Plasma oxyphytosterols most likely originate from hepatic oxidation and subsequent spill-over in the circulation

We evaluated oxyphytosterol (OPS) concentrations in plasma and various tissues of two genetically modified mouse models with either increased cholesterol (apoE KO mice) or increased cholesterol and plant sterol (PS) concentrations (apoExABCG8 dKO mice). Sixteen female apoE KO and 16 dKO mice followed the same standard, low OPS-chow diet. Animals were euthanized at 36 weeks to measure PS and OPS concentrations in plasma, brain, liver and aortic tissue. Cholesterol and oxysteml (OS) concentrations were analyzed as reference for sterol oxidation in general. Plasma campesterol (24.1 +/- 4.3 vs. 11.8 +/- 3.0 mg/dL) and sitosterol (67.4 +/- 12.7 vs. 4.9 +/- 1.1 mg/dL) concentrations were severely elevated in the dKO compared to the apoE KO mice (p < 0.001). Also, in aortic and brain tissue, PS levels were significantly elevated in dKO. However, plasma, aortic and brain OPS concentrations were comparable or even lower in the dKO mice. In contrast, in liver tissue, both PS and OPS concentrations were severely elevated in the dKO compared to apoE KO mice (sum OPS: 7.4 +/- 1.6 vs. 4.1 +/- 0.8 ng/mg, p < 0.001). OS concentrations followed cholesterol concentrations in plasma and all tissues suggesting ubiquitous oxidation. Despite severely elevated PS concentrations, OPS concentrations were only elevated in liver tissue, suggesting that OPS are primarily formed in the liver and plasma concentrations originate from hepatic spill-over into the circulation

The effect of long-term Aronia melanocarpa extract supplementation on cognitive performance, mood, and vascular function: A randomized controlled trial in healthy, middle-aged individuals

Cognitive decline is associated with lifestyle-related factors such as overweight, blood pressure, and dietary composition. Studies have reported beneficial effects of dietary anthocyanins on cognition in older adults and children. However, the effect of anthocyanin-rich Aronia melanocarpa extract (AME) on cognition is unknown. Therefore, this study aimed to determine the effect of long-term supplementation with AME on cognitive performance, mood, and vascular function in healthy, middle-aged, overweight adults. In a randomized double-blind placebo-controlled parallel study, 101 participants either consumed 90 mg AME, 150 mg AME, or placebo for 24 weeks. The grooved pegboard test, number cross-out test, and Stroop test were performed as measures for psychomotor speed, attention, and cognitive flexibility. Mood was evaluated with a visual analogue scale, serum brain-derived neurotrophic factor (BDNF) was determined, and vascular function was assessed by carotid ultrasounds and blood pressure measurements. AME improved psychomotor speed compared to placebo (90 mg AME: change = -3.37; p = 0.009). Furthermore, 150 mg AME decreased brachial diastolic blood pressure compared to 90 mg AME (change = 2.44; p = 0.011), but not compared to placebo. Attention, cognitive flexibility, BDNF, and other vascular parameters were not affected. In conclusion, AME supplementation showed an indication of beneficial effects on cognitive performance and blood pressure in individuals at risk of cognitive decline

Expression of CD39 Identifies Activated Intratumoral CD8+T Cells in Mismatch Repair Deficient Endometrial Cancer

Identification of human cancer-reactive CD8+ T cells is crucial for the stratification of patients for immunotherapy and determination of immune-therapeutic effects. To date, these T cells have been identified mainly based on cell surface expression of programmed cell death protein 1 (PD-1) or co-expression of CD103 and CD39. A small subset of CD103- CD39+ CD8+ T cells is also present in tumors, but little is known about these T cells. Here, we report that CD103- CD39+ CD8+ T cells from mismatch repair-deficient endometrial tumors are activated and characterized predominantly by expression of TNFRSF9. In vitro, transforming growth factor-beta (TGF-beta) drives the disappearance of this subset, likely through the conversion of CD103- CD39+ cells to a CD103+ phenotype. On the transcriptomic level, T cell activation and induction of CD39 was associated with a number of tissue residence and TGF-beta responsive transcription factors. Altogether, our data suggest CD39+ CD103- CD8+ tumor-infiltrating T cells are recently activated and likely rapidly differentiate towards tissue residence upon exposure to TGF-beta in the tumor micro-environment, explaining their relative paucity in human tumors

