In silico toxicology protocols

The present publication surveys several applications of in silico (i.e., computational) toxicology approaches across different industries and institutions. It highlights the need to develop standardized protocols when conducting toxicity-related predictions. This contribution articulates the information needed for protocols to support in silico predictions for major toxicological endpoints of concern (e.g., genetic toxicity, carcinogenicity, acute toxicity, reproductive toxicity, developmental toxicity) across several industries and regulatory bodies. Such novel in silico toxicology (IST) protocols, when fully developed and implemented, will ensure in silico toxicological assessments are performed and evaluated in a consistent, reproducible, and well-documented manner across industries and regulatory bodies to support wider uptake and acceptance of the approaches. The development of IST protocols is an initiative developed through a collaboration among an international consortium to reflect the state-of-the-art in in silico toxicology for hazard identification and characterization. A general outline for describing the development of such protocols is included and it is based on in silico predictions and/or available experimental data for a defined series of relevant toxicological effects or mechanisms. The publication presents a novel approach for determining the reliability of in silico predictions alongside experimental data. In addition, we discuss how to determine the level of confidence in the assessment based on the relevance and reliability of the information

Risk assessment of endometrial cancer and endometrial intraepithelial neoplasia in women with abnormal bleeding and implications for clinical management algorithms

© 2020 Background: Most endometrial cancer cases are preceded by abnormal uterine bleeding, offering a potential opportunity for early detection and cure of endometrial cancer. Although clinical guidelines exist for diagnostic workup of abnormal uterine bleeding, consensus is lacking regarding optimal management for women with abnormal bleeding to diagnose endometrial cancer. Objective: We report the baseline data from a prospective clinical cohort study of women referred for endometrial evaluation at the Mayo Clinic, designed to evaluate risk stratification in women at increased risk for endometrial cancer. Here, we introduce a risk-based approach to evaluate diagnostic tests and clinical management algorithms in a population of women with abnormal bleeding undergoing endometrial evaluation at the Mayo Clinic. Study Design: A total of 1163 women aged ≥45 years were enrolled from February 2013 to May 2019. We evaluated baseline absolute risks and 95% confidence intervals of endometrial cancer and endometrial intraepithelial neoplasia according to clinical algorithms for diagnostic workup of women with postmenopausal bleeding (assessment of initial vs recurrent bleeding episode and endometrial thickness measured through transvaginal ultrasound). We also evaluated risks among women with postmenopausal bleeding according to baseline age (\u3c60 vs 60+ years) as an alternative example. For this approach, biopsy would be conducted for all women aged 60+ years and those aged \u3c60 years with an endometrial thickness of \u3e4 mm. We assessed the clinical efficiency of each strategy by estimating the percentage of women who would be referred for endometrial biopsy, the percentage of cases detected and missed, and the ratio of biopsies per case detected. Results: Among the 593 women with postmenopausal bleeding, 18 (3.0%) had endometrial intraepithelial neoplasia, and 47 (7.9%) had endometrial cancer, and among the 570 premenopausal women with abnormal bleeding, 8 (1.4%) had endometrial intraepithelial neoplasia, and 7 (1.2%) had endometrial cancer. Maximum risk was noted in women aged 60+ years (17.7%; 13.0%–22.3%), followed by those with recurrent bleeding (14.7%; 11.0%–18.3%). Among women with an initial bleeding episode for whom transvaginal ultrasound was recommended, endometrial thickness did not provide meaningful risk stratification: risks of endometrial cancer and endometrial intraepithelial neoplasia were nearly identical in women with an endometrial thickness of \u3e4 mm (5.8%; 1.3%–10.3%) and ≤4 mm (3.6%; 0.9%–8.6%). In contrast, among those aged \u3c60 years with an endometrial thickness of \u3e4 mm, the risk of endometrial cancer and endometrial intraepithelial neoplasia was 8.4% (4.3%–12.5%), and in those with an endometrial thickness of ≤4 mm, the risk was 0% (0.0%–3.0%; P=.01). The most efficient strategy was to perform biopsy in all women aged 60+ years and among those aged \u3c60 years with an endometrial thickness of \u3e4 mm, with the lowest percentage referred to biopsy while still detecting all cases. Conclusion: Existing clinical recommendations for endometrial cancer detection in women with abnormal bleeding are not consistent with the underlying risk. Endometrial cancer risk factors such as age can provide important risk stratification compared with the assessment of recurrent bleeding. Future research will include a formal assessment of clinical and epidemiologic risk prediction models in our study population as well as validation of our findings in other populations

A prospective clinical cohort study of women at increased risk for endometrial cancer.

