620 research outputs found

    Numerical Methods for Singular Perturbation Problems

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    WWU Lifestyles Project: Patterns of Alcohol and Drug Consumption and Consequences among Western Washington University Students

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    Executive Summary: This report, besides presenting the Lifestyles Project findings, summaries and discussion, contains two important Appendices. Appendix A consists of Western\u27s Comprehensive Plan to Combat Student Alcohol Abuse, Including Underage Drinking, as as submitted to the Higher Education Coordinating Board. Appendix B consists of preliminary findings on the effectiveness of the Wellness Hall. The executive summary includes summaries of all three of these sections. Lifestyles Project Findings The WWU Lifestyles Project surveyed a randomly selected, stratified sample of 2500 students enrolled at Western during spring quarter, 1992, regarding their use of alcohol and drugs, the consequences of using, and motivation to change patterns of use. Completed questionnaires were received from 1217 students for a nearly 50% return rate Overall, the results of the survey suggested that a large proportion of the student population (76.6 %), including those under the legal age, drink alcohol at least once a month. While factors such as class standing and age affected level of alcohol consumption, differences by gender were the most dramatic. Generally speaking, while males and females keep pace in their frequency and quantity of alcohol consumption up to a point, at higher levels of consumption men tend to drink more often and in larger quantities than females. Moreover, males tend to report the highest rates of at risk drinking; that is, drinking at a binge level (5+ drinks at one setting) and higher. At Western, as nationwide, alcohol is the drug of choice for college students, with survey respondents reporting relatively scant use of drugs like cocaine and LSD, and low use of marijuana. Patterns of alcohol use at Western appear threefold: 1) nearly a quarter of survey respondents reported no drinking at all in the previous month; 2) of respondents indicating any frequency of drinking whatsoever (about three-quarters of the survey population), 31.3% reported drinking 1-2 drinks and 22.7% reported drinking 3-4 drinks on typical occasions, which places them in a low to moderate drinking norm; and 3) of respondents indicating any frequency of drinking whatsoever, 29.8% reported binge drinking on typical occasions and 57.2% reported binge drinking on peak occasions. This last drinking pattern suggests that an alcohol environment may exist at Western that contributes to substantial social and academic risks for Western students. Issues of concern include that a substantial percentage (67.4%) of those who report any frequency of drinking whatsoever were under the legal drinking age, and that well over half of the respondents overall (64.0%) reported at least one alcohol-related problem in the last six months. Of particular relevance to the academic mission of university life are the discrepancies found between students\u27 perception for risk of negative academic consequences due to alcohol-related effects and the actual occurrence of those outcomes. Actual occurrences were nearly double and sometimes treble that of perceived risk. These findings suggest that perception of vulnerability to negative alcohol effects may differ enough from actual occurrences of negative alcohol effects to pose a threat to students\u27 academic success and persistence. Although the university has raised awareness of campus alcohol and drug policies and programs--nearly two-thirds of respondents reported they knew of such efforts—most respondents stated that official university policies and programs do not effect their own personal levels of use. Comprehensive Plan to Combat Student Alcohol Abuse In response to the alcohol predicament on campus, WWU has developed a comprehensive plan for combating student alcohol abuse and its consequent negative academic, health, and social outcomes. WWU\u27s plan anticipates improvement in reducing the incidence of student alcohol abuse both on and around campus because it is based on the public health model, which views both individual students who drink and the environments in which they drink as the targets for major interventions. Based on the systems approach inherent within the public health model, WWU will utilize four major strategies to decrease both individual problem use of alcohol and the drinking norms on campus: 1) primary prevention seeks to reduce risk for alcohol problems or prevent the occurrence of alcohol abuse and/or underage drinking before those problems occur; 2) secondary prevention programs seek to halt, reverse, or retard alcohol abuse problems after they have occurred, but before they lead to life-altering or life-threatening consequences; 3) tertiary prevention efforts seek to reduce the risks of severe alcohol abuse, and 4) health promotion efforts seek to develop positive environments and community policies, rules, and norms that support and encourage students who are already making choices not to abuse alcohol or to drink illegally thereby leading to the creation of a new critical mass who do not view alcohol abuse as a typical and expected feature of college life. (See Appendix A.) Wellness Hall: Preliminary Findings University Residences and the Primary Prevention and Wellness Center collaborated to open the wellness residence hall at WWU in Fall Quarter, 1993. The creating of four floors of Nash Hall as an alcohol and drug free zone was made possible by a FIPSE grant. Participating students signed substance-free living agreements, thereby voluntarily committing to abstain from the use of alcohol, tobacco or drugs while residing on campus. During its first quarter of existence, there were no violations of this voluntary code. Furthermore, some preliminary information--reduced vandalism and fewer alcohol related incidents--suggests that students in the wellness community are consuming less alcohol than their counterparts in a correspondent freshmen residence hall. An initial administration of the CORE alcohol and drug survey also suggests that students residing in the wellness community are choosing to consume less alcohol

