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Importance: Describing the characteristics and sources of health state utility values and reporting practice in the literature of cost-utility analyses facilitates an understanding of the level of the transparency, validity, and generalizability of cost-utility analyses. Improving the quality of reporting will support investigators in describing the incremental value of emerging glaucoma interventions. Objective: To describe the state of practice among published glaucoma cost-utility analysis studies, focusing on valuation of health and the quality of reporting. Evidence review: We searched several databases including Medline, CINHAL, Embase, Web of Science, Scopus, Biosis previews, the Health Economic Evaluations Database, and the NHS Economic Evaluation Database (NHS EED). We included full-text, English, published cost-utility analyses of glaucoma interventions with quality-adjusted life years (QALYs) as the primary outcome measure to calculate incremental cost-utility ratios. Excluded studies were non-English language, reviews, editorials, protocols, or other types of economic studies (cost–benefit, cost-minimization, cost-effectiveness). Study characteristics, operational definitions of glaucoma health states and health state utilities were extracted. The original source of the health utility was reviewed to determine the scale of measurement and the source of preference weighting. Items from the Systematic Review of Utilities for Cost-Effectiveness (SpRUCE checklist) were used to assess the reporting and quality of health utilities in glaucoma CUA. Findings: 43 CUAs were included, with 11 unique sources of health utilities. A wide range of health utilities for the same Hodapp-Parrish-Anderson glaucoma health states were reported; ocular hypertension (0.84–0.95), mild (0.68–0.94), moderate (0.57–0.92), advanced (0.58–0.88), severe/blind (0.46–0.76), and bilateral blindness (0.26–0.5). Most studies reported the basis for using health utilities (34, 79%) and any assumptions or adjustments applied to the health utilities (22, 51%). Few studies reported a framework for assessing the relevance of health utilities to a decision context (8, 19%). Even fewer (3, 7%) applied a systematic search strategy to identify health utilities and used a structured assessment of quality for inclusion. Overall, reporting has not improved over time. Conclusions and relevance: This review describes that few CUAs describe important rationale for using health state utility values. Including additional details on the search, appraisal, selection, and inclusion process of health utility values improves transparency, generalizability and supports the assessment of the validity of study conclusions. Future investigations should aim to use health utilities on the same scale of measurement across health states and consider the source and relevance to the decision context/purpose of conducting that cost-utility study. [ABSTRACT FROM AUTHOR]

The CuA center is the initial electron acceptor in cytochrome c oxidase, and it consists of two copper ions bridged by two cysteines and ligated by two histidines, a methionine, and a carbonyl in the peptide backbone of a nearby glutamine. The two ligating histidines are of particular interest as they may influence the electronic and redox properties of the metal center. To test for the presence of reactive ligating histidines, a portion of cytochrome c oxidase from the bacteria Thermus thermophilus that contains the CuA site (the TtCuA protein) was treated with the chemical modifier diethyl pyrocarbonate (DEPC) and the reaction followed through UV-visible, circular dichroism, and electron paramagnetic resonance spectroscopies at pH 5.0-9.0. A mutant protein (H40A/H117A) with the non-ligating histidines removed was similarly tested. Introduction of an electron-withdrawing DEPC-modification onto the ligating histidine 157 of TtCuA increased the reduction potential by over 70 mV, as assessed by cyclic voltammetry. Results from both proteins indicate that DEPC reacts with one of the two ligating histidines, modification of a ligating histidine raises the reduction potential of the CuA site, and formation of the DEPC adduct is reversible at room temperature. The existence of the reactive ligating histidine suggests that this residue may play a role in modulating the electronic and redox properties of TtCuA through kinetically-controlled proton exchange with the solvent. Lack of reactivity by the metalloproteins Sco and azurin, both of which contain a mononuclear copper center, indicate that reactivity toward DEPC is not a characteristic of all ligating histidines.

Background: Unguided internet-based cognitive behavioral therapy (ICBT) has been proven effective for major depressive disorder (MDD). However, few studies have examined its cost-effectiveness in low-resource countries and under nonspecialist routine care., Objective: This study aimed to evaluate the short- and long-term cost utility of unguided ICBT compared to a waitlist control for persons with MDD from the perspectives of society and the health care system., Methods: This analysis was implemented alongside an 8-week 2-arm randomized controlled trial with a 12-month follow-up period conducted in Shenzhen, China. Outcomes including cost and health utility were collected at the pretreatment and posttreatment time points and 3, 6, and 12 months after the intervention. Direct medical costs and indirect costs were prospectively collected using the hospital information system and the Sheehan Disability Scale. Health outcomes were measured using the Chinese version of the Short-Form Six-Dimension health index. The primary outcome was incremental cost utility ratio (ICUR) expressed as the difference in costs between 2 therapies by the difference in quality-adjusted life years (QALYs). The seemingly unrelated regression model and the bootstrap method were performed to estimate adjusted ICURs. Cost-effectiveness planes and cost-effectiveness acceptability curves were used to demonstrate uncertainty. A series of scenario analyses were conducted to verify the robustness of base-case results., Results: In total, 244 participants with MDD were randomly allocated to the ICBT (n=122, 50%) or waitlist control (n=122, 50%) groups. At the pretreatment time point, no statistically significant difference was observed in direct medical cost (P=.41), indirect cost (P=.10), or health utility (P=.11) between the 2 groups. In the base-case analysis, the ICBT group reported higher direct medical costs and better quality of life but lower total costs at the posttreatment time point. The adjusted ICURs at the posttreatment time point were CN ¥-194,720.38 (US $-26,551.50; 95% CI CN ¥-198,766.78 to CN ¥-190,673.98 [US $-27,103.20 to US $-25,999.70]) and CN ¥49,700.33 (US $6776.99; 95% CI CN ¥46,626.34-CN ¥52,774.31 [US $6357.83-$7196.15]) per QALY from the societal and health care system perspectives, respectively, with a probability of unguided ICBT being cost-effective of 75.93% and 54.4%, respectively, if the willingness to pay was set at 1 time the per-capita gross domestic product. In the scenario analyses, the probabilities increased to 76.85% and 77.61%, respectively, indicating the potential of ICBT to be cost-effective over the long term., Conclusions: Unguided ICBT is a cost-effective treatment for MDD. This intervention not only helps patients with MDD improve clinically but also generates societal savings. These findings provide health economic evidence for a potential scalable MDD treatment method in low- and middle-income countries., Trial Registration: Chinese Clinical Trial Registry (ChiCTR) ChiCTR2100046425; https://tinyurl.com/bdcrj4zv., (©Wenjing Zhou, Yan Chen, Herui Wu, Hao Zhao, Yanzhi Li, Guangduoji Shi, Wanxin Wang, Yifeng Liu, Yuhua Liao, Huimin Zhang, Caihong Gao, Jiejing Hao, Gia Han Le, Roger S McIntyre, Xue Han, Ciyong Lu. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 19.02.2025.)

