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Human papillomavirus (HPV)-associated high-grade vulvar intraepithelial lesion (HSIL) is a precursor of vulvar squamous cell carcinoma (VSCC). Because of the 8% cancer risk, many vulvar HSIL patients undergo aggressive and mutilating treatments. Characterizing HSIL by their progression risk can help individualize treatment strategies. Accordingly, copy number alterations (CNAs) and DNA methylation have been identified as biomarkers for cancer risk stratification of HSIL. Here, we assessed their potential correlation, and relation to HPV16 (sub)lineages and progression to vulvar cancer. Eighty-two vulvar formalin-fixed paraffin-embedded (FFPE) samples, including controls, HSIL, HSIL adjacent to VSCC and VSCC, with previously determined DNA methylation profiles, were analysed for CNAs using mFAST-SeqS. Genome-wide z-scores were calculated to determine overall aneuploidy (aneuploidy scores), and compared to the methylation levels and status of marker panel ZNF582/SST/miR124-2. For 52 HPV16-positive cases, HPV (sub)lineages were determined by Sanger sequencing. HPV16 lineage A was predominant (86.4%), followed equally by lineages B, C, and D. Frequent chromosomal alterations included chr1pq, chr3q, chr9q gains, and chr2q, chr4q losses. Median aneuploidy scores increased across disease categories, from 0 in controls, to 3 in HSIL, 16 in HSIL adjacent to VSCC and 29 in VSCC. A positive relationship between aneuploidy scores and DNA methylation levels was found (ρ = 0.61, Spearman's rank correlation test). Aneuploidy scores were significantly higher in methylation-positive samples (p < .001). In conclusion, we showed that DNA methylation and CNAs both rise with increasing severity of disease, indicating their prognostic value for cancer risk stratification of HSIL, while no relation to HPV16 (sub)lineages was found., (© 2025 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Symptom-only case definitions are insufficient to discriminate COVID-like illness from acute respiratory infection (ARI) or influenza-like illness (ILI), due to the overlap in case definitions. Our objective was to develop a statistical method that does not rely on case definitions to determine the contribution of influenza virus and SARS-CoV-2 to the ARI burden during periods when both viruses are circulating. Data sources used for testing the approach were weekly ARI syndrome reports from the Infectieradar participatory syndromic surveillance system during the analysis period (the first 25 weeks of 2022, in which SARS-CoV-2 and influenza virus co-circulated in the Netherlands) and data from virologically tested ARI (including ILI) patients who consulted a general practitioner in the same period. Estimation of the proportions of ARI attributable to influenza virus, SARS-CoV-2, or another cause was framed as an inference problem, through which all data sources are combined within a Bayesian framework to infer the weekly numbers of ARI reports attributable to each cause. Posterior distributions for the attribution proportions were obtained using Markov Chain Monte-Carlo methods. Application of the approach to the example data sources indicated that, of the total ARI reports (total of 11,312; weekly mean of 452) during the analysis period, the model attributed 35.4% (95% CrI: 29.2-40.0%) and 27.0% (95% CrI: 19.3-35.2%) to influenza virus and SARS-CoV-2, respectively. The proposed statistical model allows the attribution of respiratory syndrome reports from participatory surveillance to either influenza virus or SARS-CoV-2 infection in periods when both viruses are circulating, but comparability of the participatory surveillance and virologically tested populations is important. Portability for use by other countries with established participatory respiratory surveillance systems is an asset., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 McDonald et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Although older people in nursing homes have a larger susceptibility to infectious diseases, the extent to which infectious diseases contribute to their mortality is unknown. Therefore, we quantified the associations between seasonal infectious diseases and all-cause mortality in Dutch nursing homes., Methods: We analyzed time series (January 2009 to December 2021) of the weekly sentinel surveillance of infectious diseases in Dutch nursing homes. A generalized linear model with binomial distribution and identity link was used to associate the proportion of all-cause mortality with the incidence of infections: COVID-19 (2020-2021), gastroenteritis (GE), influenza-like illness (ILI), and lower respiratory tract infections (LRTIs) at 0- to 4-week time-lags (mortality incidence at 0 to 4 weeks after infections incidence)., Results: Over 13 years, 81 nursing homes participated, with 20 to 35 homes each year (mean: 26). A total of 11,555 all-cause deaths occurred over 1,864,667 resident weeks, averaging a mortality incidence of 6.2 per 1000 resident weeks. All 4 tested infectious diseases exhibited a significant association with all-cause mortality in nursing homes (P ≤ .01). Collectively, these infectious diseases were associated with 18.6% (95% CI, 17.8%-19.3%) of all deaths. The association between mortality and ILI was significant in 7 of 12 ILI seasons. Yearly mortality associated with the specific infectious diseases was as follows: LRTI (10.2%; 95% CI, 9.6%-10.8%), ILI (8.2%; 95% CI, 7.5%-8.9%) (over the 7 of 12 significant seasons), COVID-19 (6.5%; 95% CI, 5.4%-7.7%) (over 2019-2021 as there was no previous SARS-CoV-2 circulation), and GE (2.3%; 95% CI, 2.0%-2.5%)., Conclusion and Implications: In nursing homes, the occurrence of seasonal respiratory and gastrointestinal infections is associated with nearly one-fifth of all-cause deaths. Although infection prevention and surveillance may already be performed in some nursing homes, it is vital to implement, and enhance targeted strategies like (hand) hygiene protocols, environmental cleaning practices, reducing droplet and aerosol transmission, and vaccination to effectively address specific infections., Competing Interests: Disclosure H.v.W. declares financial and nonfinancial research support from DaVolterrra and bioMérieux; financial research support from LimmaTech; and consultancy fees from MSD and Sanofi-Pasteur. All payments to the University Medical Centre Utrecht. The other authors declare no conflict of interest., (Copyright © 2024 Post-Acute and Long-Term Care Medical Association. Published by Elsevier Inc. All rights reserved.)