    A conserved population of MHC II-restricted, innate-like, commensal-reactive T cells in the gut of humans and mice

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    Interactions with commensal microbes shape host immunity on multiple levels and play a pivotal role in human health and disease. Tissue-dwelling, antigen-specific T cells are poised to respond to local insults, making their phenotype important in the relationship between host and microbes. Here we show that MHC-II restricted, commensal-reactive T cells in the colon of both humans and mice acquire transcriptional and functional characteristics associated with innate-like T cells. This cell population is abundant and conserved in the human and murine colon and endowed with polyfunctional effector properties spanning classic Th1- and Th17-cytokines, cytotoxic molecules, and regulators of epithelial homeostasis. T cells with this phenotype are increased in ulcerative colitis patients, and their presence aggravates pathology in dextran sodium sulphate-treated mice, pointing towards a pathogenic role in colitis. Our findings add to the expanding spectrum of innate-like immune cells positioned at the frontline of intestinal immune surveillance, capable of acting as sentinels of microbes and the local cytokine milieu

    Implications of the school-household network structure on SARS-CoV-2 transmission under school reopening strategies in England.

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    In early 2020 many countries closed schools to mitigate the spread of SARS-CoV-2. Since then, governments have sought to relax the closures, engendering a need to understand associated risks. Using address records, we construct a network of schools in England connected through pupils who share households. We evaluate the risk of transmission between schools under different reopening scenarios. We show that whilst reopening select year-groups causes low risk of large-scale transmission, reopening secondary schools could result in outbreaks affecting up to 2.5 million households if unmitigated, highlighting the importance of careful monitoring and within-school infection control to avoid further school closures or other restrictions

    A Federated Database for Obesity Research:An IMI-SOPHIA Study

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    Obesity is considered by many as a lifestyle choice rather than a chronic progressive disease. The Innovative Medicines Initiative (IMI) SOPHIA (Stratification of Obesity Phenotypes to Optimize Future Obesity Therapy) project is part of a momentum shift aiming to provide better tools for the stratification of people with obesity according to disease risk and treatment response. One of the challenges to achieving these goals is that many clinical cohorts are siloed, limiting the potential of combined data for biomarker discovery. In SOPHIA, we have addressed this challenge by setting up a federated database building on open-source DataSHIELD technology. The database currently federates 16 cohorts that are accessible via a central gateway. The database is multi-modal, including research studies, clinical trials, and routine health data, and is accessed using the R statistical programming environment where statistical and machine learning analyses can be performed at a distance without any disclosure of patient-level data. We demonstrate the use of the database by providing a proof-of-concept analysis, performing a federated linear model of BMI and systolic blood pressure, pooling all data from 16 studies virtually without any analyst seeing individual patient-level data. This analysis provided similar point estimates compared to a meta-analysis of the 16 individual studies. Our approach provides a benchmark for reproducible, safe federated analyses across multiple study types provided by multiple stakeholders.</p

