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Background: Respiratory syncytial virus (RSV) causes a considerable disease burden in young children globally, but reliable estimates of RSV-related costs and health-related quality-of-life (HRQoL) are scarce. This study aimed to evaluate the RSV-associated costs and HRQoL effects in infants and their caregivers in four European countries. Methods: Healthy term-born infants were recruited at birth and actively followed up in four European countries. Symptomatic infants were systematically tested for RSV. Caregivers recorded the daily HRQoL of their child and themselves, measured by a modified EQ-5D with Visual Analogue Scale, for 14 consecutive days or until symptoms resolved. At the end of each RSV episode, caregivers reported healthcare resource use and work absenteeism. Direct medical costs per RSV episode were estimated from a healthcare payer’s perspective and indirect costs were estimated from a societal perspective. Means and 95% confidence intervals (CI) of direct medical costs, total costs (direct costs + productivity loss) and quality-adjusted life-day (QALD) loss per RSV episode were estimated per RSV episode, as well as per subgroup (medical attendance, country). Results: Our cohort of 1041 infants experienced 265 RSV episodes with a mean symptom duration of 12.5 days. The mean (95% CI) cost per RSV episode was €399.5 (242.3, 584.2) and €494.3 (317.7, 696.1) from the healthcare payer’s and societal perspective, respectively. The mean QALD loss per RSV episode of 1.9 (1.7, 2.1) was independent of medical attendance (in contrast to costs, which also differed by country). Caregiver and infant HRQoL evolved similarly. Conclusion: This study fills essential gaps for future economic evaluations by prospectively estimating direct and indirect costs and HRQoL effects on healthy term infants and caregivers separately, for both medically attended (MA) and non-MA laboratory-confirmed RSV episodes. We generally observed greater HRQoL losses than in previous studies which used non-community and/or non-prospective designs.

Objectives: The ALIC4E trial has shown that oseltamivir reduces recovery time while increasing the risk of nausea. This secondary analysis of the ALIC4E trial aimed to determine the gain in quality-adjusted life-years (QALYs) associated with adding oseltamivir to usual primary care in patients presenting with influenza-like illness (ILI). Methods: Patients with ILI were recruited during the influenza season (2015-2018) in 15 European countries. Patients were assigned to usual care with or without oseltamivir through stratified randomization (age, severity, comorbidities, and symptom onset). Patients' health status was valued with the EQ-5D and visual analog scale (VAS) for up to 28 days. Average EQ-5D and VAS scores over time were estimated for both treatment groups using one-inflated beta regression in children (-13 years old). QALY gain was calculated as the difference between the groups. Sensitivity analysis considered the value set to convert EQ-5D answers to summary scores and the follow-up period. Results: In adults, oseltamivir gained 0.0006 (95% confidence interval 0.0002-0.0010) QALYs, whereas no statistically significant gain was found in children (14-day follow-up, EQ-5D). QALY gains were statistically significant in patients aged >-65 years, patients without relevant comorbidities, or patients experiencing symptoms for

Background. Threshold analysis is used to determine the threshold value of an input parameter at which a health care strategy becomes cost-effective. Typically, it is performed in a deterministic manner, in which inputs are varied one at a time while the remaining inputs are each fixed at their mean value. This approach will result in incorrect threshold values if the cost-effectiveness model is nonlinear or if inputs are correlated.Objective. To propose a probabilistic method for performing threshold analysis, which accounts for the joint uncertainty in all input parameters and makes no assumption about the linearity of the cost-effectiveness model.Methods. Three methods are compared: 1) deterministic threshold analysis (DTA); 2) a 2-level Monte Carlo approach, which is considered the gold standard; and 3) a regression-based method using a generalized additive model (GAM), which identifies threshold values directly from a probabilistic sensitivity analysis sample.Results. We applied the 3 methods to estimate the minimum probability of hospitalization for typhoid fever at which 3 different vaccination strategies become cost-effective in Uganda. The threshold probability of hospitalization at which routine vaccination at 9 months with catchup campaign to 5 years becomes cost-effective is estimated to be 0.060 and 0.061 (95% confidence interval [CI], 0.058-0.064), respectively, for 2-level and GAM. According to DTA, routine vaccination at 9 months with catchup campaign to 5 years would never become cost-effective. The threshold probability at which routine vaccination at 9 months with catchup campaign to 15 years becomes cost-effective is estimated to be 0.092 (DTA), 0.074 (2-level), and 0.072 (95% CI, 0.069-0.075) (GAM). GAM is 430 times faster than the 2-level approach.Conclusions. When the cost-effectiveness model is nonlinear, GAM provides similar threshold values to the 2-level Monte Carlo approach and is computationally more efficient. DTA provides incorrect results and should not be used. Financial support for this study was provided in part by grants from the Bill and Melinda Gates Foundation (OPP1116967, OPP1151153) (VEP), Research Foundation–Flanders (JB), and the Methusalem financing program of the Flemish government (ZP). The funding agreements ensured the authors’ independence in designing the study, interpreting the data, writing, and publishing the report. Pieters, Z (corresponding author), Univ Antwerp, Hasselt Univ, Data Sci Inst, I BioStat, DS-243,Univ Pl 1, B-2610 Antwerp, Belgium. zoe.pieters@uantwerpen.be

