High-Sensitivity Cardiac Troponin T to Exclude Cardiac Involvement in TTR Variant Carriers and ATTRv Amyloidosis Patients.

(1) Background: Individuals carrying a pathogenic transthyretin gene variant (TTRv) are at high risk for developing hereditary transthyretin (ATTRv) amyloidosis and are routinely screened for the development of cardiomyopathy (ATTRv-CM). This study aims to evaluate whether the cardiac biomarkers N-terminal pro B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) can be used to rule out ATTRv-CM. (2) Methods: In this retrospective case-control study, data from 46 ATTRv-CM patients and 101 TTRv carriers and ATTRv amyloidosis patients without cardiomyopathy were included. Binary logistic regression models were used to assess the ability of NT-proBNP and hs-cTnT to predict the diagnosis of ATTRv-CM. An optimal cutoff for the relevant biomarker(s) was determined based on a sensitivity of ≥99% and the highest possible percentage of additional tests avoided (%ATA) in the index dataset. (3) Results: Hs-cTnT demonstrated the highest predictive capabilities for ATTRv-CM. The addition of NT-proBNP did not improve the predictive model. A hs-cTnT cutoff of <6 ng/L resulted in a 97% sensitivity and a negative predictive value of 95% with a %ATA of 30% in the validation dataset. (4) Conclusion: In conclusion, hs-cTnT is a useful biomarker for excluding cardiac involvement in TTRv carriers and ATTRv amyloidosis patients and it has the potential to prevent unnecessary diagnostic procedures.

The influence of mixing international and domestic students on competency learning in small groups in undergraduate medical education.

BACKGROUND: Medical curricula are increasingly internationalized, with international students being mixed with domestic students in small group learning. Small group learning is known to foster competency learning in undergraduate medical education, specifically Communication, Collaboration, Leadership, and Professionalism. However, it is unclear what happens with the learning of competencies when international students are introduced in small groups. This study explores if students in international small groups master the competencies Collaboration, Leadership and Professionalism at the same level as students in domestic groups in an undergraduate medical curriculum. METHOD: In total, 1215 Students of three academic year cohorts participated in the study. They were divided into four learning communities (LCs), per year cohort, in which tutor groups were the main instructional format. The tutorials of two learning communities were taught in English, with a mix of international and Dutch students. The tutorials of the other two learning communities were taught in Dutch with almost all domestic students. Trained tutors assessed three competencies (Collaboration, Leadership, Professionalism) twice per semester, as 'Not-on-track', 'On-track', or 'Fast-on-track'. By using Chi-square tests, we compared students' competencies performance twice per semester between the four LCs in the first two undergraduate years. RESULTS: The passing rate ('On-track' plus 'Fast-on-track') for the minimum level of competencies did not differ between the mixed and domestic groups. However, students in the mixed groups received more excellent performance evaluations ('Fast-on-track') than the students in the homogenous groups of Dutch students. This higher performance was true for both international and Dutch students of the mixed groups. Prior knowledge, age, gender, and nationality did not explain this phenomenon. The effect could also not be explained by a bias of the tutors. CONCLUSION: When students are educated in mixed groups of international and Dutch students, they can obtain the same basic competency levels, no matter what mix of students is made. However, students in the mixed international groups outperformed the students in the homogenous Dutch groups in achieving excellent performance scores. Future research should explore if these findings can be explained from differences in motivation, perceived grading or social network interactions.

Rethinking clinical governance: healthcare professionals' views: a Delphi study.

