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Mind the Gap! - Geographic transferability of economic evaluation in health
This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University.Background: Transferring cost-effectiveness information between geographic domains offers the potential for more efficient use of analytical resources. However, it is difficult for decision-makers to know when they can rely on costeffectiveness evidence produced for another context. Objectives: This thesis explores the transferability of economic evaluation results produced for one
geographic area to another location of interest, and develops an approach to identify factors to predict when this is appropriate. Methods: Multilevel statistical
models were developed for the integration of published international costeffectiveness
data to assess the impact of contextual effects on country-level; whilst controlling for baseline characteristics within, and across, a set of economic evaluation studies. Explanatory variables were derived from a list of factors suggested in the literature as possible constraints on the transferability of costeffectiveness evidence. The approach was illustrated using published estimates of the cost-effectiveness of statins for the primary and secondary prevention of cardiovascular disease from 67 studies and related to 23 geographic domains, together with covariates on data, study and country-level. Results: The proportion of variation at the country-level observed depends on the appropriate multilevel model structure and never exceeds 15% for incremental effects and 21% for
incremental cost. Key sources of variability are patient and disease characteristics,
intervention cost and a number of methodological characteristics defined on the
data-level. There were fewer significant covariates on the study and country-levels.
Conclusions: Analysis suggests that variability in cost-effectiveness data is primarily due to differences between studies, not countries. Further, comparing different models suggests that data from multinational studies severely underestimates
country-level variability. Additional research is needed to test the robustness of
these conclusions on other sets of cost-effectiveness data, to further explore the
appropriate set of covariates, and to foster the development of multilevel statistical
modelling for economic evaluation data in health.This study is funded by MATCH, the Engineering and Physical Science Research Council (EPSRC), and the German Academic Merit Foundation
Extended Nitric Oxide Measurements in Exhaled Air of Cystic Fibrosis and Healthy Adults
In cystic fibrosis (CF) lung disease, exhaled nitric oxide (FeNO) is not raised, but rather is normal or even decreased when measured at a single expiratory flow. FeNO measurements at several flow rates allow differentiation between alveolar and bronchial nitric oxide (NO) production. Extended FeNO measurements therefore should be useful to localize the FeNO deficit in CF airways. FeNO was measured in stable CF adults with moderate lung disease and in healthy controls. Bronchial NO fluxes (JNO,Br) and alveolar NO concentrations (CAlv) were calculated from FeNO measurements at flow rates of 100, 150 and 200ml/s using a method previously described. Thirty-two adults were included in the study, 12 of whom had CF. CF adults had significantly lower FeNO values at all flow rates. The median JNO,Br was significantly lower in CF adults than in healthy controls [0.31nl/s (range=0.11-0.63) vs. 0.70nl/s (0.27-3.52); P<0.001], while the median CAlv was similar in both groups [1.7ppb (0.3-3.9) vs. 1.2 (0.1-5.2)]. Pulmonary NO exchange did not differ significantly between subgroups of CF patients with and without chronic Pseudomonas aeruginosa infection. No significant correlation was detectable between FEV1/VC and JNO,Br and CAlv, respectively. Extended FeNO measurements can separate alveolar and bronchial NO outputs in CF adults. The lower FeNO in adults with moderate to severe CF lung disease is likely to be the result of lower bronchial NO outpu
Donor predicted post-operative forced expiratory volume in one second predicts recipients' best forced expiratory volume in one second following size-reduced lung transplantation
