A systematic review of the literature on the development of condition-specific preference-based measures of health

This is the author accepted manuscript. The final version is available from Springer Verlag via the DOI in this record.Background. Health state utility values (HSUVs) are required to calculate quality-adjusted life-years (QALYs). They are frequently derived from generic preference-based measures of health. However, such generic measures may not capture health attributes of relevance to specific conditions. In such cases, a condition-specific preference-based measure (CSPBM) may be more appropriate. Objective. This systematic review aimed to identify all published accounts of developing CSPBMs, to describe and appraise the methods used. Method. A systematic search (of Embase, Medline, PsycINFO, Web of Science, the Cochrane Library, CINAHL, EconLit, ASSIA and the Health Management Information Consortium database) was undertaken to identify published accounts of CSPBM development up to July 2015. Studies were reviewed to investigate the methods used to design classification systems, estimate HSUVs, and validate the measures. Results. Eighty-six publications were identified, describing 51 CSPBMs. Around two-thirds of these were QALY measures; the remainder were designed for clinical decision-making only. Classification systems for 33 CSPBMs were derived from existing instruments; 18 were developed de novo. HSUVs for 34 instruments were estimated using a ‘composite’ approach, involving statistical modelling; the remainder used a ‘decomposed’ approach based on multi-attribute utility theory. Half of the papers that described the estimation of HSUVs did not report validating their measures. Conclusion. Various methods have been used at all stages of CSPBM development. The choice between developing a classification system de novo or from an existing instrument may depend on the availability of a suitable existing measure, while the choice between a decomposed or composite approach appears to be determined primarily by the purpose for which the instrument is designed. The validation of CSPBMs remains an area for further development.The Multiple Sclerosis Society of Great Britain and Northern IrelandNational Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care South West Peninsula at the Royal Devon and Exeter NHS Foundation Trus

Using the Fatigue Severity Scale to inform healthcare decision-making in multiple sclerosis: mapping to three quality-adjusted life-year measures (EQ-5D-3L, SF-6D, MSIS-8D)

This is the author accepted manuscript. The final version is available from BioMed Central via the DOI in this recordBackground:Fatigue has a major influence on the quality of life of people with multiple sclerosis. The Fatigue Severity Scale is a frequently used patient-reported measure of fatigue impact, but does not generate the health state utility values required to inform cost-effectiveness analysis, limiting its applicability within decision-making contexts. The objective of this study was to use statistical mapping methods to convert Fatigue Severity Scale scores to health state utility values from three preference-based measures: the EQ-5D-3L, SF-6D and Multiple Sclerosis Impact Scale-8D. Methods: The relationships between the measures were estimated through regression analysis using cohort data from 1056 people with multiple sclerosis in South West England. Estimation errors were assessed and predictive performance of the best models were tested in a separate sample (n=352). Results: For the EQ-5D and the Multiple Sclerosis Impact Scale-8D, the best performing models used a censored least absolute deviation specification, with Fatigue Severity Scale total score, age and gender as predictors. For the SF-6D, the best performing model used an ordinary least squares specification, with Fatigue Severity Scale total score as the only predictor. Conclusions: Here we present algorithms to convert Fatigue Severity Scales scores into health state utility values based on three preference-based measures. These values may be used to estimate quality adjusted life-years for use in cost-effectiveness analyses and to consider the health-related quality of life of people with multiple sclerosis, thereby informing health policy decisions.Multiple Sclerosis SocietyPenCLAHR

Effects of Catheterization on Artery Function and Health: When Should Patients Start Exercising Following Their Coronary Intervention?

Coronary artery disease (CAD) is a leading cause of death worldwide, and percutaneous transluminal coronary angiography (PTCA) and/or percutaneous coronary intervention (PCI; angioplasty) are commonly used to diagnose and/or treat the obstructed coronaries. Exercise-based rehabilitation is recommended for all CAD patients; however, most guidelines do not specify when exercise training should commence following PTCA and/or PCI. Catheterization can result in arterial dysfunction and acute injury, and given the fact that exercise, particularly at higher intensities, is associated with elevated inflammatory and oxidative stress, endothelial dysfunction and a pro-thrombotic milieu, performing exercise post-PTCA/PCI may transiently elevate the risk of cardiac events. This review aims to summarize extant literature relating to the impacts of coronary interventions on arterial function, including the time-course of recovery and the potential deleterious and/or beneficial impacts of acute versus long-term exercise. The current literature suggests that arterial dysfunction induced by catheterization recovers 4-12 weeks following catheterization. This review proposes that a period of relative arterial vulnerability may exist and exercise during this period may contribute to elevated event susceptibility. We therefore suggest that CAD patients start an exercise training programme between 2 and 4 weeks post-PCI, recognizing that the literature suggest there is a 'grey area' for functional recovery between 2 and 12 weeks post-catheterization. The timing of exercise onset should take into consideration the individual characteristics of patients (age, severity of disease, comorbidities) and the intensity, frequency and duration of the exercise prescription

