144 research outputs found

    Human Brain Microvascular Endothelial Cells and Umbilical Vein Endothelial Cells Differentially Facilitate Leukocyte Recruitment and Utilize Chemokines for T Cell Migration

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    Endothelial cells that functionally express blood brain barrier (BBB) properties are useful surrogates for studying leukocyte-endothelial cell interactions at the BBB. In this study, we compared two different endothelial cellular models: transfected human brain microvascular endothelial cells (THBMECs) and human umbilical vein endothelial cells (HUVECs). With each grow under optimal conditions, confluent THBMEC cultures showed continuous occludin and ZO-1 immunoreactivity, while HUVEC cultures exhibited punctate ZO-1 expression at sites of cell-cell contact only. Confluent THBMEC cultures on 24-well collagen-coated transwell inserts had significantly higher transendothelial electrical resistance (TEER) and lower solute permeability than HUVECs. Confluent THBMECs were more restrictive for mononuclear cell migration than HUVECs. Only THBMECs utilized abluminal CCL5 to facilitate T-lymphocyte migration in vitro although both THBMECs and HUVECs employed CCL3 to facilitate T cell migration. These data establish baseline conditions for using THBMECs to develop in vitro BBB models for studying leukocyte-endothelial interactions during neuroinflammation

    Understanding and Evaluating Quality of Life for Individuals with Intellectual Disabilities: A Northwestern Vermont Population Study

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    Introduction There are 7-8 million individuals with intellectual or developmental disabilities living in the US. • 91,795 of this population lives in Vermont • Historically marginalized and isolated community • Socioeconomic, health-related, and emotional burden • Public health-related disparity Champlain Community Services (CCS): non-profit service provider and coordinator for 86 persons with intellectual disabilities in Northwestern Vermont Objectives: • Develop and apply measures to better understand and evaluate quality of life in the population CCS serves. • Recommend improvement to CCS data collection and evaluation methods. • Provide a basis for future recommendations to CCS services that are aligned to the needs of consumers.https://scholarworks.uvm.edu/comphp_gallery/1275/thumbnail.jp

    The academic backbone: longitudinal continuities in educational achievement from secondary school and medical school to MRCP(UK) and the specialist register in UK medical students and doctors

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    Background: Selection of medical students in the UK is still largely based on prior academic achievement, although doubts have been expressed as to whether performance in earlier life is predictive of outcomes later in medical school or post-graduate education. This study analyses data from five longitudinal studies of UK medical students and doctors from the early 1970s until the early 2000s. Two of the studies used the AH5, a group test of general intelligence (that is, intellectual aptitude). Sex and ethnic differences were also analyzed in light of the changing demographics of medical students over the past decades. Methods: Data from five cohort studies were available: the Westminster Study (began clinical studies from 1975 to 1982), the 1980, 1985, and 1990 cohort studies (entered medical school in 1981, 1986, and 1991), and the University College London Medical School (UCLMS) Cohort Study (entered clinical studies in 2005 and 2006). Different studies had different outcome measures, but most had performance on basic medical sciences and clinical examinations at medical school, performance in Membership of the Royal Colleges of Physicians (MRCP(UK)) examinations, and being on the General Medical Council Specialist Register. Results: Correlation matrices and path analyses are presented. There were robust correlations across different years at medical school, and medical school performance also predicted MRCP(UK) performance and being on the GMC Specialist Register. A-levels correlated somewhat less with undergraduate and post-graduate performance, but there was restriction of range in entrants. General Certificate of Secondary Education (GCSE)/O-level results also predicted undergraduate and post-graduate outcomes, but less so than did A-level results, but there may be incremental validity for clinical and post-graduate performance. The AH5 had some significant correlations with outcome, but they were inconsistent. Sex and ethnicity also had predictive effects on measures of educational attainment, undergraduate, and post-graduate performance. Women performed better in assessments but were less likely to be on the Specialist Register. Non-white participants generally underperformed in undergraduate and post-graduate assessments, but were equally likely to be on the Specialist Register. There was a suggestion of smaller ethnicity effects in earlier studies. Conclusions: The existence of the Academic Backbone concept is strongly supported, with attainment at secondary school predicting performance in undergraduate and post-graduate medical assessments, and the effects spanning many years. The Academic Backbone is conceptualized in terms of the development of more sophisticated underlying structures of knowledge ('cognitive capital’ and 'medical capital’). The Academic Backbone provides strong support for using measures of educational attainment, particularly A-levels, in student selection

