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Frailty models are often used in survival analysis to model multivariate time-to-event data. In infectious disease epidemiology, frailty models have been proposed to model heterogeneity in the acquisition of infection and to accommodate association in the occurrence of multiple types of infection. Although traditional frailty models rely on the assumption of lifelong immunity after recovery, refinements have been made to account for reinfections with the same pathogen. Recently, Abrams and Hens quantified the effect of misspecifying the underlying infection process on the basic and effective reproduction number in the context of bivariate current status data on parvovirus B19 and varicella zoster virus. Furthermore, Farrington, Unkel and their co-workers introduced and applied time varying shared frailty models to paired bivariate serological data. In this paper, we consider an extension of the proposed frailty methodology by Abrams and Hens to account for age-dependence in individual heterogeneity through the use of age-dependent shared and correlated gamma frailty models. The methodology is illustrated by using two data applications. ; The authors gratefully acknowledge support by the Research Fund of Hasselt University (grantBOF11NI31) and support of the University of Antwerp Scientific Chair in Evidence-based Vaccinology sponsored in 2009–2016 by a gift from Pfizer and GlaxoSmithKline. The work of AW was supported by the German Research Council, project WI 3288/1-2. This research is part of a project that has received funding from the European Research Council under the European Union's 'Horizon 2020' research and innovation program (grant agreement 682540—TransMID). The computational resources and services used in this work were provided by the Flemish Supercomputer Center, funded by the Research Foundation—Flanders and the Flemish Government—Department Economy, Science and Innovation.

Frailty models have a prominent place in survival analysis to model univariate and multivariate time-to-event data, often complicated by the presence of different types of censoring. In recent years, frailty modeling gained popularity in infectious disease epidemiology to quantify unobserved heterogeneity using Type I interval-censored serological data or current status data. In a multivariate setting, frailty models prove useful to assess the association between infection times related to multiple distinct infections acquired by the same individual. In addition to dependence among individual infection times, overdispersion can arise when the observed variability in the data exceeds the one implied by the model. In this article, we discuss parametric overdispersed frailty models for time-to-event data under Type I interval-censoring, building upon the work by Molenberghs et al. (2010) and Hens et al. (2009). The proposed methodology is illustrated using bivariate serological data on hepatitis A and B from Flanders, Belgium anno 1993–1994. Furthermore, the relationship between individual heterogeneity and overdispersion at a stratum-specific level is studied through simulations. Although it is important to account for overdispersion, one should be cautious when modeling both individual heterogeneity and overdispersion based on current status data as model selection is hampered by the loss of information due to censoring. ; This work was supported by the Research Fund of Hasselt University (grant BOF11NI31 to S.A.). N.H. received support from the University of Antwerp by way of the Scientific Chair in Evidence-based Vaccinology, financed in 2009–2014 by a gift from Pfizer, Inc., New York. The authors gratefully acknowledge financial support from the IAP research Network P7/06 of the Belgian Government (Belgian Science Policy). This research is part of a project that has received funding from the European Research Council (ERC) under the European Unions Horizon 2020 research and innovation programme (grant agreement 682540 – TransMID).

Background: Large measles and mumps outbreaks recently occurred throughout Europe and the United States. Aim: Our aim was to estimate and map the risk of resurgence for measles, mumps and rubella in France. Methods: We used a multi-cohort model combining seroprevalence information, vaccine coverage and social contact data. Results: The overall outbreak risk for France in 2018 was highest for mumps, remained significant for measles despite a recent measles outbreak and was low for rubella. Outbreak risks were heterogeneous between departments, as the effective reproduction numbers for 2018 ranged from 1.08 to 3.66. The seroprevalence, and therefore the risk of measles and rubella infection, differed significantly between mates and females. There was a lower seroprevalence, and therefore a higher risk, for males. Infants of less thane year would be seriously affected in a future outbreak of measles, mumps or rubella, but the highest overall caseload contribution would come from teenagers and young adults (10-25 years old). Conclusions: The high risk for teenagers and young adults is of concern in view of their vulnerability to more severe measles, mumps and rubella disease and complications. ; NH gratefully acknowledges the support from the University of Antwerp scientific chair in Evidence-Based Vaccinology, which was financed by a gift from Pfizer (2009-2017) and GlaxoSmithKline (2016). This project was supported by the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement 682540 - TransMID). GB gratefully acknowledges special research funding provided by Hasselt University (BOF14BL07). SA gratefully acknowledges support by the Research Fund of Hasselt University (Grant BOF11NI31). GB gratefully acknowledges special research funding provided by Hasselt University (BOF14BL07). SA gratefully acknowledges support by the Research Fund of Hasselt University (Grant BOF11NI31).

