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Here, we present the complete genome sequence of a Campylobacter strain isolated in the Netherlands from a patient with gastroenteritis. The strain showed >98% sequence identity to the novel Campylobacter species sequence recently recovered from metagenomic data, isolated from breastfed infants with diarrheal disease, and named " Candidatus Campylobacter infans.", (Copyright © 2021 Duim et al.)

BackgroundDuring the COVID-19 pandemic, many countries have implemented physical distancing measures to reduce transmission of SARS-CoV-2.AimTo measure the actual reduction of contacts when physical distancing measures are implemented.MethodsA cross-sectional survey was carried out in the Netherlands in 2016-17, in which participants reported the number and age of their contacts the previous day. The survey was repeated among a subsample of the participants in April 2020, after strict physical distancing measures were implemented, and in an extended sample in June 2020, after some measures were relaxed.ResultsThe average number of community contacts per day was reduced from 14.9 (interquartile range (IQR): 4-20) in the 2016-17 survey to 3.5 (IQR: 0-4) after strict physical distancing measures were implemented, and rebounded to 8.8 (IQR: 1-10) after some measures were relaxed. All age groups restricted their community contacts to at most 5, on average, after strict physical distancing measures were implemented. In children, the number of community contacts reverted to baseline levels after measures were eased, while individuals aged 70 years and older had less than half their baseline levels.ConclusionStrict physical distancing measures greatly reduced overall contact numbers, which likely contributed to curbing the first wave of the COVID-19 epidemic in the Netherlands. However, age groups reacted differently when measures were relaxed, with children reverting to normal contact numbers and elderly individuals maintaining restricted contact numbers. These findings offer guidance for age-targeted measures in future waves of the pandemic.

Estimation of the effective reproductive number Rt is important for detecting changes in disease transmission over time. During the Coronavirus Disease 2019 (COVID-19) pandemic, policy makers and public health officials are using Rt to assess the effectiveness of interventions and to inform policy. However, estimation of Rt from available data presents several challenges, with critical implications for the interpretation of the course of the pandemic. The purpose of this document is to summarize these challenges, illustrate them with examples from synthetic data, and, where possible, make recommendations. For near real-time estimation of Rt, we recommend the approach of Cori and colleagues, which uses data from before time t and empirical estimates of the distribution of time between infections. Methods that require data from after time t, such as Wallinga and Teunis, are conceptually and methodologically less suited for near real-time estimation, but may be appropriate for retrospective analyses of how individuals infected at different time points contributed to the spread. We advise caution when using methods derived from the approach of Bettencourt and Ribeiro, as the resulting Rt estimates may be biased if the underlying structural assumptions are not met. Two key challenges common to all approaches are accurate specification of the generation interval and reconstruction of the time series of new infections from observations occurring long after the moment of transmission. Naive approaches for dealing with observation delays, such as subtracting delays sampled from a distribution, can introduce bias. We provide suggestions for how to mitigate this and other technical challenges and highlight open problems in Rt estimation., Competing Interests: The authors have declared that no competing interests exist.

Estimation of the effective reproductive number, R t , is important for detecting changes in disease transmission over time. During the COVID-19 pandemic, policymakers and public health officials are using R t to assess the effectiveness of interventions and to inform policy. However, estimation of R t , such as Wallinga and Teunis (2004), are conceptually and methodologically less suited for near real-time estimation, but may be appropriate for retrospective analyses of how individuals infected at different time points contributed to spread. We advise against using methods derived from Bettencourt and Ribeiro (2008), as the resulting R t , we recommend the approach of Cori et al. (2013), which uses data from before time t and empirical estimates of the distribution of time between infections. Methods that require data from after time t , such as Wallinga and Teunis (2004), are conceptually and methodologically less suited for near real-time estimation, but may be appropriate for retrospective analyses of how individuals infected at different time points contributed to spread. We advise against using methods derived from Bettencourt and Ribeiro (2008), as the resulting R t estimates may be biased if the underlying structural assumptions are not met. Two key challenges common to all approaches are accurate specification of the generation interval and reconstruction of the time series of new infections from observations occurring long after the moment of transmission. Naive approaches for dealing with observation delays, such as subtracting delays sampled from a distribution, can introduce bias. We provide suggestions for how to mitigate this and other technical challenges and highlight open problems in R t estimation.

Objectives: To investigate the impact and efficiency of combined testing for HIV and other STIs on HIV and STI transmission among men who have sex with men (MSM) and to assess what subgroups of MSM should be targeted for frequent testing., Methods: We developed an agent-based transmission model that simulates infection with HIV or Neisseria gonorrhoeae (NG) among MSM. We examined scenarios with increased percentages of MSM getting tested six monthly, among all MSM or only specific subgroups of MSM (defined according to recent gonorrhoea, number of partners and engagement in condomless anal intercourse (CAI)) and scenarios with reduced intervals between HIV/STI tests., Results: The most efficient strategies were those with increased percentage of MSM getting tested every 6 months among MSM with a recent gonorrhoea diagnosis; or among MSM who had CAI and ≥10 partners; or MSM who had ≥10 partners. Over 10 years, these strategies resulted in 387-718 averted HIV infections and required 29-164 additional HIV tests per averted HIV infection or one to seven additional gonorrhoea tests per averted NG infection. The most effective strategy in reducing HIV transmission was the one where the intervals between tests were reduced by half, followed by the strategy with increased percentage of MSM getting tested every 6 months among all MSM. Over 10 years, these strategies resulted in 1362 and 1319 averted HIV infections, but required 663 and 584 additional HIV tests per averted HIV infection, respectively., Conclusions: Targeting MSM with recent gonorrhoea diagnosis or MSM with many partners is efficient in terms of HIV/STI tests needed to prevent new HIV or NG infections. Major reductions in HIV incidence can be achieved with consistent HIV/STI testing every 6 months among larger groups, including low-risk MSM. To impede HIV transmission, frequent testing should be combined with other prevention measures., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To obtain comprehensive insight into the association of ciprofloxacin use at different times in the past with the current risk of detecting resistance., Methods: This retrospective nested case-control study of ciprofloxacin users used Dutch data from the PHARMO Database Network and one laboratory for the period 2003-14. Cases and controls were selected as patients with an antibiotic susceptibility test (AST) indicating ciprofloxacin resistance or susceptibility, respectively. We performed univariable and multivariable conditional logistic regression analyses, defining time-dependent exposure using standard definitions (current ciprofloxacin use, used 0-30, 31-90, 91-180 and 181-360 days ago) and a flexible weighted cumulative effect (WCE) model with four alternative time windows of past doses (0-30, 0-90, 0-180 and 0-360 days)., Results: The study population consisted of 230 cases and 909 controls. Under the standard exposure definitions, the association of ciprofloxacin use with resistance decreased with time [current use: adjusted OR 6.8 (95% CI 3.6-12.4); used 181-360 days ago: 1.3 (0.8-1.9)]. Under the 90 day WCE model (best-fitting model), more recent doses were more strongly associated with resistance than past doses, as was longer or repeated treatment. The 180 day WCE model, which fitted the data equally well, suggested that doses taken 91-180 days ago were also significantly associated with resistance., Conclusions: The estimates for the association between ciprofloxacin use at different times and resistance show that ciprofloxacin prescribers should consider ciprofloxacin use 0-180 days ago to ensure that patients receive suitable treatment. The OR of ciprofloxacin resistance could be reduced by eliminating repeated ciprofloxacin prescription within 180 days and by treating for no longer than necessary., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

We collated contact tracing data from COVID-19 clusters in Singapore and Tianjin, China and estimated the extent of pre-symptomatic transmission by estimating incubation periods and serial intervals. The mean incubation periods accounting for intermediate cases were 4.91 days (95%CI 4.35, 5.69) and 7.54 (95%CI 6.76, 8.56) days for Singapore and Tianjin, respectively. The mean serial interval was 4.17 (95%CI 2.44, 5.89) and 4.31 (95%CI 2.91, 5.72) days (Singapore, Tianjin). The serial intervals are shorter than incubation periods, suggesting that pre-symptomatic transmission may occur in a large proportion of transmission events (0.4-0.5 in Singapore and 0.6-0.8 in Tianjin, in our analysis with intermediate cases, and more without intermediates). Given the evidence for pre-symptomatic transmission, it is vital that even individuals who appear healthy abide by public health measures to control COVID-19., Competing Interests: LT, JS, MC, EG, WL, MS, LZ, DC No competing interests declared, JW, CC Reviewing editor, eLife, (© 2020, Tindale et al.)

