The daily updated Dutch national database on COVID-19 epidemiology, vaccination and sewage surveillance.

The Dutch national open database on COVID-19 has been incrementally expanded since its start on 30 April 2020 and now includes datasets on symptoms, tests performed, individual-level positive cases and deaths, cases and deaths among vulnerable populations, settings of transmission, hospital and ICU admissions, SARS-CoV-2 variants, viral loads in sewage, vaccinations and the effective reproduction number. This data is collected by municipal health services, laboratories, hospitals, sewage treatment plants, vaccination providers and citizens and is cleaned, analysed and published, mostly daily, by the National Institute for Public Health and the Environment (RIVM) in the Netherlands, using automated scripts. Because these datasets cover the key aspects of the pandemic and are available at detailed geographical level, they are essential to gain a thorough understanding of the past and current COVID-19 epidemiology in the Netherlands. Future purposes of these datasets include country-level comparative analysis on the effect of non-pharmaceutical interventions against COVID-19 in different contexts, such as different cultural values or levels of socio-economic disparity, and studies on COVID-19 and weather factors.

The impact of influenza vaccination on infection, hospitalisation and mortality in the Netherlands between 2003 and 2015.

Influenza epidemics annually cause substantial morbidity and mortality. For this reason, vaccination is offered yearly to persons with an elevated risk for complications. Assessments of the impact of vaccination are, however, hampered by year-to-year variation in epidemic size and vaccine effectiveness. We estimate the impact of the current vaccination programme comparing simulations with vaccination to counterfactual simulations without vaccination. The simulations rely on an age- and risk-structured transmission model that tracks the build-up and loss of immunity over successive seasons, and that allows the vaccine match to vary between seasons. The model parameters are estimated with a particle Monte Carlo method and approximate Bayesian computation, using epidemiological data on vaccine effectiveness and epidemic size in the Netherlands over a period of 11 years. The number of infections, hospitalisations and deaths vary greatly between years because waning of immunity and vaccine match may differ every season, which is in line with observed variation in influenza epidemic sizes. At an overall coverage of 21%, vaccination has averted on average 13% (7.2-19%, 95% range) of infections, 24% (16-36%) of hospitalisations, and 35% (16-50%) of deaths. This suggests that vaccination is mainly effective in protecting vaccinees from infection rather than reducing transmission. As the Dutch population continues to grow and age, the vaccination programme is projected (up to 2025) to gain in impact, despite a decreasing infection attack rate.

Vaccinating children against influenza increases variability in epidemic size.

Seasonal influenza causes a high disease burden. Many influenza vaccination programmes target the elderly and persons at high risk of complications. Some countries have recommended or even implemented a paediatric vaccination programme. Such a programme is expected to reduce influenza transmission in the population, offering direct protection to the vaccinated children and indirect protection to the elderly. We study the impact of a child vaccination programme with an age- and risk-structured transmission model, calibrated to data of 11 influenza seasons in the Netherlands. The model tracks the build-up of immunes and susceptibles in each age cohort over time, and it allows for seasonal variation in vaccine match and antigenic drift. Different vaccination strategies are evaluated for three target age groups (2-3, 2-12 and 2-16 year olds) over the full range of vaccination coverages (0-100%). The results show that the paediatric vaccination programme has only a limited impact on the elderly age groups, which account for most influenza morbidity and mortality. This is due to two notable changes in infection dynamics. First, an age shift is observed: influenza infections are reduced in vaccinated children, but are increased in young adults with limited natural immunity after years of vaccination. These young adults assume the role of driving the epidemic. Second, a year with low influenza activity can be followed by a large epidemic due to build-up of susceptibles. This variation of the infection attack rate increases with increasing vaccination coverage. The increased variability in the infection attack rate implies that health care facilities should be prepared for rare but larger peaks in influenza patients. Moreover, vaccinating the group with the highest transmission potential, results in a larger dependency on a secure vaccine supply. These arguments should be taken into account in the decision to introduce mass vaccination of school-aged children against influenza.