The role of the environment in transmission of healthcare associated infection

Infectious diseases are the current leading cause of human death and within this category nosocomial infections remain the most frequent complication of hospitalization. A range of infection prevention and control activities are employed to combat the selection and spread of these organisms. The principle components of which are: early identification of carriage/infection, patient isolation, improved hand hygiene, environmental control and good antimicrobial stewardship. In order to properly focus these interventions, it is essential to know how and when cross transmission has occurred. There is an ongoing debate about the role of the environment in the spread of healthcare associated infections and to what extent if any it acts as a potential vector for transmission. Within the healthcare setting patients spend a substantial amount of time surrounded by equipment and environmental surfaces that may be contaminated with microorganisms. In order to establish what role the environment could play, tracking the spread of organisms by molecular typing is key. The current methods used to do this are complex and often are only available at reference laboratories. This means that turnaround times are slow and only provide retrospective confirmation of cross-transmission events. Infection control interventions that can be used prior to receiving results play an important role. The selection and effectiveness of these interventions are often poorly supported by research studies, leading to problems with the introduction of evidence based practice and thus difficulty in selecting the most appropriate response to suspected cross transmission. This thesis aims to explore the role of the environment in cross transmission of infection by developing sampling methodologies to permit environmental surveillance, validating and developing typing techniques in order to establish epidemiological links between patients and environmental contamination and to evaluate infection control interventions to aid in prevention of cross transmission events

D-Brane Wess-Zumino Terms and U-Duality

We construct gauge-invariant and U-duality covariant expressions for Wess-Zumino terms corresponding to general Dp-branes (for any p<D) in arbitrary 2<D<11 dimensions. A distinguishing feature of these Wess-Zumino terms is that they contain twice as many scalars as the 10-D compactified dimensions, in line with doubled geometry. We find that for D<10 the charges of the higher-dimensional branes can all be expressed as products of the 0-brane charges, which include the D0-brane and the NS-NS 0-brane charges. We give the general expressions for these charges and show how they determine the non-trivial conjugacy class to which some of the higher-dimensional D-branes belong.Comment: 42 pages. Typos corrected, an error in table 6 corrected, comments in the conclusions adde

Breast cancer histologic grading using digital microscopy: concordance and outcome association

Aims: Virtual microscopy utilising digital whole slide imaging (WSI) is increasingly used in breast pathology. Histologic grade is one of the strongest prognostic factors in breast cancer (BC). This study aims at investigating the agreement between BC grading using traditional light microscopy (LM) and digital whole slide imaging (WSI) with consideration of reproducibility and impact on outcome prediction. Methods: A large (n=1675) well-characterised cohort of BC originally graded by LM was re-graded using WSI. Two separate virtual-based grading sessions (V1 and V2) were performed with a three months washout period. Outcome was assessed using breast cancer specific and distant metastasis free survival. Results: The concordance between LM grading and WSI was strong (LM/SWI Cramer’s V: V1=0.576, and V2=0.579). The agreement regarding grade components was as follows: Tubule formation=0.538, Pleomorphism=0.422 and Mitosis=0.514. Greatest discordance was observed between adjacent grades whereas high/low grade discordance was uncommon (1.5%). The intra-observer agreement for the two WSI sessions was substantial for grade (V1/V2 Cramer’s V=0.676; kappa=0.648) and grade components (Cramer’s V T=0.628, P=0.573 and M=0.580). Grading using both platforms showed strong association with outcome (All p-value <0.001). Although mitotic scores assessed using both platforms were strongly associated with outcome, WSI tends to underestimate mitotic counts. Conclusions: Virtual microscopy is a reliable and reproducible method for assessing BC histologic grade. Regardless of the observer or assessment platform, histologic grade is a significant predictor of outcome. Continuing advances in imaging technology could potentially provide improved performance of WSI BC grading and in particular mitotic count assessment

Impact of handgrip exercise intensity on brachial artery flow-mediated dilation.