Background: To optimize the focus of future public information campaigns in The Netherlands promoting the uptake of vaccines among adults and children, we quantified the contribution of several attributes to the vaccination decision., Method: We performed a discrete choice experiment (DCE) among Dutch adults including six attributes, i.e. vaccine effectiveness, vaccine-preventable burden of disease (specified in severity and frequency), accessibility of vaccination in terms of co-payment and prescription requirements, frequency of mild side-effects, population-level vaccination coverage and local vaccination coverage among family and friends. Participants answered the DCE from their own perspective ('oneself' group) or with regard to a vaccine decision for their youngest child ('child' group). The data was analysed by means of panel mixed logit models., Results: We included 1547 adult participants (825 'oneself' and 722 'child'). Vaccine effectiveness was the most important attribute in the 'oneself' group, followed by burden of disease (relative importance (RI) 78%) and accessibility (RI 76%). In the 'child' group, burden of disease was most important, but tied closely with vaccine effectiveness (RI 97%). Of less importance was the risk of mild vaccine-related side-effects and both population and local vaccination coverage. Interestingly, participants were more willing to vaccinate when uptake among the population or family and friends was high, indicating that social influence and social norms plays a role., Conclusions: Vaccine effectiveness and disease severity are key attributes in vaccination decision-making for adults making a decision for themselves and for parents who decide for their children. Hence, public information campaigns for both adult and child vaccination should primarily focus on these two attributes. In addition, reinforcing social norms may be considered.

The national vaccination rate in young children in the Netherlands has decreased in recent years. This has led to social and political discussions, for instance about compulsory vaccination for children in child-care. The national commission on child-care and vaccination has advised that vaccination should be made compulsory when the rate of vaccination has declined to a pre-determined lower threshold, to be determined by the government. A frequently quoted lower threshold is 95%. The idea behind this is the concept of a critical vaccination rate, a threshold needed for elimination of an infection in a large, well-mixed population. In this article we argue why the critical vaccination rate does not offer a scientific basis for a lower threshold to the national vaccination rate.

BackgroundEstimating key infectious disease parameters from the coronavirus disease (COVID-19) outbreak is essential for modelling studies and guiding intervention strategies.AimWe estimate the generation interval, serial interval, proportion of pre-symptomatic transmission and effective reproduction number of COVID-19. We illustrate that reproduction numbers calculated based on serial interval estimates can be biased.MethodsWe used outbreak data from clusters in Singapore and Tianjin, China to estimate the generation interval from symptom onset data while acknowledging uncertainty about the incubation period distribution and the underlying transmission network. From those estimates, we obtained the serial interval, proportions of pre-symptomatic transmission and reproduction numbers.ResultsThe mean generation interval was 5.20 days (95% credible interval (CrI): 3.78-6.78) for Singapore and 3.95 days (95% CrI: 3.01-4.91) for Tianjin. The proportion of pre-symptomatic transmission was 48% (95% CrI: 32-67) for Singapore and 62% (95% CrI: 50-76) for Tianjin. Reproduction number estimates based on the generation interval distribution were slightly higher than those based on the serial interval distribution. Sensitivity analyses showed that estimating these quantities from outbreak data requires detailed contact tracing information.ConclusionHigh estimates of the proportion of pre-symptomatic transmission imply that case finding and contact tracing need to be supplemented by physical distancing measures in order to control the COVID-19 outbreak. Notably, quarantine and other containment measures were already in place at the time of data collection, which may inflate the proportion of infections from pre-symptomatic individuals.

An outbreak of measles in the Netherlands in 2013-2014 provided an opportunity to assess the effect of MMR vaccination on severity and infectiousness of measles.Measles is notifiable in the Netherlands. We used information on vaccination, hospitalisation, complications, and most likely source(s) of infection from cases notified during the outbreak. When a case was indicated as a likely source for at least one other notified case, we defined it as infectious. We estimated the age-adjusted effect of vaccination on severity and infectiousness with logistic regression.Of 2676 notified cases, 2539 (94.9%) were unvaccinated, 121 (4.5%) were once-vaccinated and 16 (0.6%) were at least twice-vaccinated; 328 (12.3%) cases were reported to have complications and 172 (6.4%) cases were hospitalised. Measles in twice-vaccinated cases led less often to complications and/or hospitalisation than measles in unvaccinated cases (0% and 14.5%, respectively, aOR 0.1 (95% CI 0-0.89), P = 0.03). Of unvaccinated, once-vaccinated and twice-vaccinated cases, respectively, 194 (7.6%), seven (5.1%) and 0 (0%) were infectious. These differences were not statistically significant (P > 0.05).Our findings suggest a protective effect of vaccination on the occurrence of complications and/or hospitalisation as a result of measles and support the WHO recommendation of a two-dose MMR vaccination schedule.

Objectives: To assess the impact of a preexposure prophylaxis (PrEP) programme for high-risk men who have sex with men (MSM), which includes gonorrhoea testing and treatment, on the transmission of HIV and Neisseria among MSM in the Netherlands and the cost-effectiveness of such programme with and without risk compensation (in the form of reduced condom use)., Methods: We developed a stochastic agent-based transmission model of HIV and gonorrhoea. We simulated a capped (max 2.5% of MSM) and uncapped (5.5% of MSM in 2018 declining to 3% in 2027) daily PrEP programme for high-risk MSM, with 3-monthly HIV and gonorrhoea testing, with and without risk compensation. Epidemiological outcomes were calculated from the transmission model and used in an economic model to calculate costs, quality-adjusted life-years (QALY), and incremental cost-effectiveness ratios (ICER), over 2018-2027, taking a healthcare payer perspective., Results: Without risk compensation, PrEP can lead to a reduction of 61 or 49% in the total number of new HIV infections in 2018-2027, if the programme is uncapped or capped to 2.5% of MSM, respectively. With risk compensation, this reduction can be 63 or 46% in the uncapped and capped programmes, respectively. In all scenarios, gonorrhoea prevalence decreased after introducing PrEP. Without risk compensation, 92% of simulations were cost-effective (of which 52% cost-saving). With risk compensation, 73% of simulations were cost-effective (of which 23% was cost-saving)., Conclusion: A nationwide PrEP programme for high-risk MSM can result in substantial reductions in HIV and gonorrhoea transmission and be cost-effective, even with risk compensation.

A novel coronavirus (2019-nCoV) is causing an outbreak of viral pneumonia that started in Wuhan, China. Using the travel history and symptom onset of 88 confirmed cases that were detected outside Wuhan in the early outbreak phase, we estimate the mean incubation period to be 6.4 days (95% credible interval: 5.6-7.7), ranging from 2.1 to 11.1 days (2.5th to 97.5th percentile). These values should help inform 2019-nCoV case definitions and appropriate quarantine durations.