Background: Alternative data sources for surveillance have gained importance in maintaining coronavirus disease 2019 (COVID-19) situational awareness as nationwide testing has drastically decreased. Therefore, we explored whether rates of sick-leave from work are associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) notification trends and at which lag, to indicate the usefulness of sick-leave data for COVID-19 surveillance., Methods: We explored trends during the COVID-19 epidemic of weekly sick-leave rates and SARS-CoV-2 notification rates from 1 June 2020 to 10 April 2022. Separate time series were inspected visually. Then, Spearman correlation coefficients were calculated at different lag and lead times of zero to four weeks between sick-leave and SARS-CoV-2 notification rates. We distinguished between four SARS-CoV-2 variant periods, two labour sectors and overall, and all-cause sick-leave versus COVID-19-specific sick-leave., Results: The correlation coefficients between weekly all-cause sick-leave and SARS-CoV-2 notification rate at optimal lags were between 0.58 and 0.93, varying by the variant period and sector (overall: 0.83, lag -1; 95% CI [0.76, 0.88]). COVID-19-specific sick-leave correlations were higher than all-cause sick-leave correlations. Correlations were slightly lower in healthcare and education than overall. The highest correlations were mostly at lag -2 and -1 for all-cause sick-leave, meaning that sick-leave preceded SARS-CoV-2 notifications. Correlations were highest mostly at lag zero for COVID-19-specific sick-leave (coinciding with SARS-CoV-2 notifications)., Conclusion: All-cause sick-leave might offer an earlier indication and evolution of trends in SARS-CoV-2 rates, especially when testing is less available. Sick-leave data may complement COVID-19 and other infectious disease surveillance systems as a syndromic data source., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Public Health Association.)

Since the end of November 2023, the European Mortality Monitoring Network (EuroMOMO) has observed excess mortality in Europe. During weeks 48 2023-6 2024, preliminary results show a substantially increased rate of 95.3 (95% CI:  91.7-98.9) excess all-cause deaths per 100,000 person-years for all ages. This excess mortality is seen in adults aged 45 years and older, and coincides with widespread presence of COVID-19, influenza and respiratory syncytial virus (RSV) observed in many European countries during the 2023/24 winter season.

Background: Multidrug-resistant (MDR) bacteria are a growing global threat, especially in healthcare facilities. Faecal microbiota transplantation (FMT) is an effective prevention strategy for recurrences of Clostridioides difficile infections and can also be useful for other microbiota-related diseases., Methods: We study the effect of FMT in patients with multiple recurrent C. difficile infections on colonisation with MDR bacteria and antibiotic resistance genes (ARG) on the short (3 weeks) and long term (1-3 years), combining culture methods and faecal metagenomics., Results: Based on MDR culture (n = 87 patients), we notice a decrease of 11.5% in the colonisation rate of MDR bacteria after FMT (20/87 before FMT = 23%, 10/87 3 weeks after FMT). Metagenomic sequencing of patient stool samples (n = 63) shows a reduction in relative abundances of ARGs in faeces, while the number of different resistance genes in patients remained higher compared to stools of their corresponding healthy donors (n = 11). Furthermore, plasmid predictions in metagenomic data indicate that patients harboured increased levels of resistance plasmids, which appear unaffected by FMT. In the long term (n = 22 patients), the recipients' resistomes are still donor-like, suggesting the effect of FMT may last for years., Conclusions: Taken together, we hypothesise that FMT restores the gut microbiota to a composition that is closer to the composition of healthy donors, and potential pathogens are either lost or decreased to very low abundances. This process, however, does not end in the days following FMT. It may take months for the gut microbiome to re-establish a balanced state. Even though a reservoir of resistance genes remains, a notable part of which on plasmids, FMT decreases the total load of resistance genes., (© 2024. The Author(s).)