There are different patterns in the COVID-19 outbreak in the general population and amongst nursing home patients. We investigate the time from symptom onset to diagnosis and hospitalization or the length of stay (LoS) in the hospital, and whether there are differences in the population. Sciensano collected information on 14,618 hospitalized patients with COVID-19 admissions from 114 Belgian hospitals between 14 March and 12 June 2020. The distributions of different event times for different patient groups are estimated accounting for interval censoring and right truncation of the time intervals. The time between symptom onset and hospitalization or diagnosis are similar, with median length between symptom onset and hospitalization ranging between 3 and 10.4 days, depending on the age of the patient (longest delay in age group 20-60 years) and whether or not the patient lives in a nursing home (additional 2 days for patients from nursing home). The median LoS in hospital varies between 3 and 10.4 days, with the LoS increasing with age. The hospital LoS for patients that recover is shorter for patients living in a nursing home, but the time to death is longer for these patients. Over the course of the first wave, the LoS has decreased. ; This work is funded by the EpiPose project from the European Union's SC1-PHE-CORONAVIRUS-2020 programme, project number 101003688. ; Faes, C (corresponding author), Univ Hasselt, Data Sci Inst DSI, I BioStat, BE-3500 Hasselt, Belgium. christel.faes@uhasselt.be; steven.abrams@uhasselt.be; dominique.vanbeckhoven@sciensano.be; geert.meyfroidt@kuleuven.be; erika.vlieghe@uantwerpen.be; hospital_datacollection@sciensano.be

To support food security for current and future generations, there is a need to understand the relation between sustainable diets and the health of a population. In recent years, a number of studies have investigated and compared different dietary patterns to better understand which foods and eating patterns have less of an environmental impact while meeting nutritional needs and promoting health. This systematic review (SR) of population-level dietary patterns and food sustainability extends and updates the SR that was conducted by the 2015 US Dietary Guidelines Advisory Committee, an expert committee commissioned by the federal government to inform dietary guidance as it relates to the committee's original conclusions. In the original SR, 15 studies met the criteria for inclusion; since then, an additional 8 studies have been identified and included. The relations between dietary intake patterns and both health and environmental outcomes were compared across studies, with methodologies that included modeling, life cycle assessment, and land use analysis. Across studies, consistent evidence indicated that a dietary pattern higher in plant-based foods (e.g., vegetables, fruits, legumes, seeds, nuts, whole grains) and lower in animal-based foods (especially red meat), as well as lower in total energy, is both healthier and associated with a lesser impact on the environment. This dietary pattern differs from current average consumption patterns in the United States. Our updated SR confirms and strengthens the conclusions of the original US Dietary Guidelines Advisory Committee SR, which found that adherence to several well-characterized dietary patterns, including vegetarian (with variations) diets, dietary guidelines–related diets, Mediterranean-style diets, the Dietary Approaches to Stop Hypertension (DASH) diet, and other sustainable diet scenarios, promotes greater health and has a less negative impact on the environment than current average dietary intakes.

We investigated urinary N-acetyltyramine-O,beta-glucuronide (NATOG) levels as a biomarker for active Onchocerca volvulus infection in an onchocerciasis-endemic area in the Democratic Republic of Congo with a high epilepsy prevalence. Urinary NATOG was measured in non-epileptic men with and without O. volvulus infection, and in O. volvulus-infected persons with epilepsy (PWE). Urinary NATOG concentration was positively associated with microfilarial density (p < 0.001). The median urinary NATOG concentration was higher in PWE (3.67 mu M) compared to men without epilepsy (1.74 mu M), p = 0.017; and was higher in persons with severe (7.62 mu M) compared to mild epilepsy (2.16 mu M); p = 0.008. Non-epileptic participants with and without O. volvulus infection had similar NATOG levels (2.23 mu M and 0.71 mu M, p = 0.426). In a receiver operating characteristic curve analysis to investigate the diagnostic value of urinary NATOG, the area under the curve was 0.721 (95% CI: 0.633-0.797). Using the previously proposed cut-off value of 13 mu M to distinguish between an active O. volvulus infection and an uninfected state, the sensitivity was 15.9% and the specificity 95.9%. In conclusion, an O. volvulus infection is associated with an increased urinary NATOG concentration, which correlates with the individual parasitic load. However, the NATOG concentration has a low discriminating power to differentiate between infected and uninfected individuals.