Prognostic image-based quantification of CD8CD103 T cell subsets in high-grade serous ovarian cancer patients

CD103-positive tissue resident memory-like CD8+ T cells (CD8CD103 TRM) are associated with improved prognosis across malignancies, including high-grade serous ovarian cancer (HGSOC). However, whether quantification of CD8, CD103 or both is required to improve existing survival prediction and whether all HGSOC patients or only specific subgroups of patients benefit from infiltration, remains unclear. To address this question, we applied image-based quantification of CD8 and CD103 multiplex immunohistochemistry in the intratumoral and stromal compartments of 268 advanced-stage HGSOC patients from two independent clinical institutions. Infiltration of CD8CD103 immune cell subsets was independent of clinicopathological factors. Our results suggest CD8CD103 TRM quantification as a superior method for prognostication compared to single CD8 or CD103 quantification. A survival benefit of CD8CD103 TRM was observed only in patients treated with primary cytoreductive surgery. Moreover, survival benefit in this group was limited to patients with no macroscopic tumor lesions after surgery. This approach provides novel insights into prognostic stratification of HGSOC patients and may contribute to personalized treatment strategies in the future

Longitudinal Associations Between Sexual Communication With Friends and Sexual Behaviors Through Perceived Sexual Peer Norms

The role of peers in adolescents’ sexual behaviors is not yet fully understood. We investigated the association between sexual communication with friends (at T1) and subsequent changes in adolescents’ experience with sexual behaviors (between T1–T3), and examined whether this association was explained by adolescents’ perceptions of three sexual peer norms (at T2): (1) peers’ se

Model confidence sets and forecast combination: an application to age-specific mortality

Background: Model averaging combines forecasts obtained from a range of models, and it often produces more accurate forecasts than a forecast from a single model. Objective: The crucial part of forecast accuracy improvement in using the model averaging lies in the determination of optimal weights from a finite sample. If the weights are selected sub-optimally, this can affect the accuracy of the model-averaged forecasts. Instead of choosing the optimal weights, we consider trimming a set of models before equally averaging forecasts from the selected superior models. Motivated by Hansen et al. (2011), we apply and evaluate the model confidence set procedure when combining mortality forecasts. Data & Methods: The proposed model averaging procedure is motivated by Samuels and Sekkel (2017) based on the concept of model confidence sets as proposed by Hansen et al. (2011) that incorporates the statistical significance of the forecasting performance. As the model confidence level increases, the set of superior models generally decreases. The proposed model averaging procedure is demonstrated via national and sub-national Japanese mortality for retirement ages between 60 and 100+. Results: Illustrated by national and sub-national Japanese mortality for ages between 60 and 100+, the proposed model-average procedure gives the smallest interval forecast errors, especially for males. Conclusion: We find that robust out-of-sample point and interval forecasts may be obtained from the trimming method. By robust, we mean robustness against model misspecification

Optical and mid-infrared line emission in nearby Seyfert galaxies

Line ratio diagnostics provide valuable clues on the source of ionizing radiation in galaxies with intense black hole accretion and starbursting events, such as local Seyfert or galaxies at the peak of the star formation history. We aim to provide a reference joint optical and mid-IR analysis for studying AGN identification via line ratios and testing predictions from photoionization models. We obtained homogenous optical spectra with the Southern Africa Large Telescope for 42 Seyfert galaxies with Spitzer/IRS spectroscopy and X-ray to mid-IR multiband data available. After confirming the power of the main optical ([OIII]) and mid-IR ([NeV], [OIV], [NeIII]) emission lines in tracing AGN activity, we explore diagrams based on ratios of optical and mid-IR lines by exploiting photoionization models of different ionizing sources (AGN, star formation and shocks). We find that pure AGN photoionization models are good at reproducing observations of Seyfert galaxies with an AGN fractional contribution to the mid-IR (5-40 micron) emission larger than 50 per cent. For targets with a lower AGN contribution these same models do not fully reproduce the observed mid-IR line ratios. Mid-IR ratios like [NeV]/[NeII], [OIV]/[NeII] and [NeIII]/[NeII] show a dependence on the AGN fractional contribution to the mid-IR unlike optical line ratios. An additional source of ionization, either from star formation or radiative shocks, can help explain the observations in the mid-IR. Among combinations of optical and mid-IR diagnostics in line ratio diagrams, only those involving the [OI]/Halpha ratio are promising diagnostics for simultaneously unraveling the relative role of AGN, star formation and, shocks. A proper identification of the dominant ionizing source would require the exploitation of analysis tools based on advanced statistical techniques as well as spatially resolved data.Comment: 31 pages, 15 figures, 2 tables. Accepted for publication in A&