Background: The present study aims to assess the cost-effectiveness of an influenza vaccination program for children in the Netherlands. This requires an evaluation of the long-term impact of such a program on the burden of influenza across all age groups, using a transmission model that accounts for the seasonal variability in vaccine effectiveness and the shorter duration of protection following vaccination as compared to natural infection., Methods: We performed a cost-effectiveness analysis based on a stochastic dynamic transmission model that has been calibrated to reported GP visits with influenza-like illness in the Netherlands over 11 seasons (2003/2004 to 2014/2015). We analyzed the costs and effects of extending the current program with vaccination of children aged 2-16 years at 50% coverage over 20 consecutive seasons. We measured the effects in quality-adjusted life-years (QALYs) and we adopted a societal perspective., Results: The childhood vaccination program is estimated to have an average incremental cost-effectiveness ratio (ICER) of €3944 per QALY gained and is cost-effective in the general population (across 1000 simulations; conventional Dutch threshold of €20,000 per QALY gained). The childhood vaccination program is not estimated to be cost-effective for the target-group itself with an average ICER of €57,054 per QALY gained. Uncertainty analyses reveal that these ICERs hide a wide range of outcomes. Even though introduction of a childhood vaccination program decreases the number of infections, it tends to lead to larger epidemics: in 23.3% of 1000 simulations, the childhood vaccination program results in an increase in seasons with a symptomatic attack rate larger than 5%, which is expected to cause serious strain on the health care system. In 6.4% of 1000 simulations, the childhood vaccination program leads to a net loss of QALYs. These findings are robust across different targeted age groups and vaccination coverages., Conclusions: Modeling indicates that childhood influenza vaccination is cost-effective in the Netherlands. However, childhood influenza vaccination is not cost-effective when only outcomes for the children themselves are considered. In approximately a quarter of the simulations, the introduction of a childhood vaccination program increases the frequency of seasons with a symptomatic attack rate larger than 5%. The possibility of an overall health loss cannot be excluded.

Objectives: To assess the cost-effectiveness of increased consistent HIV testing among MSM in the Netherlands., Methods: Among MSM testing at sexually transmitted infection clinics in the Netherlands in 2014-2015, approximately 20% tested consistently every 6 months. We examined four scenarios with increased percentage of MSM testing every 6 months: a small and a moderate increase among all MSM; a small and a moderate increase only among MSM with at least 10 partners in the preceding 6 months. We used an agent-based model to calculate numbers of HIV infections and AIDS cases prevented with increased HIV testing. These numbers were used in an economic model to calculate costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) due to increased testing, over 2018-2027, taking a healthcare payer perspective., Results: A small increase in the percentage testing every 6 months among all MSM resulted in 490 averted HIV infections and an average ICER of &OV0556;27 900/QALY gained. A moderate increase among all MSM, resulted in 1380 averted HIV infections and an average ICER of &OV0556;36 700/QALY gained. Both were not cost-effective, with a &OV0556;20 000 willingness-to-pay threshold. Increasing the percentage testing every 6 months only among MSM with at least 10 partners in the preceding 6 months resulted in less averted HIV infections than increased testing among all MSM, but was on average cost-saving., Conclusion: Increased HIV testing can prevent considerable numbers of new HIV infections among MSM, but may be cost-effective only if targeted at high-risk individuals, such as those with many partners.

Background: Health economic evaluations are often required before implementing a vaccination programme. Such evaluations rarely consider the historical context of a vaccination programme. We review the financial history of vaccination programmes in the Netherlands, and compare these to demographic and macroeconomic developments as well as avoided mortality burden., Methods: Previously uncatalogued historical expenditures on the Dutch National Immunisation Programme (NIP) and influenza vaccination were obtained from official reports. Costs were adjusted for inflation using Consumer Price Indices and expressed in Euro of 2016. Estimates on mortality burden averted were obtained from previous research and used to calculate the ratio of expenses to averted mortality burden for vaccinations against diphtheria, tetanus, pertussis, polio, measles, mumps and rubella for birth cohorts 1953-1992., Results: Developments towards a uniform government funded NIP started early 1950s with vaccinations against diphtheria, pertussis and tetanus, culminating in its official launch in 1957 together with polio vaccinations. Since the 1980s, expenditure increased nearly five-fold mostly due to the addition of new vaccines, while spending on already implemented vaccinations tended to decline. Overall, expenditure increased from € 5 million in 1957 to € 93 million in 2014. Relative to total healthcare expenditure, the NIP contributed little, ranging between 0.05% and 0.14%. Spending on influenza vaccination increased from € 37 million in 1996 to € 52 million in 2014, while relative to total healthcare expenditure it decreased from 0.069% to 0.055%. In 2014, 0.15% of healthcare expenditure and € 533 per birth was spent on vaccination programmes. Overall, for birth cohorts 1953-1992, € 5.4 thousand (95% confidence interval: 4.0-7.3) was expended per year-of-life-lost averted., Conclusion: The actual costs per year-of-life gained are more favorable than estimated here since averted medical costs were not included. Although expenditure on vaccination programmes increased substantially, the contribution to overall healthcare expenditure remained small., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

During an infectious disease outbreak, timely information on the number of new symptomatic cases is crucial. However, the reporting of new cases is usually subject to delay due to the incubation period, time to seek care, and diagnosis. This results in a downward bias in the numbers of new cases by the times of symptoms onset towards the current day. The real-time assessment of the current situation while correcting for underreporting is called nowcasting. We present a nowcasting method based on bivariate P-spline smoothing of the number of reported cases by time of symptoms onset and delay. Our objective is to predict the number of symptomatic-but-not-yet-reported cases and combine these with the already reported symptomatic cases into a nowcast. We assume the underlying two-dimensional reporting intensity surface to be smooth. We include prior information on the reporting process as additional constraints: the smooth surface is unimodal in the reporting delay dimension, is (almost) zero at a predefined maximum delay and has a prescribed shape at the beginning of the outbreak. Parameter estimation is done efficiently by penalized iterative weighted least squares. We illustrate our method on a large measles outbreak in the Netherlands. We show that even with very limited information the method is able to accurately predict the number of symptomatic-but-not-yet-reported cases. This results in substantially improved monitoring of new symptomatic cases in real time.

Background: Researchers increasingly use social contact data to inform models for infectious disease spread with the aim of guiding effective policies about disease prevention and control. In this article, we undertake a systematic review of the study design, statistical analyses, and outcomes of the many social contact surveys that have been published., Methods: We systematically searched PubMed and Web of Science for articles regarding social contact surveys. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines as closely as possible., Results: In total, we identified 64 social contact surveys, with more than 80% of the surveys conducted in high-income countries. Study settings included general population (58%), schools or universities (37%), and health care/conference/research institutes (5%). The largest number of studies did not focus on a specific age group (38%), whereas others focused on adults (32%) or children (19%). Retrospective (45%) and prospective (41%) designs were used most often with 6% using both for comparison purposes. The definition of a contact varied among surveys, e.g., a nonphysical contact may require conversation, close proximity, or both. We identified age, time schedule (e.g., weekday/weekend), and household size as relevant determinants of contact patterns across a large number of studies., Conclusions: We found that the overall features of the contact patterns were remarkably robust across several countries, and irrespective of the study details. By considering the most common approach in each aspect of design (e.g., sampling schemes, data collection, definition of contact), we could identify recommendations for future contact data surveys that may be used to facilitate comparison between studies.

