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Previous systematic literature reviews of rotavirus genotype circulation in Europe and the Middle East are limited because they do not include country-specific prevalence data. This study documents country-specific evidence on the prevalence of rotavirus genotypes in Europe and the Middle East to enable more precise epidemiological modeling and contribute to the evidence-base about circulating rotavirus genotypes in the post-vaccination era. This study systematically searched PubMed, Embase and Scopus for all empirical epidemiological studies that presented genotype-specific surveillance data for countries in Europe and the Middle East published between 2006 and 2021. The STROBE checklist was used to assess the quality of included studies. Proportional meta-analysis was conducted using the generic inverse variance method with arcsine transformation and generalized linear-mixed models to summarize genotype prevalence. Our analysis estimated the genotype prevalence by country across three date categories corresponding with rotavirus seasons: 2006-2010, 2011-2015, 2016-2021. A total of 7601 deduplicated papers were identified of which 88 studies were included in the final review. Rotavirus genotypes exhibited significant variability across regions and time periods, with G1P[8], G2P[4], G3P[8], G4P[8], G9P[8], and, to a lesser extent G12P[8], being the most prevalent genotypes through different regions and time-periods. Uncommon genotypes included G3P[9] in Poland, G2P[6] in Iraq, G4P[4] in Qatar, and G9P[4] as reported by the European Rotavirus Network. There was high genotype diversity with routinely identified genotypes being G1P[8], G2P[4], G3P[8], G4P[8], and G9P[8]; there was high variability across time periods and regions. Continued surveillance at the national and regional levels is relevant to support further research and inform public health decision-making.

The regulation of mark-ups throughout the pharmaceutical supply and distribution chain may be a valuable approach to control prices of medicines and to achieve broader access to medicines. As part of a wider review, we aimed to systematically determine whether policies regulating mark-ups are effective in managing the prices of pharmaceutical products. We searched for studies published between January 1, 2004 and October 10, 2019, comparing policies on regulating mark-ups against other interventions or a counterfactual. Eligible study designs included randomized trials, and non-randomized or quasi-experimental studies such as interrupted time-series (ITS), repeated measures (RM), and controlled before-after studies. Studies were eligible if they included at least one of the following outcomes: price (or expenditure as a proxy for price and volume), volume, availability or affordability of pharmaceutical products. The quality of the evidence was assessed using the GRADE methodology. A total of 32,011 records were retrieved, seven of which were eligible for inclusion for this review. The limited body of evidence cautiously suggests that policies regulating mark-ups may be effective in reducing medicine prices and pharmaceutical expenditures. However, the design of mark-up regulations is a critical factor for their potential success. Additional research is required to confirm the effects of these policies on the availability, affordability or usage patterns of medicines and in low- and middle-income countries., Competing Interests: Declaration of Competing Interest This systematic review was commissioned and funded by the World Health Organization., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: This systematic review presents cost-effectiveness studies of rotavirus vaccination in high-income settings based on dynamic transmission modelling to inform policy decisions about implementing rotavirus vaccination programmes., Methods: We searched CEA Registry, MEDLINE, Embase, Health Technology Assessment Database, Scopus, and the National Health Service Economic Evaluation Database for studies published since 2002. Full economic evaluation studies based on dynamic transmission models, focusing on high-income countries, live oral rotavirus vaccine and children ≤ 5 years of age were eligible for inclusion. Included studies were appraised for quality and risk of bias using the Consensus on Health Economic Criteria (CHEC) list and the Philips checklist. The review protocol was prospectively registered with PROSPERO (CRD42020208406)., Results: A total of four economic evaluations were identified. Study settings included England and Wales, France, Norway, and the United States. All studies compared either pentavalent or monovalent rotavirus vaccines to no intervention. All studies were cost-utility analyses that reported incremental cost per quality-adjusted life year (QALY) gained. Included studies consistently concluded that rotavirus vaccination is cost-effective compared with no vaccination relative to the respective country's willingness to pay threshold when herd protection benefits are incorporated in the modelling framework., Conclusions: Rotavirus vaccination was found to be cost-effective in all identified studies that used dynamic transmission models in high-income settings where child mortality rates due to rotavirus gastroenteritis are close to zero. Previous systematic reviews of economic evaluations considered mostly static models and had less conclusive findings than the current study. This review suggests that modelling choices influence cost-effectiveness results for rotavirus vaccination. Specifically, the review suggests that dynamic transmission models are more likely to account for the full impact of rotavirus vaccination than static models in cost-effectiveness analyses., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Merck Sharp & Dohme LLC., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Robust evidence from health policy research has the potential to inform policy-making, but studies have suggested that methodological shortcomings are abundant. We aimed to identify common methodological weaknesses in pharmaceutical pricing policy analyses. A systematic review (SR) of studies examining pharmaceutical pricing policies served as basis for the present analysis. We selected all studies that were included in the SR (n = 56), and those that were excluded from the SR due to ineligible study designs only (n = 101). Risk of bias was assessed and specific study design issues were recorded to identify recurrent methodological issues. Sixty-one percent of studies with a study design eligible for the SR presented with a high risk of bias in at least one domain. Potential interference of co-interventions was a source of possible bias in 53% of interrupted time series studies. Failing to consider potential confounders was the primary cause for potential bias in difference-in-differences, regression, and panel data analyses. In 101 studies with a study design not eligible for the SR, 32% were uncontrolled before-after studies and 23% were studies without pre-intervention data. Some of the methodological issues encountered may be resolved during the design of a study. Awareness among researchers on methodological issues will help improve the rigor of health policy research in general., Competing Interests: Declaration of Competing Interest The authors report receiving funding from the World Health Organization for performing a systematic literature review on ten pharmaceutical pricing policies, which served as primary data source for the present work., (Copyright © 2022. Published by Elsevier B.V.)

