Cloning and expression of a human kinesin heavy chain gene: interaction of the COOH-terminal domain with cytoplasmic microtubules in transfected CV-1 cells.

To understand the interactions between the microtubule-based motor protein kinesin and intracellular components, we have expressed the kinesin heavy chain and its different domains in CV-1 monkey kidney epithelial cells and examined their distributions by immunofluorescence microscopy. For this study, we cloned and sequenced cDNAs encoding a kinesin heavy chain from a human placental library. The human kinesin heavy chain exhibits a high level of sequence identity to the previously cloned invertebrate kinesin heavy chains; homologies between the COOH-terminal domain of human and invertebrate kinesins and the nonmotor domain of the Aspergillus kinesin-like protein bimC were also found. The gene encoding the human kinesin heavy chain also contains a small upstream open reading frame in a G-C rich 5' untranslated region, features that are associated with translational regulation in certain mRNAs. After transient expression in CV-1 cells, the kinesin heavy chain showed both a diffuse distribution and a filamentous staining pattern that coaligned with microtubules but not vimentin intermediate filaments. Altering the number and distribution of microtubules with taxol or nocodazole produced corresponding changes in the localization of the expressed kinesin heavy chain. The expressed NH2-terminal motor and the COOH-terminal tail domains, but not the alpha-helical coiled coil rod domain, also colocalized with microtubules. The finding that both the kinesin motor and tail domains can interact with cytoplasmic microtubules raises the possibility that kinesin could crossbridge and induce sliding between microtubules under certain circumstances

Health-related quality of life measured using the EQ-5D-5L: South Australian population norms

© 2016 The Author(s). Background: Although a five level version of the widely-used EuroQol 5 dimensions (EQ-5D) instrument has been developed, population norms are not yet available for Australia to inform the future valuation of health in economic evaluations. The aim of this study was to estimate HrQOL normative values for the EQ-5D-5L preference-based measure in a large, randomly selected, community sample in South Australia. Methods: The EQ-5D-5L instrument was included in the 2013 South Australian Health Omnibus Survey, an interviewer-administered, face-to-face, cross-sectional survey. Respondents rated their level of impairment across dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) and global health rating on a visual analogue scale (EQ-VAS). Utility scores were derived using the newly-developed UK general population-based algorithm and relationships between utility and EQ-VAS scores and socio-demographic factors were also explored using multivariate regression analyses. Results: Ultimately, 2,908 adults participated in the survey (63.4 % participation rate). The mean utility and EQ-VAS scores were 0.91 (95 CI 0.90, 0.91) and 78.55 (95 % CI 77.95, 79.15), respectively. Almost half of respondents reported no problems across all dimensions (42.8 %), whereas only 7.2 % rated their health >90 on the EQ-VAS (100=the best health you can imagine). Younger age, male gender, longer duration of education, higher annual household income, employment and marriage/de facto relationships were all independent, statistically significant predictors of better health status (p<0.01) measured with the EQ-VAS. Only age and employment status were associated with higher utility scores, indicating fundamental differences between these measures of health status. Conclusions: This is the first Australian study to apply the EQ-5D-5L in a large, community sample. Overall, findings are consistent with EQ-5D-5L utility and VAS scores reported for other countries and indicate that the majority of South Australian adults report themselves in full health. When valuing health in Australian economic evaluations, the utility population norms can be used to estimate HrQOL. More generally, the EQ-VAS score may be a better measure of population health given the smaller ceiling effect and broader coverage of HrQOL dimensions. Further research is recommended to update EQ-5D-5L population norms using the Australian general population specific scoring algorithm once this becomes publically available

Analysis, Design, Implementation, and Deployment of a Prototype Maintenance Advisor Expert System for the MK92 Fire Control System

17 USC 105 interim-entered record; under review.In an effort to meet the challenges presented by the fiscal realities of today's defense budget, the Department of Defense (DoD) is seeking to exploit technology that promises to decrease operating costs, while improving operational readiness. Efforts which reduce repair costs, system down time, and the reliance upon outside technical representative are of particular interest. The development of the MK92 Maintenance Advisor Expert System (MK92 MAES) is one such effort. This paper describes the design and development of the MK92 MAES for the diagnosis and repair of the MK92 MOD 2 fire control system deployed on U.S. Navy guided missile frigates. System development is presented in terms of an expert system life cycle model which includes a thorough cost/benefit analysis, a novel approach for knowledge acquisition, an implementation strategy using a visual expert system development environment, and a phased deployment strategy. The system was developed by faculty and graduate students at the Naval Postgraduate School in cooperation with the Naval Warfare Center, Port Hueneme Division.The author thanks...Dean of Research Office at the Naval Postgraduate School for paying the publication cost

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

Clinician-reported changes in octreotide prescribing for malignant bowel obstruction as a result of an adequately powered phase III study: A transnational, online survey