Objective: Current guidelines recommend screening for latent tuberculosis infection (LTBI) with a tuberculin skin test (TST) or interferon gamma release assay (IGRA), or both. Many also recommend chest radiography (CXR), although its added value is uncertain. This systematic review assessed the prevalence of abnormalities suggestive of LTBI on CXR (LTBI-CXR lesions) and evaluated the strength of the association., Method: We searched 4 databases up to September 2017 and systematically reviewed cross-sectional and cohort studies reporting LTBI-CXR lesions in individuals with a positive TST or IGRA, or both, result. Prevalence estimates were pooled using random effects models and odds ratios (ORs) were used to calculate risk estimates., Results: In the 26 included studies, the pooled proportion of individuals with LTBI having LTBI-CXR lesions was 0.15 (95% confidence interval [CI], 0.12-0.18]. In 16 studies that reported on individuals with LTBI and uninfected controls, LTBI-CXR lesions were associated with a positive TST result ≥ 5 mm or ≥ 10 mm (OR, 2.45; 95% CI, 1.00-5.99; and OR, 2.06; 95% CI, 1.38-3.09, respectively) and with a positive QuantiFERON result (OR, 1.99; 95% CI, 1.17-3.39) compared to CXR in uninfected controls. Although few studies reported specified lesions, calcified nodules were most frequently reported in individuals with LTBI (proportion, 0.07; 95% CI, 0.02-0.11)., Conclusions: Lesions on CXR suggestive of previous infection with Mycobacterium tuberculosis were significantly associated with positive tests for LTBI, although the sensitivity was only 15%. This finding may have added value when detection of past LTBI is important but immunodiagnostic tests may be unreliable., (© The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Luminescence signals of quartz and feldspar minerals are widely used to determine the burial age of Quaternary sediments. Although luminescence signals bleach rapidly with sunlight exposure, incomplete bleaching may affect luminescence ages, in particular in fluvial settings where an unbleached remnant signal is commonly encountered in modern alluvium. Here, we use feldspar single-grain post-infrared IR stimulation (pIRIR) dating to show that recent (<11 ka) fluvial terraces of the Rangitikei River (New Zealand) were formed in a context of non-linear incision rate. We relate this pattern to the rapid reinstatement of steady-state incision following the formation of a major, climate-driven, aggradation terrace, causing a phase of accelerated incision. In addition, we show systematic variations in the proportion of unbleached grains in the fluvial sediments over time, mirroring incision rate at the time of deposition. Deposits formed during rapid incision contain fewer bleached grains, which we attribute to large input of unbleached material and limited bleaching opportunities during fluvial transport. This finding demonstrates that the luminescence signals recorded in fluvial terraces not only yield age information, but also inform us on past fluvial transport and ultimately, landscape dynamics.

Prediction of ecosystem response to global environmental change is a pressing scientific challenge of major societal relevance. Many ecosystems display nonlinear responses to environmental change, and may even undergo practically irreversible 'regime shifts' that initiate ecosystem collapse. Recently, early warning signals based on spatiotemporal metrics have been proposed for the identification of impending regime shifts. The rapidly increasing availability of remotely sensed data provides excellent opportunities to apply such model-based spatial early warning signals in the real world, to assess ecosystem resilience and identify impending regime shifts induced by global change. Such information would allow land-managers and policy makers to interfere and avoid catastrophic shifts, but also to induce regime shifts that move ecosystems to a desired state. Here, we show that the application of spatial early warning signals in real-world landscapes presents unique and unexpected challenges, and may result in misleading conclusions when employed without careful consideration of the spatial data and processes at hand. We identify key practical and theoretical issues and provide guidelines for applying spatial early warning signals in heterogeneous, real-world landscapes based on literature review and examples from real-world data. Major identified issues include (1) spatial heterogeneity in real-world landscapes may enhance reversibility of regime shifts and boost landscape-level resilience to environmental change (2) ecosystem states are often difficult to define, while these definitions have great impact on spatial early warning signals and (3) spatial environmental variability and socio-economic factors may affect spatial patterns, spatial early warning signals and associated regime shift predictions. We propose a novel framework, shifting from an ecosystem perspective towards a landscape approach. The framework can be used to identify conditions under which resilience assessment with spatial remotely sensed data may be successful, to support well-informed application of spatial early warning signals, and to improve predictions of ecosystem responses to global environmental change., (© 2019 The Authors. Global Change Biology Published by John Wiley & Sons Ltd.)

Current HPV vaccines target a subset of the oncogenic human papillomavirus (HPV) types. If HPV types compete during infection, vaccination may trigger replacement by the non-targeted types. Existing approaches to assess the risk of type replacement have focused on detecting competitive interactions between pairs of vaccine and non-vaccine types. However, methods to translate any inferred pairwise interactions into predictors of replacement have been lacking. In this paper, we develop practical predictors of type replacement in a multi-type setting, readily estimable from pre-vaccination longitudinal or cross-sectional prevalence data. The predictors we propose for replacement by individual non-targeted types take the form of weighted cross-hazard ratios of acquisition versus clearance, or aggregate odds ratios of coinfection with the vaccine types. We elucidate how the hazard-based predictors incorporate potentially heterogeneous direct and indirect type interactions by appropriately weighting type-specific hazards and show when they are equivalent to the odds-based predictors. Additionally, pooling type-specific predictors proves to be useful for predicting increase in the overall non-vaccine-type prevalence. Using simulations, we demonstrate good performance of the predictors under different interaction structures. We discuss potential applications and limitations of the proposed methodology in predicting type replacement, as compared to existing approaches. This article is part of the theme issue 'Silent cancer agents: multi-disciplinary modelling of human DNA oncoviruses'.

IntroductionWith growing amounts of data available, identification of clusters of persons linked to each other by transmission of an infectious disease increasingly relies on automated algorithms. We propose cluster finding to be a two-step process: first, possible transmission clusters are identified using a cluster algorithm, second, the plausibility that the identified clusters represent genuine transmission clusters is evaluated.AimTo introduce visual tools to assess automatically identified clusters.MethodsWe developed tools to visualise: (i) clusters found in dimensions of time, geographical location and genetic data; (ii) nested sub-clusters within identified clusters; (iii) intra-cluster pairwise dissimilarities per dimension; (iv) intra-cluster correlation between dimensions. We applied our tools to notified mumps cases in the Netherlands with available disease onset date (January 2009 - June 2016), geographical information (location of residence), and pathogen sequence data (n = 112). We compared identified clusters to clusters reported by the Netherlands Early Warning Committee (NEWC).ResultsWe identified five mumps clusters. Three clusters were considered plausible. One was questionable because, in phylogenetic analysis, genetic sequences related to it segregated in two groups. One was implausible with no smaller nested clusters, high intra-cluster dissimilarities on all dimensions, and low intra-cluster correlation between dimensions. The NEWC reports concurred with our findings: the plausible/questionable clusters corresponded to reported outbreaks; the implausible cluster did not.ConclusionOur tools for assessing automatically identified clusters allow outbreak investigators to rapidly spot plausible transmission clusters for mumps and other human-to-human transmissible diseases. This fast information processing potentially reduces workload.

Objectives: Triazole resistance in Aspergillus spp. is emerging and complicates prophylaxis and treatment of invasive aspergillosis (IA) worldwide. New polymerase chain reaction (PCR) tests on broncho-alveolar lavage (BAL) fluid allow for detection of triazole resistance at a genetic level, which has opened up new possibilities for targeted therapy. In the absence of clinical trials, a modelling study delivers estimates of the added value of resistance detection with PCR, and which empiric therapy would be optimal when local resistance rates are known., Design: A decision-analytic modelling study was performed based on epidemiological data of IA, extended with estimated dynamics of resistance rates and treatment effectiveness. Six clinical strategies were compared that differ in use of PCR diagnostics (used vs not used) and in empiric therapeutic choice in case of unknown triazole susceptibility: voriconazole, liposomal amphotericin B (LAmB) or both. Outcome measures were proportion of correct treatment, survival and serious adverse events., Results: Implementing aspergillus PCR tests was projected to result in residual treatment-susceptibility mismatches of <5% for a triazole resistance rate up to 20% (using voriconazole). Empiric LAmB outperformed voriconazole at resistance rates >5-20%, depending on PCR use and estimated survival benefits of voriconazole over LAmB. Combination therapy of voriconazole and LAmB performed best at all resistance rates, but the advantage over the other strategies should be weighed against the expected increased number of drug-related serious adverse events. The advantage of combination therapy over LAmB monotherapy became smaller at higher triazole resistance rates., Conclusions: Introduction of current aspergillus PCR tests on BAL fluid is an effective way to increase the proportion of patients that receive targeted therapy for IA. The results indicate that close monitoring of background resistance rates and adverse drug events are important to attain the potential benefits of LAmB. The choice of strategy ultimately depends on the probability of triazole resistance, the availability of PCR and individual patient characteristics., (Copyright © 2018 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.)