Abstract Background In the context of ever-growing health expenditure and limited resources, economic evaluations aid in making evidence-informed policy decisions. Cost-utility analysis (CUA) is often used, and CUA data synthesis is also desirable, but methodological issues are challenged. Hence, we aim to provide a step-by-step process to prepare the CUA data for meta-analysis. Methods Data harmonisation methods were constructed specifically considering CUA methodology, including inconsistent reports, economic parameters, heterogeneity (i.e., country’s income, time horizon, perspective, modelling approaches, currency, willingness to pay). An incremental net benefit (INB) and its variance were estimated and pooled across studies using a basic meta-analysis by COMER. Results Five scenarios show how to obtain INB and variance with various reported data: Study reports the mean and variance (Scenario 1) or 95% confidence interval (Scenario 2) of ΔC, ΔE, and ICER for INB/variance calculations. Scenario 3: ΔC, ΔE, and variances are available, but not for the ICER; a Monte Carlo was used to simulate ΔC and ΔE data, variance and covariance can be then estimated leading INB calculation. Scenario-4: Only the CE plane was available, ΔC and ΔE data can be extracted; means of ΔC, ΔE, and variance/covariance can be estimated accordingly, leading to INB/variance estimates. Scenario-5: Only mean cost/outcomes and ICER are available but not for variance and the CE-plane. A variance INB can be borrowed from other studies which are similar characteristics, including country income, ICERs, intervention-comparator, time period, country region, and model type and inputs (i.e., discounting, time horizon). Conclusion Out data harmonisation and meta-analytic methods should be useful for researchers for the synthesis of economic evidence to aid policymakers in decision making.

La variabilité des apprenants fréquentant les établissements universitaires et l’essor de la formation en ligne en situation de crise sanitaire amènent les enseignants à se questionner sur leurs pratiques. Relativement à l’évaluation des apprentissages, des questions se posent concernant les différentes pratiques visant à réduire les inégalités. Le dispositif de formation présenté dans cet article propose une façon de favoriser des pratiques pédagogiques actives dans un contexte en ligne et de penser l’évaluation de manière inclusive afin de favoriser les apprentissages et une évaluation équitable. Cette étude de cas expose la démarche effectuée dans le cadre d’un cours au cycle supérieur en sciences de l’éducation offert à un groupe de douze étudiants provenant de milieux différents et ayant des expériences éclectiques.

Abstract Background Depressive disorders are associated with a high burden of disease. However, due to the burden posed by the disease on not only the sufferers, but also on their relatives, there is an ongoing debate about which costs to include and, hence, which perspective should be applied. Therefore, the aim of this paper was to examine whether the change between healthcare payer and societal perspective leads to different conclusions of cost-utility analyses in the case of depression. Methods A systematic literature search was conducted to identify economic evaluations of interventions in depression, launched on Medline and the Cost-Effectiveness Registry of the Tufts University using a ten-year time horizon (2008–2018). In a two-stepped screening process, cost-utility studies were selected by means of specified inclusion and exclusion criteria. Subsequently, relevant findings was extracted and, if not fully stated, calculated by the authors of this work. Results Overall, 53 articles with 92 complete economic evaluations, reporting costs from healthcare payer/provider and societal perspective, were identified. More precisely, 22 estimations (24%) changed their results regarding the cost-effectiveness quadrant when the societal perspective was included. Furthermore, 5% of the ICURs resulted in cost-effectiveness regarding the chosen threshold (2% of them became dominant) when societal costs were included. However, another four estimations (4%) showed the opposite result: these interventions were no longer cost-effective after the inclusion of societal costs. Conclusions Summarising the disparities in results and applied methods, the results show that societal costs might alter the conclusions in cost-utility analyses. Hence, the relevance of the perspectives chosen should be taken into account when carrying out an economic evaluation. This systematic review demonstrates that the results of economic evaluations can be affected by different methods available for estimating non-healthcare costs.

Background: In the context of ever-growing health expenditure and limited resources, economic evaluations aid in making evidence-informed policy decisions. Cost-utility analysis (CUA) is often used, and CUA data synthesis is also desirable, but methodological issues are challenged. Hence, we aim to provide a step-by-step process to prepare the CUA data for meta-analysis.Methods: Data harmonisation methods were constructed specifically considering CUA methodology, including inconsistent reports, economic parameters, heterogeneity (i.e., country's income, time horizon, perspective, modelling approaches, currency, willingness to pay). An incremental net benefit (INB) and its variance were estimated and pooled across studies using a basic meta-analysis by COMER.Results: Five scenarios show how to obtain INB and variance with various reported data: Study reports the mean and variance (Scenario 1) or 95% confidence interval (Scenario 2) of ΔC, ΔE, and ICER for INB/variance calculations. Scenario 3: ΔC, ΔE, and variances are available, but not for the ICER; a Monte Carlo was used to simulate ΔC and ΔE data, variance and covariance can be then estimated leading INB calculation. Scenario-4: Only the CE plane was available, ΔC and ΔE data can be extracted; means of ΔC, ΔE, and variance/covariance can be estimated accordingly, leading to INB/variance estimates. Scenario-5: Only mean cost/outcomes and ICER are available but not for variance and the CE-plane. A variance INB can be borrowed from other studies which are similar characteristics, including country income, ICERs, intervention-comparator, time period, country region, and model type and inputs (i.e., discounting, time horizon).Conclusion: Out data harmonisation and meta-analytic methods should be useful for researchers for the synthesis of economic evidence to aid policymakers in decision making. [ABSTRACT FROM AUTHOR]