    A Federated Database for Obesity Research:An IMI-SOPHIA Study

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    Obesity is considered by many as a lifestyle choice rather than a chronic progressive disease. The Innovative Medicines Initiative (IMI) SOPHIA (Stratification of Obesity Phenotypes to Optimize Future Obesity Therapy) project is part of a momentum shift aiming to provide better tools for the stratification of people with obesity according to disease risk and treatment response. One of the challenges to achieving these goals is that many clinical cohorts are siloed, limiting the potential of combined data for biomarker discovery. In SOPHIA, we have addressed this challenge by setting up a federated database building on open-source DataSHIELD technology. The database currently federates 16 cohorts that are accessible via a central gateway. The database is multi-modal, including research studies, clinical trials, and routine health data, and is accessed using the R statistical programming environment where statistical and machine learning analyses can be performed at a distance without any disclosure of patient-level data. We demonstrate the use of the database by providing a proof-of-concept analysis, performing a federated linear model of BMI and systolic blood pressure, pooling all data from 16 studies virtually without any analyst seeing individual patient-level data. This analysis provided similar point estimates compared to a meta-analysis of the 16 individual studies. Our approach provides a benchmark for reproducible, safe federated analyses across multiple study types provided by multiple stakeholders

    Key questions for modelling COVID-19 exit strategies

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    Combinations of intense non-pharmaceutical interventions ('lockdowns') were introduced in countries worldwide to reduce SARS-CoV-2 transmission. Many governments have begun to implement lockdown exit strategies that allow restrictions to be relaxed while attempting to control the risk of a surge in cases. Mathematical modelling has played a central role in guiding interventions, but the challenge of designing optimal exit strategies in the face of ongoing transmission is unprecedented. Here, we report discussions from the Isaac Newton Institute 'Models for an exit strategy' workshop (11-15 May 2020). A diverse community of modellers who are providing evidence to governments worldwide were asked to identify the main questions that, if answered, will allow for more accurate predictions of the effects of different exit strategies. Based on these questions, we propose a roadmap to facilitate the development of reliable models to guide exit strategies. The roadmap requires a global collaborative effort from the scientific community and policy-makers, and is made up of three parts: i) improve estimation of key epidemiological parameters; ii) understand sources of heterogeneity in populations; iii) focus on requirements for data collection, particularly in Low-to-Middle-Income countries. This will provide important information for planning exit strategies that balance socio-economic benefits with public health

    A Federated Database for Obesity Research:An IMI-SOPHIA Study

    Get PDF
    Obesity is considered by many as a lifestyle choice rather than a chronic progressive disease. The Innovative Medicines Initiative (IMI) SOPHIA (Stratification of Obesity Phenotypes to Optimize Future Obesity Therapy) project is part of a momentum shift aiming to provide better tools for the stratification of people with obesity according to disease risk and treatment response. One of the challenges to achieving these goals is that many clinical cohorts are siloed, limiting the potential of combined data for biomarker discovery. In SOPHIA, we have addressed this challenge by setting up a federated database building on open-source DataSHIELD technology. The database currently federates 16 cohorts that are accessible via a central gateway. The database is multi-modal, including research studies, clinical trials, and routine health data, and is accessed using the R statistical programming environment where statistical and machine learning analyses can be performed at a distance without any disclosure of patient-level data. We demonstrate the use of the database by providing a proof-of-concept analysis, performing a federated linear model of BMI and systolic blood pressure, pooling all data from 16 studies virtually without any analyst seeing individual patient-level data. This analysis provided similar point estimates compared to a meta-analysis of the 16 individual studies. Our approach provides a benchmark for reproducible, safe federated analyses across multiple study types provided by multiple stakeholders.</p

    Heterarchy of Transcription Factors Driving Basal and Luminal Cell Phenotypes in Human Urothelium