Policies promoting price transparency may be an important approach to control medicine prices and achieve better access to medicines. As part of a wider review, we aimed to systematically determine whether policies promoting price transparency are effective in managing the prices of pharmaceutical products. We searched for studies published between January 1, 2004 and October 10, 2019, comparing policies promoting price transparency against other interventions or a counterfactual. Eligible study designs included randomized trials, and non-randomized or quasi-experimental studies such as interrupted time-series (ITS), repeated measures (RM), and controlled before-after studies. Studies were eligible if they included at least one of the following outcomes: price (or expenditure as a proxy for price and volume), volume, availability or affordability of pharmaceutical products. The quality of the evidence was assessed using the GRADE methodology. A total of 32011 records were retrieved, two of which were eligible for inclusion. Although based on evidence from a single study, public disclosure of medicine prices may be effective in reducing prices of medicines short-term, with benefits possibly sustained long-term. Evidence on the impact of a cost-feedback approach to prescribers was inconclusive. No evidence was found for impact on the outcomes volume, availability or affordability. The overall lack of evidence on policies promoting price transparency is a clear call for further research., Competing Interests: Declaration of Competing Interest This systematic review was commissioned and funded by the World Health Organization., (Copyright © 2022. Published by Elsevier B.V.)

Background: Female genital mutilation (FGM) is a traditional harmful practice affecting 200 million women and girls globally. Health complications of FGM occur immediately and over time, and are associated with healthcare costs that are poorly understood. Quantifying the global FGM-related burden is essential for supporting programmes and policies for prevention and mitigation., Methods: Health complications of FGM are derived from a meta-analysis and stratified by acute, uro-gynaecological, obstetric and psychological/sexual. Treatment costs are calculated from national cohort models of 27 high-burden countries over 30 years. Savings associated with full/partial abandonment are compared with a current incidence reference scenario, assuming no changes in FGM practices., Results: Our model projects an increasing burden of FGM due to population growth. As a reference scenario assuming no change in practices, prevalent cases in 27 countries will rise from 119.4 million (2018) to 205.8 million (2047). Full abandonment could reduce this to 80.0 million (2047), while partial abandonment is insufficient to reduce cases. Current incidence economic burden is US$1.4 billion/year, rising to US$2.1 billion/year in 2047. Full abandonment would reduce the future burden to US$0.8 billion/year by 2047., Conclusion: FGM is a human rights violation, a public health issue and a substantial economic burden that can be avoided through effective prevention strategies. While decreasing trends are observed in some countries, these trends are variable and not consistently observed across settings. Additional resources are needed to prevent FGM to avoid human suffering and growing costs. The findings of this study warrant increased political commitment and investment in the abandonment of FGM., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: To address the growing prevalence of hearing loss, WHO has identified a compendium of key evidence-based ear and hearing care interventions to be included within countries' universal health coverage packages. To assess the cost-effectiveness of these interventions and their budgetary effect for countries, we aimed to analyse the investment required to scale up services from baseline to recommended levels, and the return to society for every US$1 invested in the compendium., Methods: We did a modelling study using the proposed set of WHO interventions (summarised under the acronym HEAR: hearing screening and intervention for newborn babies and infants, pre-school and school-age children, older adults, and adults at higher risk of hearing loss; ear disease prevention and management; access to technologies such as hearing aids, cochlear implants, or hearing assistive technologies; and rehabilitation service provision), which span the life course and include