The purpose of this study was to perform a systematic review to identify cost-analysis studies pertaining to shoulder arthroplasty, provide a comprehensive review of published studies, and critically evaluate the quality of the available literature using the Quality of Health Economic Studies (QHES) instrument. A systematic review of the literature was performed to identify cost analyses examining shoulder arthroplasty. The inclusion criteria included studies pertaining to either shoulder hemiarthroplasty (HA), total shoulder arthroplasty (TSA), or reverse TSA. Articles were excluded based on the following: nonoperative studies, nonclinical studies, studies not based in the United States, and studies in which no cost analysis was performed. The quality of studies was assessed using the QHES instrument. One-sided Fisher exact testing was performed to identify predictors of both low-quality (ie, QHES score < 25th percentile) and high-quality (ie, QHES score > 75th percentile) cost analyses based on items within the QHES checklist. Of the 196 studies screened, 9 were included. Seven studies conducted cost analyses comparing reverse TSA vs. arthroscopic rotator cuff repair, HA, or total hip arthroplasty, and 2 studies examined TSA vs. HA for primary glenohumeral arthritis. The average QHES score among all studies was 86.22 ± 13.39 points. Failure to include an annual cost discounting rate was associated with a low-quality QHES score (P =.03). In addition, including a discussion of the magnitude and direction of potential biases was associated with a high-quality score (P =.03). Shoulder arthroplasty is a cost-effective procedure when used to treat a multitude of shoulder pathologies. The overall quality of cost analysis in shoulder arthroplasty is relatively good, with an average QHES score of 86.22 points. Studies failing to include an annual cost discounting rate are more likely to score below the 25th percentile, whereas those including a discussion of the magnitude and direction of potential biases are more likely to achieve a score in excess of the 75th percentile. [ABSTRACT FROM AUTHOR]

The assembly of the CuA site in Cytochrome c Oxidase (COX) is a critical step for aerobic respiration in COX‐dependent organisms. Several gene products have been associated with the assembly of this copper site, the most conserved of them belonging to the Sco family of proteins, which have been shown to perform different roles in different organisms. Plants express two orthologs of Sco proteins: Hcc1 and Hcc2. Hcc1 is known to be essential for plant development and for COX maturation, but its precise function has not been addressed until now. Here, we report the biochemical, structural and functional characterization of Arabidopsis thaliana Hcc1 protein (here renamed Sco1). We solved the crystal structure of the Cu+1‐bound soluble domain of this protein, revealing a tri coordinated environment involving a CxxxCxnH motif. We show that AtSco1 is able to work as a copper metallochaperone, inserting two Cu+1 ions into the CuA site in a model of CoxII. We also show that AtSco1 does not act as a thiol‐disulfide oxido‐reductase. Overall, this information sheds new light on the biochemistry of Sco proteins, highlighting the diversity of functions among them despite their high structural similarities. Database: PDB entry 6N5U (Crystal structure of Arabidopsis thaliana ScoI with copper bound). [ABSTRACT FROM AUTHOR]

Calciphylaxis, also referred to as calcific uremic arteriolopathy, is a rare and often fatal disorder that is best known for causing cutaneous ischemia and subsequent necrosis due to calcification ot arterial vessels in the underlying dermis and adipose tissue. Although calciphylaxis primarily occurs in patients with end-stage kidney disease who are receiving dialysis, it can also present in patients without endstage kidney disease and in patients who have undergone kidney transplantation and is accordingly termed nonuremic calciphylaxis. Nonuremic calciphylaxis demonstrates pathologic morphology like calcific uremic calciphylaxis and has a similar mortality rate, as high as 52% (Clin J Am So c Nephrol. 2008;3(4); 1139-1143). However, nonuremic calciphylaxis is not as thoroughly detailed as calcificuremic calciphylaxis in the literature, making its diagnosis and management more difficult for providers. Our patient is a 65-year-old Caucasian female w'ho presents to die hospital with encephalopathy stemming from sepsis. Her sepsis originated from infection of chronic ulcers present on her left lower leg due to calciphylaxis. Management of her calciphylaxis is complicated by her co morbidities, and treatment is debated. [ABSTRACT FROM AUTHOR]

The CuA center is the initial electron acceptor in cytochrome c oxidase, and it consists of two copper ions bridged by two cysteines and ligated by two histidines, a methionine, and a carbonyl in the peptide backbone of a nearby glutamine. The two ligating histidines are of particular interest as they may influence the electronic and redox properties of the metal center. To test for the presence of reactive ligating histidines, a portion of cytochrome c oxidase from the bacteria Thermus thermophilus that contains the CuA site (the TtCuA protein) was treated with the chemical modifier diethyl pyrocarbonate (DEPC) and the reaction followed through UV-visible, circular dichroism, and electron paramagnetic resonance spectroscopies at pH 5.0-9.0. A mutant protein (H40A/H117A) with the non-ligating histidines removed was similarly tested. Introduction of an electron-withdrawing DEPC-modification onto the ligating histidine 157 of TtCuA increased the reduction potential by over 70 mV, as assessed by cyclic voltammetry. Results from both proteins indicate that DEPC reacts with one of the two ligating histidines, modification of a ligating histidine raises the reduction potential of the CuA site, and formation of the DEPC adduct is reversible at room temperature. The existence of the reactive ligating histidine suggests that this residue may play a role in modulating the electronic and redox properties of TtCuA through kinetically-controlled proton exchange with the solvent. Lack of reactivity by the metalloproteins Sco and azurin, both of which contain a mononuclear copper center, indicate that reactivity toward DEPC is not a characteristic of all ligating histidines. [ABSTRACT FROM AUTHOR]