The importance of job control for workers with decreased work ability to remain productive at work

Purpose: Workers with decreased work ability are at greater risk of reduced productivity at work. We hypothesized that work-related characteristics play an important role in supporting workers to remain productive despite decreased work ability. Methods: The study population consisted of 10,542 workers in 49 different companies in the Netherlands in 2005-2009. Productivity loss at work was defined on a 10-point scale by asking how much work was actually performed during regular hours on the last regular workday when compared with normal. Independent variables in the logistic regression analysis were individual characteristics, work-related factors, and the work ability index. Additive interactions between work-related factors and decreased work ability were evaluated by the relative excess risk due to interaction (RERI). Results: The odds ratios and 95% confidence intervals (CI) for the likelihood of productivity loss at work were 2.03 (1.85-2.22), 3.50 (3.10-3.95), and 5.54 (4.37-7.03) for a good, moderate, and poor work ability, compared with an excellent work ability (reference group). Productivity loss at work was associated with lack of job control, poor skill discretion, and high work demands. There was a significant interaction between decreased work ability and lack of job control (RERI = 0.63 95% CI 0.11-1.16) with productivity loss at work. Conclusion: The negative effects on work performance of decreased work ability may be partly counterbalanced by increased job control. This suggests that interventions among workers with (chronic) disease that cause a decreased work ability should include enlargement of possibilities to plan and pace their own activities at work

First Randomized, Multicenter, Placebo-Controlled Study of Self-Administered Intranasal Etripamil for Acute Conversion of Spontaneous Paroxysmal Supraventricular Tachycardia (NODE-301).

BACKGROUND: Pharmacologic termination of paroxysmal supraventricular tachycardia (PSVT) often requires medically supervised intervention. Intranasal etripamil, is an investigational fast-acting, nondihydropyridine, L-type calcium channel blocker, designed for unsupervised self-administration to terminate atrioventricular nodal-dependent PSVT. Phase 2 results showed potential safety and efficacy of etripamil in 104 patients with PSVT. METHODS: NODE-301, a phase 3, multicenter, double-blind, placebo-controlled study evaluated the efficacy and safety of etripamil nasal spray administered, unsupervised in patients with symptomatic sustained PSVT. After a medically supervised etripamil test dose while in sinus rhythm, patients were randomized 2:1 to receive etripamil 70 mg or placebo. When PSVT symptoms developed, patients applied a cardiac monitor and attempted a vagal maneuver; if symptoms persisted, they self-administered blinded treatment. An independent Adjudication Committee reviewed continuous electrocardiogram recordings. The primary efficacy endpoint was termination of adjudicated PSVT within 5 hours after study drug administration. RESULTS: NODE-301 accrued 156 positively adjudicated PSVT events treated with etripamil (n=107) or placebo (n=49). The hazard ratio for the primary endpoint, time-to-conversion to sinus rhythm during the 5-hour observation period, was 1.086 (95% CI, 0.726-1.623; P=0.12). In predefined sensitivity analyses, etripamil effects (compared with placebo) occurred at 3, 5, 10, 20, and 30 minutes (P<0.05). For example, at 30 minutes, there was a 53.7% of SVT conversion in the treatment arm compared to 34.7% in the placebo arm (hazard ratio, 1.87 [95% CI, 1.09-3.22]; P=0.02). Etripamil was well tolerated; adverse events were mainly related to transient nasal discomfort and congestion (19.6% and 8.0%, respectively, of randomized treatment-emergent adverse events. CONCLUSIONS: Although the primary 5-hour efficacy endpoint was not met, analyses at earlier time points indicated an etripamil treatment effect in terminating PSVT. Etripamil self-administration during PSVT was safe and well tolerated. These results support continued clinical development of etripamil nasal spray for self-administration during PSVT in a medically unsupervised setting. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03464019