screening and management of hearing loss and related ear diseases, costs and benefits for the national population cohorts of 172 countries. The return on investment was analysed for the period between 2020 and 2030 using three scenarios: a business-as-usual scenario, a progress scenario with a scale-up to 50% of recommended coverage, and an ambitious scenario with scale-up to 90% of recommended coverage. Using data for hearing loss burden from the Global Burden of Disease Study 2019, a transition model with three states (general population, diagnosed, and those who have died) was developed to model the national populations in countries. For the return-on-investment analysis, the monetary value of disability-adjusted life-years (DALYs) averted in addition to productivity gains were compared against the investment required in each scenario., Findings: Scaling up ear and hearing care interventions to 90% requires an overall global investment of US$238·8 billion over 10 years. Over a 10-year period, this investment promises substantial health gains with more than 130 million DALYs averted. These gains translate to a monetary value of more than US$1·3 trillion. In addition, investment in hearing care will result in productivity benefits of more than US$2 trillion at the global level by 2030. Together, these benefits correspond to a return of nearly US$15 for every US$1 invested., Interpretation: This is the first-ever global investment case for integrating ear and hearing care interventions in countries' universal health coverage services. The findings show the economic benefits of investing in this compendium and provide the basis for facilitating the increase of country's health budget for strengthening ear and hearing care services., Funding: None., Competing Interests: Declaration of interests DT, RS, and NG received consulting fees from WHO for the conduct of this study. KK, MYB, and SC declare no competing interests., (Copyright © 2022 World Health Organization; licensee Elsevier. This is an Open Access article published under the CC BY-NC-ND 3.0 IGO license which permits users to download and share the article for non-commercial purposes, so long as the article is reproduced in the whole without changes, and provided the original source is properly cited. This article shall not be used or reproduced in association with the promotion of commercial products, services or any entity. There should be no suggestion that WHO endorses any specific organisation, products or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article's original URL.)

Objectives: Testing and treatment for hepatitis B virus (HBV) and hepatitis C virus (HCV) infection are highly effective, high-impact interventions. This article aims to estimate the cost-effectiveness of scaling up these interventions by scenarios, regions, and income groups., Methods: We modeled costs and impacts of hepatitis elimination in 67 low- and middle-income countries from 2016 to 2030. Costs included testing and treatment commodities, healthcare consultations, and future savings from cirrhosis and hepatocellular carcinomas averted. We modeled disease progression to estimate disability-adjusted life-years (DALYs) averted. We estimated incremental cost-effectiveness ratios (ICERs) by regions and World Bank income groups, according to 3 scenarios: flatline (status quo), progress (testing/treatment according to World Health Organization guidelines), and ambitious (elimination)., Results: Compared with no action, current levels of testing and treatment had an ICER of $807/DALY for HBV and -$62/DALY (cost-saving) for HCV. Scaling up to progress scenario, both interventions had ICERs less than the average gross domestic product/capita of countries (HBV: $532/DALY; HCV: $613/DALY). Scaling up from flatline to elimination led to higher ICERs across countries (HBV: $927/DALY; HCV: $2528/DALY, respectively) that remained lower than the average gross domestic product/capita. Sensitivity analysis indicated discount rates and commodity costs were main factors driving results., Conclusions: Scaling up testing and treatment for HBV and HCV infection as per World Health Organization guidelines is a cost-effective intervention. Elimination leads to a much larger impact though ICERs are higher. Price reduction strategies are needed to achieve elimination given the substantial budget impact at current commodity prices., (Copyright © 2020 World Health Organization. Published by Elsevier Inc. All rights reserved.)