Background Multidrug resistance and fluoroquinolone non-susceptibility (FQNS) are major concerns for the epidemiology and treatment of typhoid fever. The 2018 prequalification of the first typhoid conjugate vaccine (TCV) by WHO provides an opportunity to limit the transmission and burden of antimicrobial-resistant typhoid fever. Methods We combined output from mathematical models of typhoid transmission with estimates of antimicrobial resistance from meta-analyses to predict the burden of antimicrobial-resistant typhoid fever across 73 lower-income countries eligible for support from Gavi, the Vaccine Alliance. We considered FQNS and multidrug resistance separately. The effect of vaccination was predicted on the basis of forecasts of vaccine coverage. We explored how the potential effect of vaccination on the prevalence of antimicrobial resistance varied depending on key model parameters. Findings The introduction of routine immunisation with TCV at age 9 months with a catch-up campaign up to age 15 years was predicted to avert 46–74% of all typhoid fever cases in 73 countries eligible for Gavi support. Vaccination was predicted to reduce the relative prevalence of antimicrobial-resistant typhoid fever by 16% (95% prediction interval [PI] 0–49). TCV introduction with a catch-up campaign was predicted to avert 42·5 million (95% PI 24·8–62·8 million) cases and 506 000 (95% PI 187 000–1·9 million) deaths caused by FQNS typhoid fever, and 21·2 million (95% PI 16·4–26·5 million) cases and 342 000 (95% PI 135 000–1·5 million) deaths from multidrug-resistant typhoid fever over 10 years following introduction. Interpretation Our results indicate the benefits of prioritising TCV introduction for countries with a high avertable burden of antimicrobial-resistant typhoid fever. Funding The Bill & Melinda Gates Foundation.

Purpose Health-related quality of life outcomes are increasingly used to monitor population health and health inequalities and to assess the (cost-) effectiveness of health interventions. The EQ-5D-5L has been included in the Belgian Health Interview Survey, providing a new source of population-based self-perceived health status information. This study aims to estimate Belgian population norms for the EQ-5D-5L by sex, age, and region and to analyze its association with educational attainment. Methods The BHIS 2018 provided EQ-5D-5L data for a nationally representative sample of the Belgian population. The dimension scores and index values were analyzed using logistic and linear regressions, respectively, accounting for the survey design. Results More than half of respondents reported problems of pain/discomfort, while over a quarter reported problems of anxiety/depression. The average index value was 0.84. Women reported more problems on all dimensions, but particularly on anxiety/depression and pain/discomfort, resulting in significantly lower index values. Problems with mobility, self-care, and usual activities showed a sharp increase after the age of 80 years. Consequently, index values decreased significantly by age. Lower education was associated with a higher prevalence of problems for all dimensions except anxiety/depression and with a significantly lower index value. Conclusion This paper presents the first nationally representative Belgian population norms using the EQ-5D-5L. Inclusion of the EQ-5D in future surveys will allow monitoring over time of self-reported health, disease burden, and health inequalities.

Background A new adjuvanted subunit vaccine (HZ/su), with higher vaccine efficacy than live-attenuated vaccine (ZVL), has been licensed in Europe since March 2018. Therefore, Belgian decision-makers might need to re-assess their recommendations for vaccination against herpes zoster (HZ). Methods We conducted a cost-effectiveness analysis, using a Markov decision tree, of vaccinating 50- to 85-year-old immunocompetent Belgian cohorts with no vaccination, HZ/su, ZVL, and ZVL with booster after 10 years. Due to the uncertainty in vaccine waning of HZ/su vaccine beyond 4 years, we used a logarithmic and 1-minus-exponential function to model respectively a long and short duration of protection. We used a lifetime time horizon and implemented the health care payer perspective throughout the analysis. Results HZ/su had the greatest impact in avoiding health and economic burden. However, it would never become cost-effective at a willingness-to-pay threshold of euro40,000 per quality-adjusted life year (QALY) gained at its market price set by the manufacturer in the USA. Depending on the waning function assumed for HZ/su, the price per dose needs to drop 60% or 83% such that vaccination with HZ/su, assuming respectively a long or short duration of protection, would become cost-effective in 50- and 80-year-old individuals. At euro40,000 per QALY gained, ZVL or ZVL with booster was never found cost-effective compared with HZ/su, even if only administration cost was considered. Conclusion HZ/su is cost-effective in the 50-year-old age cohort at the unofficial Belgian threshold of euro40,000 per QALY gained, if its price drops to euro55.40 per dose. This result is, however, very sensitive to the assumed duration of protection of the vaccine, and the assumed severity and QALY loss associated with HZ and post-herpetic neuralgia (PHN). This work was supported in part by Research Foundation-Flanders (JB), the Methusalem financing program of the Flemish government (ZP). The funding agreements ensured the authors’ independence in designing the study, interpreting the data, and writing and publishing the report. We would like to thank the colleagues from the SIMID group for their input during our monthly meetings.

This tutorial aims to help make the best available methods for generating and presenting cost-effectiveness results with uncertainty common practice. We believe there is a need for such type of tutorial because some erroneous practices persist (e.g., identifying the cost-effective intervention as the one with the highest probability to be cost-effective), while some of the more advanced methods are hardly used (e.g., the net loss statistic ‘NL’, expected net loss curves and frontier). The tutorial explains with simple examples the pros and cons of using ICER, incremental net benefit and NL to identify the cost-effective intervention, both with and without uncertainty accounted for probabilistically. A flowchart provides practical guidance on when and how to use ICER, incremental net benefit or NL. Different ways to express and present uncertainty in the results are described, including confidence and credible intervals, the probability that a strategy is cost-effective (as usually shown with cost-effectiveness acceptability curves (CEACs)) and the expected value of perfect information (EVPI). The tutorial clarifies and illustrates why EVPI is the only measure accounting fully for decision uncertainty, and why NL curves and the NL frontier may be preferred over CEACs and other plots for presenting cost-effectiveness results in the context of uncertainty. The easy calculations and a worked-out real-life example will help users to thoroughly understand and correctly interpret key cost-effectiveness results. Examples with mathematical calculations, interpretation, plots and R code are provided.