OBJECTIVE: To evaluate endometrial cancer (EC) risk assessment and early detection strategies in high-risk populations, we designed a large, prospective cohort study of women undergoing endometrial biopsy to assess risk factors and collect novel biospecimens for future testing of emerging EC biomarkers. Here we report on the baseline findings of this study. METHODS: Women aged ≥45 years were enrolled at the Mayo Clinic from February 2013 – June 2018. Risk factors included age, body mass index (BMI), smoking, oral contraceptive and hormone therapy use, and parity. We collected vaginal tampons, endometrial biopsies, and Tao brush samples. We estimated mutually-adjusted odds ratios (OR) and 95% confidence intervals (CI) using multinomial logistic regression; outcomes included EC, atypical hyperplasia, hyperplasia without atypia, disordered proliferative endometrium, and polyps, versus normal endometrium. RESULTS: Subjects included 1,205 women with a mean age of 55 years; 55% were postmenopausal, and 90% had abnormal uterine bleeding. The prevalence of EC was 4.1% (n=49), predominantly diagnosed in postmenopausal women (85.7%). Tampons and Tao brushings were obtained from 99% and 68% of women, respectively. Age (OR 1.14, 95% CI 1.1– 1.2) and BMI (OR 1.39, 95% CI 1.1–1.7) were positively associated with EC; atypical hyperplasia (OR 1.07, 95% CI 1.0–1.1; OR 2.00, 95% CI 1.5–2.6, respectively), and polyps (OR 1.06, 95% CI 1.0–1.1; OR 1.17, 95% CI 1.0–1.3, respectively); hormone therapy use and smoking were inversely associated with EC (OR 0.42, 95%, 0.2–0.9; OR 0.43, 95% CI, 0.2–0.9, respectively). Parity and past oral contraception use were not associated with EC. CONCLUSIONS: Well-established EC risk factors may have less discriminatory accuracy in high-risk populations. Future analyses will integrate risk factor assessment with biomarker testing for EC detection

Domestic work and psychological distress : what is the importance of relative socioeconomic position and gender inequality in the couple relationship?

Aims: The aim of this study was to investigate whether the relation between responsibility for domestic work and psychological distress was influenced by perception of gender inequality in the couple relationship and relative socioeconomic position. Methods: In the Northern Swedish Cohort, all pupils who studied in the last year of compulsory school in a northern Swedish town in 1981 have been followed regularly until 2007. In this study, participants living with children were selected (n = 371 women, 352 men). The importance of relative socioeconomic position and perception of gender inequality in the couple relationship in combination with domestic work for psychological distress was examined through logistic regression analysis. Results: Two combinations of variables including socioeconomic position ('having less than half of the responsibility for domestic work and partner higher socioeconomic position' and 'having more than half the responsibility for domestic work and equal socioeconomic position') were related to psychological distress. There were also higher ORs for psychological distress for the combinations of having 'less than half of the responsibility for domestic work and gender-unequal couple relationship' and 'more than half the responsibility for domestic work and gender-unequal couple relationship'. Having a lower socioeconomic position than the partner was associated with higher ORs for psychological distress among men. Conclusions: This study showed that domestic work is a highly gendered activity as women tend to have a greater and men a smaller responsibility. Both these directions of inequality in domestic work, in combination with experiencing the couple relationship as gender-unequal, were associated with psychological distress There is a need for more research with a relational approach on inequalities in health in order to capture the power relations within couples in various settings

Obesity effects on depression: systematic review of epidemiological studies

Background: Obesity is a well-known cause of cardiovascular disease burden and premature death, but effects on psychological morbidity remain uncertain. This article reports findings following a systematic review of epidemiological studies to determine whether obesity causes depression. Methods: Multiple databases were searched for English-language studies of etiology of obesity (exposure variable, analyzed as an ordered category) on depression outcomes (dependent variables, continuous or categorical). Studies in children and in women during pregnancy or postpartum were excluded, as were nonrepresentative cross-sectional studies. Searches and identification of studies for inclusion were performed by EA, whereas a descriptive synthesis of important study characteristics was undertaken independently by us. Results: We reviewed 24 out of approximately 4500 potentially relevant studies; 4 were prospective cohort studies and 20 were cross-sectional studies (10 from the United States). Effect measures reported in all prospective cohort studies were consistent and suggested that obesity may increase the odds of future depression outcomes (symptoms or nonclinical diagnosis of depression). Effect measures reported in most cross-sectional studies from the United States supported the hypothesized association between obesity and prevalence of depression outcomes for women but not men, in contrast most cross-sectional studies from populations other than the United States consistently failed to find such associations. Conclusions: Overall, there is a weak level of evidence supporting the hypothesis that obesity increases the incidence of depression outcomes. Few high-quality prospective cohort studies exist, and cross-sectional studies account for the vast body of published evidence, and therefore firm conclusions for causality cannot yet be drawn. Our finding warrants additional high-quality etiological research on this topic.E Atlantis and M Bake

Guidelines for the use and interpretation of assays for monitoring autophagy

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field