was demonstrated when the level of complexity increased from shared random coefficient models to the separate random coefficient alternatives with SPRI showing to have the best fit and most accurate estimates.

Overview of knowledge, attitudes and barriers associated with HPV vaccination in Beirut, Lebanon.

BACKGROUND: Human Papillomavirus (HPV), a prevalent sexually transmitted infection carrying significant risks ranging from benign lesions to various types of malignancies, represents a matter of great public health concern. Notably, most Arab countries lack public awareness campaigns or national immunization programs. This study aims at assessing the overall knowledge on HPV and HPV vaccination among the Lebanese population, exploring the prevalent attitude on the matter, and identifying barriers and misconceptions that prevent individuals from receiving the HPV vaccine. METHODS: A cross-sectional study was conducted in Beirut, on 201 participants aged between 18 and 36 years old. We performed ordinal analysis to assess the trend between Knowledge levels, attitude levels and hesitancy Levels. RESULTS: Majority of participants (77%) demonstrated a low level of knowledge on HPV vaccination, 50% held a positive attitude, with only 18.4% being already vaccinated. Negative trend was identified between levels of knowledge, attitude and hesitancy (gamma = -0.7415, p-value < 0.01; gamma= -0.58, p-value < 0.01 respectively). Unavailability or limited access to the vaccine, and misconceptions about HPV immunization were shown to be impeding vaccination. CONCLUSION: Analysis of our results strongly suggests that improving knowledge and attitudes is likely to foster trust and reduce hesitancy, thereby promoting higher vaccine uptake.

Development of alginate and alginate sulfate/polycaprolactone nanoparticles for growth factor delivery in wound healing therapy.

Connective tissue growth factor (CTGF) holds great promise for enhancing the wound healing process; however, its clinical application is hindered by its low stability and the challenge of maintaining its effective concentration at the wound site. Herein, we developed novel double-emulsion alginate (Alg) and heparin-mimetic alginate sulfate (AlgSulf)/polycaprolactone (PCL) nanoparticles (NPs) for controlled CTGF delivery to promote accelerated wound healing. The NPs' physicochemical properties, cytocompatibility, and wound healing activity were assessed on immortalized human keratinocytes (HaCaT), primary human dermal fibroblasts (HDF), and a murine cutaneous wound model. The synthesized NPs had a minimum hydrodynamic size of 200.25 nm. Treatment of HaCaT and HDF cells with Alg and AlgSulf2.0/PCL NPs did not show any toxicity when used at concentrations <50 µg/mL for up to 72 h. Moreover, the NPs' size was not affected by elevated temperatures, acidic pH, or the presence of a protein-rich medium. The NPs have slow lysozyme-mediated degradation implying that they have an extended tissue retention time. Furthermore, we found that treatment of HaCaT and HDF cells with CTGF-loaded Alg and AlgSulf2.0/PCL NPs, respectively, induced rapid cell migration (76.12% and 79.49%, P<0.05). Finally, in vivo studies showed that CTGF-loaded Alg and AlgSulf2.0/PCL NPs result in the fastest and highest wound closure at the early and late stages of wound healing, respectively (36.49%, P<0.001 on day 1; 90.45%, P<0.05 on day 10), outperforming free CTGF. Double-emulsion NPs based on Alg or AlgSulf represent a viable strategy for delivering heparin-binding GF and other therapeutics, potentially aiding various disease treatments.

Social and racial inequalities in diabetes and cancer in the United States.

Background: Cancer and diabetes are among the leading causes of morbidity and mortality worldwide. Several studies have reported diabetes as a risk factor for developing cancer, a relationship that may be explained by associated factors shared with both diseases such as age, sex, body weight, smoking, and alcohol consumption. Social factors referred to as social determinants of health (SDOH) were shown to be associated with the risk of developing cancer and diabetes. Despite that diabetes and social factors were identified as significant determinants of cancer, no studies examined their combined effect on the risk of developing cancer. In this study, we aim at filling this gap in the literature by triangulating the association between diabetes, indices of SDOH, and the risk of developing cancer. Methods: We have conducted a quantitative study using data from the Behavioral Risk Factor Surveillance System (BRFSS), whereby information was collected nationally from residents in the United States (US) with respect to their health-related risk behaviors, chronic health conditions, and the use of preventive services. Data analysis using weighted regressions was conducted on 389,158 study participants. Results: Our findings indicated that diabetes is a risk factor that increases the likelihood of cancer by 13% (OR 1.13; 95%CI: 1.05-1.21). People of White race had higher odds for cancer compared to African Americans (OR 0.44; 95%CI: 0.39-0.49), Asians (OR 0.27; 95%CI: 0.20-0.38), and other races (OR 0.56; 95%CI: 0.46-0.69). The indices of SDOH that were positively associated with having cancer encompassed unemployment (OR 1.78; 95%CI: 1.59-1.99), retirement (OR 1.54; 95%CI: 1.43-1.67), higher income levels with ORs ranging between 1.16-1.38, college education (OR 1.10; 95%CI: 1.02-1.18), college graduates (OR 1.31; 95%CI: 1.21-1.40), and healthcare coverage (OR 1.44; 95%CI: 1.22-1.71). On the other hand, the indices of SDOH that were protective against having cancer were comprised of renting a home (OR 0.86; 95%CI: 0.79-0.93) and never married (OR 0.73; 95%CI: 0.65-0.81). Conclusion: This study offers a novel social dimension for the association between diabetes and cancer that could guide setting strategies for addressing social inequities in disease prevention and access to healthcare.

