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 (sic)18 557 per life year gained and (sic)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. Pharmacogenetics and Genomics 21: 417-425 (C) 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins

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

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

Predictors for distant metastasis in head and neck cancer, with emphasis on age

PURPOSE: Distant metastasis (DM) in patients with head and neck squamous cell carcinoma (HNSCC) is uncommon, but strongly deteriorates prognosis. Controversy exists regarding age as a predictor for the presence and development of DM. The aim of this study was to investigate age and other predictors for DM in HNSCC patients. METHODS: From 1413 patients diagnosed with a primary HNSCC between 1999 and 2010 in a tertiary referral centre, patient, disease and pathological characteristics were extracted from patient files. Uni- and multivariable Cox regression analyses were performed to identify risk factors for DM as primary outcome. RESULTS: DM occurred in 131 (9.3%) patients, of which 27 (1.9%) were diagnosed simultaneously with the primary tumour, 27 (1.9%) were diagnosed synchronous, and 77 (5.4%) were diagnosed metachronous. The most common site of DM was lung (51.1%), followed by bone (19.1%) and liver (11.5%). Multivariable analysis identified male gender (HR = 1.95, 95% CI 1.23-3.10) hypopharyngeal tumours (HR = 3.28, 95% CI 1.75-6.14), advanced T-stage (HR = 1.61, 95% CI 1.09-2.38), poor differentiation grade (HR = 2.49, 95% CI 1.07-5.78), regional lymph node metastasis (HR = 5.35, 95% CI 3.25-8.79) and extranodal extension of regional lymph nodes metastasis (HR = 3.06, 95% CI 1.39-6.72) as independent prognostic factors for the presence or development of DM. No relation with age was found. CONCLUSION: Age is not related to the presence or development of DM. This study emphasizes the importance of screening for DM, especially in males, patients with hypopharyngeal tumours, advanced T-stage, histopathological poor differentiation grade, regional lymph node metastasis and extranodal extension

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

Extra-Intestinal Manifestations of Familial Adenomatous Polyposis

Familial adenomatous polyposis (FAP) is an autosomal dominantly inherited disorder, which results from a germ line mutation in the APC (adenomatous polyposis coli) gene. FAP is characterized by the formation of hundreds to thousands of colorectal adenomatous polyps. Although the development of colorectal cancer stands out as the most prevalent complication, FAP is a multisystem disorder of growth. This means, it is comparable to other diseases such as the MEN syndromes, Von Hippel-Lindau disease and neurofibromatosis. However, the incidence of many of its clinical features is much lower. Therefore, a specialized multidisciplinary approach to optimize health care—common for other disorders—is not usually taken for FAP patients. Thus, clinicians that care for and counsel members of high-risk families should have familiarity with all the extra-intestinal manifestations of this syndrome. FAP-related complications, for which medical attention is essential, are not rare and their estimated lifetime risk presumably exceeds 30%. Affected individuals can develop thyroid and pancreatic cancer, hepatoblastomas, CNS tumors (especially medulloblastomas), and various benign tumors such as adrenal adenomas, osteomas, desmoid tumors and dental abnormalities. Due to improved longevity, as a result of better prevention of colorectal cancer, the risk of these clinical problems will further increase

Incidence of and sequels to medical problems discovered in medical students during study-related activities

PURPOSE: Students often act as subjects during practical and clinical skills training sessions. This routine seems to be quite acceptable for them but may present side-effects. Disorders, sometimes of a serious nature, have been discovered in medical students during clinical skills training. Because the incidence of and sequels to medical problems discovered in medical students during study-related activities are unknown, we carried out an explorative study. METHODS: An anonymous questionnaire was administered to 1132 students (85%) in our medical school. RESULTS: A total of 740 students (65% response rate) returned the questionnaire. Of them 124 (16.8% of respondents) reported 139 incidents. The estimated incidence was 1.5% per year. In 63 cases (45%) the diagnosis of a consulted doctor was known. Pathology (e.g. a ventricular septal defect) was revealed in 30 students (21%), a normal physiological variation (e.g. a functional cardiac murmur) in 22 (16%) and no abnormality was found in 11 (8%). Most of the incidents (65%) occurred during clinical skills training. The incidents were experienced negatively by 35% of the students. CONCLUSION: Based on these findings, we estimate the incidence of medical problems discovered in medical students during study-related activities to be 1.5%. This and the moral and legal implications emphasise that every medical school should realise the possibility of consequences. In our opinion, this realisation should result, minimally, in the development of a protocol for students and faculty that outlines procedures for handling such incidents. Information should also be provided explaining these possible side-effects of medical education