    Construct-level predictive validity of educational attainment and intellectual aptitude tests in medical student selection: meta-regression of six UK longitudinal studies

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    Background: Measures used for medical student selection should predict future performance during training. A problem for any selection study is that predictor-outcome correlations are known only in those who have been selected, whereas selectors need to know how measures would predict in the entire pool of applicants. That problem of interpretation can be solved by calculating construct-level predictive validity, an estimate of true predictor-outcome correlation across the range of applicant abilities. Methods: Construct-level predictive validities were calculated in six cohort studies of medical student selection and training (student entry, 1972 to 2009) for a range of predictors, including A-levels, General Certificates of Secondary Education (GCSEs)/O-levels, and aptitude tests (AH5 and UK Clinical Aptitude Test (UKCAT)). Outcomes included undergraduate basic medical science and finals assessments, as well as postgraduate measures of Membership of the Royal Colleges of Physicians of the United Kingdom (MRCP(UK)) performance and entry in the Specialist Register. Construct-level predictive validity was calculated with the method of Hunter, Schmidt and Le (2006), adapted to correct for right-censorship of examination results due to grade inflation. Results: Meta-regression analyzed 57 separate predictor-outcome correlations (POCs) and construct-level predictive validities (CLPVs). Mean CLPVs are substantially higher (.450) than mean POCs (.171). Mean CLPVs for first-year examinations, were high for A-levels (.809; CI: .501 to .935), and lower for GCSEs/O-levels (.332; CI: .024 to .583) and UKCAT (mean = .245; CI: .207 to .276). A-levels had higher CLPVs for all undergraduate and postgraduate assessments than did GCSEs/O-levels and intellectual aptitude tests. CLPVs of educational attainment measures decline somewhat during training, but continue to predict postgraduate performance. Intellectual aptitude tests have lower CLPVs than A-levels or GCSEs/O-levels. Conclusions: Educational attainment has strong CLPVs for undergraduate and postgraduate performance, accounting for perhaps 65% of true variance in first year performance. Such CLPVs justify the use of educational attainment measure in selection, but also raise a key theoretical question concerning the remaining 35% of variance (and measurement error, range restriction and right-censorship have been taken into account). Just as in astrophysics, ‘dark matter’ and ‘dark energy’ are posited to balance various theoretical equations, so medical student selection must also have its ‘dark variance’, whose nature is not yet properly characterized, but explains a third of the variation in performance during training. Some variance probably relates to factors which are unpredictable at selection, such as illness or other life events, but some is probably also associated with factors such as personality, motivation or study skills

    Peripheral blood clinical laboratory variables associated with outcomes following combination nivolumab and ipilimumab immunotherapy in melanoma

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    Both the combination of nivolumab + ipilimumab and single-agent anti-PD- 1 immunotherapy have demonstrated survival benefit for patients with advanced melanoma. As the combination has a high rate of serious side effects, further analyses in randomized trials of combination versus anti-PD- 1 immunotherapy are needed to understand who benefits most from the combination. Clinical laboratory values that were routinely collected in randomized studies may provide information on the relative benefit of combination immunotherapy. To prioritize which clinical laboratory factors to ultimately explore in these randomized studies, we performed a single-center, retrospective analysis of patients with advanced melanoma who received nivolumab + ipilimumab either as part of a clinical trial (n = 122) or commercial use (n = 87). Baseline routine laboratory values were correlated with overall survival (OS) and overall response rate (ORR). Kaplan–Meier estimation and Cox regression were performed. Median OS was 44.4 months, 95% CI (32.9, Not Reached). A total of 110 patients (53%) responded (CR/PR). Significant independent variables for favorable OS included the following: high relative eosinophils, high relative basophils, low absolute monocytes, low LDH, and a low neutrophil-to- lymphocyte ratio. These newly identified factors, along with those previously reported to be associated with anti-PD- 1 monotherapy outcomes, should be studied in the randomized trials of nivolumab + ipilimumab versus anti-PD- 1 monotherapies to determine whether they help define the patients who benefit most from the combination versus anti-PD- 1 alone
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