Aims: This paper investigates the distributional implications for eight population groups of using six different instruments to measure wellbeing and to prioritise access to health services. Specifically, it examines the importance of different physical and psycho-social problems for the scores obtained using each instrument and whether scores differ because of differences in the concept measured by the instrument or because of the instrument's construction. Methods: Patients with seven chronic conditions and a sample of the 'healthy' public were administered six instruments: two utility instruments; two self-rating scales; a subjective wellbeing instrument and the ICECAP measure of capability. Scores were regressed upon the subscales of the SF-36 and the AQoL-8D. Each instrument's 'problem mix' was measured by the numerical importance of the subscales for the instrument's score and compared with the problem mix of patients constructed from all of the instruments. Results: The apparent importance of different problems varied significantly with the instrument used to assess welfare but not with the chronic conditions. The correspondence between an instrument's problem mix and the patients' problem mix was highly variable. Conclusion: Different instruments give prominence to different physical and psycho-social problems and consequently favour different groups of patients. Budgetary decisions which appear to be based on efficiency criteria such as the cost per quality-adjusted life year (QALY) conceal distributive effects attributable to the instrument used in the analysis. The effects are additional to the ethical questions considered in making an equity–efficiency trade-off as they arise from the measurement of efficiency. [ABSTRACT FROM AUTHOR]

The Sco protein from Thermus thermophilus has previously been shown to perform a disulfide bond reduction in the CuA protein from T. thermophilus, which is a soluble protein engineered from subunit II of cytochrome ba3 oxidase that lacks the transmembrane helix. The native cysteines on TtSco and TtCuA were mutated to serine residues to probe the reactivities of the individual cysteines. Conjugation of TNB to the remaining cysteine in TtCuA and subsequent release upon incubation with the complementary TtSco protein demonstrated the formation of the mixed disulfide intermediate. The cysteine of TtSco that attacks the disulfide bond in the target TtCuA protein was determined to be TtSco Cysteine 49. This cysteine is likely more reactive than Cysteine 53 due to a higher degree of solvent exposure. Removal of the metal binding histidine, His 139, does not change MDI formation. However, altering the arginine adjacent to the reactive cysteine in Sco (Arginine 48) does alter the formation of the MDI. Binding of Cu2+ or Cu+ to TtSco prior to reaction with TtCuA was found to preclude formation of the mixed disulfide intermediate. These results shed light on a mechanism of disulfide bond reduction by the TtSco protein and may point to a possible role of metal binding in regulating the activity. Importance The function of Sco is at the center of many studies. The disulfide bond reduction in CuA by Sco is investigated herein and the effect of metal ions on the ability to reduce and form a mixed disulfide intermediate are also probed. [ABSTRACT FROM AUTHOR]

Objectives: To test the hypothesis that the "severity effect"-the preference for more than utility-maximizing expenditure on severe health states-may be the result of, or exacerbated by, the uncertainty associated with the chance of contracting the illness that causes the severe health state.Methods: Survey respondents were asked to imagine that they will contract one of two illnesses and asked to allocate a budget between two insurance policies, each of which provides services for the treatment of one of the illnesses. A person's final health state varied with the amount of insurance purchased for the illness that occurred and therefore with the level of treatment. The relative cost of the two policies was altered and the selected levels of insurance compared with the levels that would be provided by a health authority that sought to maximize total utility or quality-adjusted life-years from its own budget.Results: Respondents selected more than utility-maximizing insurance for protection against severe health states. A number of psychological factors that affect measurement under uncertainty do not affect utility as currently measured. This difference may explain the present results and also explain the "severity paradox" that personal preferences as presently measured imply less expenditure on severe health states than do "social preferences" for the treatment of strangers.Conclusions: Uncertainty alters preferences. Incorporating these preferences in decision making would result in greater spending on severe health states. [ABSTRACT FROM AUTHOR]

Introduction Calciphylaxis is a rare condition including patchy dermal necrosis that mostly affects chronic hemodialysis patients. The syndrome usually heralds impending death although patients may survive following a set of measures including an adapted dialysis regimen. The present case is a unique patient who recovered from an earlier episode of upper leg calciphylaxis 5 years previously but developed fatal bilateral breast necrosis. Presentation of case A 69 year old Caucasian woman with a history of atrial fibrillation, hypertension, CVA, hyperparathyroidectomy for secondary hyperparathyroidism and end stage renal disease with hemodialysis recovered in 2012 from extensive symptomatic left upper leg necrosis due to calciphylaxis. In 2017, she developed painful, necrotic ulcers on both breasts, again due to calciphylaxis. She had no history of anticoagulants use but she did use prednisolone 5mg/day. She received adequate wound care, pain medication, antibiotics and dialysis frequency was increased with an addition of sodium thiosulfate. A bilateral ablation was discussed but she decided to stop all treatment following pulmonary aspiration and passed away one week later. Discussion C alciphylaxis is a rare diagnosis that should be considered in patients with renal insufficiency developing painful patches of skin necrosis. Conclusion A multidisciplinary treatment approach including hyperparathyroidectomy, modified hemodialysis and wound treatment is recommended. There is limited evidence for surgical intervention. [ABSTRACT FROM AUTHOR]

The paper concerns with mutual interconnection of goals of municipal development concepts and methods of their assessment. Based on grant policy of selected municipalities (regions, communities) and on the principles of program financing, a specific method of evaluation performance is suggested, which enables to evaluate closer control of sport development, visions, proclaimed goals and sport support programs. The principle of the proposed procedure is based on the use of indicators and methods: CEA, CBA, CUA and CMA in program financing of sport - a field where it is not possible to calculate only direct economic results but it is necessary to consider the impact of externalities (benefits). The authors suggest procedures, which lead to a higher level of control, transparency and efficiency of public spending in the municipal sphere. The goal of this contribution is to point out possible means of assessing grant proposals, as a support tool for decision-making and subsequent control.

