Learning from Health Care Exemplars: How The Best Produce Extraordinary Results

Health care is once again in the midst of turmoil, and the need for effective leadership in this domain is as strong as ever. We can intuitively understand that leadership in this complex system is hard and that leading through chaos and change is particularly challenging and difficult, potentially predisposing these leaders to burnout. There has been little if any research into flourishing health care leadership. I hypothesized that health care leaders who produce exceptional results would exemplify characteristics from which rising leaders could learn, and particularly these leaders’ attitudes, behaviors and values would exemplify constructs of human flourishing, the goal of positive psychology. A small sample of exemplar leaders were interviewed to learn what factors they perceive contribute to their success. The results identified the strengths of courage, humanity and transcendence as foundational to their health care leadership. These results open the door to further inquiry and to the development of a character strength-based model for flourishing health care leadership

Age-related mitochondrial DNA depletion and the impact on pancreatic beta cell function

Type 2 diabetes is characterised by an age-related decline in insulin secretion. We previously identified a 50% age-related decline in mitochondrial DNA (mtDNA) copy number in isolated human islets. The purpose of this study was to mimic this degree of mtDNA depletion in MIN6 cells to determine whether there is a direct impact on insulin secretion. Transcriptional silencing of mitochondrial transcription factor A, TFAM, decreased mtDNA levels by 40% in MIN6 cells. This level of mtDNA depletion significantly decreased mtDNA gene transcription and translation, resulting in reduced mitochondrial respiratory capacity and ATP production. Glucose-stimulated insulin secretion was impaired following partial mtDNA depletion, but was normalised following treatment with glibenclamide. This confirms that the deficit in the insulin secretory pathway precedes K+ channel closure, indicating that the impact of mtDNA depletion is at the level of mitochondrial respiration. In conclusion, partial mtDNA depletion to a degree comparable to that seen in aged human islets impaired mitochondrial function and directly decreased insulin secretion. Using our model of partial mtDNA depletion following targeted gene silencing of TFAM, we have managed to mimic the degree of mtDNA depletion observed in aged human islets, and have shown how this correlates with impaired insulin secretion. We therefore predict that the age-related mtDNA depletion in human islets is not simply a biomarker of the aging process, but will contribute to the age-related risk of type 2 diabetes

Impact of cryopreservation on tetramer, cytokine flow cytometry, and ELISPOT

BACKGROUND: Cryopreservation of PBMC and/or overnight shipping of samples are required for many clinical trials, despite their potentially adverse effects upon immune monitoring assays such as MHC-peptide tetramer staining, cytokine flow cytometry (CFC), and ELISPOT. In this study, we compared the performance of these assays on leukapheresed PBMC shipped overnight in medium versus cryopreserved PBMC from matched donors. RESULTS: Using CMV pp65 peptide pool stimulation or pp65 HLA-A2 tetramer staining, there was significant correlation between shipped and cryopreserved samples for each assay (p ≤ 0.001). The differences in response magnitude between cryopreserved and shipped PBMC specimens were not significant for most antigens and assays. There was significant correlation between CFC and ELISPOT assay using pp65 peptide pool stimulation, in both shipped and cryopreserved samples (p ≤ 0.001). Strong correlation was observed between CFC (using HLA-A2-restricted pp65 peptide stimulation) and tetramer staining (p < 0.001). Roughly similar sensitivity and specificity were observed between the three assays and between shipped and cryopreserved samples for each assay. CONCLUSION: We conclude that all three assays show concordant results on shipped versus cryopreserved specimens, when using a peptide-based readout. The assays are also concordant with each other in pair wise comparisons using equivalent antigen systems

Exile Vol. XXXVII No. 2

Once and for All by Michael Payne 1 Alone Over The Trees by John Stoddard 2 Caught You by Nancy Booth 3 Mother\u27s Words by Julie Green 4-10 His Token by Donna Marie Voldness 11-12 Global Warming by Eric Franzon 13-14 Amish Mystery by Shannon Salser 15 For Peace by Robin Schneider 16-18 Elvis, the Lizard King, and Me by Stewart Engesser 19-22 Norpell Woods by Brandon Pfeiffer 23 Blue Suit, Red Dog by Jack Beck 24 I Am Without My List of Excusses [sic] by Douglas George 25 Somtimes - Satre Would Not Be Proud by Dana Wells 26 The Flock by Carter Holland 27-33 Dance of Alabaster by Jay Speiden 34 Winter Solstice by K. Lynn Rogers 35-36 Fish Story by Jim Dixon 37-42 Slumming by Stewart Engesser 43 Beached by Chris Dealy 44 The Missing Man by Tom Ream 45-47 Elegy by Scott Dexter 48 Close Range by Jay Speiden 49 No Longer by Shannon Salser 50 In A Bar In Georgetown, Colorado 1990 by John Stoddard 51 untitled by Brian Wills 52 Editorial decision is shared equally among the Editorial Board. -i Cover: Megan Doyle -i NOTE: I Am Without My List of Excusses [sic] by Douglas George 25 is listed as I Am Without My List of Excuses on page 25. The published table of contents is followed here