Background and Objective Influenza-like illness (ILI) leads to a substantial disease burden every winter in Europe; however, oseltamivir is not frequently prescribed to ILI patients in the primary-care setting. An open-label, multi-country, multi-season, randomised controlled trial investigated the effectiveness of oseltamivir for treating ILI in 15 European countries. We aimed to evaluate whether patients presenting with ILI in primary care and being managed with the addition of oseltamivir to usual care had lower average direct and indirect costs compared to patients with usual care alone. Methods Resource use data were extracted from participants' daily diaries. Itemised country-specific unit costs were collected through official tariffs, pharmacies or literature. Costs were converted to 2018 values. The null hypothesis was tested based on one-sided credible intervals (CrIs) obtained by bootstrapping. Base-case analysis estimated direct cost and productivity losses using itemised costed resource use and the human capital approach. Scenario analyses with self-reported spending rather than itemised costing were also performed. Results Patients receiving oseltamivir (N = 1306) reported fewer healthcare visits, medication uses, hospital attendances and paid-work hours lost than the other patients (N = 1298). Excluding the oseltamivir cost, the average direct costs were lower in patients treated with oseltamivir from all perspectives, but these differences were not statistically significant (perspective of patient: euro17 [0-95% Crl: 16-19] vs. euro24 [5-100% Crl: 18-29]; healthcare provider: euro37 [28-67] vs. euro44 [25-55]; healthcare payers: euro54 [45-85] vs. euro68 [45-81]; and society: euro423 [399-478] vs. euro451 [390-478]). Scenario and age-group analyses confirmed these findings, but with some between-country differences. Conclusion The average direct and indirect costs were consistently lower in patients treated with oseltamivir than in patients without from four perspectives (excluding the oseltamivir cost). However, these differences were not statistically significant. The ALIC4E trial and the contributions of AWV, EB, SC, NF, PS, NJH, PaB, AGS, DG, KK, RMP, RRJ, BS, NT, RA, CCB and PB were funded by the European Commission’s Seventh Framework Programme: Platform for European Preparedness Against (Re-)emerging Epidemics (PREPARE) (grant HEALTH-F3-2013-602525). PB, XL, JB and RB acknowledge partial Methusalem funding from the VAXIDEA and ASCID Centres of Excellence in vaccination and infectious diseases at the University of Antwerp. JB and RB were funded by their personal postdoctoral grants from the Research Foundation—Flanders (FWO). PS acknowledges that The Healthcare Committee, Region Västra Götaland, Sweden, partially funded the Swedish part of the study.

Plants acquire carbon through photosynthesis to sustain biomass production, autotrophic respiration and production of non-structural compounds for multiple purposes(1). The fraction of photosynthetic production used for biomass production, the biomass production efficiency(2), is a key determinant of the conversion of solar energy to biomass. In forest ecosystems, biomass production efficiency was suggested to be related to site fertility(2). Here we present a database of biomass production effciency from 131 sites compiled from individual studies using harvest, biometric, eddy covariance, or process-based model estimates of production. The database is global, but dominated by data from Europe and North America. We show that instead of site fertility, ecosystem management is the key factor that controls biomass production efficiency in terrestrial ecosystems. In addition, in natural forests, grasslands, tundra, boreal peatlands and marshes, biomass production efficiency is independent of vegetation, environmental and climatic drivers. This similarity of biomass production efficiency across natural ecosystem types suggests that the ratio of biomass production to gross primary productivity is constant across natural ecosystems. We suggest that plant adaptation results in similar growth efficiency in high- and low-fertility natural systems, but that nutrient influxes under managed conditions favour a shift to carbon investment from the belowground flux of non-structural compounds to aboveground biomass.

Background Health-related quality of life outcomes are increasingly used to monitor population health and health inequalities, and to assess the (cost-)effectiveness of health interventions. The EQ-5D-5L has been included in the Belgian Health Interview Survey (BHIS), providing a new source of population-based self-perceived health status information. The aim of this study is to estimate Belgian population norms for the EQ-5D-5L by sex, age, and region, and to analyse its association with educational attainment. Methods The BHIS 2013 and 2018 provided EQ-5D-5L data for a nationally representative sample of the Belgian population. The dimension scores and index values were analysed using logistic regression and linear regression, respectively, taking into account the survey design. Results The majority of respondents reported problems of pain/discomfort, while over a quarter reported problems of anxiety/depression in both surveys. The average index value was 0.81 in 2013 and decreased significantly to 0.79 in 2018. Women reported more problems on the dimensions, but particularly on anxiety/depression and pain/discomfort, resulting in significantly lower index values. Problems with mobility, self-care, and usual activities showed a sharp increase after the age of 80 years. Consequently, index values decreased significantly by age. Lower education was associated with a higher prevalence of problems for all dimensions except pain/discomfort in 2013 and anxiety/depression in 2018, and with a significantly lower index value. Conclusions This paper presents the first nationally representative Belgian population norms using the EQ-5D-5L. Inclusion of the EQ-5D in future surveys will allow monitoring over time of self-reported health, disease burden, and health inequalities. Key messages This study is the first to provide Belgian population norms for the EQ-5D-5L and consequently increases the evidence base regarding country-specific population norms. Our results help policy makers in understanding and monitoring the self-perceived health status of the Belgian population according to age, gender, and educational attainment.