Background: High prices of pharmaceutical products are an increasing challenge in high- and low-income countries. Governments in many countries have implemented pricing policies to ensure affordability of medicines to patients and healthcare systems. The World Health Organization published in 2015 the Guideline on Country Pharmaceutical Pricing Policies, which was based on a series of evidence reviews in the preceding years.As part of the ongoing update of this guideline, we present a protocol for 10 systematic literature reviews on pharmaceutical pricing policies to be covered by the updated guideline., Methods: The systematic literature reviews will be undertaken according to the principles embodied in the Cochrane Handbook and Centre for Reviews and Dissemination. The interventions studied are pharmaceutical pricing policies implemented by public institutions or a group of purchasing organizations/individuals (e.g. health services). Studies reporting price, volume, availability and/or affordability as the primary outcomes will be eligible for inclusion. Studies in any country or jurisdiction, in any language and in any setting published in 2004 or later are eligible. Eligible study designs are randomized and non-randomized trials, and observational studies including cohort studies, panel data analyses, comparative time series design (including interrupted time-series and repeated measures studies), and controlled before-after studies. A list of 21 databases of peer-reviewed and grey literature will be searched, along with supplementary searches of relevant national and international organizational and governmental websites. Risk of bias will be assessed according to the Cochrane Effective Practice and Organisation of Care (EPOC) guidelines. A summary table according to the EPOC Worksheets for preparing a Summary of Findings table (SoF) using GRADE will be provided., Discussion: The results of the review will be used as part of the update of the WHO Guideline on Country Pharmaceutical Pricing Policies. The current protocol may serve as an example for performing systematic literature reviews to inform policy makers., Competing Interests: Competing interestsJG declares that she has, within the past 4 years, undertaken consulting work for and received research support (e.g. grants, collaborations, sponsorships or other funding) from commercial entities or other organizations with an interest related to the subject of the work. DT declares that he has, within the past 4 years, undertaken consulting work for commercial entities or other organizations with an interest related to the subject of the work. AKMT has received, within the past 4 years, funding from de Dutch Health Care Institute. HAvdH does not declare any competing interest. All authors declare that these interests have not and will not influence the work undertaken., (© The Author(s) 2020.)

Background: The World Health Assembly calls for elimination of viral hepatitis as a public health threat by 2030 (ie, -90% incidence and -65% mortality). However, WHO's 2017 cost projections to achieve health-related Sustainable Development Goals did not include the resources needed for hepatitis testing and treatment. We aimed to estimate the incremental commodity cost of adding scaled up interventions for testing and treatment of hepatitis to WHO's investment scenarios., Methods: We added modelled costs for implementing WHO recommended hepatitis testing and treatment to the 2017 WHO cost projections. We quantified additional requirements for diagnostic tests, medicines, health workers' time, and programme support across 67 low-income and middle-income countries, from 2016-30. A progress scenario scaled up interventions and a more ambitious scenario was modelled to reach elimination by 2030. We used 2018 best available prices of diagnostics and generic medicines. We estimated total costs and the additional investment needed over the projection of the 2016 baseline cost., Findings: The 67 countries considered included 230 million people living with hepatitis B virus (HBV) and 52 million people living with hepatitis C virus (HCV; 90% and 73% of the world's total, respectively). Under the progress scenario, 3250 million people (2400 million for HBV and 850 million for HCV) would be tested and 58·2 million people (24·1 million for HBV and 34·1 million for HCV) would be treated (total additional cost US$ 27·1 billion). Under the ambitious scenario, 11 631 million people (5502 million for HBV and 6129 million for HCV) would be tested and 93·8 million people (32·2 million for HBV and 61·6 million for HCV) would be treated (total additional cost $58·7 billion), averting 4·5 million premature deaths and leading to a gain of 51·5 million healthy life-years by 2030. However, if affordable HCV medicines remained inaccessible in 13 countries where medicine patents are protected, the additional cost of the ambitious scenario would increase to $118 billion. Hepatitis elimination would account for a 1·5% increase to the WHO ambitious health-care strengthening scenario costs, avert an additional 4·6% premature deaths, and add an additional 9·6% healthy life-years from 2016-30., Interpretation: Access to affordable medicines in all countries will be key to reach hepatitis elimination. This study suggests that elimination is feasible in the context of universal health coverage. It points to commodities as key determinants for the overall price tag and to options for cost reduction strategies., Funding: WHO, United States Centers for Disease Control and Prevention, Unitaid., (© 2019 World Health Organization; licensee Elsevier. This is an Open Access article published under the CC BY 3.0 IGO license which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In any use of this article, there should be no suggestion that WHO endorses any specific organisation, products or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article's original URL.)