Using a discrete choice experiment involving cost to value a classification system measuring the quality of life impact of self-management for diabetes

Objective: This paper describes the use of a novel approach in health valuation of a discrete choice experiment (DCE) including a cost attribute to value a recently developed classification system for measuring the quality of life impact (both health and treatment experience) of self-management for diabetes. Methods: A large online survey was conducted using DCE with cost on UK respondents from the general population (n=1,497) and individuals with diabetes (n=405). The data was modelled using a conditional logit model with robust standard errors. The marginal rate of substitution (MRS) was used to generate willingness to pay estimates for every state defined by the classification system. Robustness of results was assessed by including interaction effects for household income. Results: There were some logical inconsistencies and insignificant coefficients for the milder levels of some attributes. There were some differences in the rank ordering of different attributes for the general population and diabetes patients. The willingness to pay to avoid the most severe state was £1,118.53 per month for the general population and £2,356.02 per month for the diabetes patient population. The results were largely robust. Conclusion: Health and self-management can be valued in a single classification system using DCE with cost. The MRS for key attributes can be used to inform cost-benefit analysis of self-management interventions in diabetes using results from clinical studies where this new classification system has been applied. The method shows promise, but found large willingness to pay estimates exceeding the cost levels used in the survey

Generation of Functional Human Hepatic Endoderm from Human Induced Pluripotent Stem Cells

With the advent of induced pluripotent stem cell (iPSC) technology, it is now feasible to generate iPSCs with a defined genotype or disease state. When coupled with direct differentiation of defined lineage, such as hepatic endoderm (HE). iPSC would revolutionise the way we study human liver biology and generate efficient “off the shelf” models of human liver disease. Here we show the `proof of concept' that iPSC lines representing both male and female sexes and two ethnic origins can be differentiated to HE at efficiencies of between 70–90%, using a method mimicking a physiological condition. iPSC-derived HE exhibited hepatic morphology, and expressed the hepatic markers, Albumin and E-Cadherin as assessed by immuno-histochemistry. They also expressed alpha fetal protein (AFP), HNF4a, and a metabolic marker, Cyp7A1, demonstrating a definitive endodermal lineage differentiation. Furthermore, iPSC-derived hepatocytes produced and secreted the plasma proteins, fibrinogen, fibronectin, transthyretin (TTR) and AFP, an essential feature for functional HE. Additionally iPSC-derived HE supported both CYP1A2 and 3A4 metabolism, which is essential for drug and toxicology testing. CONCLUSION: This work is first to demonstrate the efficient generation of hepatic endodermal lineage from human iPSC that exhibits key attributes of hepatocytes, and the potential application of iPSC-derived HE in studying human liver biology. In particular, iPSC from individuals representing highly polymorphic variants in metabolic genes and different ethnic groups will provide pharmaceutical development and toxicology studies a unique opportunity to revolutionise predictive drug toxicology assays and allow the creation of in vitro hepatic disease models

Estimating a Dutch value set for the paediatric preference-based CHU-9D using a discrete choice experiment with duration

Objective: This paper presents the development of the Dutch value set for the CHU-9D, a paediatric preference-based measure of quality of life that can be used to generate quality adjusted life years (QALYs). Methods: A large online survey was conducted using a discrete choice experiment (DCE) including a duration attribute with adult members of the Netherlands general population (n=1,276) who were representative in terms of age, gender, marital status, employment, education and region. Respondents were asked which of two health states they prefer, where each health state was described using the nine dimensions of the CHU-9D (worried, sad, pain, tired, annoyed, school work/homework, sleep, daily routine, able to join in activities) and duration. The data was modelled using conditional logit with robust standard errors to produce utility values for every health state described by the CHU-9D. Results: The majority of the dimension level coefficients were monotonic, leading to a decrease in utility as severity increases. However there was evidence of some logical inconsistencies particularly for the school work/homework dimension. The value set produced was based on the ordered model and ranges from -0.568 for the worst state to 1 for the best state. Conclusion: The valuation of the CHU-9D using online DCE with duration with adult members of the Dutch general population was feasible and produced a valid model for use in cost utility analysis. Normative questions are raised around the valuation of paediatric preference-based measures including the appropriate perspective for imagining hypothetical paediatric health states