Protocol for a systematic review of preference-based instruments for measuring care-related outcomes and their suitability for the palliative care setting

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/ INTRODUCTION: Despite informal caregivers' integral role in supporting people affected by disease or disability, economic evaluations often ignore the costs and benefits experienced by this group, especially in the palliative setting. The purpose of this systematic review is to identify preference-based instruments for measuring care-related outcomes and provide guidance on the selection of instrument in palliative care economic evaluations.METHODS AND ANALYSIS: A comprehensive search of the literature will be conducted from database inception (ASSIA; CINAHL; Cochrane library including DARE, NHS EED, HTA; Econlit; Embase; PsychINFO; PubMed). Published peer-reviewed, English-language articles reporting preference-based instruments for measuring care-related outcomes in any clinical area will be included. One researcher will complete the searches and screen the results for potentially eligible studies. A randomly selected subset of 10% citations will be independently screened by two researchers. Any disagreement will be resolved by consensus among the research team. Subsequently, a supplementary search will identify studies detailing the development, valuation, validation and application of the identified instruments. The degree of suitability of the instruments for palliative economic evaluations will be assessed using criteria in the International Society for Quality of Life Research minimum standards for patient-reported outcome measures, the checklist for reporting valuation studies of multiattribute utility-based instruments and information on the development of the instrument in the palliative setting. A narrative summary of the included studies and instruments will be provided; similarities and differences will be described and possible reasons for variations explored. Recommendations for practice on selection of instruments in palliative care economic analyses will be provided.ETHICS AND DISSEMINATION: This is a planned systematic review of published literature. Therefore, ethics approval to conduct this research is not required. Findings will be presented at leading palliative care and health economic conferences and published in a peer-reviewed journal.TRIAL REGISTRATION NUMBER: CRD42016034188

Better informing decision making with multiple outcomes cost-effectiveness analysis under uncertainty in ost-disutility space

© 2015 McCaffrey et al. Introduction: Comparing multiple, diverse outcomes with cost-effectiveness analysis (CEA) is important, yet challenging in areas like palliative care where domains are unamenable to integration with survival. Generic multi-attribute utility values exclude important domains and nonhealth outcomes, while partial analyses - where outcomes are considered separately, with their joint relationship under uncertainty ignored - lead to incorrect inference regarding preferred strategies. Objective: The objective of this paper is to consider whether such decision making can be better informed with alternative presentation and summary measures, extending methods previously shown to have advantages in multiple strategy comparison. Methods: Multiple outcomes CEA of a home-based palliative care model (PEACH) relative to usual care is undertaken in cost disutility (CDU) space and compared with analysis on the cost-effectiveness plane. Summary measures developed for comparing strategies across potential threshold values for multiple outcomes include: expected net loss (ENL) planes quantifying differences in expected net benefit; the ENL contour identifying preferred strategies minimising ENL and their expected value of perfect information; and cost-effectiveness acceptability planes showing probability of strategies minimising ENL.Results: Conventional analysis suggests PEACH is cost-effective when the threshold value per additional day at home ( K1) exceeds 1,068 or dominated by usual care when only the proportion of home deaths is considered. In contrast, neither alternative dominate in CDU space where cost and outcomes are jointly considered, with the optimal strategy depending on threshold values. For example, PEACH minimises ENL when K1=2,000 and K2=2,000 (threshold value for dying at home), with a 51.6% chance of PEACH being cost-effective. Conclusion: Comparison in CDU space and associated summary measures have distinct advantages to multiple domain comparisons, aiding transparent and robust joint comparison of costs and multiple effects under uncertainty across potential threshold values for effect, better informing net benefit assessment and related reimbursement and research decisions

Preliminary development and validation of a new endof-life patient-reported outcome measure assessing the ability of patients to finalise their affairs at the end of life

Introduction:The ability of patients to finalise their affairs at the end of life is an often neglected aspect of quality of life (QOL) measurement in palliative care effectiveness research despite compelling evidence of the high value patients place on this domain. Objective: This paper describes the preliminary development and evaluation of a new, single-item, end-of-life patientreported outcome measure (EOLPRO) designed to capture changes in the ability of patients to finalise their affairs at the end of life. Methods: Cognitive interviews with purposively sampled Australian palliative care patients (N = 9) were analysed thematically to explore content validity. Simultaneously, secondary analysis of data from a randomised controlled trial comparing ketamine and placebo for the management of cancer pain (N = 185) evaluated: construct validity; test-retest reliability; and responsiveness. Results:Preliminary findings suggest patients interpret the new measure consistently. The EOLPRO captures the ability to complete physical tasks and finalise practical matters although it is unclear whether emotional tasks or resolution of relationship issues are considered. Personal and financial affairs should be separated to allow for differences in ability for these two types of affairs. The significant correlation between performance status and EOLPRO scores (r = 0.41, p,<.01, n = 137) and expected relationships between EOLPRO and proximity to death and constipation demonstrated construct validity. Pre-and post-treatment EOLPRO scores moderately agreed (n = 14, k = 0.52 [95% CI 0.19, 0.84]) supporting reliability. The measure's apparent lack of sensitivity to discriminate between treatment responders and non-responders may be confounded. Conclusion:Based on the preliminary findings, the EOLPRO should be separated into 'personal' and 'financial' affairs with further testing suggested, particularly to verify coverage and responsiveness. Initial evaluation suggests that the single-item EOLPRO is a useful addition to QOL outcome measurement in palliative care effectiveness research because common palliative care specific QOL questionnaires do not include or explicitly capture this domain. © 2014 McCaffrey et al

Open and Closed Conformations of the Isolated Transmembrane Domain of Death Receptor 5 Support a New Model of Activation