We investigated urinary N-acetyltyramine-O,β-glucuronide (NATOG) levels as a biomarker for active Onchocerca volvulus infection in an onchocerciasis-endemic area in the Democratic Republic of Congo with a high epilepsy prevalence. Urinary NATOG was measured in non-epileptic men with and without O. volvulus infection, and in O. volvulus-infected persons with epilepsy (PWE). Urinary NATOG concentration was positively associated with microfilarial density (p < 0.001). The median urinary NATOG concentration was higher in PWE (3.67 µM) compared to men without epilepsy (1.74 µM), p = 0.017; and was higher in persons with severe (7.62 µM) compared to mild epilepsy (2.16 µM); p = 0.008. Non-epileptic participants with and without O. volvulus infection had similar NATOG levels (2.23 µM and 0.71 µM, p = 0.426). In a receiver operating characteristic curve analysis to investigate the diagnostic value of urinary NATOG, the area under the curve was 0.721 (95% CI: 0.633–0.797). Using the previously proposed cut-off value of 13 µM to distinguish between an active O. volvulus infection and an uninfected state, the sensitivity was 15.9% and the specificity 95.9%. In conclusion, an O. volvulus infection is associated with an increased urinary NATOG concentration, which correlates with the individual parasitic load. However, the NATOG concentration has a low discriminating power to differentiate between infected and uninfected individuals.

Background In response to the ongoing COVID-19 pandemic, several countries adopted measures of social distancing to a different degree. For many countries, after successfully curbing the initial wave, lockdown measures were gradually lifted. In Belgium, such relief started on May 4th with phase 1, followed by several subsequent phases over the next few weeks. Methods We analysed the expected impact of relaxing stringent lockdown measures taken according to the phased Belgian exit strategy. We developed a stochastic, data-informed, meta-population model that accounts for mixing and mobility of the age-structured population of Belgium. The model is calibrated to daily hospitalization data and is able to reproduce the outbreak at the national level. We consider different scenarios for relieving the lockdown, quantified in terms of relative reductions in pre-pandemic social mixing and mobility. We validate our assumptions by making comparisons with social contact data collected during and after the lockdown. Results Our model is able to successfully describe the initial wave of COVID-19 in Belgium and identifies interactions during leisure/other activities as pivotal in the exit strategy. Indeed, we find a smaller impact of school re-openings as compared to restarting leisure activities and re-openings of work places. We also assess the impact of case isolation of new (suspected) infections, and find that it allows re-establishing relatively more social interactions while still ensuring epidemic control. Scenarios predicting a second wave of hospitalizations were not observed, suggesting that the per-contact probability of infection has changed with respect to the pre-lockdown period. Conclusions Contacts during leisure activities are found to be most influential, followed by professional contacts and school contacts, respectively, for an impending second wave of COVID-19. Regular re-assessment of social contacts in the population is therefore crucial to adjust to evolving behavioral changes that can affect epidemic diffusion. ; This work received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (PC and NH, grant number 682540 – TransMID project, PL, NH, PB grant number 101003688 – EpiPose project). SA and NH gratefully acknowledge support from the Fonds voor Wetenschappelijk Onderzoek (FWO) (RESTORE project – G0G2920N). LW received funding from the Research Foundation Flanders (1234620N). PL received funding from the Research Foundation Flanders (post-doctoral grant 1242021N). The resources and services used in this work were provided by the VSC (Flemish Supercomputer Center), funded by the Research Foundation – Flanders (FWO) and the Flemish Government. We thank several researchers from the SIMID COVID-19 consortium from the University of Antwerp and Hasselt University for numerous constructive discussions and meetings. We thank Giulia Pullano, Laura Di Domenico and Vittoria Colizza for useful discussions. The authors are also very grateful for access to the data from the Belgian Scientific Institute for Public Health, Sciensano.