Objective: The limited number of available grafts is one of the major obstacles of lung transplantation. Size-reduced lung transplantation allows the use of oversized grafts for small recipients. Optimal lung size matching is vital to achieve best functional outcome and avoid potential problems when using oversized grafts. We hypothesise that donor-predicted postoperative forced expiratory volume in 1s (ppoFEV1) correlates with the recipient best FEV1 after size-reduced lung transplant, being useful for the estimation of function outcome. Methods: All patients undergoing size-reduced or standard bilateral lung transplantation were included (1992-2007). Donor ppoFEV1 was calculated and corrected with respect to size reduction and correlated with recipient measured best FEV1 post-transplant. In addition, pre- and postoperative clinical data including surgical complications and outcome of all size-reduced lung transplant recipients were compared with standard lung transplant recipients. Results: A total of 61 size-reduced lung transplant recipients (lobar transplants, n=20; anatomic or non-anatomic resection, n=41) were included and compared to 145 standard transplants. The mean donor-recipient height difference was statistically significant between the two groups (p=0.0001). The mean donor ppoFEV1 was comparable with recipient best FEV1 (2.7±0.6 vs 2.6±0.7 l). There was a statistically significant correlation between donor ppoFEV1 and recipient best FEV1 (p=0.01, r=0.688). The 30-day mortality rate and 3-month, 1- and 5-year survival rates were comparable between the two groups. Conclusions: In size-reduced lung transplantation, postoperative recipient best FEV1 could be predicted from donor-calculated and corrected FEV1 with respect to its size reduction. Compared to standard lung transplantation, equivalent morbidity, mortality and functional results could be obtained after size-reduced lung transplantatio
Lung transplantation for cystic fibrosis: a single center experience of 100 consecutive cases†
OBJECTIVE Lung transplantation is the ultimate treatment option for patients with end-stage cystic fibrosis (CF) lung disease. Despite poorer reports on survival benefit for CF patients undergoing lung transplantation, several centers, including ours were able to show a survival benefit. This study compares our center's experience with 100 consecutive recipients in two different eras. METHODS All CF patients who underwent lung transplantation at our center were included (1992-2009). Survival rates were calculated and compared between the earlier era (before 2000) and later era (since 2000). RESULTS CF patients constituted 35% of all transplantations performed at our institution. Mean age at transplantation was 27 years (range 12-52). Fifty-one percent of the patients were female. Waiting list time was lower in the earlier era compared to the later era (p=0.04). Lobar transplantation was performed in 10 cases. Thirty-four percent of the cases required downsizing of the graft. In 33% of the cases, transplantations were done on cardiopulmonary bypass. There were no anastomotic complications. Total intensive care unit stay was significantly lower in the later era compared to earlier era (p=0.001). The other parameters such as C-reactive protein at the time of transplantation, total cold ischemic time, and total operation time were comparable between the two eras. Overall 30-day mortality was 5%. The 30-day mortality was significantly lower in the second period (p=0.006). In the earlier era, 3-month, 1-year, and 5-year survival were 85±6%, 77±8%, and 60±9%, respectively, and in the later era improved to 96±2%, 92±3%, and 78±5% (p=0.03). CONCLUSION Improved results obtained in the early postoperative period since 2000 is most likely due to change in surgical management approach. Improved surgical outcome for CF patients can be obtained, especially in experienced transplant center
Chronic stability of a neuroprosthesis comprising multiple adjacent Utah arrays in monkeys
