Dose-dependent Transmissibility of Chromosome Aberrations at First Mitosis after Exposure to Gamma Rays. I. Modeling and Implications Related to Risk Assessment

The relationship between certain chromosomal aberration (CA) types and cell lethality is well established. On that basis we used multi-fluor in situ hybridization (mFISH) to tally the number of mitotic human lymphocytes exposed to graded doses of gamma rays that carried either lethal or nonlethal CA types. Despite the fact that a number of nonlethal complex exchanges were observed, the cells containing them were seldom deemed viable, due to coincident lethal chromosome damage. We considered two model variants for describing the dose responses. The first assumes independent linear-quadratic (LQ) dose response shapes for the yields of both lethal and nonlethal CAs. The second (simplified) variant assumes that the mean number of nonlethal CAs per cell is proportional to the mean number of lethal CAs per cell, meaning that the shapes and magnitudes of both aberration types differ only by a multiplicative proportionality constant. Using these models allowed us to assemble dose response curves for the frequency of aberration-bearing cells that would be expected to survive. This took the form of a joint probability distribution for cells containing ≥1 nonlethal CAs but having zero lethal CAs. The simplified second model variant turned out to be marginally better supported than the first, and the joint probability distribution based on this model yielded a crescent-shaped dose response reminiscent of those observed for mutagenesis and transformation for cells “at risk” (i.e. not corrected for survival). Among the implications of these findings is the suggestion that similarly shaped curves form the basis for deriving metrics associated with radiation risk models.

Dose-response relationship of reported lifetime meditation practice with mental-health and wellbeing: A cross sectional study

Objectives: Experimental studies of meditation practice predominantly examine short-term programs and reveal modest benefits. Thus it is not clear to what degree these results represent how contemporary meditators practice nor the dose-response relationship between amount of practice and outcome. This study sought to characterize how contemporary meditators practice; examine any possible dose-response relationships between historical practice and measures of psychological wellbeing; and explore which characteristics of practice most strongly predict positive psychological outcomes.Methods: 1,668 meditators completed demographic and practice characteristics, and outcome measures assessing positive and negative affect, psychological distress, and life satisfaction.Results: We observed a positive relationship between historical meditation practice (accumulated lifetime hours) and improvements in psychological outcomes. Model fit was optimized with a generalized additive model, indicating non-linear effects. The strength of the relationship between practice time and outcomes was generally strongest for the first ~500 hours, before plateauing to some degree. Several practice types, including Vipassana (as taught by S.N. Goenka) and cultivating practices (e.g. compassion, lovingkindness) were more strongly associated with favorable psychological outcomes.Conclusions: Benefits of meditation accrue over time in a non-linear manner, and show variation based on the context within which the meditator practices. These results highlight the importance of understanding how the benefits of meditation accrue over longer time durations than typical standardized programs that have been subject to most empirical investigations in the field.

A model-based approach to designing developmental toxicology experiments using sea urchin embryos

The key aim of this paper is to suggest a more quantitative approach to designing a dose–response experiment, and more specifically, a concentration–response experiment. The work proposes a departure from the traditional experimental design to determine a dose–response relationship in a developmental toxicology study. It is proposed that a model-based approach to determine a dose–response relationship can provide the most accurate statistical inference for the underlying parameters of interest, which may be estimating one or more model parameters or pre-specified functions of the model parameters, such as lethal dose, at maximal efficiency. When the design criterion or criteria can be determined at the onset, there are demonstrated efficiency gains using a more carefully selected model-based optimal design as opposed to an ad-hoc empirical design. As an illustration, a model-based approach was theoretically used to construct efficient designs for inference in a developmental toxicity study of sea urchin embryos exposed to trimethoprim. This study compares and contrasts the results obtained using model-based optimal designs versus an ad-hoc empirical design.

Cardiorespiratory fitness and mortality from all causes, cardiovascular disease and cancer: dose–response meta-analysis of cohort studies

ObjectiveCurrent evidence of the associations between cardiorespiratory fitness (CRF) and mortality is limited. We performed a meta-analysis to assess the dose–response association of CRF with mortality from all causes, cardiovascular disease (CVD) and cancer in healthy population.MethodsPubMed, EMBASE and Web of Science were searched up to 26 December 2019 for reports of cohort studies giving risk estimates for all-cause, CVD and cancer mortality by level of CRF. Cohort studies were included if CRF was assessed by an exercise stress test and reported as at least three levels or per incremental increase, and the association of CRF with all-cause, CVD and cancer mortality was evaluated. Generalised least-squares regression models were used to assess the quantitative relation of CRF with all-cause, CVD and cancer mortality.Results34 cohort studies were eligible for the meta-analysis. The pooled relative risks (RRs) for all-cause, CVD and cancer mortality per one-metabolic equivalent increase in CRF were 0.88 (95% CI 0.83 to 0.93), 0.87 (95% CI0.83 to 0.91) and 0.93 (95% CI 0.91 to 0.96), respectively. As compared with lowest CRF, with intermediate CRF, the summary RRs for all-cause, CVD and cancer mortality were 0.67 (95% CI 0.61 to 0.74), 0.60 (95% CI 0.51 to 0.69) and 0.76 (95% CI 0.69 to 0.84), respectively, and with highest CRF were 0.47 (95% CI 0.39 to 0.56), 0.49 (95% CI 0.42 to 0.56) and 0.57 (95% CI 0.46 to 0.70), respectively.ConclusionOur analysis showed inverse dose–response associations of CRF with all-cause, CVD and cancer mortality, which provides evidence for public health recommendations for preventing all-cause, CVD and cancer mortality.PROSPERO registration numberCRD42020208883.

Prebiotic Galacto-Oligosaccharides Impact Stool Frequency and Fecal Microbiota in Self-Reported Constipated Adults: A Randomized Clinical Trial

Constipation is a major issue for 10–20% of the global population. In a double-blind randomized placebo-controlled clinical trial, we aimed to determine a dose-response effect of galacto-oligosaccharides (GOS) on stool characteristics and fecal microbiota in 132 adults with self-reported constipation according to Rome IV criteria (including less than three bowel movements per week). Subjects (94% females, aged: 18–59 years) received either 11 g or 5.5 g of BiotisTM GOS, or a control product, once daily for three weeks. Validated questionnaires were conducted weekly to study primarily stool frequency and secondary stool consistency. At base- and endline, stool samples were taken to study fecal microbiota. A trend towards an increased stool frequency was observed after the intervention with 11 g of GOS compared to control. While during screening everybody was considered constipated, not all subjects (n = 78) had less than three bowel movements per week at baseline. In total, 11 g of GOS increased stool frequency compared to control in subjects with a low stool frequency at baseline (≤3 bowel movements per week) and in self-reported constipated adults 35 years of age or older. A clear dose-response of GOS was seen on fecal Bifidobacterium, and 11 g of GOS significantly increased Anaerostipes hadrus. In conclusion, GOS seems to be a solution to benefit adults with a low stool frequency and middle-aged adults with self-reported constipation.