Onchocerciasis is diagnosed by detecting microfilariae in skin snips or by detecting OV16 IgG4 antibodies in blood by either enzyme linked immunosorbent assay (ELISA) or a rapid diagnostic test (RDT). Here, we compare the sensitivity and specificity of these three tests in persons with epilepsy living in an onchocerciasis endemic region in the Democratic Republic of Congo. Skin snips and blood samples were collected from 285 individuals for onchocerciasis diagnosis. Three tests were performed: the OV16 RDT (SD Bioline) and the OV16 ELISA both on serum samples, and microscopic detection of microfilariae in skin snips. The sensitivity and specificity of each test was calculated with the combined other tests as a reference. Microfilariae were present in 105 (36.8%) individuals, with a median of 18.5 (6.5–72.0) microfilariae/skin snip. The OV16 RDT and OV16 ELISA were positive in, respectively, 112 (39.3%) and 143 (50.2%) individuals. The OV16 ELISA had the highest sensitivity among the three tests (83%), followed by the OV16 RDT (74.8%) and the skin snip (71.4%). The OV16 RDT had a higher specificity (98.6%) compared to the OV16 ELISA (84.8%). Our study confirms the need to develop more sensitive tests to ensure the accurate detection of ongoing transmission before stopping elimination efforts.

Assessing the bioavailability of non-heme iron and zinc is essential for recommending diets that meet the increased growth-related demand for these nutrients. We studied the bioavailability of iron and zinc from a rice-based meal in 16 adolescent boys and girls, 13–15 y of age, from 2 government-run residential schools. Participants were given a standardized rice meal (regular) and the same meal with 100 g of guava fruit (modified) with 57Fe on 2 consecutive days. A single oral dose of 58Fe in orange juice was given at a separate time as a reference dose. Zinc absorption was assessed by using 70Zn, administered intravenously, and 67Zn given orally with meals. The mean hemoglobin concentration was similar in girls (129 ± 7.8 g/L) and boys (126 ± 7.1 g/L). There were no sex differences in the indicators of iron and zinc status except for a higher hepcidin concentration in boys (P 1:1, but the modified diet had 20 times greater ascorbic acid content. The absorption of 57Fe from the modified meal, compared with regular meal, was significantly (P < 0.05) greater in both girls (23.9 ± 11.2 vs. 9.7 ± 6.5%) and boys (19.2 ± 8.4 vs. 8.6 ± 4.1%). Fractional zinc absorption was similar between the regular and modified meals in both sexes. Hepcidin was found to be a significant predictor of iron absorption (standardized β = −0.63, P = 0.001, R2 = 0.40) from the reference dose. There was no significant effect of sex on iron and zinc bioavailability from meals. We conclude that simultaneous ingestion of guava fruit with a habitual rice-based meal enhances iron bioavailability in adolescents.

A clinical trial performed in the Democratic Republic of Congo (DRC), among persons with epilepsy (PWE) infected with Onchocerca volvulus treated with anti-seizure medication suggested that ivermectin reduces the seizure frequency. We assessed the effect of ivermectin treatment on seizure frequency in PWE with and without anti-seizure medication in three onchocerciasis endemic areas (Maridi, South Sudan; Aketi, DRC; and Mahenge, Tanzania). Pre- and 3-5 months post-ivermectin microfilariae densities in skin snips and seizure frequency were assessed. After ivermectin, the median (IQR) percentage reduction in seizure frequency in the study sites ranged from 73.4% (26.0-90.0) to 100% (50.0-100.0). A negative binomial mixed model showed that ivermectin significantly reduced the seizure frequency, with a larger decrease in PWE with a high baseline seizure frequency. Mediation analysis showed that ivermectin reduced the seizure frequencies indirectly through reduction in microfilariae densities but also that ivermectin may have a direct anti-seizure effect. However, given the short half-life of ivermectin and the fact that ivermectin does not penetrate the healthy brain, such a direct anti-seizure effect is unlikely. A randomized controlled trial assessing the ivermectin effect in people infected with O. volvulus who are also PWE on a stable anti-seizure regimen may be needed to clarify the causal relationship between ivermectin and seizure frequency. ; European Research Council (ERC 671055) and VLIR-UOS. ; VLIR-UOS ; Dusabimana, A; Colebunders, R (corresponding author), Univ Antwerp, Global Hlth Inst, Doornstr 331, B-2610 Antwerp, Belgium. alfred.dusabimana@uantwerpen.be; swafula@musph.ac.ug; Stephen.Jada@amref.org; josephnelson.siewefodjo@uantwerpen.be; dan.bhwana@nimr.or.tz; floritepage@yahoo.fr; gasim4u83@gmail.com; an.hotterbeekx@uantwerpen.be; steven.abrams@uantwerpen.be; robert.colebunders@uantwerpen.be