AbstractIt has long been presumed that activation of the apoptosis-initiating Death Receptor 5, as well as other structurally homologous members of the TNF-receptor superfamily, relies on ligand-stabilized trimerization of noninteracting receptor monomers. We and others have proposed an alternate model in which the TNF-receptor dimer—sitting at the vertices of a large supramolecular receptor network of ligand-bound receptor trimers—undergoes a closed-to-open transition, propagated through a scissorslike conformational change in a tightly bundled transmembrane (TM) domain dimer. Here we have combined electron paramagnetic resonance spectroscopy and potential-of-mean force calculations on the isolated TM domain of the long isoform of DR5. The experiments and calculations both independently validate that the opening transition is intrinsic to the physical character of the TM domain dimer, with a significant energy barrier separating the open and closed states

Study protocol: A phase III randomised, double-blind, parallel arm, stratified, block randomised, placebo-controlled trial investigating the clinical effect and cost-effectiveness of sertraline for the palliative relief of breathlessness in people with chronic breathlessness

© Published by the BMJ Publishing Group Limited. Introduction: Breathlessness remains a highly prevalent and distressing symptom for many patients with progressive life-limiting illnesses. Evidence-based interventions for chronic breathlessness are limited, and there is an ongoing need for high-quality research into developing management strategies for optimal palliation of this complex symptom. Previous studies have suggested that selective serotonin reuptake inhibitors such as sertraline may have a role in reducing breathlessness. This paper presents the protocol for a large, adequately powered randomised study evaluating the use of sertraline for chronic breathlessness in people with progressive life-limiting illnesses. Methods and analysis: A total of 240 participants with modified Medical Research Council Dyspnoea Scale breathlessness of level 2 or higher will be randomised to receive either sertraline or placebo for 28 days in this multisite, double-blind study. The dose will be titrated up every 3 days to a maximum of 100 mg daily. The primary outcome will be to compare the efficacy of sertraline with placebo in relieving the intensity of worst breathlessness as assessed by a 0-100 mm Visual Analogue Scale. A number of other outcome measures and descriptors of breathlessness as well as caregiver assessments will also be recorded to ensure adequate analysis of participant breathlessness and to allow an economic analysis to be performed. Participants will also be given the option of continuing blinded treatment until either study data collection is complete or net benefit ceases. Appropriate statistical analysis of primary and secondary outcomes will be used to describe the wealth of data obtained. Ethics and dissemination: Ethics approval was obtained at all participating sites. Results of the study will be submitted for publication in peer-reviewed journals and the key findings presented at national and international conferences. Trial registration number ACTRN12610000464066

The effect of pre-shot routines on golf wedge shot performance

The objective of this study was to examine the effect of pre-performance routines among golfers of low skill and non-golfers on wedge golf shot performance. The intervention strategies involved a physical skill and cognitive-behavioral routine program, as well as a physical skills-only program. Performance was measured on a pre-intervention test, postintervention test, and following a period of time without treatment, and involved wedge shots being played from distances of 40, 50, and 60 m from a target. Participants in this study (N = 68) were assigned to either a golfer or non-golfer group. Participants in the treatment groups attended 2 practice sessions per week during the acquisition phase. A variable practice design was incorporated during the intervention phase. Non-golfers in both intervention groups improved performance following the acquisition phase and maintained these levels of performance in the retention test. Greater improvements in performance were found in the non-golfer physical skills and cognitive-behavioral routine group. The non-golfer physical skills and cognitive-behavioral routine group was the only group to realize significant improvements in performance when comparing initial test performance measures to post-intervention and retention test performance measures across all test distances. Although the golfer treatment groups had consistent improvement in performance measures following the intervention phase, these improvements did not reach statistical significance in the majority of cases

Human Genome-Wide RNAi Screen Identifies an Essential Role for Inositol Pyrophosphates in Type-I Interferon Response

The pattern recognition receptor RIG-I is critical for Type-I interferon production. However, the global regulation of RIG-I signaling is only partially understood. Using a human genome-wide RNAi-screen, we identified 226 novel regulatory proteins of RIG-I mediated interferon-β production. Furthermore, the screen identified a metabolic pathway that synthesizes the inositol pyrophosphate 1-IP7 as a previously unrecognized positive regulator of interferon production. Detailed genetic and biochemical experiments demonstrated that the kinase activities of IPPK, PPIP5K1 and PPIP5K2 (which convert IP5 to1-IP7) were critical for both interferon induction, and the control of cellular infection by Sendai and influenza A viruses. Conversely, ectopically expressed inositol pyrophosphate-hydrolases DIPPs attenuated interferon transcription. Mechanistic experiments in intact cells revealed that the expression of IPPK, PPIP5K1 and PPIP5K2 was needed for the phosphorylation and activation of IRF3, a transcription factor for interferon. The addition of purified individual inositol pyrophosphates to a cell free reconstituted RIG-I signaling assay further identified 1-IP7 as an essential component required for IRF3 activation. The inositol pyrophosphate may act by β-phosphoryl transfer, since its action was not recapitulated by a synthetic phosphonoacetate analogue of 1-IP7. This study thus identified several novel regulators of RIG-I, and a new role for inositol pyrophosphates in augmenting innate immune responses to viral infection that may have therapeutic applications

On the problem of the justification of river rights

This article aims to work out the social conditions that determine whether the communication of river rights finds success in society. Employing the context of hydropower development in the Mekong region, the article finds that an essentialist strategy which claims that river rights have unlimited ‘moral’ validity regardless of any of the decision consequences is unlikely to succeed. Instead, it is proposed that moral conflicts over river rights may ultimately only be resolvable ‘unmorally’, that is, by procedural legitimacy – and this is best captured by employing a methodological framework composed of thematic, social and temporal dimension