Background: Previous studies have shown limited availability of medicines in health facilities in Bangladesh. While medicines are dispensed for free in public facilities, they are paid out-of-pocket in private pharmacies. Availability, price and affordability are key concerns for access to medicines in Bangladesh., Methods: The World Health Organization/Health Action International survey methodology was used to determine price, availability and affordability of 61 lowest price generic (LPG) and originator branded medicines in public facilities, private retail pharmacies and private clinics across 6 regions of Bangladesh. Medicines for non-communicable and infectious diseases, and both on and off the national Essential Medicines List were included. Prices were compared internationally using Median Price Ratio (MPR)., Results: Mean LPG (originator brand) availability in the public sector, private retail pharmacies, and private clinics was 37%, 63 (4) percent, and 54 (2) percent, respectively. Medicines for Non-Communicable Diseases (NCD) and essential medicines were significantly less available than infectious disease medicines and non-essential medicines, respectively. Mean LPG (originator brand) MPR was 0.977 in the public sector, 1.700 (3.698) in private retail pharmacies and 1.740 (3.758) in private clinics. Six medicines were expensive by international standards across all sectors. The least affordable treatments in both private sectors were bisoprolol (hypertension), metformin (diabetes) and atorvastatin (hypercholesterolemia)., Conclusion: Availability and affordability of NCD medicines are key concerns where the burden of NCD is rising. These findings show improvement from earlier studies, but room for further advances in availability and affordability of NCD medicines in Bangladesh. A small number of medicines are consistently expensive across sectors in Bangladesh, suggesting the need for strategies to address prices for certain medicines.

Aims: The aim of this systematic review of economic evaluations alongside randomised controlled trials (RCTs) was to provide a comprehensive overview of the evidence concerning cost-effectiveness analyses of common treatment options for major depression., Methods: An existing database was used to identify studies reporting cost-effectiveness results from RCTs. This database has been developed by a systematic literature search in the bibliographic databases of PubMed, PsychINFO, Embase and Cochrane library from database inception to December 2014. We evaluated the quality of economic evaluations using a 10-item short version of the Drummond checklist. Results were synthesised narratively. The risk of bias of the included RCTs was assessed, based on the Cochrane risk of bias assessment tool., Results: Fourteen RCTs were included from the 5580 articles screened on titles and abstracts. The methodological quality of the health economic evaluations was relatively high and the majority of the included RCTs had low risk of bias in most of Cochrane items except blinding of participants and personnel. Cognitive behavioural therapy was examined in seven trials as part of a variety of treatment protocols and seems cost-effective compared with pharmacotherapy in the long-term. However cost-effectiveness results for the combination of psychotherapy with pharmacotherapy are conflicting and should be interpreted with caution due to limited comparability between the examined trials. For several treatments, only a single economic evaluation was reported as part of a clinical trial. This was the case for comparisons between different classes of antidepressants, for several types of psychotherapy (behavioural activation, occupational therapy, interpersonal psychotherapy, short-term psychotherapy, psychodynamic psychotherapy, rational emotive behavioural therapy, solution focused therapy), and for transcranial magnetic stimulation v. electroconvulsive therapy. The limited evidence base for these interventions means generalisations, based on economic evaluation alongside clinical trials, cannot easily be made., Conclusions: There is some economic evidence underpinning many of the common treatment options for major depression. Wide variability was observed in study outcomes, probably attributable to differences in population, interventions or follow-up periods. For many interventions, only a single economic evaluation alongside clinical trials was identified. Thus, significant economic evidence gaps remain in the area of major depressive disorder.

