Inflammatory Cytokines and Risk of Ischemic Stroke: A Mendelian Randomization Study

Background: Observational studies have revealed the association between some inflammatory cytokines and the occurrence of ischemic stroke, but the causal relationships remain unclear.Methods: We conducted a two-sample Mendelian randomization (MR) analysis to assess the causal effects of thirty inflammatory cytokines and the risk of ischemic stroke. For exposure data, we collected genetic variants associated with inflammatory cytokines as instrumental variables (IVs) from a genome-wide association study (GWAS) meta-analysis from Finland (sample size up to 8,293). For the outcome data, we collected summary data of ischemic stroke from a large-scale GWAS meta-analysis involved 17 studies (34,217 cases and 406,111 controls). We further performed a series of sensitivity analyses as validation of primary MR results.Results: According to the primary MR estimations and further sensitivity analyses, we established one robust association after Bonferroni correction: the odds ratio (95% CI) per unit change in genetically increased IL-4 was 0.84 (0.89–0.95) for ischemic stroke. The chemokine MCP3 showed a nominally significant association with ischemic stroke risk (OR: 0.93, 95% CI: 0.88–0.99, unadjusted p < 0.05). There was no evidence of a causal effect of other inflammatory cytokines and the risk of ischemic stroke.Conclusions: Our study suggested that genetically increased IL-4 levels showed a protective effect on the risk of ischemic stroke, which provides important new insights into the potential therapeutic target for preventing ischemic stroke.

Modeling the Transmission of the SARS-CoV-2 Delta Variant in a Partially Vaccinated Population

In a population with ongoing vaccination, the trajectory of a pandemic is determined by how the virus spreads in unvaccinated and vaccinated individuals that exhibit distinct transmission dynamics based on different levels of natural and vaccine-induced immunity. We developed a mathematical model that considers both subpopulations and immunity parameters, including vaccination rates, vaccine effectiveness, and a gradual loss of protection. The model forecasted the spread of the SARS-CoV-2 delta variant in the US under varied transmission and vaccination rates. We further obtained the control reproduction number and conducted sensitivity analyses to determine how each parameter may affect virus transmission. Although our model has several limitations, the number of infected individuals was shown to be a magnitude greater (~10×) in the unvaccinated subpopulation compared to the vaccinated subpopulation. Our results show that a combination of strengthening vaccine-induced immunity and preventative behavioral measures like face mask-wearing and contact tracing will likely be required to deaccelerate the spread of infectious SARS-CoV-2 variants.

Dispositional optimism and depression risk in older women in the Nurses´ Health Study: a prospective cohort study

Dispositional optimism is a potentially modifiable factor and has been associated with multiple physical health outcomes, but its relationship with depression, especially later in life, remains unclear. In the Nurses´ Health Study (n = 33,483), we examined associations between dispositional optimism and depression risk in women aged 57–85 (mean = 69.9, SD = 6.8), with 4,051 cases of incident depression and 10 years of follow-up (2004–2014). We defined depression as either having a physician/clinician-diagnosed depression, or regularly using antidepressants, or the presence of severe depressive symptoms using validated self-reported scales. Age- and multivariable-adjusted Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (95% CIs) across optimism quartiles and for a 1-standard deviation (SD) increment of the optimism score. In sensitivity analyses we explored more restrictive definitions of depression, potential mediators, and moderators. In multivariable-adjusted models, women with greater optimism (top vs. bottom quartile) had a 27% (95%CI = 19–34%) lower risk of depression. Every 1-SD increase in the optimism score was associated with a 15% (95%CI = 12–18%) lower depression risk. When applying a more restrictive definition for clinical depression, the association was considerably attenuated (every 1-SD increase in the optimism score was associated with a 6% (95%CI = 2–10%-) lower depression risk. Stratified analyses by baseline depressive symptoms, age, race, and birth region revealed comparable estimates, while mediators (emotional support, social network size, healthy lifestyle), when combined, explained approximately 10% of the optimism-depression association. As social and behavioral factors only explained a small proportion of the association, future research should investigate other potential pathways, such as coping strategies, that may relate optimism to depression risk.

