38 research outputs found

    Integrating machine learning algorithms to systematically assess reactive oxygen species levels to aid prognosis and novel treatments for triple -negative breast cancer patients

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    IntroductionBreast cancer has become one of the top health concerns for women, and triple-negative breast cancer (TNBC) leads to treatment resistance and poor prognosis due to its high degree of heterogeneity and malignancy. Reactive oxygen species (ROS) have been found to play a dual role in tumors, and modulating ROS levels may provide new insights into prognosis and tumor treatment.MethodsThis study attempted to establish a robust and valid ROS signature (ROSig) to aid in assessing ROS levels. The driver ROS prognostic indicators were searched based on univariate Cox regression. A well-established pipeline integrating 9 machine learning algorithms was used to generate the ROSig. Subsequently, the heterogeneity of different ROSig levels was resolved in terms of cellular communication crosstalk, biological pathways, immune microenvironment, genomic variation, and response to chemotherapy and immunotherapy. In addition, the effect of the core ROS regulator HSF1 on TNBC cell proliferation was detected by cell counting kit-8 and transwell assays.ResultsA total of 24 prognostic ROS indicators were detected. A combination of the Coxboost+ Survival Support Vector Machine (survival-SVM) algorithm was chosen to generate ROSig. ROSig proved to be the superior risk predictor for TNBC. Cellular assays show that knockdown of HSF1 can reduce the proliferation and invasion of TNBC cells. The individual risk stratification based on ROSig showed good predictive accuracy. High ROSig was identified to be associated with higher cell replication activity, stronger tumor heterogeneity, and an immunosuppressive microenvironment. In contrast, low ROSig indicated a more abundant cellular matrix and more active immune signaling. Low ROSig has a higher tumor mutation load and copy number load. Finally, we found that low ROSig patients were more sensitive to doxorubicin and immunotherapy.ConclusionIn this study, we developed a robust and effective ROSig model that can be used as a reliable indicator for prognosis and treatment decisions in TNBC patients. This ROSig also allows a simple assessment of TNBC heterogeneity in terms of biological function, immune microenvironment, and genomic variation

    How Much Schizophrenia Do Famines Cause?

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    Since the 1970s, famines have been widely invoked as natural experiments in research into the long-term impact of foetal exposure to nutritional shocks. That research has produced compelling evidence for a robust link between foetal exposure and the odds of developing schizophrenia. However, the implications of that research for the human cost of famines in the longer run has not been investigated. We address the connection between foetal origins and schizophrenia with that question in mind. The impact turns out to be very modest – much less than one per cent of the associated famine death tolls – across a selection of case studies

    Evaluation of a flipped classroom approach to learning introductory epidemiology

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    Background Although the flipped classroom model has been widely adopted in medical education, reports on its use in graduate-level public health programs are limited. This study describes the design, implementation, and evaluation of a flipped classroom redesign of an introductory epidemiology course and compares it to a traditional model. Methods One hundred fifty Masters-level students enrolled in an introductory epidemiology course with a traditional format (in-person lecture and discussion section, at-home assignment; 2015, N = 72) and a flipped classroom format (at-home lecture, in-person discussion section and assignment; 2016, N = 78). Using mixed methods, we compared student characteristics, examination scores, and end-of-course evaluations of the 2016 flipped classroom format and the 2015 traditional format. Data on the flipped classroom format, including pre- and post-course surveys, open-ended questions, self-reports of section leader teaching practices, and classroom observations, were evaluated. Results There were no statistically significant differences in examination scores or students’ assessment of the course between 2015 (traditional) and 2016 (flipped). In 2016, 57.1% (36) of respondents to the end-of-course evaluation found watching video lectures at home to have a positive impact on their time management. Open-ended survey responses indicated a number of strengths of the flipped classroom approach, including the freedom to watch pre-recorded lectures at any time and the ability of section leaders to clarify targeted concepts. Suggestions for improvement focused on ways to increase regular interaction with lecturers. Conclusions There was no significant difference in students’ performance on quantitative assessments comparing the traditional format to the flipped classroom format. The flipped format did allow for greater flexibility and applied learning opportunities at home and during discussion sections

    Investigating the relationships between unfavourable habitual sleep and metabolomic traits:evidence from multi-cohort multivariable regression and Mendelian randomization analyses