Optically stimulated luminescence (OSL) dating of sediment, based on the accumulation of trapped charge in natural crystals since their last exposure to daylight, has revolutionised our understanding of the late Quaternary period. Recently, a complementary technique called luminescence rock surface dating (RSD), which uses differential spatial eviction of trapped charges in rocks exposed to daylight, has been developed to derive exposure and burial ages, and hard-rock erosion rates. In its current form, the RSD technique suffers from labour intensive sample preparation, uncertainties in the depth and dose rate estimates, and poor resolution of the luminescence-depth profile. Here, we develop a novel, 2D luminescence imaging technique for RSD of large rock slabs (3 × 5 cm) to overcome these challenges. We utilize the recently discovered infrared photoluminescence (IRPL) signal for direct, non-destructive imaging of the luminescence-depth profile in a sub-aerially exposed granitic rock, with an unprecedented spatial resolution of ~140 µm. We further establish a correlation between luminescence and geochemistry using micro X-ray fluorescence (µXRF) spectroscopy. Our study promises a substantial advancement in luminescence imaging and paves the path towards novel applications using 2D dating, micro-dosimetry in mixed composition samples, and portable instrumentation for in-situ luminescence measurements.

Introduction: Typhoid fever is a global health problem, causing significant morbidity and mortality. Currently, the most widely used vaccine is the typhoid Vi capsular polysaccharide (Vi-PS) vaccine. While epidemiological studies on its efficacy have been performed in children in endemic countries, there are no efficacy studies evaluating its use in travel medicine. Response to vaccination may differ in travellers receiving immunosuppressive therapy. This study investigates the humoral response to Vi-PS vaccination in travellers receiving immunosuppressive therapy for rheumatoid disease., Methods: We recruited patients from the LUMC rheumatology outpatient clinic and travellers from the travel clinic who had previously received Vi-PS vaccination and also immunosuppressive therapy for rheumatoid disease. We analysed blood samples acquired from 42 patients over a period of 3 years. We estimated the length of persistence of protective titres using the survival analysis using multiple cut-off values for protection and measured titre half-life and the influence of immunosuppressive medication on titre half-life using mixed models., Results: Anti-Vi-PS antibody levels stayed above 10 EU/ml for a mean of 13.3 years, above 15 EU/ml for a mean of 10.1 years and above 20 EU/ml for a mean of 8.6 years after Vi-PS vaccination. Titre half-life was 7.5 years (95% CI 5.0-14.7 years, P < 0.001). No significant influence of medication on titre half-life was found., Conclusion: Both persistence of protective antibody titres and titre half-life are longer than expected based on other studies. This warrants further study in adult volunteers, both in healthy individuals and patients suffering from rheumatoid disease.

BackgroundIn the Netherlands, echovirus type 6 (E6) is identified through clinical and environmental enterovirus surveillance (CEVS and EEVS). AimWe aimed to identify E6 transmission clusters and to assess the role of EEVS in surveillance and early warning of E6. MethodsWe included all E6 strains from CEVS and EEVS from 2007 through 2016. CEVS samples were from patients with enterovirus illness. EEVS samples came from sewage water at pre-specified sampling points. E6 strains were defined by partial VP1 sequence, month and 4-digit postcode. Phylogenetic E6 clusters were detected using pairwise genetic distances. We identified transmission clusters using a combined pairwise distance in time, place and phylogeny dimensions. ResultsE6 was identified in 157 of 3,506 CEVS clinical episodes and 92 of 1,067 EEVS samples. Increased E6 circulation was observed in 2009 and from 2014 onwards. Eight phylogenetic clusters were identified; five included both CEVS and EEVS strains. Among these, identification in EEVS did not consistently precede CEVS. One phylogenetic cluster was dominant until 2014, but genetic diversity increased thereafter. Of 14 identified transmission clusters, six included both EEVS and CEVS; in two of them, EEVS identification preceded CEVS identification. Transmission clusters were consistent with phylogenetic clusters, and with previous outbreak reports. ConclusionAlgorithms using combined time-place-phylogeny data allowed identification of clusters not detected by any of these variables alone. EEVS identified strains circulating in the population, but EEVS samples did not systematically precede clinical case surveillance, limiting EEVS usefulness for early warning in a context where E6 is endemic.

Background: Influenza vaccination is recommended in patients with cancer to reduce influenza-related complications. Recently, more immune-related adverse events (irAEs) were demonstrated in patients with lung cancer who were vaccinated with the trivalent seasonal influenza vaccine during anti-programmed death receptor 1 (PD-1) immunotherapy. Confirmation of these findings is essential before recommendations on influenza vaccination may be revoked., Methods: In this cohort study in patients with lung cancer receiving nivolumab 3 mg/kg every 2 weeks during two influenza seasons (2015/16-2016/17), irAEs have been monitored. Incidence, timing and severity of irAEs were compared between vaccinated patients and non-vaccinated patients., Findings: In a compassionate use programme, 127 patients with lung cancer had been treated with at least one dose of nivolumab during two national influenza vaccination campaigns from September until December of 2015 and 2016. Forty-two patients had received the influenza vaccine, and 85 patients were not vaccinated. Median follow-up period was 118 days (interquartile range 106-119). Mean age was 64 years (range 46-83). In vaccinated and non-vaccinated patients, the incidence of irAEs was 26% and 22%, respectively, rate ratio 1.20 (95% confidence interval [CI] 0.51-2.65). The incidence of serious irAEs was 7% and 4%, respectively, rate ratio 2.07 (95% CI 0.28-15.43). Influenza vaccination while receiving nivolumab did not result in significant differences in the rates of discontinuation, death, clinical deterioration or tumour response between the groups., Interpretation: Influenza vaccination in patients with lung cancer receiving anti-PD-1 immunotherapy does not induce irAEs in our cohort. With this result, influenza vaccination should not be deterred from this group of patients., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Measles is a notifiable disease, but not everyone infected seeks care, nor is every consultation reported. We estimated the completeness of reporting during a measles outbreak in The Netherlands in 2013-2014. Children below 15 years of age in a low vaccination coverage community (n = 3422) received a questionnaire to identify measles cases. Cases found in the survey were matched with the register of notifiable diseases to estimate the completeness of reporting. Second, completeness of reporting was assessed by comparing the number of susceptible individuals prior to the outbreak with the number of reported cases in the surveyed community and on a national level.We found 307 (15%) self-identified measles cases among 2077 returned questionnaires (61%), of which 27 could be matched to a case reported to the national register; completeness of reporting was 8.8%. Based on the number of susceptible individuals and number of reported cases in the surveyed community and on national level, the completeness of reporting was estimated to be 9.1% and 8.6%, respectively. Estimating the completeness of reporting gave almost identical estimates, which lends support to the credibility and validity of both approaches. The size of the 2013-2014 outbreak approximated 31 400 measles infections.

Objective: To quantify the impact of long-standing vaccination programmes on notified cases in the Netherlands., Design: Estimates based on model projections of historical morbidity data., Method: We collected and digitised previously unavailable monthly case notifications of diphtheria, poliomyelitis, mumps and rubella in the Netherlands over the period 1919-2015. Poisson regression models accounting for seasonality, multi-year cycles, secular trends and auto-correlation were fit to pre-vaccination periods. Cases averted were calculated as the difference between observed and expected cases based on model projections., Results: In the first 13 years of mass vaccinations, case notifications declined rapidly with 18,900 (95%-CI: 12,000-28,600) notified cases of diphtheria averted, 5100 (95%-CI: 2200-13,500) cases of poliomyelitis, and 1800 (95%-CI: 1000-3200) cases of mumps. Vaccination of 11-year-old girls against rubella averted 13700 (95%-CI: 1400-38,300) cases, while universal rubella vaccination averted 700 (95%-CI: 80-2300) cases., Conclusion: These findings show that vaccination programmes have contributed substantially to the reduction of infectious diseases in the Netherlands.