Pneumococcal carriage studies have suggested that pneumococcal colonization in adults is largely limited to the oral cavity and oropharynx. In this study, we used total abundance-based β-diversity (dissimilarity) and β-diversity components to characterize age-related differences in pneumococcal serotype composition of respiratory samples. quantitative PCR (qPCR) was applied to detect pneumococcal serotypes in nasopharyngeal samples collected from 946 toddlers and 602 adults, saliva samples collected from a subset of 653 toddlers, and saliva and oropharyngeal samples collected from a subset of 318 adults. Bacterial culture rates from nasopharyngeal samples were used to characterize age-related differences in rates of colonizing bacteria. Dissimilarity in pneumococcal serotype composition was low among saliva and nasopharyngeal samples from children. In contrast, respiratory samples from adults exhibited high serotype dissimilarity, which predominantly consisted of abundance gradients and was associated with reduced nasopharyngeal colonization. Age-related serotype dissimilarity was high among nasopharyngeal samples and relatively low for saliva samples. Reduced nasopharyngeal colonization by pneumococcal serotypes coincided with significantly reduced Moraxella catarrhalis and Haemophilus influenzae and increased Staphylococcus aureus nasopharyngeal colonization rates among adults. Findings from this study suggest that within-host environmental conditions, utilized in the upper airways by pneumococcus and other bacteria, undergo age-related changes. It may result in a host-driven ecological succession of bacterial species colonizing the nasopharynx and lead to competitive exclusion of pneumococcus from the nasopharynx but not from the oral habitat. This explains the poor performance of nasopharyngeal samples for pneumococcal carriage among adults and indicates that in adults saliva more accurately represents the epidemiology of pneumococcal carriage than nasopharyngeal samples., Competing Interests: UKHSA provides vaccine manufacturers (GSK, Pfizer, and Sanofi) with postmarketing surveillance reports on pneumococcal infection which the companies are required to submit to the UK licensing authority in compliance with their Risk Management Strategy. A cost recovery charge is made for these reports. UKHSA has received unrestricted research grants from Pfizer to participate in pneumococcal surveillance projects. K.T. received funds for an unrestricted research grant from GlaxoSmithKline Biologicals SA, consultation fees, fees for participation in advisory boards, speaking fees, and funds for unrestricted research grants from Pfizer, funds for an unrestricted research grant, and fees for participating in advisory boards from Merck Sharp & Dohme, all paid directly to his home institution. Except for the funds from GlaxoSmithKline Biologicals SA, none was received in relation to the work reported here. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© The Author(s) [2024]. Published by Oxford University Press on behalf of the International Society for Microbial Ecology.)

Background: We describe how rates of two frequently occurring notifiable diseases-diphtheria and scarlet fever-varied between regions of The Netherlands in the early twentieth century, and identify potential factors underlying this variation., Methods: Digitized weekly mandatory notification data for 1905-1925, municipality level, were aggregated into 27 'spatial units' defined by unique combinations of province and population density category (high: more than 4500; mid : 1250-4500; low: less than 1250 inhabitants km - ). Generalized additive regression models were fitted to estimate the associations between notification rates and population density, infant mortality rate and household income, while adjusting for temporal trends per spatial unit.2 ). Generalized additive regression models were fitted to estimate the associations between notification rates and population density, infant mortality rate and household income, while adjusting for temporal trends per spatial unit., Results: Annual per capita notification rates for both diphtheria and scarlet fever tended to rise from the beginning of the period 1905-1925 until peaking around 1918/1919. Adjusted diphtheria notification rates were higher for high- and mid- compared with low-density municipalities (by 71.6 cases per 100 000, 95% confidence interval (CI) : 52.7-90.5; 39.0/100 k, 95% CI : 24.7-53.3, respectively). Scarlet fever showed similar associations with population density (35.7 cases per 100 000, 95% CI : 9.4-62.0; 21.4/100 k, 95% CI: 1.5-41.3)., Conclusions: There was considerable spatial variation in notification rates for both diseases in early twentieth century Netherlands, which could partly be explained by factors capturing variation in living conditions and socio-economic circumstances. These findings aid understanding of contemporary respiratory infection transmission., Competing Interests: All authors declare that they have no competing interests., (© 2023 The Authors.)