Following the onset of the ongoing COVID-19 pandemic throughout the world, a large fraction of the global population is or has been under strict measures of physical distancing and quarantine, with many countries being in partial or full lockdown. These measures are imposed in order to reduce the spread of the disease and to lift the pressure on healthcare systems. Estimating the impact of such interventions as well as monitoring the gradual relaxing of these stringent measures is quintessential to understand how resurgence of the COVID-19 epidemic can be controlled for in the future. In this paper we use a stochastic age-structured discrete time compartmental model to describe the transmission of COVID-19 in Belgium. Our model explicitly accounts for age-structure by integrating data on social contacts to (i) assess the impact of the lockdown as implemented on March 13, 2020 on the number of new hospitalizations in Belgium; (ii) conduct a scenario analysis estimating the impact of possible exit strategies on potential future COVID-19 waves. More specifically, the aforementioned model is fitted to hospital admission data, data on the daily number of COVID-19 deaths and serial serological survey data informing the (sero)prevalence of the disease in the population while relying on a Bayesian MCMC approach. Our age-structured stochastic model describes the observed outbreak data well, both in terms of hospitalizations as well as COVID-19 related deaths in the Belgian population. Despite an extensive exploration of various projections for the future course of the epidemic, based on the impact of adherence to measures of physical distancing and a potential increase in contacts as a result of the relaxation of the stringent lockdown measures, a lot of uncertainty remains about the evolution of the epidemic in the next months. ; We thank several researchers from the SIMID COVID-19 consortium from the University of Antwerp and Hasselt University for numerous constructive discussions and meetings. SA and NH gratefully acknowledge support from the Research Foundation Flanders (FWO), Belgium (RESTORE project — G0G2920N). This work also received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (PC and NH, grant number 682540 – TransMID project, NH, PB grant number 101003688 – EpiPose project). The authors are also very grateful for access to the data from the Belgian Scientific Institute for Public Health, Sciensano, and from the Vaccine & Infectious Disease Institute (VaxInfectio), University of Antwerp. LW and PL gratefully acknowledge funding from the Research Foundation Flanders, Belgium (postdoctoral fellowships 1234620N and 1242021N). We acknowledge support from the Antwerp Study Centre for Infectious Diseases (ASCID). The resources and services used in this work were provided by the VSC (Flemish Supercomputer Center), funded by the FWO and the Flemish Government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. All authors contributed to the final version of the paper and approved the final version of the manuscript.