A budget impact analysis of substituting sitagliptin with liraglutide in type 2 diabetes from a private health insurance perspective in Egypt

Introduction Type 2 diabetes mellitus causes a sizable burden globally from both health and economic points of view. This study aimed to assess the budget impact of substituting sitagliptin with liraglutide versus other glucose-lowering drugs from the private health insurance perspective in Egypt over a 3-year time horizon. Methods Two budget impact models were compared with the standard of care (metformin, pioglitazone, gliclazide, insulin glargine, repaglinide, and empagliflozin) administered in addition to liraglutide or sitagliptin versus the standard of care with placebo. A gradual market introduction of liraglutide or sitagliptin was assumed, and the existing market shares for the other glucose-lowering drugs were provided and validated by the Expert Panel. The event rates were extracted from the LEADER and TECOS trials. Direct and mortality costs were measured. Sensitivity analyses were performed. Results The estimated target population of 120,574 type 2 diabetic adult patients was associated with cardio vascular risk. The budget impact per patient per month for liraglutide is EGP29 ($6.7), EGP39 ($9), and EGP49 ($11.3) in the 1st, 2nd, and 3rd years, respectively. The budget impact per patient per month for sitagliptin is EGP11 ($2.5), EGP14 ($3.2), and EGP18 ($4.1) in the 1st, 2nd, and 3rd years, respectively. Furthermore, adoption of liraglutide resulted in 203 fewer deaths and 550 avoided hospitalizations, while sitagliptin resulted in 43 increased deaths and 14 avoided hospitalizations. The treatment costs of liraglutide use are mostly offset by substantial savings due to fewer cardiovascular-related events, avoided mortality and avoided hospitalizations over 3 years. Conclusion Adding liraglutide resulted in a modest budget impact, suggesting that the upfront drug costs were offset by budget savings due to fewer cardiovascular-related complications and deaths avoided compared to the standard of care. Sitagliptin resulted in a small budget impact but was associated with increased deaths and fewer hospitalizations avoided.

Gratitude as Mood Mediates the Effects of a 6-Weeks Gratitude Intervention on Mental Well-Being: Post hoc Analysis of a Randomized Controlled Trial

There is a gap of knowledge about the extent to which gratitude is indeed the working mechanism of change in gratitude interventions aiming to promote mental well-being. This study explores the mediational role of gratitude as mood in the context of a recently conducted randomized controlled trial on the effects of a 6-week gratitude intervention on mental well-being in comparison with a waitlist control group. Gratitude as mood was measured at 2, 4, and 6 weeks. Both simple and multiple mediation models were conducted as well as various sensitivity analyses. Results showed a gradual increase of gratitude as mood during the intervention. The effects of the 6-week gratitude intervention on mental well-being were mediated by increases of gratitude as mood at 4 weeks but not at 2 weeks. These findings suggest a dose-response relationship for gratitude interventions, but more research is warranted.

Maize stalk stiffness and strength are primarily determined by morphological factors

The maize (Zea mays) stem is a biological structure that must balance both biotic and structural load bearing duties. These competing requirements are particularly relevant in the design of new bioenergy crops. Although increased stem digestibility is typically associated with a lower structural strength and higher propensity for lodging, with the right balance between structural and biological activities it may be possible to design crops that are high-yielding and have digestible biomass. This study investigates the hypothesis that geometric factors are much more influential in determining structural strength than tissue properties. To study these influences, both physical and in silico experiments were used. First, maize stems were tested in three-point bending. Specimen-specific finite element models were created based on x-ray computed tomography scans. Models were validated by comparison with experimental data. Sensitivity analyses were used to assess the influence of structural parameters such as geometric and material properties. As hypothesized, geometry was found to have a much stronger influence on structural stability than material properties. This information reinforces the notion that deficiencies in tissue strength could be offset by manipulation of stalk morphology, thus allowing the creation of stalks which are both resilient and digestible.