Objectives: (i) to demonstrate a method which ameliorates the problem of self-selection in the estimation of population norms from web-based data and (ii) to use the method to calculate population norms for two multi-attribute utility (MAU) instruments, the AQoL-6D and AQoL-8D, and population norms for the sub-scales from which they are constructed.Methods: A web-based survey administered the AQoL-8D MAU instrument (which subsumes the AQoL-6D questionnaire), to members of the public along with the AQoL-4D which has extant population norms. Age, gender and the AQoL-4D were used as post-stratification auxiliary variables to construct weights to ameliorate the potential effects of self-selection associated with web-based surveys. The weights were used to estimate unbiased population norms. Standard errors from the weighted samples were calculated using Jackknife estimation.Results: For both AQoL-6D and AQoL-8D, physical health dimensions decline significantly with age. In contrast, for the majority of the psycho-social dimensions there is a significant U-shaped profile. The net effect is a shallow U-shaped relationship between age and both the AQoL-6D and AQoL-8D utilities. This contrasts with the almost monotonic decline in the utilities derived from the AQoL-4D and SF-6D MAU instruments.Conclusions: Post-stratification weights were used to ameliorate potential bias in the derivation of norms from web-based data for the AQoL-6D and AQoL-8D. The methods may be used generally to obtain norms when suitable auxiliary variables are available. The inclusion of an enlarged psycho-social component in the two instruments significantly alters the demographic profile. [ABSTRACT FROM AUTHOR]

Background: This is an incident series of five dialysis patients with late-diagnosed calcific uraemic arteriolophathy (CUA), severe uncontrolled hyperparathyroidism and infected skin ulcerations. Methods: A multimodal intervention was based on wound care, antibiotics, surgical debridement, sodium thiosulphate and cinacalcet and associated with regression of skin disease in four cases after varying treatment time periods ranging from 4 to 33 months. Methods: A multimodal intervention was based on wound care, antibiotics, surgical debridement, sodium thiosulphate and cinacalcet and associated with regression of skin disease in four cases after varying treatment time periods ranging from 4 to 33 months. Conclusions: This series contributes to the build-up of case series reporting on the treatment of CUA, and will hopefully serve as a basis ofwell-conceived comparative effectiveness studies investigating the value of the combined interventions applied so far in this severe condition. [ABSTRACT FROM AUTHOR]

Abstract: In this overview we present recent combined electrochemical, spectroelectrochemical, spectroscopic and computational studies from our group on the electron transfer reactions of cytochrome c and of the primary electron acceptor of cytochrome c oxidase, the CuA site, in biomimetic complexes. Based on these results, we discuss how protein dynamics and thermal fluctuations may impact on protein ET reactions, comment on the possible physiological relevance of these results, and finally propose a regulatory mechanism that may operate in the Cyt/CcO electron transfer reaction in vivo. This article is part of a Special Issue entitled: 18th European Bioenergetic Conference. [Copyright &y& Elsevier]

Introduction: Hearth disease is a major worldwide health problem with high incidence and prevalence in developed countries and rising incidence in developing countries. During last ten years, almost 20% of all acute hospital admissions are cardiac-related. More than 25,000 bypass procedures, about 40,000 angioplasty, and other coronary intervention procedures are carried out annually in the UK. CHD burdens the UK economy by £7.06 billion. Methods: Economic evaluation involves three basic steps of cost identification, cost valuation and cost measurement. The most accepted perspective is societal. Patient data are extracted from the patient file record or patients’ questionnaire or interview. Both quantitative and qualitative analyses are used. Discussion: Management is important clinically and from the economics viewpoint (e.g.; individuals and society) must be considered. CHD management is becoming increasingly costly. Direct and indirect costs divert scarce resources (patient’s or family and society) to medical care. Economic evaluation assesses the value of heart management in terms of their expected costs and expected benefits, if it includes an analysis of all direct and indirect cost and also all benefits forgone. Increasingly technical solutions are deployed and consideration must be given to which would better meet health sector objectives. Health care expectations: The basic principle is simple- comprehensive, high quality medical care should be available to all without financial barriers to access. However, in the face of increasing costs and ever more patients, this is under threat. In addition, sometimes, populations in greatest need are those least likely to receive it. It is expected economic evaluation aid to define choices on how best to use resources. The current distribution of resources leaves some high- priority demands unmet. The challenge of meeting the demand free public services is increasing. Demand for CHD treatment is undoubtedly rising. Rationing and allocation choice: Resource allocation strategies are designed to manage different areas of NHS effectively. There are several approaches to rationing however; there are moral considerations that ought to be recognised. Currently, rationing is according to a range of criteria that seem challenging. With scarce resources, it is important that services be provided efficiently. Efficiency within the NHS involved improving both productive efficiency and allocative efficiency. Equity in healthcare has become a priority. Willingness to pay (WTP): By evaluating WTP, patients’ preferences can be taken into account though there are difficulties in comparing user (patient) values with non-user (non-patient) values. There are also moral issues regarding the use of only economics data in decision-making. Moreover, there is need and preference conflict and requires to be managed appropriately. Conclusion: CHD growth in both developed and developing countries put health systems faced on greater demand to appropriate care. Thus, the notion of economic evaluation is to help health professional to divert resources to achieve the best health outcomes for individuals. There is an urgent need to develop preventive strategies in developing countries. Prevention and treatment strategies in developed countries should be modified for developing countries. These strategies should include approaches to prevent the development of risk factors in the population as a whole by changes in public policy as well as approaches that can be applied to high-risk individuals.

