Estimating EQ-5D utilities based on the Short-Form Long Term Conditions Questionnaire (LTCQ-8)

Purpose: The aim of this work was to develop a mapping algorithm for estimating EuroQoL 5 Dimension (EQ-5D) utilities from responses to the Long-Term Conditions Questionnaire (LTCQ), thus increasing LTCQ’s potential as a comprehensive outcome measure for evaluating integrated care initiatives. Methods: We combined data from three studies to give a total sample of 1334 responses. In each of the three datasets, we randomly selected 75% of the sample and combined the selected random samples to generate the estimation dataset, which consisted of 1001 patients. The unselected 25% observations from each dataset were combined to generate an internal validation dataset of 333 patients. We used direct mapping models by regressing responses to the LTCQ-8 directly onto EQ-5D-5L and EQ-5D-3L utilities as well as response (or indirect) mapping to predict the response level that patients selected for each of the five EQ-5D-5L domains. Several models were proposed and compared on mean squared error and mean absolute error. Results: A two-part model with OLS was the best performing based on the mean squared error (0.038) and mean absolute error (0.147) when estimating the EQ-5D-5L utilities. A multinomial response mapping model using LTCQ-8 responses was used to predict EQ-5D-5L responses levels. Conclusions: This study provides a mapping algorithm for estimating EQ-5D utilities from LTCQ responses. The results from this study can help broaden the applicability of the LTCQ by producing utility values for use in economic analyses

How does reorganisation in child and adolescent mental health services affect access to services? An observational study of two services in England.

BackgroundChild and Adolescent Mental Health Services (CAMHS) in England are making significant changes to improve access and effectiveness. This 'transformation' variously involves easier access to services through a Single Point of Access (SPA), more integrated services within CAMHS and enhanced co-provision across education and third sector or non-profit organisations.MethodsA mixed-methods observational study was conducted to explore the process and impact of transformation over four years in two services. Ethnographic observations and in-depth interviews were conducted and Electronic Patient Records with over one million contacts analysed. Difference-in-differences analysis with propensity score matching to estimate the causal impact of the transformation on patient access was utilised.OutcomesSpend and staffing increased across both CAMHS. The SPA had growing rates of self-referral and new care pathways were seeing patients according to expected degree of psychopathology. Third sector partners were providing increasing numbers of low-intensity interventions. Although the majority of staff were supportive of the changes, the process of transformation led to service tensions. In the first year after transformation there was no change in the rate of new patients accessing services or new spells (episodes of care) in the services. However, by year three, the number of new patients accessing CAMHS was 19% higher (Incidence Rate Ratio: 1·19, CI: 1·16, 1·21) and the rate of new spells was 12% higher (Incidence Rate Ratio: 1·12, CI: 1·05, 1·20).InterpretationTransformation investment, both financial and intellectual, can help to increase access to CAMHS in England, but time is needed to realise the benefits of reorganisation

The use of multicriteria decision analysis to support decision making in healthcare: an updated systematic literature review

Objectives Multicriteria decision analysis (MCDA) is increasingly used for decision making in healthcare. However, its application in different decision-making contexts is still unclear. This study aimed to provide a comprehensive review of MCDA studies performed to inform decisions in healthcare and to summarize its application in different decision contexts. Methods We updated a systematic review conducted in 2013 by searching Embase, MEDLINE, and Google Scholar for MCDA studies in healthcare, published in English between August 2013 and November 2020. We also expanded the search by reviewing grey literature found via Trip Medical Database and Google, published between January 1990 and November 2020. A comprehensive template was developed to extract information about the decision context, criteria, methods, stakeholders involved, and sensitivity analyses conducted. Results From the 4295 identified studies, 473 studies were eligible for full-text review after assessing titles and abstracts. Of those, 228 studies met the inclusion criteria and underwent data extraction. The use of MCDA continues to grow in healthcare literature, with most of the studies (49%) informing priority-setting decisions. Safety, cost, and quality of care delivery are the most frequently used criteria, although there are considerable differences across decision contexts. Almost half of the MCDA studies used the linear additive model whereas scales and the analytical hierarchy process were the most used techniques for scoring and weighting, respectively. Not all studies report on each one of the MCDA steps, consider axiomatic properties, or justify the methods used. Conclusions A guide on how to conduct and report MCDA that acknowledges the particularities of the different decision contexts and methods needs to be developed

Poor agreement between commercial ELISAs for plasma fetuin-A: an effect of protein glycosylation?