Objective. Electrical stimulation of visual cortex via a neuroprosthesis induces the perception of dots of light (\u27phosphenes\u27), potentially allowing recognition of simple shapes even after decades of blindness. However, restoration of functional vision requires large numbers of electrodes, and chronic, clinical implantation of intracortical electrodes in the visual cortex has only been achieved using devices of up to 96 channels. We evaluated the efficacy and stability of a 1024-channel neuroprosthesis system in non-human primates (NHPs) over more than 3 years to assess its suitability for long-term vision restoration. Approach. We implanted 16 microelectrode arrays (Utah arrays) consisting of 8 x 8 electrodes with iridium oxide tips in the primary visual cortex (V1) and visual area 4 (V4) of two sighted macaques. We monitored the animals\u27 health and measured electrode impedances and neuronal signal quality by calculating signal-to-noise ratios of visually driven neuronal activity, peak-to-peak voltages of the waveforms of action potentials, and the number of channels with high-amplitude signals. We delivered cortical microstimulation and determined the minimum current that could be perceived, monitoring the number of channels that successfully yielded phosphenes. We also examined the influence of the implant on a visual task after 2-3 years of implantation and determined the integrity of the brain tissue with a histological analysis 3-3.5 years post-implantation. Main results. The monkeys remained healthy throughout the implantation period and the device retained its mechanical integrity and electrical conductivity. However, we observed decreasing signal quality with time, declining numbers of phosphene-evoking electrodes, decreases in electrode impedances, and impaired performance on a visual task at visual field locations corresponding to implanted cortical regions. Current thresholds increased with time in one of the two animals. The histological analysis revealed encapsulation of arrays and cortical degeneration. Scanning electron microscopy on one array revealed degradation of IrOx coating and higher impedances for electrodes with broken tips. Significance. Long-term implantation of a high-channel-count device in NHP visual cortex was accompanied by deformation of cortical tissue and decreased stimulation efficacy and signal quality over time. We conclude that improvements in device biocompatibility and/or refinement of implantation techniques are needed before future clinical use is feasible
A National Survey Comparing Patients' and Transplant Professionals' Research Priorities in the Swiss Transplant Cohort Study
We aimed to identify, assess, compare and map research priorities of patients and professionals in the Swiss Transplant Cohort Study. The project followed 3 steps. 1) Focus group interviews identified patients' (n = 22) research priorities. 2) A nationwide survey assessed and compared the priorities in 292 patients and 175 professionals. 3) Priorities were mapped to the 4 levels of Bronfenbrenner's ecological framework. The 13 research priorities (financial pressure, medication taking, continuity of care, emotional well-being, return to work, trustful relationships, person-centredness, organization of care, exercise and physical fitness, graft functioning, pregnancy, peer contact and public knowledge of transplantation), addressed all framework levels: patient (n = 7), micro (n = 3), meso (n = 2), and macro (n = 1). Comparing each group's top 10 priorities revealed that continuity of care received highest importance rating from both (92.2% patients, 92.5% professionals), with 3 more agreements between the groups. Otherwise, perspectives were more diverse than congruent: Patients emphasized patient level priorities (emotional well-being, graft functioning, return to work), professionals those on the meso level (continuity of care, organization of care). Patients' research priorities highlighted a need to expand research to the micro, meso and macro level. Discrepancies should be recognized to avoid understudying topics that are more important to professionals than to patients
Estimating weights for the active ageing index (AAI) from stated preferences: Proposal for a discrete choice experiment (DCE)
This chapter outlines how Discrete Choice Experiments (DCEs) could be used to estimate alternative weights for the Active Ageing Index (AAI) based on stated preferences. The approach is based on Random Utility Theory and could provide valuable information on marginal substitution rates between AAI indicators and domains. Complementing the current AAI methodology with preference-based weights may also allow assessing preference variation across different social, cultural or geographic contexts. This would help define more targeted active and healthy ageing policies and interventions, incorporate stakeholders’ views in the valuation of policy outcomes and enhance the acceptance of the Index as a tool for policy analysis
A National Survey Comparing Patients' and Transplant Professionals' Research Priorities in the Swiss Transplant Cohort Study.