Shared parameter and copula models for analysis of semicontinuous longitudinal data with nonrandom dropout and informative censoring.

Analysis of longitudinal semicontinuous data characterized by subjects' attrition triggered by nonrandom dropout is complex and requires accounting for the within-subject correlation, and modeling of the dropout process. While methods that address the within-subject correlation and missing data are available, approaches that incorporate the nonrandom dropout, also referred to informative right censoring, in the modeling step are scarce due to the computational intensity and possible intractable integration needed for its implementation. Appreciating the complexity of this problem and the need for a new methodology that is feasible for implementation, we propose to extend a framework of likelihood-based marginalized two-part models to account for informative right censoring. The censoring process is modeled using two approaches: (1) Poisson censoring for the count of visits before dropout and (2) survival time to dropout. Novel consideration was given to the proposed joint modeling approaches for the semicontinuous and censoring components of the likelihood function which included (1) shared parameter, and (2) Clayton copula. The cross-part and within-part correlations were accounted for through a complex random effect structure that models correlated random intercepts and slopes. Feasibility of implementation, and accuracy of these approaches were investigated using extensive simulation studies and clinical application.

Genetic variant in the promoter of connective tissue growth factor gene confers susceptibility to nephropathy in type 1 diabetes.

BACKGROUND The evidence for genetic susceptibility in the pathogenesis of diabetic nephropathy is well recognised, but the genes involved remain to be identified. It is hypothesised that mutations within the gene encoding connective tissue growth factor (CTGF/CCN2) will increase the propensity of diabetic subjects to develop nephropathy. METHODS AND RESULTS Genomic screening was performed for single nucleotide polymorphisms (SNPs) within the CTGF gene in 862 subjects from the DCCT/EDIC cohort of type 1 diabetes. A novel SNP was identified in the promoter region that changes a C-G at the position -20. The frequency of GG genotype in microalbuminuric patients (albumin excretion rate (AER) >40 mg/24 h) is significantly greater than diabetics with AER <40 mg/24 h, p<0.0001. The relative risk (RR) to develop microalbuminuria in diabetic subjects with the polymorphism is 3X higher than diabetic subjects without the polymorphism (RR 3.142, 95% CI 1.9238 to 5.1249; p<0.05). Kaplan-Meier survival curves demonstrated that the GG genotype group developed microalbuminuria and macroalbuminuria at a more rapid rate than the GC or CC genotypes. Functional studies demonstrated that the basal activity of the substituted allele/promoter (-20 GG allele) was significantly greater than that of the wild type promoter (-20 CC genotype). This higher level of basal activity of substituted allele CTGF/CCN2 promoter was abrogated upon suppression of Smad1 levels, indicating that SNP region in the CTGF/CCN2 promoter plays a vital role in the gene expression. CONCLUSIONS These findings provide the first evidence that variants within the promoter region of the CTGF/CCN2 gene predisposes diabetic subjects to develop albuminuria and demonstrate that Smad1 [corrected] controls the expression of CTGF/CCN2 promoter through this region.

The association of cardiovascular mortality with a first-degree family member history of different cardiovascular diseases.