Background: The importance of economic evaluation in decision making is growing with increasing budgetary pressures on health systems. Diverse economic evidence is available for a range of interventions across national contexts within Europe, but little attention has been given to identifying evidence gaps that, if filled, could contribute to more efficient allocation of resources. One objective of the Research Agenda for Health Economic Evaluation project is to determine the most important methodological evidence gaps for the ten highest burden conditions in the European Union (EU), and to suggest ways of filling these gaps., Methods: The highest burden conditions in the EU by Disability Adjusted Life Years were determined using the Global Burden of Disease study. Clinical interventions were identified for each condition based on published guidelines, and economic evaluations indexed in MEDLINE were mapped to each intervention. A panel of public health and health economics experts discussed the evidence during a workshop and identified evidence gaps., Results: The literature analysis contributed to identifying cross-cutting methodological and technical issues, which were considered by the expert panel to derive methodological research priorities., Conclusions: The panel suggests a research agenda for health economics which incorporates the use of real-world evidence in the assessment of new and existing interventions; increased understanding of cost-effectiveness according to patient characteristics beyond the "-omics" approach to inform both investment and disinvestment decisions; methods for assessment of complex interventions; improved cross-talk between economic evaluations from health and other sectors; early health technology assessment; and standardized, transferable approaches to economic modeling.

Cost-of-illness studies, the systematic quantification of the economic burden of diseases on the individual and on society, help illustrate direct budgetary consequences of diseases in the health system and indirect costs associated with patient or carer productivity losses. In the context of the BURQOL-RD project ("Social Economic Burden and Health-Related Quality of Life in patients with Rare Diseases in Europe") we studied the evidence on direct and indirect costs for 10 rare diseases (Cystic Fibrosis [CF], Duchenne Muscular Dystrophy [DMD], Fragile X Syndrome [FXS], Haemophilia, Juvenile Idiopathic Arthritis [JIA], Mucopolysaccharidosis [MPS], Scleroderma [SCL], Prader-Willi Syndrome [PWS], Histiocytosis [HIS] and Epidermolysis Bullosa [EB]). A systematic literature review of cost of illness studies was conducted using a keyword strategy in combination with the names of the 10 selected rare diseases. Available disease prevalence in Europe was found to range between 1 and 2 per 100,000 population (PWS, a sub-type of Histiocytosis, and EB) up to 42 per 100,000 population (Scleroderma). Overall, cost evidence on rare diseases appears to be very scarce (a total of 77 studies were identified across all diseases), with CF (n=29) and Haemophilia (n=22) being relatively well studied, compared to the other conditions, where very limited cost of illness information was available. In terms of data availability, total lifetime cost figures were found only across four diseases, and total annual costs (including indirect costs) across five diseases. Overall, data availability was found to correlate with the existence of a pharmaceutical treatment and indirect costs tended to account for a significant proportion of total costs. Although methodological variations prevent any detailed comparison between conditions and based on the evidence available, most of the rare diseases examined are associated with significant economic burden, both direct and indirect., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objectives: In many economic evaluations and reimbursement decisions, quality-adjusted life-years (QALYs) are used as a measure of benefit to assess effectiveness of novel therapies, often based on the EQ-5D 3-level questionnaire. As only five dimensions of physical and mental well-being are reflected in this tool, significant aspects of the patient experience may be missed. We evaluate the use of the EQ-5D as a measurement of clinical change across a wide range of disorders from dermatological (acne) to life-threatening (metastatic cancers)., Methods: We analyze published studies on the psychometric properties of the EQ-5D 3-level questionnaire, extracting information on the Visual Analogue Scale versus Index score, Standardized Response Mean, and Effect Size. These are compared with ranges generally accepted to represent good responsiveness in the psychometric literature., Results: We find that only approximately one in five study populations report subjective health state valuation of patients within 5 percent of the score attributed by the EQ-5D index, and more than 40 percent of studies report unacceptable ceiling effects. In the majority of studies, responsiveness of the EQ-5D index was found to be poor to moderate, based on Effect Size (63 percent poor–moderate) and Standardized Response Mean (72 percent poor–moderate)., Conclusions: We conclude that the EQ-5D index does not adequately reflect patient health status across a range of conditions, and it is likely that a significant proportion of the subjective patient experience is not accounted for by the index. This has implications for economic evaluations of novel drugs based on evidence generated with the EQ-5D.