Quantitative CT analysis using functional imaging is superior in describing disease progression in idiopathic pulmonary fibrosis compared to forced vital capacity.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is chronic fibrosing pneumonia with an unpredictable natural disease history. Functional respiratory imaging (FRI) has potential to better characterize this disease. The aim of this study was to identify FRI parameters, which predict FVC decline in patients with IPF. METHODS: An IPF-cohort (treated with pamrevlumab for 48 weeks) was retrospectively studied using FRI. Serial CT's were compared from 66 subjects. Post-hoc analysis was performed using FRI, FVC and mixed effects models. RESULTS: Lung volumes, determined by FRI, correlated with FVC (lower lung volumes with lower FVC) (R2 = 0.61, p < 0.001). A negative correlation was observed between specific image based airway radius (siRADaw) at total lung capacity (TLC) and FVC (R2 = 0.18, p < 0.001). Changes in FVC correlated significantly with changes in lung volumes (R2 = 0.18, p < 0.001) and siRADaw (R2 = 0.15, p = 0.002) at week 24 and 48, with siRADaw being more sensitive to change than FVC. Loss in lobe volumes (R2 = 0.33, p < 0.001), increasing fibrotic tissue (R2 = 0.33, p < 0.001) and airway radius (R2 = 0.28, p < 0.001) at TLC correlated with changes in FVC but these changes already occur in the lower lobes when FVC is still considered normal. CONCLUSION: This study indicates that FRI is a superior tool than FVC in capturing of early and clinically relevant, disease progression in a regional manner.

Hepatic Changes in the Fontan Circulation: Identification of Liver Dysfunction and an Attempt to Streamline Follow-up Screening.

We tried to identify structural and functional liver aberrances in a palliated Fontan population and sought to determine useful screening modalities, in order to propose a screening protocol to detect patients at risk. Twenty nine patients, median age 23.7 years (interquartile range (IQR) 20.5-27.2) and median Fontan interval 19.7 years (IQR 4.5-21.4), were prospectively studied with echocardiography, blood analysis (including serum fibrosis scores Forns, APRI and FIB4), liver imaging (ultrasound (US), Doppler), and shear wave elastography to determine liver stiffness (LS). Laboratory tests predominantly showed abnormal values for gamma-glutamyltransferase. Forns index indicated moderate fibrosis in 29% of patients and correlated with Fontan interval (p = 0.034). US liver morphology was deviant in 46% of patients, with surface nodularity in 21% and nodular hyperplasia in 29%. Doppler assessment of flow velocities was within normal ranges for most patients. LS (mean 10.4 ± 3.7 kPa) was elevated in 96% of our population and higher LS values were significantly related to longer Fontan interval (p = 0.018). Adolescent and adult Fontan patients show moderate signs of liver dysfunction. Usefulness of serum parameters and fibrosis scores in post-Fontan screening remains ambiguous. The high percentage of morphologic liver changes in palliated patients supports the use of US in periodic follow-up. LS likely overestimates fibrosis due to liver congestion, arguing for the need of validation through sequential measurements. Screening should minimally encompass US assessment in combination with selective liver fibrosis scores. The role of LS measurement in Fontan follow-up and liver screening needs to be further elucidated.

Modelling the Innate Immune Response against Avian Influenza Virus in Chicken.

At present there is limited understanding of the host immune response to (low pathogenic) avian influenza virus infections in poultry. Here we develop a mathematical model for the innate immune response to avian influenza virus in chicken lung, describing the dynamics of viral load, interferon-α, -ß and -γ, lung (i.e. pulmonary) cells and Natural Killer cells. We use recent results from experimentally infected chickens to validate some of the model predictions. The model includes an initial exponential increase of the viral load, which we show to be consistent with experimental data. Using this exponential growth model we show that the duration until a given viral load is reached in experiments with different inoculation doses is consistent with a model assuming a linear relationship between initial viral load and inoculation dose. Subsequent to the exponential-growth phase, the model results show a decline in viral load caused by both target-cell limitation as well as the innate immune response. The model results suggest that the temporal viral load pattern in the lungs displayed in experimental data cannot be explained by target-cell limitation alone. For biologically plausible parameter values the model is able to qualitatively match to data on viral load in chicken lungs up until approximately 4 days post infection. Comparison of model predictions with data on CD107-mediated degranulation of Natural Killer cells yields some discrepancy also for earlier days post infection.