OBJECTIVE: To investigate which history of cardiovascular disease [coronary heart disease (CHD), stroke, or peripheral arterial disease] in a first-degree family member predicts cardiovascular mortality. METHODS: We studied a prospective cohort (the Lipid Research Clinics Prevalence Study) from ten primary care centers across North America. The primary outcome was cardiovascular mortality, assessed using Cox survival models. RESULTS: There were 8,646 participants (mean age: 47.4 ± 12.1 years, 46% women, 52% of participants with hyperlipidemia) who were followed up for a mean duration of 19.4 ± 4.9 years. There were 1,851 deaths (21%), including 852 cardiovascular deaths. A paternal, maternal or sibling history of premature CHD (before 60 years) was present in 26% of participants, of stroke in 27% of participants, and of peripheral arterial disease in 24% of participants. After adjusting for risk factors (age, sex, systolic blood pressure, diastolic blood pressure, body mass index, smoking, fasting glucose, low-density lipoprotein cholesterol and triglycerides), only a paternal history of premature or any CHD, a maternal history of diabetes mellitus or premature or any CHD, and a sibling history of premature CHD, hypertension, or hyperlipidemia were individually predictive of cardiovascular mortality. After adjusting for risk factors and the mentioned familial factors, only paternal and maternal histories of CHD, especially before 60 years, remained predictive of cardiovascular mortality, with a somewhat higher association for a maternal history [adjusted hazard ratio (aHR) = 1.99, 95% CI: 1.36-2.92,P < 0.001 for maternal history of premature CHD; aHR = 1.52, 95% CI: 1.10-2.10, P = 0.011 for paternal history of premature CHD]. Family history of stroke or peripheral arterial disease did not predict cardiovascular mortality. Parental history of premature CHD predicted cardiovascular mortality independently of baseline age (< 60 years and ≥ 60 years), hypertension, or hyperlipidemia and carried more important prognostic value in men rather than women. CONCLUSIONS: In this study, a parental history of CHD, especially before 60 years, best predicted cardiovascular mortality. This finding could help more accurately identify high-risk patients who would benefit from preventive strategies.

Exercise-Induced Ventricular Ectopy and Cardiovascular Mortality in Asymptomatic Individuals.

BACKGROUND: The prognosis of exercise-induced premature ventricular contractions (PVCs) in asymptomatic individuals is unclear. OBJECTIVES: This study sought to investigate whether high-grade PVCs during stress testing predict mortality in asymptomatic individuals. METHODS: A cohort of 5,486 asymptomatic individuals who took part in the Lipid Research Clinics prospective cohort had baseline interview, physical examination, blood tests, and underwent Bruce protocol treadmill testing. Adjusted Cox survival models evaluated the association of exercise-induced high-grade PVCs (defined as either frequent (>10 per minute), multifocal, R-on-T type, or ≥2 PVCs in a row) with all-cause and cardiovascular mortality. RESULTS: Mean baseline age was 45.4 ± 10.8 years; 42% were women. During a mean follow-up of 20.2 ± 3.9 years, 840 deaths occurred, including 311 cardiovascular deaths. High-grade PVCs occurred during exercise in 1.8% of individuals, during recovery in 2.4%, and during both in 0.8%. After adjusting for age, sex, diabetes, hypertension, lipids, smoking, body mass index, and family history of premature coronary disease, high-grade PVCs during recovery were associated with cardiovascular mortality (hazard ratio [HR]: 1.82; 95% CI: 1.19-2.79; P = 0.006), which remained significant after further adjusting for exercise duration, heart rate recovery, achieving target heart rate, and ST-segment depression (HR: 1.68; 95% CI: 1.09-2.60; P = 0.020). Results were similar by clinical subgroups. High-grade PVCs occurring during the exercise phase were not associated with increased risk. Recovery PVCs did not improve 20-year cardiovascular mortality risk discrimination beyond clinical variables. CONCLUSIONS: High-grade PVCs occurring during recovery were associated with long-term risk of cardiovascular mortality in asymptomatic individuals, whereas PVCs occurring only during exercise were not associated with increased risk.

Sulfated alginate/polycaprolactone double-emulsion nanoparticles for enhanced delivery of heparin-binding growth factors in wound healing applications.