PURPOSE: Previous studies that have examined the impact of exercise intensity on conduit artery endothelial function have involved large muscle group exercise which induces local and systemic effects. The aim of this study was to examine flow-mediated dilation (FMD) before and after incremental intensities of handgrip exercise (HE), to assess the role of local factors such as blood flow and shear rate on post-exercise brachial artery function. METHODS: Eleven healthy men attended the laboratory on three occasions. Subjects undertook 30 min of handgrip exercise at three intensities (5, 10 or 15 % MVC). Brachial artery FMD, shear and blood flow patterns were examined before, immediately after and 60 min post exercise. RESULTS: Handgrip exercise increased mean and antegrade shear rate (SR) and blood flow (BF) and reduced retrograde SR and BF (all P < 0.01). Exercise intensity was associated with a dose-dependent increase in both mean and antegrade BF and SR (interaction, P < 0.01). Post-hoc tests revealed that, whilst handgrip exercise did not immediately induce post-exercise changes, FMD was significantly higher 60 min post-exercise following the highest exercise intensity (5.9 ± 2.8-10.4 ± 5.8 %, P = 0.01). CONCLUSIONS: Handgrip exercise leads to intensity-and time-dependent changes in conduit artery function, possibly mediated by local increases in shear, with improvement in function evident at 1 h post-exercise when performed at a higher intensity

Targeting BRCA1-BER deficient breast cancer by ATM or DNA-PKcs blockade either alone or in combination with cisplatin for personalized therapy

BRCA1, a key factor in homologous recombination repair may also regulate base excision repair (BER). Targeting BRCA1-BER deficient cells by blockade of ATM and DNA-PKcs could be a promising strategy in breast cancer. We investigated BRCA1, XRCC1 and pol β protein expression in two cohorts (n=1602 sporadic and n=50 germ-line BRCA1 mutated) and mRNA expression in two cohorts (n=1952 and n=249). Artificial neural network analysis for BRCA1-DNA repair interacting genes was conducted in 249 tumours. Pre-clinically, BRCA1 proficient and deficient cells were DNA repair expression profiled and evaluated for synthetic lethality using ATM and DNA-PKcs inhibitors either alone or in combination with cisplatin. In human tumours, BRCA1 negativity was strongly associated with low XRCC1, and low pol β at mRNA and protein levels (p<0.0001). In patients with BRCA1 negative tumours, low XRCC1 or low pol β expression was significantly associated with poor survival in univariate and multivariate analysis compared to high XRCC1 or high pol β expressing BRCA1 negative tumours (ps<0.05). Pre-clinically, BRCA1 negative cancer cells exhibit low mRNA and low protein expression of XRCC1 and pol β. BRCA1-BER deficient cells were sensitive to ATM and DNA-PKcs inhibitor treatment either alone or in combination with cisplatin and synthetic lethality was evidenced by DNA double strand breaks accumulation, cell cycle arrest and apoptosis. We conclude that XRCC1 and pol β expression status in BRCA1 negative tumours may have prognostic significance. BRCA1-BER deficient cells could be targeted by ATM or DNA-PKcs inhibitors for personalized therapy

Willingness to Pay for Genetic Testing for Alzheimer's Disease: A Measure of Personal Utility

Background: The increased availability of genetic tests for common, complex diseases, such as Alzheimer's disease (AD), raises questions about what people are willing to pay for these services. Methods: We studied willingness-to-pay for genetic testing in a study of AD risk assessment that included APOE genotype disclosure among 276 first-degree relatives of persons with AD. Results: Seventy-one percent reported that they would ask for such testing from their doctor if it were covered by health insurance, and 60% would ask for it even if it required self-pay. Forty-one percent were willing to pay more than $100 for testing, and more than half would have been willing to pay for the test out of pocket. Participants who learned that they were APOE -4 positive and those who had higher education were less likely to want testing if covered by insurance, possibly to avoid discrimination. Conclusion: This is the first report to examine willingness to pay for susceptibility genetic testing in a sample of participants who had actually undergone such testing. These findings reveal that some participants find valuable personal utility in genetic risk information even when such information does not have proven clinical utility.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90504/1/gtmb-2E2011-2E0028.pd