Assessment of lung deposition and analysis of the effect of fluticasone/salmeterol hydrofluoroalkane (HFA) pressurized metered dose inhaler (pMDI) in stable persistent asthma patients using functional respiratory imaging.

BACKGROUND: Unambiguously for inhaled products, PK measures are best suited for ensuring that the total systemic exposure is equivalent for two products but cannot provide regional information about lung deposition and structural changes. Functional respiratory imaging (FRI) has been demonstrated to be sensitive for distinguishing small but imperative differences related to a single treatment. METHODS: In this study FRI is used in 16 asthmatic patients to assess equivalence in regional deposition for two products (fluticasone/salmeterol, test and reference) by directly measuring regional functional and structural changes within the lungs following its administration. RESULTS: No differences were observed between the lung deposition patterns and the effects on lung structure and function of two products, having the same formulation and manufactured by different organizations using FRI. CONCLUSIONS: Results using FRI complement PK assessments. The added value of this approach to the conventional clinical methods could be significant.

Analysis of Q fever in Dutch dairy goat herds and assessment of control measures by means of a transmission model.

Between 2006 and 2009 the largest human Q fever epidemic ever described occurred in the Netherlands. The source of infection was traced back to dairy goat herds with abortion problems due to Q fever. The first aim of control measures taken in these herds was the reduction of human exposure. To analyze Q fever dynamics in goat herds and to study the effect of control measures, a within-herd model of Coxiella burnetii transmission in dairy goat herds was developed. With this individual-based stochastic model we evaluated six control strategies and three herd management styles and studied which strategy leads to a lower Q fever prevalence and/or to disease extinction in a goat herd. Parameter values were based on literature and on experimental work. The model could not be validated with independent data. The results of the epidemiological model were: (1) Vaccination is effective in quickly reducing the prevalence in a dairy goat herd. (2) When taking into account the average time to extinction of the infection and the infection pressure in a goat herd, the most effective control strategy is preventive yearly vaccination, followed by the reactive strategies to vaccinate after an abortion storm or after testing BTM (bulk tank milk) positive. (3) As C. burnetii in dried dust may affect public health, an alternative ranking method is based on the cumulative amount of C. burnetii emitted into the environment (from disease introduction until extinction). Using this criterion, the same control strategies are effective as when based on time to extinction and infection pressure (see 2). (4) As the bulk of pathogen excretion occurs during partus and abortion, culling of pregnant animals during an abortion storm leads to a fast reduction of the amount of C. burnetii emitted into the environment. However, emission is not entirely prevented and Q fever will not be eradicated in the herd by this measure. (5) A search & destroy (i.e. test and cull) method by PCR of individual milk samples with a detection probability of 50% of detecting and culling infected goats - that excrete C. burnetii intermittently - will not result in eradication of Q fever in the herd. This control strategy was the least effective of the six evaluated strategies. Subject to model limitations, our results indicate that only vaccination is capable of preventing and controlling Q fever outbreaks in dairy goat farms. Thus, preventive vaccination should be considered as an ongoing control measure.

[Music therapy and depression]. / Muziektherapie bij depressie.

BACKGROUND: Music therapy is a predominantly non-verbal psychotherapy based on music improvisation, embedded in a therapeutic relationship. This is the reason why music therapy is also used to treat depression. AIM: To examine the efficacy of music therapy and to report on the results of recent research into the value of music therapy as a treatment for depression. METHOD: We reviewed the literature on recent research into music therapy and depression, reporting on the methods used and the results achieved, and we assessed the current position of music therapy for depression in the context of evidence-based scientific research. RESULTS: A wide variety of research methods was used to investigate the effects of using music therapy as a psychotherapy. Most studies focused usually on the added value that music therapy brings to the standard form of psychiatric treatment, when administered with or without psychopharmacological support. Music therapy produced particularly significant and favourable results when used to treat patients with depression. CONCLUSION: Current research into music therapy and depression points to a significant and persistent reduction in patients' symptoms and to improvements in their quality of life. However, further research is needed with regard to the best methods of illustrating the effects of music therapy.

Economic aspects of Q fever control in dairy goats.