Holocene drift-sand activity in the northwest European sand belt is commonly directly linked to population pressure (agricultural activity) or to climate change (e.g. storminess). In the Pleistocene sand areas of the Netherlands, small-scale Holocene drift-sand activity began in the Mesolithic, whereas large-scale sand drifting started during the Middle Ages. This last phase not only coincides with the intensification of farming and demographic pressure but also is commonly associated with a colder climate and enhanced storminess. This raises the question to what extent drift-sand activity can be attributed to either human activities or natural forcing factors. In this study, we compare the spatial and temporal patterns of drift-sand occurrence for the four characteristic Pleistocene sand regions in the Netherlands for the period between 1000 BC and AD 1700. To this end, we compiled a new supra-regional overview of drift-sand activity based on age estimates ( 14 C, optically stimulated luminescence (OSL), archaeological and historical ages). The occurrence of sand drifting was then compared in time and space with historical-route networks, relative vegetation openness and climate. Results indicate a constant but low drift-sand activity between 1000 BC and AD 1000, interrupted by a remarkable decrease in activity around the BC/AD transition. It is evident that human pressure on the landscape was most influential on initiating sand drifting: this is supported by more frequent occurrences close to routes and the uninterrupted increase of drift-sand activity from AD 900 onwards, a period of high population density and large-scale deforestation. Once triggered by human activities, this drift-sand development was probably further intensified several centuries later during the cold and stormier 'Little Ice Age' (LIA; AD 1570-1850).

Background: Many multivalent vaccines target only a subset of all pathogenic types. If vaccine and nonvaccine types compete, vaccination may lead to type replacement. The plausibility of type replacement has been assessed using the odds ratio (OR) of co-infections in cross-sectional prevalence data, with OR > 1 being interpreted as low risk of type replacement. The usefulness of the OR as a predictor for type replacement is debated, as it lacks a theoretical justification, and there is no framework explaining under which assumptions the OR predicts type replacement., Methods: We investigate the values that the OR can take based on deterministic S usceptible- I infected- S usceptible and S usceptible- Infected- Recovered- S usceptible multitype transmission models. We consider different mechanisms of type interactions and explore parameter values ranging from synergistic to competitive interactions., Results: We find that OR > 1 might mask competition because of confounding due to unobserved common risk factors and cross-immunity, as indicated by earlier studies. We prove mathematically that unobserved common risk factors lead to an elevation of the OR, and present an intuitive explanation why cross-immunity increases the OR. We find that OR < 1 is predictive for type replacement in the absence of immunity. With immunity, OR < 1 remains predictive under biologically reasonable assumptions of unidirectional interactions during infection, and an absence of immunity-induced synergism., Conclusions: Using the OR in cross-sectional data to predict type replacement is justified, but is only unambiguous under strict assumptions. An accurate prediction of type replacement requires pathogen-specific knowledge on common risk factors and cross-immunity.

We estimated the influenza mortality burden in adults aged 60 years or older in the Netherlands in terms of years of life lost, taking into account competing mortality risks. Weekly laboratory surveillance data for influenza and other respiratory pathogens and weekly extreme temperature served as covariates in Poisson regression models fitted to weekly mortality data, specific to age group, for the period 1999-2000 through 2012-2013. Burden for age groups 60-64 years through 85-89 years was computed as years of life lost before age 90 (YLL90), using restricted mean lifetime survival analysis and accounting for competing risks. Influenza-attributable mortality burden was greatest for persons aged 80-84 years, at 914 YLL90 per 100,000 persons (95% uncertainty interval: 867, 963), followed by persons aged 85-89 years (787 YLL90/100,000; 95% uncertainty interval: 741, 834). Ignoring competing mortality risks in the computation of influenza-attributable YLL90 would lead to substantial overestimation of burden, from 3.5% for persons aged 60-64 years to 82% for those aged 80-89 years at death. Failure to account for competing mortality risks has implications for the accuracy of disease-burden estimates, especially among persons aged 80 years or older. Because the mortality burden borne by the elderly is notably high, prevention initiatives may benefit from being redesigned to more effectively prevent infection in the oldest age groups.

Background: Control efforts for measles and rubella are intensifying globally. It becomes increasingly important to identify and reach remaining susceptible populations as elimination is approached., Methods: Serological surveys for measles and rubella can potentially measure susceptibility directly, but their use remains rare. In this study, using simulations, we outline key subtleties in interpretation associated with the dynamic context of age-specific immunity, highlighting how the patterns of immunity predicted from disease surveillance and vaccination coverage data may be misleading., Results: High-quality representative serosurveys could provide a more accurate assessment of immunity if challenges of conducting, analyzing, and interpreting them are overcome. We frame the core disease control and elimination questions that could be addressed by improved serological tools, discussing challenges and suggesting approaches to increase the feasibility and sustainability of the tool., Conclusions: Accounting for the dynamical context, serosurveys could play a key role in efforts to achieve and sustain elimination.

Background: Historically, measles incidence has shown clear seasonal patterns driven by the school calendar, but since the start of mass vaccination in developed countries there are only occasional outbreaks, which may have changed the effect of school vacations on transmission. In 2013-2014, a large measles epidemic took place in a low vaccination coverage area in The Netherlands, allowing us to quantify current-day measles transmission and the effect of school vacations., Methods: We fitted a dynamic transmission model to notification and hospitalization time series data of the Dutch 2013-2014 measles epidemic. Our primary aim was to estimate the reduction in contact rate during school vacations and the number of cases averted due to the vacation. In addition, because the summer vacations were time-staggered in three regions, we could distinguish within-region from across-region effects of school vacations., Results: We estimated a 53% (95% credible interval: 45%, 60%) reduction in contact rate during school vacations, resulting in 4900 (3400-7100) averted cases (estimated outbreak size: 16,600 [12,600-23,200]). There was a shift from mainly local transmission during school term to mainly cross-regional transmission during vacations. With seroprevalence data, we derived a current-day estimate of 15 to 27 for R0 (number of secondary cases per primary case in a susceptible population)., Conclusions: School vacations are associated with greatly reduced overall measles transmission. However, transmission is not eliminated, and increased long-distance travel may even promote spread to other areas. Therefore, we estimate that school closure is unlikely to prevent measles epidemics unless there are still few cases and the community is well vaccinated.

The decline of several of the world's largest deltas has spurred interest in expensive coastal restoration projects to make these economically and ecologically vital regions more sustainable. The success of these projects depends, in part, on our understanding of how delta plains evolve over time scales longer than the instrumental record. Building on a new set of optically stimulated luminescence ages, we demonstrate that a large portion (~10,000 km 2 ) of the late Holocene river-dominated Mississippi Delta grew in a radially symmetric fashion for almost a millennium before abandonment. Sediment was dispersed by deltaic distributaries that formed by means of bifurcations at the coeval shoreline and remained active throughout the life span of this landform. Progradation rates (100 to 150 m/year) were surprisingly constant, producing 6 to 8 km 2 of new land per year. This shows that robust rates of land building were sustained under preindustrial conditions. However, these rates are several times lower than rates of land loss over the past century, indicating that only a small portion of the Mississippi Delta may be sustainable in a future world with accelerated sea-level rise.

Vaccination programmes are considered a main contributor to the decline of infectious diseases over the 20th century. In recent years, the national vaccination coverage in the Netherlands has been declining, highlighting the need for continuous monitoring and evaluation of vaccination programmes. Our aim was to quantify the impact of long-standing vaccination programmes on notified cases in the Netherlands. We collected and digitised previously unavailable monthly case notifications of diphtheria, poliomyelitis, mumps and rubella in the Netherlands over the period 1919-2015. Poisson regression models accounting for seasonality, multi-year cycles, secular trends and auto-correlation were fit to pre-vaccination periods. Cases averted were calculated as the difference between observed and expected cases based on model projections. In the first 13 years of mass vaccinations, case notifications declined rapidly with 82.4% (95% credible interval (CI): 74.9-87.6) of notified cases of diphtheria averted, 92.9% (95% CI 85.0-97.2) cases of poliomyelitis, and 79.1% (95% CI 67.1-87.4) cases of mumps. Vaccination of 11-year-old girls against rubella averted 49.9% (95% CI 9.3-73.5) of cases, while universal vaccination averted 68.1% (95% CI 19.4-87.3) of cases. These findings show that vaccination programmes have contributed substantially to the reduction of infectious diseases in the Netherlands.