Impact of 25-Hydroxy Vitamin D on White Matter Hyperintensity in Elderly Patients: A Systematic Review and Meta-Analysis

Some studies show that low serum vitamin D levels are associated with white matter hyperintensity (WMH), while other studies report no association. This meta-analysis aimed to investigate the presence of an association between serum 25-hydroxy vitamin D [25(OH)D] levels and WMH. PubMed, Embase, the Cochrane Library, CNKI, WANFANG, and VIP were searched for available papers published up to December 2020. The outcomes were the odds ratios (ORs) with 95% confidence intervals (CIs) for the association between different vitamin D statuses and WMH. All meta-analyses were performed using a random-effects model. Five studies (4393 patients) were included. Compared with sufficient 25(OH)D levels, 25(OH)D deficiency was not associated with WMH (OR = 1.67, 95%CI: 0.92–3.04; I2 = 70.2%, Pheterogeneity = 0.009), nor was 25(OH)D insufficiency (OR = 1.21, 95%CI: 0.89–1.65; I2 = 48.1%, Pheterogeneity = 0.103). A decrease of 25 nmol/L in 25(OH)D levels was associated with WMH (OR = 1.83, 95%CI: 1.34-2.49; I2 = 0%, Pheterogeneity= 0.512). The sensitivity analyses showed that the results were robust. 25(OH)D deficiency and insufficiency are not associated with WMH. A decrease of 25 nmol/L in 25(OH)D levels was associated with WMH, but this result will have to be confirmed. Prospective trials, both cross-sectional and longitudinal, are necessary to examine the association between 25(OH)D levels and WMH.

Improving the Numerical Modelling of In-Situ Rock Bolts Using Axial and Bending Strain Data from Instrumented Bolts

Numerical modelling has become an important tool in the underground rock bolt reinforcement designing process. Numerical modelling provides the advantage of easily and quickly simulating complex underground geometries and mechanisms with sensitivity analyses. However, a numerical model needs to be calibrated using mathematical solutions, lab testing or with actual in-situ observations and measurements (which is the preferred method) before its results can be quantitatively applied to reinforcement design. Instrumented rock bolts provide a useful data source for calibrating in-situ rock bolt models. In this work, procedures have been presented to identify and determine the orientation of structures in the rock mass based on the strains on the instrumented rock bolts. A method to calibrate the rock bolt model with in-situ data is also presented. The results of the presented procedures have been validated with laboratory tests and numerical modelling. The procedures have been applied to create and calibrate an in-situ rock bolt model in FLAC3D and the results are validated using in-situ data.

Variability, mean, and baseline values of metabolic parameters in predicting the risk of type 2 diabetes

Context Impact of baseline and alteration of metabolic parameters (MPs), including plasma glucose (PGs) testing, insulin resistance surrogates, and lipid profile and their mutual interactions on the development of type 2 diabetes (T2DM) has not been investigated systematically. Objective To access the association of the past variability (V), past mean (M), and the baseline (B) values of various MPs and their mutual interaction with the risk of T2DM. Design Longitudinal analysis from the Korean Genome and Epidemiology Study. Setting Community-based Participants 3829 non-diabetic participants with completed MPs measurements during three biannually visits were followed up over the next 10 years. Outcomes Incidence of T2DM during the follow up. Results Among predictors, PG concentrations measured during the oral glucose tolerance test were the most prominent T2DM determinants, in which the M of the average value of fasting PG, 1-h, and 2-h PGs had the strongest discriminative power (hazard ratios and 95% CI for an increment of SD: 3.00 (2.5–3.26), AUC: 0.82). The M values of MPs were superior to their B and V values in predicting T2DM, especially among post-load PGs. Various mutual interactions between indices and among MPs were found. The most consistent interactants were the M values of high-density lipoprotein cholesterol and the M and V values of fasting PG. The findings were similar in normal tolerance glucose participants and were confirmed by sensitivity analyses. Conclusion The post-load PGs, past alteration of measurements, and mutual interactions among indices of MPs are important risk factors for T2DM development.