This paper presents an economic analysis of Q fever control strategies in dairy goat herds in The Netherlands. Evaluated control strategies involved vaccination strategies (being either preventive or reactive) and reactive non-vaccination strategies (i.e., culling or breeding prohibition). Reactive strategies were initiated after PCR positive bulk tank milk or after an abortion storm (abortion percentage in the herd of 5% or more). Preventive vaccination eradicates Q fever in a herd on average within 2 and 7 years (depending on breeding style and vaccination strategy). Economic outcomes reveal that preventive vaccination is always the preferred Q fever control strategy on infected farms and this even holds for a partial analysis if only on-farm costs and benefits are accounted for and human health costs are ignored. Averted human health costs depend to a large extend on the number of infected human cases per infected farm or animal. Much is yet unknown with respect to goat-human transmission rates. When the pathogen is absent in both livestock and farm environment then the "freedom of Q fever disease" is achieved. This would enable a return to non-vaccinated herds but more insight is required with respect to the mechanisms and probability of re-infection.

Controlling highly pathogenic avian influenza outbreaks: An epidemiological and economic model analysis.

Outbreaks of highly pathogenic avian influenza (HPAI) can cause large losses for the poultry sector and for animal disease controlling authorities, as well as risks for animal and human welfare. In the current simulation approach epidemiological and economic models are combined to compare different strategies to control highly pathogenic avian influenza in Dutch poultry flocks. Evaluated control strategies are the minimum EU strategy (i.e., culling of infected flocks, transport regulations, tracing and screening of contact flocks, establishment of protection and surveillance zones), and additional control strategies comprising pre-emptive culling of all susceptible poultry flocks in an area around infected flocks (1 km, 3 km and 10 km) and emergency vaccination of all flocks except broilers around infected flocks (3 km). Simulation results indicate that the EU strategy is not sufficient to eradicate an epidemic in high density poultry areas. From an epidemiological point of view, this strategy is the least effective, while pre-emptive culling in 10 km radius is the most effective of the studied strategies. But these two strategies incur the highest costs due to long duration (EU strategy) and large-scale culling (pre-emptive culling in 10 km radius). Other analysed pre-emptive culling strategies (i.e., in 1 km and 3 km radius) are more effective than the analysed emergency vaccination strategy (in 3 km radius) in terms of duration and size of the epidemics, despite the assumed optimistic vaccination capacity of 20 farms per day. However, the total costs of these strategies differ only marginally. Extending the capacity for culling substantially reduces the duration, size and costs of the epidemic. This study demonstrates the strength of combining epidemiological and economic model analysis to gain insight in a range of consequences and thus to serve as a decision support tool in the control of HPAI epidemics.

Evaluating vaccination strategies to control foot-and-mouth disease: a model comparison study.

Simulation models can offer valuable insights into the effectiveness of different control strategies and act as important decision support tools when comparing and evaluating outbreak scenarios and control strategies. An international modelling study was performed to compare a range of vaccination strategies in the control of foot-and-mouth disease (FMD). Modelling groups from five countries (Australia, New Zealand, USA, UK, The Netherlands) participated in the study. Vaccination is increasingly being recognized as a potentially important tool in the control of FMD, although there is considerable uncertainty as to how and when it should be used. We sought to compare model outputs and assess the effectiveness of different vaccination strategies in the control of FMD. Using a standardized outbreak scenario based on data from an FMD exercise in the UK in 2010, the study showed general agreement between respective models in terms of the effectiveness of vaccination. Under the scenario assumptions, all models demonstrated that vaccination with 'stamping-out' of infected premises led to a significant reduction in predicted epidemic size and duration compared to the 'stamping-out' strategy alone. For all models there were advantages in vaccinating cattle-only rather than all species, using 3-km vaccination rings immediately around infected premises, and starting vaccination earlier in the control programme. This study has shown that certain vaccination strategies are robust even to substantial differences in model configurations. This result should increase end-user confidence in conclusions drawn from model outputs. These results can be used to support and develop effective policies for FMD control.

Transmission rate of African swine fever virus under experimental conditions.