Background Individual-based models (IBMs) are useful to simulate events subject to stochasticity and/or heterogeneity, and have become well established to model the potential (re)emergence of pathogens (e.g., pandemic influenza, bioterrorism). Individual heterogeneity at the host and pathogen level is increasingly documented to influence transmission of endemic diseases and it is well understood that the final stages of elimination strategies for vaccine-preventable childhood diseases (e.g., polio, measles) are subject to stochasticity. Even so it appears IBMs for both these phenomena are not well established. We review a decade of IBM publications aiming to obtain insights in their advantages, pitfalls and rationale for use and to make recommendations facilitating knowledge transfer within and across disciplines. Methods We systematically identified publications in Web of Science and PubMed from 2006-2015 based on title/abstract/keywords screening (and full-text if necessary) to retrieve topics, modeling purposes and general specifications. We extracted detailed modeling features from papers on established vaccine-preventable childhood diseases based on full-text screening. Results We identified 698 papers, which applied an IBM for infectious disease transmission, and listed these in a reference database, describing their general characteristics. The diversity of disease-topics and overall publication frequency have increased over time (38 to 115 annual publications from 2006 to 2015). The inclusion of intervention strategies (8 to 52) and economic consequences (1 to 20) are increasing, to the detriment of purely theoretical explorations. Unfortunately, terminology used to describe IBMs is inconsistent and ambiguous. We retrieved 24 studies on a vaccine-preventable childhood disease (covering 7 different diseases), with publication frequency increasing from the first such study published in 2008. IBMs have been useful to explore heterogeneous between- and within-host interactions, but combined applications are still sparse. The amount of missing information on model characteristics and study design is remarkable. Conclusions IBMs are suited to combine heterogeneous within- and between-host interactions, which offers many opportunities, especially to analyze targeted interventions for endemic infections. We advocate the exchange of (open-source) platforms and stress the need for consistent “branding”. Using (existing) conventions and reporting protocols would stimulate cross-fertilization between research groups and fields, and ultimately policy making in decades to come. Electronic supplementary material The online version of this article (doi:10.1186/s12879-017-2699-8) contains supplementary material, which is available to authorized users.

To identify determinants of health-related quality-of-life in the Belgian population and to provide age-specific population norms of health-related quality-of-life. Between September 2010 and February 2011, a representative sample of 1774 persons (age 0-99) was surveyed using the standard Euroqol questionnaire (EQ-5D-3L) with a Visual Analogue Scale (VAS). Significant determinants were identified using multivariate beta (VAS) and one-inflated beta (EQ-5D) regression, the latter modelling the probability to be in perfect health separately from the average EQ-5D score if not in perfect health. Health-related quality-of-life depends largely on age and experience with severe disease. The probability to be in perfect health is highest for children. For 0-2 years children who are not in perfect health, proxies report EQ-5D and VAS scores as low as that of the elderly. Also smoking behaviour, educational attainment, pet ownership, working or having worked in health care, and potentially household size and 60+ living on their own (yes/no) are associated with health-related quality-of-life, whereas no association was found with gender, living in a single-parent home, educational attainment of mothers, alcohol consumption of 60+, having (grand-) children and the frequency of seeing them. The same determinants are significant for VAS and the probability to be in perfect health, but not for the average EQ-5D score if not in perfect health. The population norms provided can be used directly as input in health economic evaluations. Estimating health-related quality-of-life in children and developing statistical tools capturing the particular features of health-related quality-of-life measures are important areas for future research. JB is supported by a postdoctoral grant from the Research Foundation-Flanders (FWO). Support from the IAP Research Network P7/06 of the Belgian State (Belgian Science Policy) is gratefully acknowledged. This study was supported by the Research Foundation Flanders project G0D5917N. NH gratefully acknowledges support from the University of Antwerp scientific chair in Evidence-Based Vaccinology, financed in 2009-2015 by a gift from Pfizer. The authors acknowledge support of the Antwerp Study Centre for Infectious Diseases (ASCID) at the University of Antwerp. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Background Case management is one of the principal strategies for malaria control. This study aimed to estimate the economic costs of uncomplicated malaria case management and explore the influence of health-seeking behaviours on those costs. Methods A knowledge, attitudes and practices (KAP) survey was applied to 680 households of fifteen communities in Mazan-Loreto in March 2017, then a socio-economic survey was conducted in September 2017 among 161 individuals with confirmed uncomplicated malaria in the past 3 months. Total costs per episode were estimated from both provider (Ministry of Health, MoH) and patient perspectives. Direct costs were estimated using a standard costing estimation procedure, while the indirect costs considered the loss of incomes among patients, substitute labourers and companions due to illness in terms of the monthly minimum wage. Sensitivity analysis evaluated the uncertainty of the average cost per episode. Results The KAP survey showed that most individuals (79.3%) that had malaria went to a health facility for a diagnosis and treatment, 2.7% received those services from community health workers, and 8% went to a drugstore or were self-treated at home. The average total cost per episode in the Mazan district was US$ 161. The cost from the provider’s perspective was US$ 30.85 per episode while from the patient’s perspective the estimated cost was US$ 131 per episode. The average costs per Plasmodium falciparum episode (US$ 180) were higher than those per Plasmodium vivax episode (US$ 156) due to longer time lost from work by patients with P. falciparum infections (22.2 days) than by patients with P. vivax infections (17.0 days). The delayed malaria diagnosis (after 48 h of the onset of symptoms) was associated with the time lost from work due to illness (adjusted mean ratio 1.8; 95% CI 1.3, 2.6). The average cost per malaria episode was most sensitive to the uncertainty around the lost productivity cost due to malaria. Conclusions Despite the provision of free malaria case management by MoH, there is delay in seeking care and the costs of uncomplicated malaria are mainly borne by the families. These costs are not well perceived by the society and the substantial financial impact of the disease can be frequently undervalued in public policy planning.