Background: Contact tracing can provide accurate information on relevant parameters of an ongoing emerging infectious disease outbreak. This is crucial to investigators seeking to control such an outbreak. However, crude contact tracing data are difficult to interpret and methods for analyzing these data are scarce. We present a method to estimate and visualize key outbreak parameters from contact tracing information in real time by taking into account data censoring., Methods/results: Exposure type-specific attack rates and the reproduction number R(t) are estimated from contact tracing data by using maximum likelihood estimation to account for censored data. The attack rates reflect, in the context of contact tracing, the specificity of the contact definition; a higher value indicates relatively efficient contact tracing. The evolution of R(t) over time provides information regarding the effectiveness of interventions. To allow a real-time overview of the outbreak, the attack rates and the evolution of R(t) over time are visualized together with the case-contact network and epicurve. We applied the method to a well-documented smallpox outbreak in The Netherlands to demonstrate the added value., Conclusion: Our method facilitates the analysis of contact tracing information by quickly turning it into accessible information, helping outbreak investigators to make real-time decisions to more effectively and efficiently control infectious disease outbreaks.

Background: There are few estimates of the effectiveness of long-standing vaccination programs in developed countries. To fill this gap, we investigate the direct and indirect effectiveness of childhood vaccination programs on mortality at the population level in the Netherlands., Methods: We focused on three communicable infectious diseases, diphtheria, pertussis, and poliomyelitis, for which we expect both direct and indirect effects. As a negative control, we used tetanus, a noncommunicable infectious disease for which only direct effects are anticipated. Mortality data from 1903 to 2012 were obtained from Statistics Netherlands. Vaccination coverage data were obtained from various official reports. For the birth cohorts 1903 through 1975, all-cause and cause-specific childhood mortality burden was estimated using restricted mean lifetime survival methods, and a model was used to describe the prevaccination decline in burden. By projecting model results into the vaccination era, we obtained the expected burden without vaccination. Program effectiveness was estimated as the difference between observed and expected mortality burden., Results: Each vaccination program showed a high overall effectiveness, increasing to nearly 100% within 10 birth cohorts. For diphtheria, 14.9% (95% uncertainty interval [UI] = 12.3%, 17.6%) of mortality burden averted by vaccination was due to indirect protection. For pertussis, this was 32.1% (95% UI = 31.3%, 32.8%). No indirect effects were observed for poliomyelitis or tetanus with -2.4% (UI = -16.7%, 7.1%) and 0.6% (UI = -17.9%, 10.7%), respectively., Conclusion: Vaccination programs for diphtheria and pertussis showed substantial indirect effects, providing evidence for herd protection.

Vaccination is an effective way to prevent an epidemic. It results in immunity for the vaccinated individuals, but it also reduces the infection pressure for unvaccinated people. Thus people may actually escape infection without being vaccinated: the so-called "herd effect." We analytically study the relation between the herd effect and the vaccination fraction for the seminal SIR compartmental model, which consists of a set of differential equations describing the time course of an epidemic. We prove that the herd effect is in general convex-concave in the vaccination fraction and give precise conditions on the epidemic for the convex part to arise. We derive the significant consequences of these structural insights for allocating a limited vaccine stockpile to multiple non-interacting populations. We identify for each population a unique vaccination fraction that is most efficient per dose of vaccine: our dose-optimal coverage. We characterize the solution of the vaccine allocation problem and we show the crucial importance of the dose-optimal coverage. A single dose of vaccine may be a drop in the ocean, but multiple doses together can save a population. To benefit from this, policy makers should select a subset of populations to which the vaccines are allocated. Focusing on a limited number of populations can make a significant difference, whereas allocating equally to all populations would be substantially less effective., (© 2017 Production and Operations Management Society.)

Background: Protective antibody immunity against the influenza A virus wanes in 2-7 years due to antigenic drift of the virus' surface proteins. The duration of immune protection is highly variable because antigenic evolution of the virus is irregular. Currently, the variable nature of the duration of immunity has had little attention in analyses of the impact of vaccination, including cost-effectiveness studies., Methods: We developed a range of mathematical transmission models to investigate the effect of variable duration of immunity on the size of seasonal epidemics. The models range from simple conceptual to more realistic, by distinguishing between infection- versus vaccination-induced immunity, by inclusion of primary vaccine failure, by assuming a leaky vaccine, and by the inclusion of age-dependent contact patterns., Results: We show that annual variation in the duration of immunity causes large variation in the size of epidemics, and affects the effectiveness of vaccination. Accumulation of susceptible individuals in one or more mild seasons results in a disproportionately large outbreak in a subsequent season. Importantly, variation in the duration of immunity increases the average infection attack rate when the vaccination coverage is around the outbreak threshold. Specifically, in a tailored age-stratified model with a realistic reproduction number (R 0 = 1.4) and vaccination coverage of 25%, we find that the attack rate in unvaccinated children (<10 years old) is negligible if the duration of immunity is constant, while on average 2.8% (2.5-97.5% percentiles: 1.8-4.1%) of the children are infected if the duration of immunity is variable. These findings stem from the buildup of susceptibility over multiple seasons by waning of immunity, and the nonlinear relation between susceptibility and infection attack rates., Conclusions: The models illustrate that variation in the duration of immunity impacts the long-term effectiveness of vaccination, and that vaccine effectiveness cannot be judged for each year in isolation. Our findings have implications for vaccination strategies that aim to maximize the vaccination coverage while extending the age range of persons eligible for vaccination.

Background: Estimation of the national-level incidence of seasonal influenza is notoriously challenging. Surveillance of influenza-like illness is carried out in many countries using a variety of data sources, and several methods have been developed to estimate influenza incidence. Our aim was to obtain maximally informed estimates of the proportion of influenza-like illness that is true influenza using all available data., Methods: We combined data on weekly general practice sentinel surveillance consultation rates for influenza-like illness, virologic testing of sampled patients with influenza-like illness, and positive laboratory tests for influenza and other pathogens, applying Bayesian evidence synthesis to estimate the positive predictive value (PPV) of influenza-like illness as a test for influenza virus infection. We estimated the weekly number of influenza-like illness consultations attributable to influenza for nine influenza seasons, and for four age groups., Results: The estimated PPV for influenza in influenza-like illness patients was highest in the weeks surrounding seasonal peaks in influenza-like illness rates, dropping to near zero in between-peak periods. Overall, 14.1% (95% credible interval [CrI]: 13.5%, 14.8%) of influenza-like illness consultations were attributed to influenza infection; the estimated PPV was 50% (95% CrI: 48%, 53%) for the peak weeks and 5.8% during the summer periods., Conclusions: The model quantifies the correspondence between influenza-like illness consultations and influenza at a weekly granularity. Even during peak periods, a substantial proportion of influenza-like illness-61%-was not attributed to influenza. The much lower proportion of influenza outside the peak periods reflects the greater circulation of other respiratory pathogens relative to influenza.

Rotavirus is a common viral infection among young children. As in many countries, the infection dynamics of rotavirus in the Netherlands are characterized by an annual winter peak, which was notably low in 2014. Previous study suggested an association between weather factors and both rotavirus transmission and incidence. From epidemic theory, we know that the proportion of susceptible individuals can affect disease transmission. We investigated how these factors are associated with rotavirus transmission in the Netherlands, and their impact on rotavirus transmission in 2014. We used available data on birth rates and rotavirus laboratory reports to estimate rotavirus transmission and the proportion of individuals susceptible to primary infection. Weather data were directly available from a central meteorological station. We developed an approach for detecting determinants of seasonal rotavirus transmission by assessing nonlinear, delayed associations between each factor and rotavirus transmission. We explored relationships by applying a distributed lag nonlinear regression model with seasonal terms. We corrected for residual serial correlation using autoregressive moving average errors. We inferred the relationship between different factors and the effective reproduction number from the most parsimonious model with low residual autocorrelation. Higher proportions of susceptible individuals and lower temperatures were associated with increases in rotavirus transmission. For 2014, our findings suggest that relatively mild temperatures combined with the low proportion of susceptible individuals contributed to lower rotavirus transmission in the Netherlands. However, our model, which overestimated the magnitude of the peak, suggested that other factors were likely instrumental in reducing the incidence that year.