African swine fever (ASF) is a highly lethal, viral disease of swine. No vaccine is available, so controlling an ASF outbreak is highly dependent on zoosanitary measures, such as stamping out infected herds and quarantining of affected areas. Information on ASF transmission parameters could allow for more efficient application of outbreak control measures. Three transmission experiments were carried out to estimate the transmission parameters of two ASF virus isolates: Malta'78 (in two doses) and Netherlands'86. Different criteria were used for onset of infectiousness of infected pigs and moment of infection of contact pigs. The transmission rate (ß), estimated by a Generalized Linear Model, ranged from 0.45 to 3.63 per day. For the infectious period, a minimum as well as a maximum infectious period was determined, to account for uncertainties regarding infectiousness of persistently infected pigs. While the minimum infectious period ranged from 6 to 7 days, the average maximum infectious period ranged from approximately 20 to nearly 40 days. Estimates of the reproduction ratio (R) for the first generation of transmission ranged from 4.9 to 24.2 for the minimum infectious period and from 9.8 to 66.3 for the maximum infectious period, depending on the isolate. A first approximation of the basic reproduction ratio (R0) resulted in an estimate of 18.0 (6.90-46.9) for the Malta'78 isolate. This is the first R0 estimate of an ASFV isolate under experimental conditions. The estimates of the transmission parameters provide a quantitative insight into ASFV epidemiology and can be used for the design and evaluation of more efficient control measures.

Functional respiratory imaging as a tool to assess upper airway patency in children with obstructive sleep apnea.

OBJECTIVE: We aim to investigate if anatomical and functional properties of the upper airway using computerized 3D models derived from computed tomography (CT) scans better predict obstructive sleep apnea (OSA) severity than standard clinical markers. METHODS: Consecutive children with suspected OSA underwent polysomnography, clinical assessment of upper airway patency, and a CT scan while awake. A three-dimensional (3D) reconstruction of the pharyngeal airway was built from these images, and computational fluid dynamics modeling of low inspiratory flow was performed using open-source software. RESULTS: Thirty-three children were included (23 boys; mean age, was 6.0±3.2y). OSA was diagnosed in 23 patients. Children with OSA had a significantly lower volume of the overlap region between tonsils and the adenoids (median volume, 1408 mm compared to 2173 mm; p=0.04), a lower mean cross-sectional area at this location (median volume, 69.3mm(2) compared to 114.3mm2; p=0.04), and a lower minimal cross-sectional area (median volume, 17.9 mm2 compared to 25.9 mm2; p=0.05). Various significant correlations were found between several imaging parameters and the severity of OSA, most pronounced for upper airway conductance (r=-0.46) (p<0.01) for correlation between upper airway conductance and the apnea-hypopnea index. No differences or significant correlations were observed with clinical parameters of upper airway patency. Preliminary data after treatment showed that none of the patients with residual OSA had their smallest cross-sectional area located in segment 3, and this frequency was significantly lower than in their peers whose sleep study normalized (64%; p=0.05). CONCLUSION: Functional imaging parameters are highly correlated with OSA severity and are a more powerful correlate than clinical scores of upper airway patency. Preliminary data also showed that we could identify differences in the upper airway of those subjects who did not benefit from a local upper airway treatment.

Questioning the Pathogenic Role of the GLA p.Ala143Thr "Mutation" in Fabry Disease: Implications for Screening Studies and ERT.

Fabry disease is an X-linked inborn error of glycosphingolipid metabolism caused by quantitative or qualitative defects in the lysosomal enzyme alfa-Galactosidase A (aGAL A), ultimately resulting in vital organ dysfunction. Mainly the kidneys, the heart, and the central nervous system are involved. While the classical phenotype of Fabry disease is readily recognizable, screening studies have identified clinical variants. Here, we report the phenotype associated with the GLA p.Ala143Thr (c.427G>A) mutation in 12 patients aged 42-83 years. None of the patients had classical Fabry signs or symptoms as angiokeratoma, hypohidrosis, acroparesthesia, or cornea verticillata. Possible Fabry manifestations were renal failure (5/12), stroke (7/12), and left ventricular hypertrophy (5/12), but these were not necessarily attributable to the p.Ala143Thr mutation, as a cardiac biopsy in one female and left ventricular hypertrophy and kidney biopsies in two males with renal failure and microalbuminuria lacked Gb-3 deposits. The literature data on this mutation as well as data collected in the Fabry Outcome Survey (FOS) database confirm these findings. The association of renal failure, stroke, and left ventricular hypertrophy with this mutation could be the result of selection bias, as most patients were detected in screening studies.We conclude that care should be taken with attribution of vital organ dysfunction to GLA sequence alterations. In case of the p.Ala143Thr mutation, and possibly also other mutations associated with an attenuated phenotype, diagnostic tools such as biopsy and imaging should critically evaluate the relation of end-organ failure with Fabry disease, as this has important consequences for enzyme replacement therapy.