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    BACKGROUND: Sleep traits are associated with cardiometabolic disease risk, with evidence from Mendelian randomization (MR) suggesting that insomnia symptoms and shorter sleep duration increase coronary artery disease risk. We combined adjusted multivariable regression (AMV) and MR analyses of phenotypes of unfavourable sleep on 113 metabolomic traits to investigate possible biochemical mechanisms linking sleep to cardiovascular disease.METHODS: We used AMV (N = 17,368) combined with two-sample MR (N = 38,618) to examine effects of self-reported insomnia symptoms, total habitual sleep duration, and chronotype on 113 metabolomic traits. The AMV analyses were conducted on data from 10 cohorts of mostly Europeans, adjusted for age, sex, and body mass index. For the MR analyses, we used summary results from published European-ancestry genome-wide association studies of self-reported sleep traits and of nuclear magnetic resonance (NMR) serum metabolites. We used the inverse-variance weighted (IVW) method and complemented this with sensitivity analyses to assess MR assumptions.RESULTS: We found consistent evidence from AMV and MR analyses for associations of usual vs. sometimes/rare/never insomnia symptoms with lower citrate (- 0.08 standard deviation (SD)[95% confidence interval (CI) - 0.12, - 0.03] in AMV and - 0.03SD [- 0.07, - 0.003] in MR), higher glycoprotein acetyls (0.08SD [95% CI 0.03, 0.12] in AMV and 0.06SD [0.03, 0.10) in MR]), lower total very large HDL particles (- 0.04SD [- 0.08, 0.00] in AMV and - 0.05SD [- 0.09, - 0.02] in MR), and lower phospholipids in very large HDL particles (- 0.04SD [- 0.08, 0.002] in AMV and - 0.05SD [- 0.08, - 0.02] in MR). Longer total sleep duration associated with higher creatinine concentrations using both methods (0.02SD per 1 h [0.01, 0.03] in AMV and 0.15SD [0.02, 0.29] in MR) and with isoleucine in MR analyses (0.22SD [0.08, 0.35]). No consistent evidence was observed for effects of chronotype on metabolomic measures.CONCLUSIONS: Whilst our results suggested that unfavourable sleep traits may not cause widespread metabolic disruption, some notable effects were observed. The evidence for possible effects of insomnia symptoms on glycoprotein acetyls and citrate and longer total sleep duration on creatinine and isoleucine might explain some of the effects, found in MR analyses of these sleep traits on coronary heart disease, which warrant further investigation.</p

    Early-Life Exposure to the Chinese Famine of 1959&ndash;1961 and Type 2 Diabetes in Adulthood: A Systematic Review and Meta-Analysis

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    Background: The fast-growing literature suggests that the Chinese famine of 1959&ndash;1961 drives current and future type 2 diabetes (T2D) epidemics in China. This conclusion may be premature, as many Chinese famine studies have major methodological problems. We examine these problems, demonstrate how they bias the study results, and formulate recommendations to improve the quality of future studies. Methods: We searched English and Chinese databases for studies that examined the relationship between prenatal exposure to the Chinese famine and adult T2D from inception to 8 February 2022. We extracted information on T2D cases and study populations of individuals born during the famine (famine births), before the famine (prefamine births), and after the famine (postfamine births). We used random-effects models to compare the odds of T2D in famine births to several control groups, including postfamine births, combined pre- and postfamine births, and prefamine births. We used meta-regressions to examine the impacts of age differences between comparison groups on famine effect estimates and the role of other characteristics, including participant sex, age, and T2D assessments; famine intensity; residence; and publication language. Potential sources of heterogeneity and study quality were also evaluated. Results: Twenty-three studies met our inclusion criteria. The sample sizes ranged from less than 300 to more than 360,000 participants. All studies defined the famine exposure based on the participants&rsquo; dates of birth, and 18 studies compared famine births and postfamine births to estimate famine effects on T2D. The famine and postfamine births had an age difference of three years or more in all studies. The estimates of the famine effect varied by the selection of controls. Using postfamine births as controls, the OR for T2D among famine births was 1.50 (95% CI 1.34&ndash;1.68); using combined pre- and postfamine births as controls, the OR was 1.12 (95% CI 1.02&ndash;1.24); using prefamine births as controls, the OR was 0.89 (95% CI 0.79&ndash;1.00). The meta-regressions further showed that the famine effect estimates increased by over 1.05 times with each one-year increase in ignored age differences between famine births and controls. Other newly identified methodological problems included the poorly assessed famine intensity, unsuitable study settings for famine research, and poor confounding adjustment. Interpretation: The current estimates of a positive relationship between prenatal exposure to the Chinese famine and adult T2D are mainly driven by uncontrolled age differences between famine births and postfamine births. Studies with more rigorous methods, including age-balanced controls and robust famine intensity measures, are needed to quantify to what extent the famine exposure is related to current T2D patterns in China

    How much schizophrenia do famines cause?

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    Abstract Since the 1970s, famines have been widely invoked as natural experiments in research into the long-term impact of foetal exposure to nutritional shocks. That research has produced compelling evidence for a robust link between foetal exposure and the odds of developing schizophrenia. However, the implications of that research for the human cost of famines in the longer run have not been investigated. We address the connection between foetal origins and schizophrenia with that question in mind. The impact turns out to be very modest—much less than one per cent of the associated famine death tolls—across a selection of case studies
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