Abstract: Highly covalent copper-thiolate bonds are salient features of ubiquitous type 1 (T1) blue copper and purple CuA electron transfer (ET) centers in proteins. These centers are found in a wide variety of proteins, each having its own electron transfer partners, requiring the centers to possess a broad range of reduction potentials to match those of their redox partners and to perform ET functions under various driving forces, all while maintaining high ET efficiency. Unraveling the secrets of the success realized by these ET centers has relied upon the expertise of many scientific disciplines and sub-disciplines, including inorganic chemistry, microbiology, biochemistry, and biophysical chemistry. Here, we review the contribution of protein engineering approaches—namely, the incorporation of unnatural amino acids and a biosynthetic CuA cofactor into the T1 copper protein azurin—to advancing the current understanding of how the unique structures of T1 copper and CuA centers confer their proteins with efficient and tailored ET properties. [Copyright &y& Elsevier]

Abstract: Empirical evidence indicates that people consider sharing health resources to be important even in the absence of the attributes usually associated with equity (age, social class, ethnicity, disease severity or geographic location). If government is to take account of these preferences then survey methods are needed which allow their measurement. The present paper presents a new technique for measuring these preferences and reports the results of a representative survey of 626 Australians which employed the technique. The online and postal survey did not include any of the attributes usually associated with equity but was designed to quantify the respective importance of sharing life years (outcome egalitarianism), resource sharing per se and the changing importance of total health as other attributes varied. Results indicate respondents were primarily concerned with outcome egalitarianism, and that cost per life year had a relatively small effect upon their allocative decisions. [Copyright &y& Elsevier]

Abstract: The α proteobacter Rhodobacter sphaeroides accumulates two cytochrome c oxidases (CcO) in its cytoplasmic membrane during aerobic growth: a mitochondrial-like aa 3-type CcO containing a di-copper CuA center and mono-copper CuB, plus a cbb 3-type CcO that contains CuB but lacks CuA. Three copper chaperones are located in the periplasm of R. sphaeroides, PCuAC, PrrC (Sco) and Cox11. Cox11 is required to assemble CuB of the aa 3-type but not the cbb 3-type CcO. PrrC is homologous to mitochondrial Sco1; Sco proteins are implicated in CuA assembly in mitochondria and bacteria, and with CuB assembly of the cbb 3-type CcO. PCuAC is present in many bacteria, but not mitochondria. PCuAC of Thermus thermophilus metallates a CuA center in vitro, but its in vivo function has not been explored. Here, the extent of copper center assembly in the aa 3- and cbb 3-type CcOs of R. sphaeroides has been examined in strains lacking PCuAC, PrrC, or both. The absence of either chaperone strongly lowers the accumulation of both CcOs in the cells grown in low concentrations of Cu2+. The absence of PrrC has a greater effect than the absence of PCuAC and PCuAC appears to function upstream of PrrC. Analysis of purified aa 3-type CcO shows that PrrC has a greater effect on the assembly of its CuA than does PCuAC, and both chaperones have a lesser but significant effect on the assembly of its CuB even though Cox11 is present. Scenarios for the cellular roles of PCuAC and PrrC are considered. The results are most consistent with a role for PrrC in the capture and delivery of copper to CuA of the aa 3-type CcO and to CuB of the cbb 3-type CcO, while the predominant role of PCuAC may be to capture and deliver copper to PrrC and Cox11. This article is part of a Special Issue entitled: Biogenesis/Assembly of Respiratory Enzyme Complexes. [Copyright &y& Elsevier]

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Coherent Raman detected electron spin resonance spectroscopy is a technique that bridges the established fields of magnetic resonance and magneto-optics. By exploiting the orientational selectivity of the microwave resonance condition it becomes possible to measure the relative orientations of the magnetic and optical anisotropies of paramagnetic chromophores, and thereby to test models of their electronic structure. This paper reports the application of this method to the CuA centre from Paracoccus pantotrophus nitrous oxide reductase, an unusual mixed valence copper, Cu(I)/Cu(II), dimer centre also found in some heme-copper terminal oxidases. Data from the principal visible bands (at 476, 514 and 750 nm) shows that their magnetic circular dichroism is almost entirely aligned with the g-value z-axis. This is consistent with previous models of the electronic structure in which the optical transitions are polarized within the copper-thiolate plane of the centre, and the g-value z-axis is orientated normal to this plane. [ABSTRACT FROM AUTHOR]

An ensemble of structural models of the adduct between cytochrome c and cytochrome c oxidase from Paracoccus denitrificans has been calculated based on the experimental data from site-directed mutagenesis and NMR experiments that have accumulated over the last years of research on this system. The residues from each protein that are at the protein–protein interface have been identified by the above experimental work, and this information has been converted in a series of restraints explicitly used in calculations. It is found that a single static structural model cannot satisfy all experimental data simultaneously. Therefore, it is proposed that the adduct exists as a dynamic ensemble of different orientations in equilibrium, and may be represented by a combination or average of the various limiting conformations calculated here. The equilibrium involves both conformations that are competent for electron transfer and conformations that are not. Long-range recognition of the partners is driven by non-specific electrostatic interactions, while at shorter distances hydrophobic contacts tune the reciprocal orientation. Electron transfer from cytochrome bc 1 to cytochrome c oxidase is mediated through cytochrome c experiencing multiple encounters with both of its partners, only part of which are productive. The number of encounters, and thus the electron transfer rate, may be increased by the formation of a cytochrome bc 1–cytochrome c oxidase supercomplex and/or (in human) by increasing the concentration of the two enzymes in the membrane space. [ABSTRACT FROM AUTHOR]