Summary Background Typhoid fever is a major cause of morbidity and mortality in low-income and middle-income countries. In 2017, WHO recommended the programmatic use of typhoid Vi-conjugate vaccine (TCV) in endemic settings, and Gavi, The Vaccine Alliance, has pledged support for vaccine introduction in these countries. Country-level health economic evaluations are now needed to inform decision-making. Methods In this modelling study, we compared four strategies: no vaccination, routine immunisation at 9 months, and routine immunisation at 9 months with catch-up campaigns to either age 5 years or 15 years. For each of the 54 countries eligible for Gavi support, output from an age-structured transmission-dynamic model was combined with country-specific treatment and vaccine-related costs, treatment outcomes, and disability weights to estimate the reduction in typhoid burden, identify the strategy that maximised average net benefit (ie, the optimal strategy) across a range of country-specific willingness-to-pay (WTP) values, estimate and investigate the uncertainties surrounding our findings, and identify the epidemiological conditions under which vaccination is optimal. Findings The optimal strategy was either no vaccination or TCV immunisation including a catch-up campaign. Routine vaccination with a catch-up campaign to 15 years of age was optimal in 38 countries, assuming a WTP value of at least US$200 per disability-adjusted life-year (DALY) averted, or assuming a WTP value of at least 25% of each country's gross domestic product (GDP) per capita per DALY averted, at a vaccine price of $1·50 per dose (but excluding Gavi's contribution according to each country's transition phase). This vaccination strategy was also optimal in 48 countries assuming a WTP of at least $500 per DALY averted, in 51 with assumed WTP values of at least $1000, in 47 countries assuming a WTP value of at least 50% of GDP per capita per DALY averted, and in 49 assuming a minimum of 100%. Vaccination was likely to be cost-effective in countries with 300 or more typhoid cases per 100 000 person-years. Uncertainty about the probability of hospital admission (and typhoid incidence and mortality) had the greatest influence on the optimal strategy. Interpretation Countries should establish their own WTP threshold and consider routine TCV introduction, including a catch-up campaign when vaccination is optimal on the basis of this threshold. Obtaining improved estimates of the probability of hospital admission would be valuable whenever the optimal strategy is uncertain. Funding Bill & Melinda Gates Foundation, Research Foundation–Flanders, and the Belgian–American Education Foundation.

We conducted a systematic literature review and meta-analysis and estimated the case fatality rate of enteric fever to be 2.49% (95% confidence interval, 1.65%–3.75%; n = 44), 2.5 times higher than what was assumed up until now., Enteric fever is a febrile illness, occurring mostly in Asia and Africa, which can present as a severe and possibly fatal disease. Currently, a case fatality rate (CFR) of 1% is assumed when evaluating the global burden of enteric fever. Until now, no meta-analysis has been conducted to summarize mortality from enteric fever. Therefore, we conducted a systematic review and meta-analysis to aggregate all available evidence. We estimated an overall CFR of 2.49% (95% confidence interval, 1.65%–3.75%; n = 44), and a CFR in hospitalized patients of 4.45% (2.85%–6.88%; n = 21 of 44). There was considerably heterogeneity in estimates of the CFR from individual studies. Neither age nor antimicrobial resistance were significant prognostic factors, but limited data were available for these analyses. The combined estimate of the CFR for enteric fever is higher than previously estimated, and the evaluation of prognostic factors, including antimicrobial resistance, urgently requires more data.

Streptococcus pneumoniae causes a high disease burden including pneumonia, meningitis and septicemia. Both a polysaccharide vaccine targeting 23serotypes (PPV23) and a 13-valent conjugate vaccine (PCV13) are indicated for persons aged over 50years. We developed and parameterized a static multi-cohort model to estimate the incremental cost-effectiveness and budget-impact of these vaccines at different uptake levels. Using three different vaccine efficacy scenarios regarding non-invasive pneumococcal pneumonia and extensive uni- and multivariate sensitivity analyses, we found a strong preference for PPV23 over PCV13 in all age groups at willingness to pay levels below Euro300 000 per quality adjusted life year (QALY). PPV23 vaccination would cost on average about Euro83000, Euro60000 and Euro52000 per QALY gained in 50-64, 65-74 and 75-84year olds, whereas for PCV13 this is about Euro171000, Euro201000 and Euro338000, respectively. Strategies combining PPV23 and PCV13 vaccines were most effective but generally less cost-effective. When assuming a combination of increased duration of PCV13 protection, increased disease burden preventable by PCV13 and a 75% reduction of the PCV13 price, PCV13 could become more attractive in

Aim: To assess the effectiveness and cost-effectiveness of a universal childhood varicella-zoster vaccination programme in Belgium (1) using the most recent Belgian data on varicella-zoster burden, (2) exploring different options for the timing of the second dose, (3) obtaining results with and without exogenous natural boosting, and (4) investigating the possible additional benefit of zoster booster vaccination for adults at age 50 or 60 years. Methods: An extensively studied and improved dynamic model is used to estimate primary and breakthrough chickenpox and zoster cases over time. For a range of vaccination options, we compared the direct costs (health care payer perspective) and health outcomes (including Quality-Adjusted Life-Years (QALYs) lost) associated with chickenpox and herpes zoster. Estimates of social contact patterns, health care use, costs and QALY losses are almost exclusively based on Belgian databases and surveys. Results and Conclusions: If exogenous natural boosting exists, a net loss in QALYs is expected for several decades after implementing a universal chickenpox vaccination programme, due to an increase in zoster mainly in persons aged 50-80 years. This result holds also for scenarios that minimise or counteract the expected increase in zoster incidence (e.g. additional booster vaccinations in adults). However, if the boosting hypothesis is not true or if costs and QALYs are cumulated over at least 33 to more than 100 years after vaccination (depending on the assumptions made), different options for universal 2-dose vaccination against chickenpox in Belgium would be cost-effective at a vaccine price of 43/dose or lower.