The COVID-19 pandemic caused many governments to impose policies restricting social interactions. A controlled and persistent release of lockdown measures covers many potential strategies and is subject to extensive scenario analyses. Here, we use an individual-based model (STRIDE) to simulate interactions between 11 million inhabitants of Belgium at different levels including extended household settings, i.e., "household bubbles". The burden of COVID-19 is impacted by both the intensity and frequency of physical contacts, and therefore, household bubbles have the potential to reduce hospital admissions by 90%. In addition, we find that it is crucial to complete contact tracing 4 days after symptom onset. Assumptions on the susceptibility of children affect the impact of school reopening, though we find that business and leisure-related social mixing patterns have more impact on COVID-19 associated disease burden. An optimal deployment of the mitigation policies under study require timely compliance to physical distancing, testing and self-isolation. ; The COVID-19 pandemic caused many governments to impose policies restricting social interactions. A controlled and persistent release of lockdown measures covers many potential strategies and is subject to extensive scenario analyses. Here, we use an individual-based model (STRIDE) to simulate interactions between 11 million inhabitants of Belgium at different levels including extended household settings, i.e., "household bubbles". The burden of COVID-19 is impacted by both the intensity and frequency of physical contacts, and therefore, household bubbles have the potential to reduce hospital admissions by 90%. In addition, we find that it is crucial to complete contact tracing 4 days after symptom onset. Assumptions on the susceptibility of children affect the impact of school reopening, though we find that business and leisure-related social mixing patterns have more impact on COVID-19 associated disease burden. An optimal deployment of the mitigation policies under study require timely compliance to physical distancing, testing and self-isolation. The COVID-19 pandemic caused many governments to impose policies restricting social interactions. Here, the authors implement an age-specific, individual-based model with data on social contacts for the Belgian population and investigate the effect of non-pharmaceutical interventions.

A clinical trial performed in the Democratic Republic of Congo (DRC), among persons with epilepsy (PWE) infected with Onchocerca volvulus treated with anti-seizure medication suggested that ivermectin reduces the seizure frequency. We assessed the effect of ivermectin treatment on seizure frequency in PWE with and without anti-seizure medication in three onchocerciasis endemic areas (Maridi, South Sudan; Aketi, DRC; and Mahenge, Tanzania). Pre- and 3–5 months post-ivermectin microfilariae densities in skin snips and seizure frequency were assessed. After ivermectin, the median (IQR) percentage reduction in seizure frequency in the study sites ranged from 73.4% (26.0–90.0) to 100% (50.0–100.0). A negative binomial mixed model showed that ivermectin significantly reduced the seizure frequency, with a larger decrease in PWE with a high baseline seizure frequency. Mediation analysis showed that ivermectin reduced the seizure frequencies indirectly through reduction in microfilariae densities but also that ivermectin may have a direct anti-seizure effect. However, given the short half-life of ivermectin and the fact that ivermectin does not penetrate the healthy brain, such a direct anti-seizure effect is unlikely. A randomized controlled trial assessing the ivermectin effect in people infected with O. volvulus who are also PWE on a stable anti-seizure regimen may be needed to clarify the causal relationship between ivermectin and seizure frequency.

Despite long-standing two-dose measles-mumpsrubella (MMR) vaccination, measles outbreaks still occur in highly vaccinated European populations. For instance, large measles outbreaks occurred in France (2008–13), the United Kingdom (2012–13) and the Netherlands (2012). Based on a multicohort model approach, using spatial serological survey data, MMR vaccination coverage data and data on social contacts, we found effective reproduction numbers significantly higher than 1 for measles in Belgium. This indicates that at one of the expected re-introductions, a measles outbreak is likely to spread, especially when it occurs during school term. The predicted average effective reproduction number increased over a 30-year time span from 1.3 to 2.2 and from 1.9 to 3.2 for basic reproduction numbers of 12 and 18, respectively. The expected relative measles incidence was highest in infants under one year of age, in adolescents and young adults. In conclusion, gradually increasing proportions of susceptible adolescents and young adults provide through their highly active social life an avenue for measles to resurge in large outbreaks upon re-introduction in Belgium, especially during school terms. Infants form an important vulnerable group during future measles outbreaks. ; The authors would like to acknowledge the colleagues of the Flemish Agency for Care and Health, the Scientific Institute of Public Health and the measles elimination committee for fruitful discussions related to this research. NH acknowledges support of the University of Antwerp Scientific Chair in Evidence-based Vaccinology sponsored in 2009-2014 by a gift from Pfizer. SA acknowledges support by the Research Fund of Hasselt University (Grant BOF11NI31). ES and HG acknowledge support from a Methusalem research grant from the Flemish government. NG is beneficiary of a postdoctoral grant from the AXA Research Fund. Support from the IAP Research Network P7/06 of the Belgian State (Belgian Science Policy) is gratefully acknowledged. HT and EL are postdoctoral researchers for the Fund of Scientific Research - Flanders (FWO). The computational resources and services used in this work were provided by the Hercules Foundation and the Flemish Government - department EWI.