© The Author(s) 2018. Background: Translating research evidence into clinical practice often has a long lag time. Aim: To determine the impact of a phase III randomised controlled trial on palliative care clinicians’ self-reported practice change. Design: Online survey about use of octreotide in managing inoperable malignant bowel obstruction due to cancer or its treatments distributed in November 2016, 2 years after the first publication of the study in a peer-reviewed journal. Demographic, self-reported practice and the reasons underpinning this were collected. Responses were aggregated to ‘practice modified’ or ‘practice not modified’. A multinomial regression model explored predictors of practice change. Setting: Members of the Australian New Zealand Society of Palliative Medicine. Results: Response rate was 20.8% (106/509): 55.6% were aged >50 years, 56.5% were female and 77% had previously prescribed octreotide for this clinical indication. Out of 106 respondents, 52 (49.1%) indicated modified practice (60.9% of those who had previously prescribed octreotide in this setting). In those who reported practice change, most frequently octreotide was now used when other therapies failed; for not changing practice, ‘more confirmatory evidence was needed’ was most often cited. In the regression model, older age (clinician age = 50–59 years; relative risk = 0.147; 95% confidence interval = 0.024–0.918; p = 0.04) and having practices with lower proportions of people treated with octreotide (0%–20%; relative risk = 0.039; 95% confidence interval = 0.002–0.768; p = 0.033) predicted greater self-reported practice change. Conclusion: Clinician-reported change in practice in the survey is seen in the majority of respondents. This suggests that there is a cohort of ‘early adopters’ within palliative care practice as new evidence becomes available

Fluvio-Marine Sediment Partitioning as a Function of Basin Water Depth

Progradational fluvio-deltaic systems tend towards but cannot reach equilibrium, a state in which the longitudinal profile does not change shape and all sediment is bypassed beyond the shoreline. They cannot reach equilibrium because progradation of the shoreline requires aggradation along the longitudinal profile. Therefore progradation provides a negative feedback, unless relative sea level falls at a sufficient rate to cause non-aggradational extension of the longitudinal profile. How closely fluvio-deltaic systems approach equilibrium is dependent on their progradation rate, which is controlled by water depth and downstream allogenic controls, and governs sediment partitioning between the fluvial, deltaic, and marine domains. Here, six analogue models of coastal fluvio-deltaic systems and small prograding shelf margins are examined to better understand the effect of water depth, subsidence, and relative sea-level variations upon longitudinal patterns of sediment partitioning and grain-size distribution that eventually determine large-scale stratigraphic architecture. Fluvio-deltaic systems prograding in relatively deep-water environments are characterized by relatively low progradation rates compared to shallow-water systems. This allows these deeper water systems to approach equilibrium more closely, enabling them to construct less concave and steeper longitudinal profiles that provide low accommodation to fluvial systems. Glacio-eustatic sea-level variations and subsidence modulate the effects of water depth on the longitudinal profile. Systems are closest to equilibrium during falling relative sea level and early lowstand, resulting in efficient sediment transport towards the shoreline at those times. Additionally, the strength of the response to relative sea-level fall differs dependent on water depth. In systems prograding into deep water, relative sea-level fall causes higher sediment bypass rates and generates significantly stronger erosion than in shallow-water systems, which increases the probability of incised-valley formation. Water depth in the receiving basin thus forms a first-order control on the sediment partitioning along the longitudinal profile of fluvio-deltaic systems and the shelf clinoform style. It also forms a control on the availability of sand-grade sediment at the shoreline that can potentially be remobilized and redistributed into deeper marine environments. Key findings are subsequently applied to literature of selected shelf clinoform successions

A phase III wait-listed randomised controlled trial of novel targeted inter-professional clinical education intervention to improve cancer patients' reported pain outcomes (The Cancer Pain Assessment (CPAS) Trial): Study protocol

© 2019 The Author(s). Background: Variations in care models contribute to cancer pain being under-recognised and under-treated in half of all patients with cancer. International and national cancer pain management guidelines are achievable with minimal investment but require practice changes. While much of the cancer pain research over the preceding decades has focused on management interventions, little attention has been given to achieving better adherence to recommended cancer pain guideline screening and assessment practices. This trial aims to reduce unrelieved cancer pain by improving cancer and palliative doctors' and nurses' ('clinicians') pain assessment capabilities through a targeted inter-professional clinical education intervention delivered to participants' mobile devices ('mHealth'). Methods: A wait-listed, randomised control trial design. Cancer and/or palliative care physicians and nurses employed at one of the six participating sites across Australia will be eligible to participate in this trial and, on enrolment, will be allocated to the active or wait-listed arm. Participants allocated to the active arm will be invited to complete the mHealth cancer pain assessment intervention. In this trial, mHealth is defined as medical or public health practice supported by mobile devices (i.e. phones, patient monitoring devices, personal digital assistants and other wireless devices). This mHealth intervention integrates three evidence-based elements, namely: the COM-B theoretical framework; spaced learning pedagogy; and audit and feedback. This intervention will be delivered via the QStream online platform to participants' mobile devices over four weeks. The trial will determine if a tailored mHealth intervention, targeting clinicians' cancer pain assessment capabilities, is effective in reducing self-reported cancer pain scores, as measured by a Numerical Rating Scale (NRS). Discussion: If this mHealth intervention is found to be effective, in addition to improving cancer pain assessment practices, it will provide a readily transferable evidence-based framework that could readily be applied to other evidence practice gaps and a scalable intervention that could be administered simultaneously to multiple clinicians across diverse geographical locations. Moreover, if found to be cost-effective, it will help transform clinical continuing professional development. In summary, this mHealth intervention will provide health services with an opportunity to offer an evidence-based, pedagogically robust, cost-effective, scalable training alternative. Trial registration: Australian New Zealand Clinical Trials Registry (ANZCTR), ACTRN12618001103257. Registered on 3 July 2018

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