Geographical mapping of infectious diseases is an important tool for detecting and characterising outbreaks. Two common mapping methods, dot maps and incidence maps, have important shortcomings. The former does not represent population density and can compromise case privacy, and the latter relies on pre-defined administrative boundaries. We propose a method that overcomes these limitations: dot map cartograms. These create a point pattern of cases while reshaping spatial units, such that spatial area becomes proportional to population size. We compared these dot map cartograms with standard dot maps and incidence maps on four criteria, using two example datasets. Dot map cartograms were able to illustrate both incidence and absolute numbers of cases (criterion 1): they revealed potential source locations (Q fever, the Netherlands) and clusters with high incidence (pertussis, Germany). Unlike incidence maps, they were insensitive to choices regarding spatial scale (criterion 2). Dot map cartograms ensured the privacy of cases (criterion 3) by spatial distortion; however, this occurred at the expense of recognition of locations (criterion 4). We demonstrate that dot map cartograms are a valuable method for detection and visualisation of infectious disease outbreaks, which facilitates informed and appropriate actions by public health professionals, to investigate and control outbreaks., (This article is copyright of The Authors, 2017.)

Some past epidemics of different influenza subtypes (particularly A/H3N2) in the US saw co-circulation of vaccine-type and variant strains. There is evidence that natural infection with one influenza subtype offers short-term protection against infection with another influenza subtype (henceforth, cross-immunity). This suggests that such cross-immunity for strains within a subtype is expected to be strong. Therefore, while vaccination effective against one strain may reduce transmission of that strain, this may also lead to a reduction of the vaccine-type strain's ability to suppress spread of a variant strain. It remains unclear what the joint effect of vaccination and cross-immunity is for co-circulating influenza strains within a subtype, and what is the potential benefit of a bivalent vaccine that protects against both strains. We simulated co-circulation of vaccine-type and variant strains under a variety of scenarios. In each scenario, we considered the case when the vaccine efficacy against the variant strain is lower than the efficacy against the vaccine-type strain (monovalent vaccine), as well the case when vaccine is equally efficacious against both strains (bivalent vaccine). Administration of a bivalent vaccine results in a significant reduction in the overall incidence of infection compared to administration of a monovalent vaccine, even with lower coverage by the bivalent vaccine. Additionally, we found that with greater cross-immunity, increasing coverage levels for the monovalent vaccine becomes less beneficial, while introducing the bivalent vaccine becomes more beneficial. Our work exhibits the limitations of influenza vaccines that have low efficacy against non-vaccine strains, and demonstrates the benefits of vaccines that offer good protection against multiple influenza strains. The results elucidate the need for guarding against the potential co-circulation of non-vaccine strains for an influenza subtype, at least during select seasons, possibly through inclusion of multiple strains within a subtype (particularly A/H3N2) in a vaccine., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Whole-genome sequencing of pathogens from host samples becomes more and more routine during infectious disease outbreaks. These data provide information on possible transmission events which can be used for further epidemiologic analyses, such as identification of risk factors for infectivity and transmission. However, the relationship between transmission events and sequence data is obscured by uncertainty arising from four largely unobserved processes: transmission, case observation, within-host pathogen dynamics and mutation. To properly resolve transmission events, these processes need to be taken into account. Recent years have seen much progress in theory and method development, but existing applications make simplifying assumptions that often break up the dependency between the four processes, or are tailored to specific datasets with matching model assumptions and code. To obtain a method with wider applicability, we have developed a novel approach to reconstruct transmission trees with sequence data. Our approach combines elementary models for transmission, case observation, within-host pathogen dynamics, and mutation, under the assumption that the outbreak is over and all cases have been observed. We use Bayesian inference with MCMC for which we have designed novel proposal steps to efficiently traverse the posterior distribution, taking account of all unobserved processes at once. This allows for efficient sampling of transmission trees from the posterior distribution, and robust estimation of consensus transmission trees. We implemented the proposed method in a new R package phybreak. The method performs well in tests of both new and published simulated data. We apply the model to five datasets on densely sampled infectious disease outbreaks, covering a wide range of epidemiological settings. Using only sampling times and sequences as data, our analyses confirmed the original results or improved on them: the more realistic infection times place more confidence in the inferred transmission trees.

Since the early 1990s, the Netherlands has experienced several large measles epidemics, in 1992-94, 1999-2000 and in 2013-14. These outbreaks mainly affected orthodox Protestants, a geographically clustered population with overall lower measles-mumps-rubella first dose (MMR-1) vaccination coverage (60%) than the rest of the country (> 95%). In the 2013-14 epidemic described here, which occurred between 27 May 2013 and 12 March 2014, 2,700 cases were reported. Several control measures were implemented including MMR vaccination for 6-14-month-olds and recommendations to reduce the risk in healthcare workers. The vast majority of reported cases were unvaccinated (94%, n = 2,539), mostly for religious reasons (84%, n = 2,135). The median age in the epidemic was 10 years, 4 years older than in the previous epidemic in 1999-2000. A likely explanation is that the inter-epidemic interval before the 2013-2014 epidemic was longer than the interval before the 1999-2000 epidemic. The size of the unvaccinated orthodox Protestant community is insufficient to allow endemic transmission of measles in the Netherlands. However, large epidemics are expected in the future, which is likely to interfere with measles elimination in the Netherlands and elsewhere., (This article is copyright of The Authors, 2017.)

Background: Mumps emerged among highly vaccinated populations in the Netherlands. This offered a unique opportunity to study mumps virus transmission. In particular the extent to which asymptomatic infections in vaccinated people contribute to ongoing mumps virus transmission is uncertain. Insight into this could help project the future burden of mumps in vaccinated populations. We therefore studied the relative infectiousness of symptomatic and asymptomatic cases., Methods: In a cohort study we followed contacts of notified mumps cases (ring 1) and contacts' contacts (ring 2) for 40 days to ascertain symptoms of mumps and social contacts by weekly diaries and questionnaires, and mumps virus infections by taking finger stick dried blood spot specimens (DBS) that were tested for mumps-specific IgG antibodies. Mumps IgG concentrations >1500 RU/ml in a single sample, a four-fold increase in IgG antibody concentration in paired samples, or a positive oral fluid PCR were defined as recent infection., Results: We recruited 99 contacts (40 in ring 1 and 59 in ring 2) of 10 mumps index cases. The median age of participants was 23 years (range 18-57 years), 31 (31%) were male. At study entry, DBS of 4 out of 78 (5%) participants with samples showed serological evidence of recent mumps virus infection. Three of these reported mumps symptoms. Among the 59 participants who provided DBS at the beginning and end of the follow-up period, none had serological evidence of infection during this period. Of 72 participants who provided at least one oral fluid sample, one participant (1%) who also reported mumps symptoms, was found PCR positive. Of all 99 participants, the attack rate of self-reported mumps was 4% (95% CI 1.1-10.0%). Of the 5 laboratory confirmed mumps cases, 1 reported no mumps symptoms (percentage asymptomatic 20% (95% CI 0-71%)). Compared to non-students, students had larger households and more household members who were born after 1980 (p < 0.01 and <0.01, respectively)., Conclusions: We demonstrated that this prospective cohort study design allows for inference of the proportion of asymptomatic mumps infections. Because we only detected one asymptomatic mumps virus infection, we could not assess the relative infectiousness of asymptomatic mumps. Household characteristics of students differed from non-students. This may partly explain recent mumps epidemiology in the Netherlands.