Vaccination can place selective pressures on viral populations, leading to changes in the distribution of strains as viruses evolve to escape immunity from the vaccine. Vaccine-driven strain replacement is a major concern after nationwide rotavirus vaccine introductions. However, the distribution of the predominant rotavirus genotypes varies from year to year in the absence of vaccination, making it difficult to determine what changes can be attributed to the vaccines. To gain insight in the underlying dynamics driving changes in the rotavirus population, we fitted a hierarchy of mathematical models to national and local genotype-specific hospitalization data from Belgium, where large-scale vaccination was introduced in 2006. We estimated that natural- and vaccine-derived immunity was strongest against completely homotypic strains and weakest against fully heterotypic strains, with an intermediate immunity amongst partially heterotypic strains. The predominance of G2P[4] infections in Belgium after vaccine introduction can be explained by a combination of natural genotype fluctuations and weaker natural and vaccine-induced immunity against infection with strains heterotypic to the vaccine, in the absence of significant variation in strain-specific vaccine effectiveness against disease. However, the incidence of rotavirus gastroenteritis is predicted to remain low despite vaccine-driven changes in the distribution of genotypes. ispartof: Scientific Reports vol:5 issue:1 pages:18585- ispartof: location:England status: published

In 2006, Belgium was the first country in the European Union to recommend rotavirus vaccination in the routine infant vaccination schedule and rapidly achieved high vaccine uptake (86-89% in 2007). We used regional and national data sources up to 7 years post-vaccination to study the impact of vaccination on laboratory-confirmed rotavirus cases and rotavirus-related hospitalisations and deaths. We showed that (i) from 2007 until 2013, vaccination coverage remained at 79-88% for a complete course, (ii) in children 0-2 years, rotavirus cases decreased by 79% (95% confidence intervals (CI): 68-89%) in 2008-2014 compared to the pre-vaccination period (1999-2006) and by 50% (95% CI: 14-82%) in the age group >= 10 years, (iii) hospitalisations for rotavirus gastroenteritis decreased by 87% (95% CI: 84-90%) in 2008-2012 compared to the pre-vaccination period (2002-2006), (iv) median age of rotavirus cases increased from 12 months to 17 months and (v) the rotavirus seasonal peak was reduced and delayed in all post-vaccination years. The substantial decline in rotavirus gastroenteritis requiring hospitalisations and in rotavirus activity following introduction of rotavirus vaccination is sustained over time and more pronounced in the target age group, but with evidence of herd immunity. JB is supported by a postdoctoral grant from the Research Foundation - Flanders (FWO). BO is supported by a PhD fellowship from the Research Foundation - Flanders (FWO). AB is supported by the University of Antwerp's concerted research action number 23405 (BOF-GOA). The authors thank the sentinel laboratory network for their collaboration.

The evolution of aquatic prey-capture strategies in snakes has been suggested as a model system for the study of convergence. However, hypotheses of correlated evolution of prey-capture strategy with different aspects of foraging niche have never been tested quantitatively. Whereas a considerable amount of data is available for North American species, data for European species are scarce. In this study we combine original data on prey-capture strategies and strike velocities for European natricines with data for North American Natricinae obtained from the literature. We did not find any evidence for correlated evolution between prey-capture strategy and strike velocity with diet, but there was a significant correlation with prey density. Thus, our study suggests that prey density, rather than diet, played an important role in the evolution of the different prey-capture strategies and strike velocities of natricine snakes. © 2006 The Linnean Society of London, Biological Journal of the Linnean Society , 2006, 88 , 73‐83. ADDITIONAL KEYWORDS: diet ‐ foraging behaviour ‐ Natrix maura ‐ Natrix tesselata ‐ prey density ‐ strike velocity.

Background: Incremental cost-effectiveness and cost-utility analyses [health economic evaluations (HEEs)] of vaccines are routinely considered in decision making on immunization in various industrialized countries. While guidelines advocating more standardization of such HEEs (mainly for curative drugs) exist, several immunization-specific aspects (e.g. indirect effects or discounting approach) are still a subject of debate within the scientific community. Objective: The objective of this study was to develop a consensus framework for HEEs of vaccines to support the development of national guidelines in Europe. Methods: A systematic literature review was conducted to identify prevailing issues related to HEEs of vaccines. Furthermore, European experts in the field of health economics and immunization decision making were nominated and asked to select relevant aspects for discussion. Based on this, a workshop was held with these experts. Aspects on ‘mathematical modelling’, ‘health economics’ and ‘decision making’ were debated in group-work sessions (GWS) to formulate recommendations and/or—if applicable—to state ‘pros’ and ‘contras’. Results: A total of 13 different aspects were identified for modelling and HEE: model selection, time horizon of models, natural disease history, measures of vaccine-induced protection, duration of vaccine-induced protection, indirect effects apart from herd protection, target population, model calibration and validation, handling uncertainty, discounting, health-related quality of life, cost components, and perspectives. For decision making, there were four aspects regarding the purpose and the integration of HEEs of vaccines in decision making as well as the variation of parameters within uncertainty analyses and the reporting of results from HEEs. For each aspect, background information and an expert consensus were formulated. Conclusions: There was consensus that when HEEs are used to prioritize healthcare funding, this should be done in a consistent way across all interventions, including vaccines. However, proper evaluation of vaccines implies using tools that are not commonly used for therapeutic drugs. Due to the complexity of and uncertainties around vaccination, transparency in the documentation of HEEs and during subsequent decision making is essential. © 2015, The Author(s). Federal Ministry of Health Germany