Background: Universal access to health care in most western European countries has been a given for many decades; however, macroeconomic developments and increased pressure on health care budgets could mean the status quo cannot be maintained. As populations age, a declining proportion of economically active citizens are being required to support a larger burden of health and social care, while increasing availability of novel technologies for extending and improving life continues to push health care costs upwards. With health expenditure continuing to rise as a proportion of national income, concerns are raised about the current and future financial sustainability of Organisation for Economic Co-Operation and Development (OECD) health care systems. Against this backdrop, a discussion about options to fund health care in the future, including whether to raise additional health care finance (and the ways to do so), reallocate resources and/or ration services becomes very pertinent., Objective: This study elicits preferences among a group of key stakeholders (payers, providers, government, academia and health-related industry) on the issue of health care financial sustainability and the future funding of health care services, with a view to understanding the different degrees of acceptability between policy interventions and future funding options as well as their feasibility., Study Design and Participants: We invited 842 individuals from academia, other research organisations (eg. think tanks), national health services, providers, health insurance organisations, government representatives and health-related industry and related advisory stakeholders to participate in an online survey collecting preferences on a variety of revenue-generating mechanisms and cost/demand reducing policies. Respondents represented the 28 EU member states as well as Norway, Iceland, Switzerland, Australia, Russian Federation, Canada and New Zealand., Results: We received 494 responses to our survey from all stakeholder groups. Across all groups, the highest preference was for policies to modify lifestyle and implement more extensive screening within risk groups for high burden illnesses. There was a broad consensus not to reallocate resources from social security/education. Between stakeholders, there were differences of opinion between industry/advisory and a range of other groups, with industry being generally more in favour of market-based interventions and an increased role for the private sector in health care financing/delivery. Conversely, stakeholders from academia, government, national health services and insurance were relatively more in favour of more restrictive purchasing of new and expensive technologies, and (to varying extent) of higher income/corporate taxes. Taxes on cigarettes/alcohol were by far considered the most politically feasible option., Conclusions: According to this study, policy options that are broadly acceptable across stakeholder groups with different inherent interests exist but are limited to lifestyle modification, screening interventions and excise taxes on harmful products. Representatives from the private sector tend to view solutions rooted in the private sector as both effective and politically feasible options, while stakeholders from academia and the public sector seem to place more emphasis on solutions that do not disproportionately impact certain population groups.

We present an attractive new system for the specific and sensitive detection of the malaria-causing Plasmodium parasites. The system relies on isothermal conversion of single DNA cleavage-ligation events catalyzed specifically by the Plasmodium enzyme topoisomerase I to micrometer-sized products detectable at the single-molecule level. Combined with a droplet microfluidics lab-on-a-chip platform, this design allowed for sensitive, specific, and quantitative detection of all human-malaria-causing Plasmodium species in single drops of unprocessed blood with a detection limit of less than one parasite/μL. Moreover, the setup allowed for detection of Plasmodium parasites in noninvasive saliva samples from infected patients. During recent years malaria transmission has declined worldwide, and with this the number of patients with low-parasite density has increased. Consequently, the need for accurate detection of even a few parasites is becoming increasingly important for the continued combat against the disease. We believe that the presented droplet microfluidics platform, which has a high potential for adaptation to point-of-care setups suitable for low-resource settings, may contribute significantly to meet this demand. Moreover, potential future adaptation of the presented setup for the detection of other microorganisms may form the basis for the development of a more generic platform for diagnosis, fresh water or food quality control, or other purposes within applied or basic science.