We aimed to identify, assess, compare and map research priorities of patients and professionals in the Swiss Transplant Cohort Study. The project followed 3 steps. 1) Focus group interviews identified patients' (n = 22) research priorities. 2) A nationwide survey assessed and compared the priorities in 292 patients and 175 professionals. 3) Priorities were mapped to the 4 levels of Bronfenbrenner's ecological framework. The 13 research priorities (financial pressure, medication taking, continuity of care, emotional well-being, return to work, trustful relationships, person-centredness, organization of care, exercise and physical fitness, graft functioning, pregnancy, peer contact and public knowledge of transplantation), addressed all framework levels: patient (n = 7), micro (n = 3), meso (n = 2), and macro (n = 1). Comparing each group's top 10 priorities revealed that continuity of care received highest importance rating from both (92.2% patients, 92.5% professionals), with 3 more agreements between the groups. Otherwise, perspectives were more diverse than congruent: Patients emphasized patient level priorities (emotional well-being, graft functioning, return to work), professionals those on the meso level (continuity of care, organization of care). Patients' research priorities highlighted a need to expand research to the micro, meso and macro level. Discrepancies should be recognized to avoid understudying topics that are more important to professionals than to patients
Chronic stability of a neuroprosthesis comprising multiple adjacent Utah arrays in monkeys
Objective. Electrical stimulation of visual cortex via a neuroprosthesis induces the perception of dots of light ('phosphenes'), potentially allowing recognition of simple shapes even after decades of blindness. However, restoration of functional vision requires large numbers of electrodes, and chronic, clinical implantation of intracortical electrodes in the visual cortex has only been achieved using devices of up to 96 channels. We evaluated the efficacy and stability of a 1024-channel neuroprosthesis system in non-human primates (NHPs) over more than 3 years to assess its suitability for long-term vision restoration. Approach. We implanted 16 microelectrode arrays (Utah arrays) consisting of 8 × 8 electrodes with iridium oxide tips in the primary visual cortex (V1) and visual area 4 (V4) of two sighted macaques. We monitored the animals' health and measured electrode impedances and neuronal signal quality by calculating signal-to-noise ratios of visually driven neuronal activity, peak-to-peak voltages of the waveforms of action potentials, and the number of channels with high-amplitude signals. We delivered cortical microstimulation and determined the minimum current that could be perceived, monitoring the number of channels that successfully yielded phosphenes. We also examined the influence of the implant on a visual task after 2-3 years of implantation and determined the integrity of the brain tissue with a histological analysis 3-3.5 years post-implantation. Main results. The monkeys remained healthy throughout the implantation period and the device retained its mechanical integrity and electrical conductivity. However, we observed decreasing signal quality with time, declining numbers of phosphene-evoking electrodes, decreases in electrode impedances, and impaired performance on a visual task at visual field locations corresponding to implanted cortical regions. Current thresholds increased with time in one of the two animals. The histological analysis revealed encapsulation of arrays and cortical degeneration. Scanning electron microscopy on one array revealed degradation of IrOxcoating and higher impedances for electrodes with broken tips. Significance. Long-term implantation of a high-channel-count device in NHP visual cortex was accompanied by deformation of cortical tissue and decreased stimulation efficacy and signal quality over time. We conclude that improvements in device biocompatibility and/or refinement of implantation techniques are needed before future clinical use is feasible
PARP3 affects the relative contribution of homologous recombination and nonhomologous end-joining pathways
The repair of toxic double-strand breaks (DSB) is critical for the maintenance of genome integrity. The major mechanisms that cope with DSB are: homologous recombination (HR) and classical or alternative nonhomologous end joining (C-NHEJ versus A-EJ). Because these pathways compete for the repair of DSB, the choice of the appropriate repair pathway is pivotal. Among the mechanisms that influence this choice, deoxyribonucleic acid (DNA) end resection plays a critical role by driving cells to HR, while accurate C-NHEJ is suppressed. Furthermore, end resection promotes error-prone A-EJ. Increasing evidence define Poly(ADP-ribose) polymerase 3 (PARP3, also known as ARTD3) as an important player in cellular response to DSB. In this work, we reveal a specific feature of PARP3 that together with Ku80 limits DNA end resection and thereby helps in making the choice between HR and NHEJ pathways. PARP3 interacts with and PARylates Ku70/Ku80. The depletion of PARP3 impairs the recruitment of YFP-Ku80 to laser-induced DNA damage sites and induces an imbalance between BRCA1 and 53BP1. Both events result in compromised accurate C-NHEJ and a concomitant increase in DNA end resection. Nevertheless, HR is significantly reduced upon PARP3 silencing while the enhanced end resection causes mutagenic deletions during A-EJ. As a result, the absence of PARP3 confers hypersensitivity to anti-tumoral drugs generating DSB
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