Multi-scale computational models of the airways to unravel the pathophysiological mechanisms in asthma and chronic obstructive pulmonary disease (AirPROM).

THE RESPIRATORY SYSTEM COMPRISES SEVERAL SCALES OF BIOLOGICAL COMPLEXITY: the genes, cells and tissues that work in concert to generate resultant function. Malfunctions of the structure or function of components at any spatial scale can result in diseases, to the detriment of gas exchange, right heart function and patient quality of life. Vast amounts of data emerge from studies across each of the biological scales; however, the question remains: how can we integrate and interpret these data in a meaningful way? Respiratory disease presents a huge health and economic burden, with the diseases asthma and chronic obstructive pulmonary disease (COPD) affecting over 500 million people worldwide. Current therapies are inadequate owing to our incomplete understanding of the disease pathophysiology and our lack of recognition of the enormous disease heterogeneity: we need to characterize this heterogeneity on a patient-specific basis to advance healthcare. In an effort to achieve this goal, the AirPROM consortium (Airway disease Predicting Outcomes through patient-specific computational Modelling) brings together a multi-disciplinary team and a wealth of clinical data. Together we are developing an integrated multi-scale model of the airways in order to unravel the complex pathophysiological mechanisms occurring in the diseases asthma and COPD.

Vaccination against foot-and-mouth disease I: epidemiological consequences.

An epidemic of foot-and-mouth disease (FMD) can have devastating effects on animal welfare, economic revenues, the export position and society as a whole, as occurred during the 2001 FMD epidemic in the Netherlands. Following the preemptive culling of 260,000 animals during this outbreak, the Dutch government adopted emergency vaccination as preferred control policy. However, a vaccination-to-live strategy has not been applied before, posing unprecedented challenges for effectively controlling the epidemic, regaining FMD-free status and minimizing economic losses. These three topics are covered in an interdisciplinary model analysis. In this first part we evaluate whether and how emergency vaccination can be effectively applied to control FMD epidemics in the Netherlands. For this purpose we develop a stochastic individual-based model that describes FMD virus transmission between animals and between herds, taking heterogeneity between host species (cattle, sheep and pigs) into account. Our results in a densely populated livestock area with >4 farms/km(2) show that emergency ring vaccination can halt the epidemic as rapidly as preemptive ring culling, while the total number of farms to be culled is reduced by a factor of four. To achieve this reduction a larger control radius around detected farms and a corresponding adequate vaccination capacity is needed. Although sufficient for the majority of simulated epidemics with a 2 km vaccination zone, the vaccination capacity available in the Netherlands can be exhausted by pig farms that are on average ten times larger than cattle herds. Excluding pig farms from vaccination slightly increases the epidemic, but more than halves the number of animals to be vaccinated. Hobby flocks - modelled as small-sized sheep flocks - do not play a significant role in propagating the epidemic, and need not be targeted during the control phase. In a more sparsely populated livestock area in the Netherlands with about 2 farms/km(2) the minimal control strategy of culling only detected farms seems sufficient to control an epidemic.

Vaccination against foot-and-mouth disease II: Regaining FMD-free status.