Risk groups with increased vulnerability for influenza complications such as pregnant women, persons with underlying illnesses as well as persons who come into contact with them, such as health care workers, are currently given priority (along with other classic target groups) to receive seasonal influenza vaccination in Belgium. We aimed to evaluate this policy from a health care payer perspective by cost-effectiveness analysis in the three specific target groups above, while accounting for effects beyond the target group. Increasing the coverage of influenza vaccination is likely to be cost-effective for pregnant women (median (sic)6589 per quality-adjusted life-year (QALY) gained [(sic)4073-(sic)10,249]) and health care workers (median (sic)24,096/QALY gained [(sic)16,442-(sic)36,342]), if this can be achieved without incurring additional administration costs. Assuming an additional physician's consult is charged to administer each additional vaccine dose, the cost-effectiveness of vaccinating pregnant women depends strongly on the extent of its impact on the neonate's health. For health care workers, the assumed number of preventable secondary infections has a strong influence on the cost-effectiveness. Vaccinating people with underlying illnesses is likely highly cost-effective above 50 years of age and borderline cost-effective for younger persons, depending on relative life expectancy and vaccine efficacy in this risk group compared to the general population. The case-fatality ratios of the target group, of the secondary affected groups and vaccine efficacy are key sources of uncertainty. (C) 2014 Elsevier Ltd. All rights reserved. This study was commissioned and co-financed by the Health Care Knowledge Centre (KCE) of the Belgian Federal government. Adriaan Blommaert acknowledges support from the University of Antwerp concerted research action number 23405 (BOE-GOA); Joke Bilcke is supported by a postdoctoral grant from the Research Foundation Flanders (FWO); Yannick Vandendijck is supported by a doctoral grant of Hasselt University (BOF11D04FAEC). We also gratefully acknowledge financial support by the IAP Research Network P7/06 of the Belgian State (Belgian Science Policy).

Reexposure to viruses is assumed to strengthen humoral and cellular immunity via the secondary immune response. We studied the effects of frequent exposure to viral infectious challenges on immunity. Furthermore, we assessed whether repetitive exposures to varicella-zoster virus (VZV) elicited persistently high immune responses. Blood samples from 11 pediatricians and matched controls were assessed at 3 time points and 1 time point, respectively. Besides the assessment of general immunity by means of measuring T-cell subset percentages, antibody titers and gamma interferon (IFN-γ)/interleukin 2 (IL-2)-producing T-cell percentages against adenovirus type 5 (AdV-5), cytomegalovirus (CMV), tetanus toxin (TT), and VZV were determined. Pediatricians had lower levels of circulating CD4+-naive T cells and showed boosting of CD8+effector memory T cells. Although no effect on humoral immunity was seen, repetitive exposures to VZV induced persistently higher percentages of IFN-γ-positive T cells against all VZV antigens tested (VZV glycoprotein E [gE], VZV intermediate-early protein 62 [IE62], and VZV IE63) than in controls. T cells directed against latency-associated VZV IE63 benefitted the most from natural exogenous boosting. Although no differences in cellular or humoral immunity were found between the pediatricians and controls for AdV-5 or TT, we did find larger immune responses against CMV antigens in pediatricians. Despite the high infectious burden, we detected a robust and diverse immune system in pediatricians. Repetitive exposures to VZV have been shown to induce a stable increased level of VZV-specific cellular but not humoral immunity. Based on our observations, VZV IE63 can be considered a candidate for a zoster vaccine.

Background: Socioeconomic support reduced nonretention in a community-based antiretroviral therapy (ART) program in Uganda. However, resource implications of expanding socioeconomic support are large, and cost-effectiveness analysis can inform budget priorities. We compared the incremental benefits and costs of providing education, food, or both forms of support (dual support) with existing ART services from a health care provider's perspective. Methods: Costs and outcome data were collected from a cohort of 2371 adult patients with HIV receiving education, food, or dual support from Reach Out Mbuya between 2004 and 2010. The primary outcome was averted loss to follow-up. The number of follow-up days was calculated for each patient along with accrued service and fixed program costs for the alternative forms of socioeconomic support in USD by standard costing methods. The socioeconomic support types were compared incrementally over the study period. Results: After 7 years, 762 (33%) of the patients were loss to follow-up with 42% of them receiving food. In the presence of providing ART, education support was less costly and more effective than the alternatives. The average unit cost for education, food, and dual support were $237, $538, and $776, respectively. The average total annual costs were $88,643 for education, $538,005 for food, and $103,045 for dual support. Conclusions: Compared with food or dual support, investing in education of the children of ART patients is less costly and more effective in improving patient retention. Reach Out Mbuya should embrace this paradigm shift and channel its resources more efficiently and effectively by focusing on education support.

SUMMARYVaricella-zoster virus causes chickenpox (CP) and after reactivation herpes zoster (HZ). Vaccines are available against both diseases warranting an assessment of the pre-vaccination burden of disease. We collected data from relevant Belgian databases and performed five surveys of CP and HZ patients. The rates at which a general practitioner is visited at least once for CP and HZ are 346 and 378/100 000 person-years, respectively. The average CP and HZ hospitalization rates are 5·3 and 14·2/100 000 person-years respectively. The direct medical cost for HZ is about twice as large as the direct medical cost for CP. The quality-adjusted life years lost for ambulatory CP patients consulting a physician is more than double that of those not consulting a physician (0·010vs. 0·004). In conclusion, both diseases cause a substantial burden in Belgium.

Background We conducted for the first time a systematic review, including a meta-analysis, of the incidence of symptomatic rotavirus (RV) infections, because (1) it was shown to be an influential factor in estimating the cost-effectiveness of RV vaccination, (2) multiple community-based studies assessed it prospectively, (3) previous studies indicated, inconclusively, it might be similar around the world. Methodology Pubmed (which includes Medline) was searched for surveys assessing prospectively symptomatic (diarrheal) episodes in a general population and situation, which also reported on the number of the episodes being tested RV+ and on the persons and the time period observed. A bias assessment tool was developed and used according to Cochrane guidelines by 4 researchers with different backgrounds. Heterogeneity was explored graphically and by comparing fits of study-homogenous ‘fixed effects’ and -heterogeneous ‘random effects’ models. Data were synthesized using these models. Sensitivity analysis for uncertainty regarding data abstraction, bias assessment and included studies was performed. Principal Findings Variability between the incidences obtained from 20 studies is unlikely to be due to study groups living in different environments (tropical versus temperate climate, slums versus middle-class suburban populations), nor due to the year the study was conducted (from 1967 to 2003). A random effects model was used to incorporate unexplained heterogeneity and resulted in a global incidence estimate of 0.31 [0.19; 0.50] symptomatic RV infections per personyear of observation for children below 2 years of age, and of 0.24 [0.17; 0.34] when excluding the extreme high value of 0.84 reported for Mayan Indians in Guatemala. Apart from the inclusion/exclusion of the latter study, results were robust. Conclusions/Significance Rather than assumptions based on an ad-hoc selection of one or two studies, these pooled estimates (together with the measure for variability between populations) should be used as an input in future cost-effectiveness analyses of RV vaccination.