Abstract: Cytochrome caa 3 from Bacillus subtilis is a member of the heme-copper oxidase family of integral membrane enzymes that includes mitochondrial cytochrome c oxidase. Subunit II of cytochrome caa 3 has an extra 100 amino acids at its C-terminus, relative to its mitochondrial counterpart, and this extension encodes a heme C binding domain. Cytochrome caa 3 has many of the properties of the complex formed between mitochondrial cytochrome c and mitochondrial cytochrome c oxidase. To examine more closely the interaction between cytochrome c and the oxidase we have cloned and expressed the CuA-cytochrome c portion of subunit II from the cytochrome caa 3 complex of B. subtilis. We are able to express about 2000nmol, equivalent to 65mg, of the CuA-cytochrome c protein per litre of Escherichia coli culture. About 500nmol is correctly targeted to the periplasmic space and we purify 50% of that by a combination of affinity chromatography and ammonium sulfate fractionation. The cytochrome c containing sub-domain is well-folded with a stable environment around the heme C center, as its mid-point potential and rates of reduction are indistinguishable from values for the cytochrome c domain of the holo-enzyme. However, the CuA site lacks copper leading to an inherent instability in this sub-domain. Expression of B. subtilis cytochrome c, as exemplified by the CuA-cytochrome c protein, can be achieved in E. coli, and we conclude that the cytochrome c and CuA sub-domains behave independently despite their close physical and functional association. [Copyright &y& Elsevier]

Cost-utility analysis is a form of cost-effectiveness analysis in which outcomes are adjusted for quality and quantity of life. This type of analysis is used widely in Europe and is being used increasingly in the United States. This article provides an overview of cost utility analysis and quality adjusted life years, a commonly used effectiveness measure in CUA when comparing two or more treatments or interventions. [ABSTRACT FROM AUTHOR]

The ligand K-edge probes the ligand 1s → valence np transitions. These transitions acquire intensity when the ligand is bound to an open shell metal ion. This intensity quantifies the amount of ligand character in the metal d orbitals, hence the covalency of the ligand–metal bond. In this review the methodology is developed and applied to copper proteins, iron–sulfur sites and nickel dithiolene complexes, as examples. These illustrate the power and impact of this method in evaluating covalency contributions to electron transfer pathways, reduction potentials, H-bond interactions, electron delocalization in mixed-valent systems and small molecule reactivity. [Copyright &y& Elsevier]

Abstract Rationale, aims and objectives The objective was to test whether individuals’ responses to standard gamble (SG) and visual analogue scale (VAS) questions do not depend on the time horizon of the health scenario presented. Methods Face-to-face interviews were conducted in a convenience sample of 18 women aged 22–50 years with no history of breast cancer or cancer requiring chemotherapy. Data were collected from March 2000 to June 2000 at a university in the Midwest of the United States of America. Preference weights were estimated using SG top-down titration method and VAS scaled from zero (death) to one (perfect health). Subjects were asked to rate their preferences if faced with two scenarios: post-chemotherapy nausea and vomiting (PCNV) occurring for 3 days (scenario 1), and PCNV lasting for the rest of their lives (scenario 2). Three PCNV health states of varying severity were tested: complete alleviation, partial alleviation, and no alleviation. Results Paired-t -test analysis showed statistically significantly lower preference weights (P < 0.05) when the health state was for the rest of the respondent's life vs. 3 days. Mean SG weights for scenario 1 vs. scenario 2 were: 0.968 vs. 0.927 (complete alleviation), 0.942 vs. 0.810 (partial alleviation) and 0.866 vs. 0.644 (no alleviation). Mean VAS weights for scenario 1 vs. scenario 2 were: 0.741 vs. 0.676 (complete alleviation), 0.490 vs. 0.307 (partial alleviation) and 0.276 vs. 0.136 (no alleviation). Discussion and conclusions For the majority of respondents the utility independence assumption for SG and VAS did not hold. Similar to Bala et al. , the results of this study indicated that preference weights as measured by SG and VAS techniques were not ‘timeless’. Regardless of the preference measure used, both SG and VAS yielded higher scores when PCNV lasted for a shorter period of time. [ABSTRACT FROM AUTHOR]

Abstract Rationale, aims and objectives The objective was to test whether individuals’ responses to standard gamble (SG) and visual analogue scale (VAS) questions do not depend on the time horizon of the health scenario presented. Methods Face-to-face interviews were conducted in a convenience sample of 18 women aged 22–50 years with no history of breast cancer or cancer requiring chemotherapy. Data were collected from March 2000 to June 2000 at a university in the Midwest of the United States of America. Preference weights were estimated using SG top-down titration method and VAS scaled from zero (death) to one (perfect health). Subjects were asked to rate their preferences if faced with two scenarios: post-chemotherapy nausea and vomiting (PCNV) occurring for 3 days (scenario 1), and PCNV lasting for the rest of their lives (scenario 2). Three PCNV health states of varying severity were tested: complete alleviation, partial alleviation, and no alleviation. Results Paired-t -test analysis showed statistically significantly lower preference weights (P < 0.05) when the health state was for the rest of the respondent's life vs. 3 days. Mean SG weights for scenario 1 vs. scenario 2 were: 0.968 vs. 0.927 (complete alleviation), 0.942 vs. 0.810 (partial alleviation) and 0.866 vs. 0.644 (no alleviation). Mean VAS weights for scenario 1 vs. scenario 2 were: 0.741 vs. 0.676 (complete alleviation), 0.490 vs. 0.307 (partial alleviation) and 0.276 vs. 0.136 (no alleviation). Discussion and conclusions For the majority of respondents the utility independence assumption for SG and VAS did not hold. Similar to Bala et al. , the results of this study indicated that preference weights as measured by SG and VAS techniques were not ‘timeless’. Regardless of the preference measure used, both SG and VAS yielded higher scores when PCNV lasted for a shorter period of time. [ABSTRACT FROM AUTHOR]