An epidemic of foot-and-mouth disease (FMD) can have devastating effects on animal welfare, economic revenues, the export position and society as a whole. The preferred control strategy in the Netherlands has recently changed to vaccination-to-live, but - not have been applied before - this poses unprecedented challenges for effectively controlling an epidemic, regaining FMD-free status and minimizing economic losses. These three topics are addressed in an interdisciplinary model analysis. In this second part we evaluate whether vaccination-to-live poses a higher risk for regaining FMD-free status than non-vaccination strategies and whether the final screening can be improved to reduce this risk. The FMD transmission model that was developed in the first part, predicted the prevalence of infected animals in undetected herds for 1000 hypothetical epidemics per control strategy. These results serve as input for the final screening model that was developed in this part. It calculates the expected number of undetected infected herds and animals per epidemic after final screening, as well as the number of herds and animals to be tested. Our results show that vaccination strategies yield a larger number of undetected infected animals in the whole country per epidemic before final screening than preemptive culling (median values and 5-95% interval): 8 (0-42) animals for 1 km preemptive culling, 50 (7-148) for 2 km vaccination and 35 (6-99) for 5 km vaccination. But the final screening reduced these to comparably low numbers: 1.0 (0-9.1) for 1 km preemptive culling, 3.5 (0.3-15) for 2 km vaccination and 2.1 (0.3-9.4) for 5 km vaccination. Undetected infected animals were mainly found in non-vaccinated sheep herds and vaccinated cattle and sheep herds. As a consequence, testing more non-vaccinated cattle and pig herds will not reduce the expected number of undetected infected animals after the final screening by much, while the required testing resources drastically increase. However, testing only a sample instead of all animals in vaccinated pig herds will not increase the expected number of undetected infected animals by much, while the required testing resources reduce by half. In conclusion, vaccination and preemptive culling strategies yield comparable numbers of undetected infected animals after final screening and the final screening costs can be reduced by testing a sample instead of all vaccinated pigs.

Transmission dynamics of hepatitis E virus in pigs: estimation from field data and effect of vaccination.

Hepatitis E is a viral disease that causes serious concerns for public health. Hepatitis E virus (HEV) genotype 3 is endemic in commercial pig farms worldwide that act as a reservoir. Pig-to-human transmission may occur when infectious animals enter the food chain at slaughter, through consumption of contaminated meat, direct exposure or use of by-products. To reduce the fraction of infectious animals at slaughter age and thus the risk for public health, it is important to understand the transmission dynamics of HEV in pig populations. In this study, we estimate the transmission rate parameter and mean infectious period of HEV in pigs from field data, using a Bayesian analysis. The data were collected in ten commercial pig herds that are each divided into three different age groups. Two transmission models were compared, assuming that animals are infected either locally by their group mates or globally by any infectious animal regardless of its group. For local and global transmission, the transmission rate parameters were 0.11 (posterior median with 95% credible interval: 0.092-0.14 day(-1)) and 0.16 (0.082-0.29 day(-1)), the mean infectious periods were 24 (18-33) days and 27 (20-39) days and the reproduction numbers were 2.7 (2.2-3.6) and 4.3 (2.8-6.9). Based on these results, global transmission is considered to be the more conservative model. Three effects of vaccination were explored separately. When vaccination is not sufficient to eliminate the virus, a shorter mean infectious period decreases the fraction of infectious animals at slaughter age, whereas a reduced transmission rate parameter adversely increases it. With a reduced susceptibility, vaccination of animals at a later age can be a better strategy than early vaccination. These effects should be taken into account in vaccine development.

The new Ghent criteria for Marfan syndrome: what do they change?

The diagnosis of Marfan syndrome (MFS) is challenging and international criteria have been proposed. The 1996 Ghent criteria were adopted worldwide, but new diagnostic criteria for MFS were released in 2010, giving more weight to aortic root aneurysm and ectopia lentis. We aimed to compare the diagnosis reached by applying this new nosology vs the Ghent nosology in a well-known series of 1009 probands defined by the presence of an FBN1 mutation. A total of 842 patients could be classified as MFS according to the new nosology (83%) as compared to 894 (89%) according to the 1996 Ghent criteria. The remaining 17% would be classified as ectopia lentis syndrome (ELS), mitral valve prolapse syndrome or mitral valve, aorta, skeleton and skin (MASS) syndrome, or potential MFS in patients aged less than 20 years. Taking into account the median age at last follow-up (29 years), the possibility has to be considered that these patients would go on to develop classic MFS with time. Although the number of patients for a given diagnosis differed only slightly, the new nosology led to a different diagnosis in 15% of cases. Indeed, 10% of MFS patients were reclassified as ELS or MASS in the absence of aortic dilatation; conversely, 5% were reclassified as MFS in the presence of aortic dilatation. The nosology is easier to apply because the systemic score is helpful to reach the diagnosis of MFS only in a minority of patients. Diagnostic criteria should be a flexible and dynamic tool so that reclassification of patients with alternative diagnosis is possible, requiring regular clinical and aortic follow-up.