OBJECTIVE: Although the guiding principle of clinical governance states that healthcare professionals are the leading contributors to quality and safety in healthcare, little is known about what healthcare professionals perceive as important for clinical governance. The aim of this study is to clarify this by exploring healthcare professionals' views on clinical governance. DESIGN: Based on a literature search, a list of 99 elements related to clinical governance was constructed. This list was refined, extended and restricted during a three-round Delphi study. SETTING AND PARTICIPANTS: The panel of experts was formed of 24 healthcare professionals from an academic hospital that is seen as a leader in terms of its clinical governance expertise in the Netherlands. MAIN OUTCOME MEASURES: Rated importance of each element on a four-point scale. RESULTS: The 50 elements that the panel perceived as most important related to adopting a bottom-up approach to clinical governance, ownership, teamwork, learning from mistakes and feedback. The panel did not reach a consensus concerning elements that referred to patient involvement. Elements that referred to a managerial approach to clinical governance and standardisation of work were rejected by the panel. CONCLUSIONS: In the views of the panel of experts, clinical governance is a practice-based, value-driven approach that has the goal of delivering the highest possible quality care and ensuring the safety of patients. Bottom-up approaches and effective teamwork are seen as crucial for high quality and safe healthcare. Striving for high quality and safe healthcare is underpinned by continuous learning, shared responsibility and good relationships and collaboration between healthcare professionals, managers and patients.

Cumulative versus end-of-course assessment: effects on self-study time and test performance.

CONTEXT: Students tend to postpone preparation for a test until the test is imminent, which raises various risks associated with 'cramming' behaviours, including that for suboptimal learning. Cumulative assessment utilises spaced testing to stimulate students to study more frequently and to prevent procrastination. This randomised controlled study investigated how cumulative assessment affects time spent on self-study and test performance compared with end-of-course assessment. METHODS: A total of 78 undergraduate medical students in a Year 2 pre-clinical course were randomly assigned to either of two conditions. Students in the cumulative assessment condition were assessed in weeks 4, 8 and 10. Students in the end-of-course assessment condition were assessed in week 10 only. Each week, students reported the number of hours they spent on self-study. RESULTS: Students in the cumulative assessment condition (n = 25) spent significantly more time on self-study than students in the end-of-course assessment condition (n = 37) in all weeks of the course except weeks 5, 9 and 10. Overall, the cumulative assessment group spent 69 hours more on self-study during the course than did the control group, although the control group spent 7 hours more in studying during the final week of the course than did the cumulative assessment group. Students in the cumulative assessment condition scored slightly higher on questions concerning the content of the last part of the course. CONCLUSIONS: Cumulative assessment encourages students to distribute their learning activities over a course, which leaves them more opportunity to study the content of the last part of the course prior to the final examination. There was no evidence for a short-term effect of cumulative assessment on overall knowledge gain. We hypothesise that larger positive effects might be found if retention were to be measured in the long term.

Lipid levels do not influence the risk of venous thromboembolism. Results of a population-based cohort study.

Studies on the association between lipid profile and venous thromboembolism (VTE) are inconsistent. This could be caused by classical lipoproteins being inferior to apolipoproteins as markers for VTE risk. Therefore, we examined whether apolipoproteins are more strongly related to VTE than lipoproteins. For this analysis we used the PREVEND prospective community based observational cohort study. Levels of apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), total cholesterol (TC), high-density lipoprotein (HDL), non-HDL, low-density lipoprotein (LDL), triglycerides (TG), lipoprotein(a), ApoB/ApoA1 and TC/HDL ratio were assessed. Subjects with VTE were identified using databases of the national registries of hospital discharge diagnoses, death certificates, and the regional anticoagulation clinic. Out of 7,627 subjects, 110 developed VTE during a median follow-up of 10.5 years. In both univariate and multivariable analyses no significant associations between apolipoproteins and overall VTE were observed. Of the classical lipoproteins, TC, non-HDL, LDL, TG, and TC/HDL ratio were significantly associated with overall VTE in univariate analysis. Significant associations were no longer present in multivariable analysis. TGL and LDL were significantly associated with unprovoked VTE in univariate analysis. After adjustment for age and sex this significance was lost. No significant associations between (apo-) lipoproteins and provoked VTE were found. We conclude that apolipoproteins are not better in predicting VTE risk than the classical lipoproteins. Our population-based cohort study does not show an association between both apolipoproteins and the classical lipoproteins and VTE risk.