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    Cell differentiation is effected by complex networks of transcription factors that co-ordinate re-organisation of the chromatin landscape. The hierarchies of these relationships can be difficult to dissect. During in vitro differentiation of normal human uro-epithelial cells, formaldehyde-assisted isolation of regulatory elements (FAIRE-seq) and RNA-seq were used to identify alterations in chromatin accessibility and gene expression changes following activation of the nuclear receptor PPARG as a differentiation-initiating event. Regions of chromatin identified by FAIRE-seq as having altered accessibility during differentiation were found to be enriched with sequence-specific binding motifs for transcription factors predicted to be involved in driving basal and differentiated urothelial cell phenotypes, including FOXA1, P63, GRHL2, CTCF and GATA3. In addition, co-occurrence of GATA3 motifs was observed within sub-sets of differentiation-specific peaks containing P63 or FOXA1 after induction of differentiation. Changes in abundance of GRHL2, GATA3, and P63 were observed in immunoblots of chromatin-enriched extracts. Transient siRNA knockdown of P63 revealed that P63 favoured a basal-like phenotype by inhibiting differentiation and promoting expression of basal marker genes. GATA3 siRNA prevented differentiation-associated downregulation of P63 protein and transcript, and demonstrated positive feedback of GATA3 on PPARG transcript, but showed no effect on FOXA1 transcript or protein expression. This approach indicates that as a transcriptionally-regulated programme, urothelial differentiation operates as a heterarchy wherein GATA3 is able to co-operate with FOXA1 to drive expression of luminal marker genes, but that P63 has potential to transrepress expression of the same genes

    Global, regional, and national estimates of the population at increased risk of severe COVID-19 due to underlying health conditions in 2020: a modelling study

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    Background: The risk of severe COVID-19 if an individual becomes infected is known to be higher in older individuals and those with underlying health conditions. Understanding the number of individuals at increased risk of severe COVID-19 and how this varies between countries should inform the design of possible strategies to shield or vaccinate those at highest risk. Methods: We estimated the number of individuals at increased risk of severe disease (defined as those with at least one condition listed as “at increased risk of severe COVID-19” in current guidelines) by age (5-year age groups), sex, and country for 188 countries using prevalence data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 and UN population estimates for 2020. The list of underlying conditions relevant to COVID-19 was determined by mapping the conditions listed in GBD 2017 to those listed in guidelines published by WHO and public health agencies in the UK and the USA. We analysed data from two large multimorbidity studies to determine appropriate adjustment factors for clustering and multimorbidity. To help interpretation of the degree of risk among those at increased risk, we also estimated the number of individuals at high risk (defined as those that would require hospital admission if infected) using age-specific infection–hospitalisation ratios for COVID-19 estimated for mainland China and making adjustments to reflect country-specific differences in the prevalence of underlying conditions and frailty. We assumed males were twice at likely as females to be at high risk. We also calculated the number of individuals without an underlying condition that could be considered at increased risk because of their age, using minimum ages from 50 to 70 years. We generated uncertainty intervals (UIs) for our estimates by running low and high scenarios using the lower and upper 95% confidence limits for country population size, disease prevalences, multimorbidity fractions, and infection–hospitalisation ratios, and plausible low and high estimates for the degree of clustering, informed by multimorbidity studies. Findings: We estimated that 1·7 billion (UI 1·0–2·4) people, comprising 22% (UI 15–28) of the global population, have at least one underlying condition that puts them at increased risk of severe COVID-19 if infected (ranging from &lt;5% of those younger than 20 years to &gt;66% of those aged 70 years or older). We estimated that 349 million (186–787) people (4% [3–9] of the global population) are at high risk of severe COVID-19 and would require hospital admission if infected (ranging from &lt;1% of those younger than 20 years to approximately 20% of those aged 70 years or older). We estimated 6% (3–12) of males to be at high risk compared with 3% (2–7) of females. The share of the population at increased risk was highest in countries with older populations, African countries with high HIV/AIDS prevalence, and small island nations with high diabetes prevalence. Estimates of the number of individuals at increased risk were most sensitive to the prevalence of chronic kidney disease, diabetes, cardiovascular disease, and chronic respiratory disease. Interpretation: About one in five individuals worldwide could be at increased risk of severe COVID-19, should they become infected, due to underlying health conditions, but this risk varies considerably by age. Our estimates are uncertain, and focus on underlying conditions rather than other risk factors such as ethnicity, socioeconomic deprivation, and obesity, but provide a starting point for considering the number of individuals that might need to be shielded or vaccinated as the global pandemic unfolds. Funding: UK Department for International Development, Wellcome Trust, Health Data Research UK, Medical Research Council, and National Institute for Health Research
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