Many ectothermic animals are subject to fluctuating environmental temperatures during incubation as well as post-birth. Numerous studies examined the effects of incubation temperature or ambient temperature on various aspects of offspring phenotype. We investigated whether incubation temperature and ambient temperature have an interactive effect on offspring performance. Our study animal, the ectothermic vertebrate Lampropholis delicata (common garden skink; De Vis 1888), experiences fluctuating environmental temperatures caused by differential invasion of an exotic plant Vinca major (blue periwinkle). In the laboratory, eggs from wild-caught females were assigned to different incubation temperatures that mimicked variation in natural nests. The feeding performance and digestion time of each hatchling was tested at ambient temperatures that represented environ- ments invaded to different degrees by periwinkle. Incubation and ambient temperature interacted to affect a lizard's mobility, the time that it took to capture, subdue and handle a prey, and the number of handling 'errors' that it made while foraging. For a number of these characteristics, incubation-induced changes to a lizard's mass significantly affected this relationship. Irrespective of size, no interaction effect was found for digestion time: lizards digested food faster at warmer temperatures, regardless of incubation temperature. Thus, temperatures experienced during incubation may alter an animal's phenotype so that the surrounding thermal environment differentially affects aspects of feeding performance. Our results also demonstrate that incubation environment can induce changes to morphology and behaviour that carry over into a lizard's early life, and that in some cases these differences in phenotype interact to affect performance.We suggest that the immediate removal of exotic plants as part of a weed control strategy could have important implications for the foraging performance, and presumably fitness, of ectothermic animals.

This is one of the first studies to (1) describe the out-of-hospital burden of influenza-like-illness (ILI) and clinically diagnosed flu, also for patients not seeking professional medical care, (2) assess influential background characteristics, and (3) formally compare the burden of ILI in patients with and without a clinical diagnosis of flu. A general population sample with recent ILI experience was recruited during the 2011-2012 influenza season in Belgium. Half of the 2250 respondents sought professional medical care, reported more symptoms (especially more often fever), a longer duration of illness, more use of medication (especially antibiotics) and a higher direct medical cost than patients not seeking medical care. The disease and economic burden were similar for ambulatory ILI patients, irrespective of whether they received a clinical diagnosis of flu. On average, they experienced 5-6 symptoms over a 6-day period; required 1.6 physician visits and 86-91% took medication. An average episode amounted to is an element of 51-is an element of 53 in direct medical costs, 4 days of absence from work or school and the loss of 0.005 quality-adjusted life-years. Underlying illness led to greater costs and lower quality-of-life. The costs of ILI patients with clinically diagnosed flu tended to increase, while those of ILI patients without clinically diagnosed flu tended to decrease with age. Recently vaccinated persons experienced lower costs and a higher quality-of-life, but this was only the case for patients not seeking professional medical care. This information can be used directly to evaluate the implementation of cost-effective prevention and control measures for influenza. In particular to inform the evaluation of more widespread seasonal influenza vaccination, including in children, which is currently considered by many countries.

This study aims to explore irregular relationships between input and outcomes in cost-effectiveness analysis, accounting for interdependencies between many input parameters. We used a dynamic infectious disease transmission model investigating the cost-effectiveness of varicella and zoster vaccination as a case study. Incremental costs and effects were used separately as the outcomes of interest, rather than the ratio between these, and a single R 2 was calculated for groups of interdependent input parameters. Partial R 2 was obtained as measure for the marginal proportion of variance explained. The most important input parameters were related to zoster epidemiology and disease transmission. In case of linear relationships, R 2 is an easy to obtain importance measure, also in the presence of interdependent input parameters.

Purpose: Exposure to air pollution has been shown to be a trigger of acute myocardial infarction (AMI). As in those studies no correction was made for other meteorological factors, the present study wants to evaluate the independent environmental triggers of AMI. Methods: Weekly counts of AMI patients that underwent primary percutaneous coronary intervention (pPCI) in the period 2006-2009 in 32 Belgian PCI centres were extracted from the national PCI database. Those data were correlated with average weekly meteorological data obtained from daily measurements in 73 meteorological sites, equally distributed in Belgium. The following meteorological measures were investigated: air pollution expressed as particulate matter both less than 10μM (PM10) and less than 2.5μM (PM2.5), black smoke, temperature and relative humidity. Time-series and Poisson regression analysis were carried out to investigate the correlation between environmental changes and the incidence of AMI. Results: During the study period a total of 15964 AMI patients (mean age 63, 24.8% female) were admitted with a weekly average admission rate of 77±11 patients. Time-series (see figure) and univariate Poisson regression revealed a significant positive correlation between AMI's and air pollution and an inverse correlation between AMI's and temperature. Multivariate analysis showed that only low temperature was significantly correlated with AMI with an increase of 7% AMI's for each 10°C decrease in minimal temperature (0R 1.07 95% CI 1.04-1.11.) and that there was no significant effect of air pollution (0R 1.01 95% CI 1.00-1.02). ![Figure][1] time series Conclusions: In a global environmental model, low temperature is by far the most important environmental trigger for AMI, whereas air pollution has a negligible effect. [1]: pending:yes