CCR5Δ32 genotype leads to a Th2 type directed immune response in ESRD patients.

BACKGROUND: In patients with end stage renal disease (ESRD) we observed protection from inflammation-associated mortality in CCR5Δ32 carriers, leading to CCR5 deficiency, suggesting impact of CCR5Δ32 on inflammatory processes. Animal studies have shown that CCR5 deficiency is associated with a more pronounced Th2 type immune response, suggesting that in human CCR5Δ32 carriers the immune response may be more Th2 type directed. So, in the present study we determined the Th1-Th2 type directed immune response in ESRD patients carrying and not carrying the CCR5Δ32 genetic variant after stimulation. METHODOLOGY/PRINCIPAL FINDINGS: We tested this hypothesis by determining the levels of IFN-γ and IL-4 and the distribution of Th1, Th2 and Th17 directed circulating CD4+ and CD8+ T cells and regulatory T cells (Tregs) after stimulation in ESRD patients with (n = 10) and without (n = 9) the CCR5Δ32 genotype. The extracellular levels of IFN-γ and IL-4 did not differ between CCR5Δ32 carriers and non carriers. However, based on their intracellular cytokine profile the percentages IL-4 secreting CD4+ and CD8+ T cells carrying the CCR5Δ32 genotype were significantly increased (p = 0.02, respectively p = 0.02) compared to non carriers, indicating a more Th2 type directed response. Based on their intracellular cytokine profile the percentages IFN-γ and IL-17 secreting T cells did not differ between carriers and non-carriers nor did the percentage Tregs, indicating that the Th1, Th17 and T regulatory response was not affected by the CCR5Δ32 genotype. CONCLUSIONS/SIGNIFICANCE: This first, functional human study shows a more pronounced Th2 type immune response in CCR5Δ32 carriers compared to non carriers. These differences may be involved in the previously observed protection from inflammation-associated mortality in ESRD patients carrying CCR5Δ32.

Using a genetic, observational study as a strategy to estimate the potential cost-effectiveness of pharmacological CCR5 blockade in dialysis patients.

BACKGROUND AND OBJECTIVE: Randomized clinical trials are expensive and time consuming. Therefore, strategies are needed to prioritise tracks for drug development. Genetic association studies may provide such a strategy by considering the differences between genotypes as a proxy for a natural, lifelong, randomized at conception, clinical trial. Previously an association with better survival was found in dialysis patients with systemic inflammation carrying a deletion variant of the CC-chemokine receptor 5 (CCR5). We hypothesized that in an analogous manner, pharmacological CCR5 blockade could protect against inflammation-driven mortality and estimated if such a treatment would be cost-effective. METHODS: A genetic screen and treat strategy was modelled using a decision-analytic Markov model, in which patients were screened for the CCR5 deletion 32 polymorphism and those with the wild type and systemic inflammation were treated with pharmacological CCR5 blockers. Kidney transplantation and mortality rates were calculated using patient level data. Extensive sensitivity analyses were performed. RESULTS: The cost-effectiveness of the genetic screen and treat strategy was &OV0556;18 557 per life year gained and &OV0556;21 896 per quality-adjusted life years gained. Concordance between the genetic association and pharmacological effectiveness was a main driver of cost-effectiveness. Sensitivity analyses showed that even a modest effectiveness of pharmacological CCR5 blockade would result in a treatment strategy that is good value for money. CONCLUSION: Pharmacological blockade of the CCR5 receptor in inflamed dialysis patients can be incorporated in a potentially cost-effective screen and treat programme. These findings provide formal rationale for clinical studies. This study illustrates the potential of genetic association studies for drug development, as a source of Mendelian randomized evidence from an observational setting.