This paper shows that when quality adjustment factors for use in constructing QALY indices are established through answers to standard-gamble questions or similar methods, the assumptions that are made by respondents about the financial consequences of changing probabilities of illness and death are critically important for the use of QALYs in cost-utility analysis (CUA). It qualifies Meltzer's [Journal of Health Economics 16 (1997) 33] result that the cost per quality-adjusted life-year (QALY) for life-saving medical interventions should include the future consumption of those who would otherwise not have survived, by showing that its validity depends on how the QALY index has been established. The paper also shows that, contrary to a widely held notion, allocation of a fixed health care budget through CUA does not generally result in a second-best efficient allocation. Another finding is that failure to specify carefully what respondents to standard-gamble questions are supposed to assume about the financial consequences of ill health may result in a bias against providing care to older individuals. [ABSTRACT FROM AUTHOR]

The branched respiratory chain of the archaeon Sulfolobus acidocaldarius contains a supercomplex, SoxM, consisting of a bc1-like subcomplex and a terminal oxidase moiety, including a subunit II analogous polypeptide, SoxH. However, the latter component has never been identified in preparations of SoxM. We demonstrate the presence of an mRNA transcript by Northern analysis. We succeeded in cloning and expressing the respective gene with truncated N-terminus by deleting a 20 AS membrane anchor, which resulted in a water-soluble purple copper protein, which was further characterized. The recombinant subunit II of the SoxM complex contains a correctly inserted binuclear CuA cluster as revealed by UV/vis and EPR spectroscopy. The protein is highly thermostable and displays a redox potential of +237 mV. In recombinant form, the metal interacts with cytochrome c as an artificial electron donor; the physiological electron donor is still unknown, since S. acidocaldarius does not contain any c-type cytochromes. The purple copper center of SoxM shows an interesting pH dependency with a pKa at 6.4, suggesting protonation of the Cu-ligating histidines. Further lowering the pH causes a reversible transition into another cluster form with concomitant liberation of one copper. It may thus provide a model for the study of cluster rearrangements in response to pH. [ABSTRACT FROM AUTHOR]

To probe the location of the quinol oxidation site and physical interactions for inter-subunit electron transfer, we constructed and characterized two chimerlc oxidases in which subunit II (CyoA) of cytochrome bo-type ubiquinol oxidase from Escherichia coli was replaced with the counterpart (CaaA) of caa3 -type cytochrome c oxidase from thermo-philic Bacillus PS3. In pHNchi5, the C-terminal hydrophilic domain except a connecting region as to transmembrane helix II of CyoA was replaced with the counterpart of CaaA, which carries the CuA site and cytochrome c domain. The resultant chimeric oxidase was detected immunochemically and spectroscopically, and the turnover numbers for Q1H2 (ubiquinol-1) and TMPD ( N, N, N', N'-tetramethyl-p-phenylenediamine) oxidation were 28 and 8.5 s-1, respectively. In pHNchi6, the chimeric oxidase was designed to carry a minimal region of the cupredoxin fold containing all the CuA ligands, and showed enzymatic activities of 65 and 5.1 s-1 and an expression level better than that of pHNchi6. Kinetic analyses proved that the apparent lower turnover of the chimeric enzyme by pHNchiB was due to the higher Km of the enzyme for Q1H2 (220 μM) than that of cytochrome bo (48 μM), while in the enzyme by pHNchi5, both substrate-binding and internal electron transfer were purturbed. These results suggest that the connecting region and the C-terminal a1-a2-β11 - a3 domain of CyoA are involved in the quinol oxidation and/or physical interactions for inter-subunit electron transfer, supporting our previous proposal [Sato-Watanabe, M., Mogi, T., Miyoshi, H., and Anraku, Y. (1998) Biochemistry 37, 12744–12752]. The close relationship of E. coli quinol oxidases to cytochrome c oxidase of Gram-positive bacteria like Bacillus was also indicated. [ABSTRACT FROM AUTHOR]

CW ENDOR (X-band) spectra for the purple mixed-valence [Cu(1.5+)...Cu(1.5+)], S = 1/2, CuA site in nitrous oxide reductase were obtained after insertion of 65Cu or both 65Cu and 15N-histidine. The 14N/15N isotopic substitution allowed for an unambiguous deconvolution of proton and nitrogen hyperfine couplings in the spectra. A single nitrogen coupling with a value of 12.9 ± 0.4 MHz for 14N was detected. Its anisotropy was characteristic for imidazole bound to copper. A spin density of 3–5% was estimated for the nitrogen donors to CuA, indicating that the ground state is 2B3u. Proton hyperfine structure was detected from four Cβ protons of coordinating cysteine residues. Their isotropic and anisotropic parts were deconvoluted by spectral simulation. From the anisotropic couplings a spin density of 16–24% was estimated for each of the cysteine thiolate donors of CuA. The [NHisCu(RS)2CuNHis]+ core structure of CuA in nitrous oxide reductase from Pseudomonas stutzeri is predicted to be similar to the crystallographically determined CuA* structure (Wilmanns M, Lappalainen P, Kelly M, Sauer-Eriksson E, Saraste M (1995) Proc Natl Acad Sci USA 92 : 11955–11959), but distinct from the CuA structure of Paracoccus denitrificans cytochrome c oxidase (Iwata S, Ostermeier C, Ludwig B, Michel H (1995) Nature 376 : 660–669). The angular dependence of the isotropic couplings as a function of the electronic ground state was calculated by the INDO/S method. The Mulliken atomic-spin populations calculated by a gradient-corrected density functional method and the semiempirical INDO/S method were compared with experimentally derived spin populations, and good agreement between theory and experiment was found for both calculations. The ground state of CuA is best represented by the resonance structures of the form [CuIS–S–CuII↔ CuIS•S–CuI↔ CuIS–S•CuI↔ CuIIS–S–CuI]. It is proposed that the Cu 4s,p as well as sulfur 3d orbitals play a role in the stabilization of this novel type of cluster. [ABSTRACT FROM AUTHOR]