BACKGROUND Fetuin-A is a circulating inhibitor of ectopic calcification. Low plasma levels have been associated in some studies with increased vascular calcification, aortic stiffness and mortality in patients with Chronic Kidney Disease (CKD). However, there are other studies examining the association of fetuin-A with vascular parameters and mortality, which do not show these associations. These conflicting data may be explained by methodological differences. METHODS We compared plasma fetuin-A measurements made with two widely-used commercial fetuin-A ELISA kits (Biovendor, Modrice, Czech Republic; Epitope Diagnostics Inc., San Diego, US) in samples from patients with and without CKD. We evaluated the effect of differences in fetuin-A glycosylation status on assay specificity. RESULTS Deming regression analysis showed poor agreement between methods (for CKD cohort: y=-0.05+2.52x, S(y|x)=0.099g/L, R(2)=0.694). The Epitope Diagnostics kit demonstrated significant positive bias and greater specificity for deglycosylated fetuin-A relative to the Biovendor assay. CONCLUSION The apparently contradictory nature of reports of the association of fetuin-A with biological variables may reflect differences in the specificity of different ELISA methods for glycosylated plasma fetuin-A

Instability of fibroblast growth factor-23 (FGF-23): implications for clinical studies

BACKGROUND Fibroblast growth factor-23 (FGF-23) is a bone secreted hormone that regulates phosphate homeostasis and calcitriol levels. FGF-23 concentrations are elevated in chronic kidney disease (CKD), oncogenic osteomalcia and a number of rare hereditary disorders. Studies systematically evaluating the pre-analytical stability of intact FGF-23 are lacking. METHODS The stability of FGF-23 was assessed in timed experiments using blood taken into K2-EDTA plasma specimen tubes from a group of healthy participants and from a group with mild-to-moderate CKD. We evaluated the use of aprotinin, a serine protease inhibitor, and a commercially available protease inhibitor cocktail to preserve intact FGF-23 after blood collection. FGF-23 measurements were made using both intact and C-terminal assays. RESULTS Both whole blood and separated sample studies demonstrated a rapid loss of intact FGF-23 within 2 h, while concentrations increased using the C-terminal assay. The addition of protease inhibitor cocktail stabilised FGF-23 concentrations for 4 h after blood collection. Intact and C-terminal assay FGF-23 measurements showed poor correlation in both healthy and CKD cohorts. CONCLUSION K2-EDTA plasma samples, even when promptly separated, are unsuitable for measurement of FGF-23 unless stabilised with a protease inhibitor cocktail

An AKAP-Lbc-RhoA interaction inhibitor promotes the translocation of aquaporin-2 to the plasma membrane of renal collecting duct principal cells

Stimulation of renal collecting duct principal cells with antidiuretic hormone (arginine-vasopressin, AVP) results in inhibition of the small GTPase RhoA and the enrichment of the water channel aquaporin-2 (AQP2) in the plasma membrane. The membrane insertion facilitates water reabsorption from primary urine and fine-tuning of body water homeostasis. Rho guanine nucleotide exchange factors (GEFs) interact with RhoA, catalyze the exchange of GDP for GTP and thereby activate the GTPase. However, GEFs involved in the control of AQP2 in renal principal cells are unknown. The A-kinase anchoring protein, AKAP-Lbc, possesses GEF activity, specifically activates RhoA, and is expressed in primary renal inner medullary collecting duct principal (IMCD) cells. Through screening of 18,431 small molecules and synthesis of a focused library around one of the hits, we identified an inhibitor of the interaction of AKAP-Lbc and RhoA. This molecule, Scaff10-8, bound to RhoA, inhibited the AKAP-Lbc-mediated RhoA activation but did not interfere with RhoA activation through other GEFs or activities of other members of the Rho family of small GTPases, Rac1 and Cdc42. Scaff10-8 promoted the redistribution of AQP2 from intracellular vesicles to the periphery of IMCD cells. Thus, our data demonstrate an involvement of AKAP-Lbc-mediated RhoA activation in the control of AQP2 trafficking

Structural insights into the mechanism of GTPase activation in the GIMAP family

SummaryGTPases of immunity-associated proteins (GIMAPs) are regulators of lymphocyte survival and homeostasis. We previously determined the structural basis of GTP-dependent GIMAP2 scaffold formation on lipid droplets. To understand how its GTP hydrolysis is activated, we screened for other GIMAPs on lipid droplets and identified GIMAP7. In contrast to GIMAP2, GIMAP7 displayed dimerization-stimulated GTP hydrolysis. The crystal structure of GTP-bound GIMAP7 showed a homodimer that assembled via the G domains, with the helical extensions protruding in opposite directions. We identified a catalytic arginine that is supplied to the opposing monomer to stimulate GTP hydrolysis. GIMAP7 also stimulated GTP hydrolysis by GIMAP2 via an analogous mechanism. Finally, we found GIMAP2 and GIMAP7 expression differentially regulated in several human T cell lymphoma lines. Our findings suggest that GTPase activity in the GIMAP family is controlled by homo- and heterodimerization. This may have implications for the differential roles of some GIMAPs in lymphocyte survival