TNF-α levels are not increased in inflamed patients carrying the CCR5 deletion 32.

BACKGROUND AND AIMS: Recently we reported on a genetically predisposed protection from C-reactive protein (CRP) related mortality in dialysis patients carrying the functional CC-chemokine receptor 5 deletion 32 allele (CCR5Δ32) mutation. Since CCR5Δ32 is associated with a less pro-inflammatory immune response in mice, we hypothesized that the observed protection is (in part) due to a less pro-inflammatory cytokine profile. METHODS: Cross-sectional observational study including 263 incident dialysis patients aged 18-70years, without clinical signs of infection and/or acute vasculitis. TNF-α, IL-6, IL-10 and hsCRP levels were determined and studied in relation to the CCR5 genotype. RESULTS: In the presence of elevated hsCRP, IL-6 concentration was higher irrespective of the CCR5 genotype. However, in patients with the CCR5 deletion, TNF-α did not differ in the presence/absence of elevated hsCRP and was not correlated with hsCRP levels in carriers of the CCR5Δ32 polymorphism. CONCLUSIONS: A possible underlying mechanism of the impact of CCR5Δ32 genotype on inflammation driven mortality in dialysis patients could be a reduced Th1 immune response as represented by decreased TNF-α levels.

CCR5Delta32 genotype is associated with outcome in type 2 diabetes mellitus.

AIMS: To test whether the genetic variant CCR5Delta32 in the CC-chemokine receptor 5, which is known to lead to CCR5 deficiency, is associated with mortality in type 2 diabetes patients. METHODS: We examined the effect of presence or absence of the CCR5Delta32 on overall and cardiovascular mortality risk in the Zwolle Outpatient Diabetes project Integrating Available Care (ZODIAC) cohort, a type 2 diabetes patient cohort. RESULTS: We studied 756 patients with a mean duration of follow-up of 5.4 (+/- 1.4) years. 194 patients died during follow up of which 83 were cardiovascular deaths. 144 subjects (19%) carried the CCR5Delta32 deletion. CCR5Delta32 carriers had an adjusted hazard ratio of 0.62 (95%CI: 0.40-0.96; p=0.03) for all-cause mortality and 0.63 (95%CI: 0.33-1.19; p=0.16) for cardiovascular mortality. CONCLUSIONS: The presence of CCR5Delta32 is associated with better survival in type 2 diabetes patients. These data suggest that it is worthwhile to explore the protective potential of pharmacological blockade of CCR5 in type 2 diabetic patients.

CCR5 deletion protects against inflammation-associated mortality in dialysis patients.

The CC-chemokine receptor 5 (CCR5) is a receptor for various proinflammatory chemokines, and a deletion variant of the CCR5 gene (CCR5 Delta 32) leads to deficiency of the receptor. We hypothesized that CCR5 Delta 32 modulates inflammation-driven mortality in patients with ESRD. We studied the interaction between CCR5 genotype and levels of high-sensitivity C-reactive protein (hsCRP) in 603 incident dialysis patients from the multicenter, prospective NEtherlands COoperative Study on the Adequacy of Dialysis (NECOSAD) cohort. CCR5 genotype and hsCRP levels were both available for 413 patients. During 5 yr of follow-up, 170 patients died; 87 from cardiovascular causes. Compared with the reference group of patients who had the wild-type CCR5 genotype and hsCRP 10 mg/L (n = 108) had an increased risk for mortality (HR: 1.82; 95% CI: 1.29 to 2.58). However, those carrying the deletion allele with hsCRP > 10 mg/L (n = 25) had a mortality rate similar to the reference group; this seemingly protective effect of the CCR5 deletion was even more pronounced for cardiovascular mortality. We replicated these findings in an independent Swedish cohort of 302 ESRD patients. In conclusion, the CCR5 Delta 32 polymorphism attenuates the adverse effects of inflammation on overall and cardiovascular mortality in ESRD.