Recent data have found that Plasmodium ovale can be separated in two distinct species: classic and variant P. ovale based on multilocus typing of different genes. This study presents a P. ovale isolate from a patient infected in Ghana together with an analysis of the small subunit RNA, cytochrome b, cytochrome c oxidase I, cysteine protease and lactate dehydrogenase genes, which show that the sample is a variant P. ovale and identical or highly similar to variant P. ovale isolated from humans in South-East Asia and Africa, and from a chimpanzee in Cameroon. The split between the variant and classic P. ovale is estimated to have occurred 1.7 million years ago.

Control of diseases inflicted by protozoan parasites such as Leishmania, Trypanosoma, and Plasmodium, which pose a serious threat to human health worldwide, depends on a rather small number of antiparasite drugs, of which many are toxic and/or inefficient. Moreover, the increasing occurrence of drug-resistant parasites emphasizes the need for new and effective antiprotozoan drugs. In the current study, we describe a synthetic peptide, WRWYCRCK, with inhibitory effect on the essential enzyme topoisomerase I from the malaria-causing parasite Plasmodium falciparum. The peptide inhibits specifically the transition from noncovalent to covalent DNA binding of P. falciparum topoisomerase I, while it does not affect the ligation step of catalysis. A mechanistic explanation for this inhibition is provided by molecular docking analyses. Taken together the presented results suggest that synthetic peptides may represent a new class of potential antiprotozoan drugs.

Human topoisomerase I has been suggested to be implicated in the maintenance of genomic stability via its ability to regulate genome topology during transcription and replication. In the present study, we demonstrate by whole-genome array comparative genomic hybridization (aCGH) and fluorescence in situ hybridisation (FISH) analysis that topoisomerase I deficiency results in chromosome 5p gain in the cervical cancer cell line, HeLa-CCL2. In contrast, chromosome 5p copy number remained unaffected by topoisomerase I down-regulation in the non-cancer cell line HEK293T, as demonstrated by FISH analysis. Chromosome 5p gain is the most frequent genetic alteration in invasive cervical cancer, which leads to overexpression of genes involved in proliferation and occurs primarily at late stages in cancer development. The amplification of this region upon topoisomerase I down-regulation specifically in HeLa-CCL2 cells may indicate an important role of topoisomerase I in preventing malignant progression of precancerous lesions in the cervix.

The assembly, structure, and stability of DNA nanocages with the shape of truncated octahedra have been studied. The cages are composed of 12 double-stranded B-DNA helices interrupted by single-stranded linkers of thymidines of varying length that constitute the truncated corners of the structure. The structures assemble with a high efficiency in a one-step procedure, compared to previously published structures of similar complexity. The structures of the cages were determined by small-angle X-ray scattering. With increasing linker length, there is a systematic increase of the cage size and decrease of the twist angle of the double helices with respect to the symmetry planes of the cage structure. In the present study, we demonstrate the length of the single-stranded linker regions, which impose a certain degree of flexibility to the structure, to be the important determinant for efficient assembly. The linker length can be decreased to three thymidines without affecting assembly yield or the overall structural characteristics of the DNA cages. A linker length of two thymidines represents a sharp cutoff abolishing cage assembly. This is supported by energy minimization calculations suggesting substantial hydrogen bond deformation in a cage with linkers of two thymidines.

A DNA nanocage has been recently characterized by small-angle X-ray scattering (SAXS) and cryo-transmission electron microscopy as a DNA octahedron having a central cavity larger than the apertures in the surrounding DNA lattice. Starting from the SAXS data, a DNA nanocage has been modeled and simulated by classical molecular dynamics to evaluate in silico its structural properties and stability. Global properties, principal component analysis, and DNA geometrical parameters, calculated along the entire trajectory, indicate that the cage is stable and that the B-DNA conformation, also if slightly distorted, is maintained for all the simulation time. Starting from the initial model, the nanocage scaffold undergoes a contraction of the thymidine strands, connecting the DNA double helices, suggesting that the length of the thymidine strands is a crucial aspect in the modulation of the nanocage stability. A comparison of the average structure as obtained from the simulation shows good agreement with the SAXS experimental data.