Diabetic foot ulcers (DFUs) that are not effectively treated could lead to partial or complete lower limb amputations. The lack of connective tissue growth factor (CTGF) and insulin-like growth factor (IGF-I) in DFUs results in limited matrix deposition and poor tissue repair. To enhance growth factor (GF) availability in DFUs, heparin (HN)-mimetic alginate sulfate/polycaprolactone (AlgSulf/PCL) double emulsion nanoparticles (NPs) with high affinity and sustained release of CTGF and IGF-I were synthesized. The NPs size, encapsulation efficiency (EE), cytotoxicity, cellular uptake and wound healing capacity in immortalized primary human adult epidermal cells (HaCaT) were assessed. The sonication time and amplitude used for NPs synthesis enabled the production of particles with a minimum of 236 ± 25 nm diameter. Treatment of HaCaT cells with up to 50 µg mL-1 of NPs showed no cytotoxic effects after 72 h. The highest bovine serum albumin EE (94.6 %, P = 0.028) and lowest burst release were attained with AlgSulf/PCL. Moreover, cells treated with AlgSulf/CTGF (250 ng mL-1) exhibited the most rapid wound closure compared to controls while maintaining fibronectin synthesis. Double-emulsion NPs based on HN-mimetic AlgSulf represent a novel approach which can significantly enhance diabetic wound healing and can be expanded for applications requiring the delivery of other HN-binding GFs.

Plasma Kallikrein as a Modulator of Liver Injury/Remodeling.

The occurrence and persistence of hepatic injury which arises from cell death and inflammation result in liver disease. The processes that lead to liver injury progression and resolution are still not fully delineated. The plasma kallikrein-kinin system (PKKS) has been shown to play diverse functions in coagulation, tissue injury, and inflammation, but its role in liver injury has not been defined yet. In this study, we have characterized the role of the PKKS at various stages of liver injury in mice, as well as the direct effects of plasma kallikrein on human hepatocellular carcinoma cell line (HepG2). Histological, immunohistochemical, and gene expression analyses were utilized to assess cell injury on inflammatory and fibrotic factors. Acute liver injury triggered by carbon tetrachloride (CCl4) injection resulted in significant upregulation of the plasma kallikrein gene (Klkb1) and was highly associated with the high mobility group box 1 gene, the marker of cell death (r = 0.75, p < 0.0005, n = 7). In addition, increased protein expression of plasma kallikrein was observed as clusters around necrotic areas. Plasma kallikrein treatment significantly increased the proliferation of CCl4-induced HepG2 cells and induced a significant increase in the gene expression of the thrombin receptor (protease activated receptor-1), interleukin 1 beta, and lectin-galactose binding soluble 3 (galectin-3) (p < 0.05, n = 4). Temporal variations in the stages of liver fibrosis were associated with an increase in the mRNA levels of bradykinin receptors: beta 1 and 2 genes (p < 0.05; n = 3-10). In conclusion, these findings indicate that plasma kallikrein may play diverse roles in liver injury, inflammation, and fibrosis, and suggest that plasma kallikrein may be a target for intervention in the states of liver injury.

Modulation of Neuro-Inflammatory Signals in Microglia by Plasma Prekallikrein and Neuronal Cell Debris.

Microglia, the resident phagocytes of the central nervous system and one of the key modulators of the innate immune system, have been shown to play a major role in brain insults. Upon activation in response to neuroinflammation, microglia promote the release of inflammatory mediators as well as promote phagocytosis. Plasma prekallikrein (PKall) has been recently implicated as a mediator of neuroinflammation; nevertheless, its role in mediating microglial activation has not been investigated yet. In the current study, we evaluate the mechanisms through which PKall contributes to microglial activation and release of inflammatory cytokines assessing PKall-related receptors and their dynamics. Murine N9-microglial cells were exposed to PKall (2.5 ng/ml), lipopolysaccharide (100 ng/ml), bradykinin (BK, 0.1 µM), and neuronal cell debris (16.5 µg protein/ml). Gene expression of bradykinin 2 receptor (B2KR), protease-activated receptor 2 (PAR-2), along with cytokines and fibrotic mediators were studied. Bioinformatic analysis was conducted to correlate altered protein changes with microglial activation. To assess receptor dynamics, HOE-140 (1 µM) and GB-83 (2 µM) were used to antagonize the B2KR and PAR-2 receptors, respectively. Also, the role of autophagy in modulating microglial response was evaluated. Data from our work indicate that PKall, LPS, BK, and neuronal cell debris resulted in the activation of microglia and enhanced expression/secretion of inflammatory mediators. Elevated increase in inflammatory mediators was attenuated in the presence of HOE-140 and GB-83, implicating the engagement of these receptors in the activation process coupled with an increase in the expression of B2KR and PAR-2. Finally, the inhibition of autophagy significantly enhanced the release of the cytokine IL-6 which were validated via bioinformatics analysis demonstrating the role of PKall in systematic and brain inflammatory processes. Taken together, we demonstrated that PKall can modulate microglial activation via the engagement of PAR-2 and B2KR where PKall acts as a neuromodulator of inflammatory processes.