Background Neisseria meningitidis is a commensal bacterium which can cause invasive disease. Colonisation studies are important to guide vaccination strategies.AimThe study's aim was to determine the prevalence of meningococcal colonisation, duration of carriage and distribution of genogroups in Iceland.MethodsWe collected samples from 1 to 6-year-old children, 15-16-year-old adolescents and 18-20-year-old young adults. Carriers were sampled at regular intervals until the first negative swab. Conventional culture methods and qPCR were applied to detect meningococci and determine the genogroup. Whole genome sequencing was done on groupable meningococci.ResultsNo meningococci were detected among 460 children, while one of 197 (0.5%) adolescents and 34 of 525 young adults (6.5 %) carried meningococci. Non-groupable meningococci were most common (62/77 isolates from 26/35 carriers), followed by genogroup B (MenB) (12/77 isolates from 6/35 carriers). Genogroup Y was detected in two individuals and genogroup W in one. None carried genogroup C (MenC). The longest duration of carriage was at least 21 months. Serial samples from persistent carriers were closely related in WGS.ConclusionsCarriage of pathogenic meningococci is rare in young Icelanders. Non-groupable meningococci were the most common colonising meningococci in Iceland, followed by MenB. No MenC were found. Whole genome sequencing suggests prolonged carriage of the same strains in persistent carriers.

The gut microbiome of humans and animals acts as a reservoir of extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-EC). Dogs are known for having a high prevalence of ESBL-EC in their gut microbiota, although their ESBL-EC carrier status often shifts over time. We hypothesized that the gut microbiome composition of dogs is implicated in ESBL-EC colonization status. Therefore, we assessed whether ESBL-EC carriage in dogs is associated with changes in the gut microbiome and resistome. Fecal samples were collected longitudinally from 57 companion dogs in the Netherlands every 2 weeks for a total of 6 weeks ( n  = 4 samples/dog). Carriage of ESBL-EC was determined through selective culturing and PCR and in line with previous studies, we observed a high prevalence of ESBL-EC carriage in dogs. Using 16s rRNA gene profiling we found significant associations between detected ESBL-EC carriage and an increased abundance of Clostridium sensu stricto 1 , Enterococcus , Lactococcus , and the shared genera of Escherichia -Shigella in the dog microbiome. A resistome capture sequencing approach (ResCap) furthermore, revealed associations between detected ESBL-EC carriage and the increased abundance of the antimicrobial resistance genes: cmlA , dfrA , dhfR , floR , and sul3 . In summary, our study showed that ESBL-EC carriage is associated with a distinct microbiome and resistome composition. IMPORTANCE The gut microbiome of humans and animals is an important source of multidrug resistant pathogens, including beta-lactamase-producing Escherichia coli (ESBL-EC). In this study, we assessed if the carriage of ESBL-EC in dogs was associated with changes in gut composition of bacteria and antimicrobial resistant genes (ARGs). Therefore, stool samples from 57 dogs were collected every 2 weeks for a total of 6 weeks. Sixty eight percent of the dogs carried ESBL-EC during at least one of the time points analyzed. By investigating the gut microbiome and resistome composition, we observed specific changes at time points when dogs were colonized with ESBL-EC compared to time points whenESBL-EC were not detected. In conclusion, our study highlights the importance to study the microbial diversity in companion animals, as gut colonization of particular antimicrobial resistant bacteria might be an indication of a changed microbial composition that is associated with the selection of particular ARGs., Competing Interests: The authors declare no conflict of interest.

In this study, we determined the presence of virulence factors in nonoutbreak, high-risk clones and other isolates belonging to less common sequence types associated with the spread of OXA-48-producing Klebsiella pneumoniae clinical isolates from The Netherlands ( n  = 61) and Spain ( n  = 53). Most isolates shared a chromosomally encoded core of virulence factors, including the enterobactin gene cluster, fimbrial fim and mrk gene clusters, and urea metabolism genes ( ureAD ). We observed a high diversity of K-Locus and K/O loci combinations, KL17 and KL24 (both 16%), and the O1/O2v1 locus (51%) being the most prevalent in our study. The most prevalent accessory virulence factor was the yersiniabactin gene cluster (66.7%). We found seven yersiniabactin lineages- ybt  9, ybt  10, ybt  13, ybt  14, ybt  16, ybt  17, and ybt  27-which were chromosomally embedded in seven integrative conjugative elements (ICE Kp ): ICE Kp3 , ICE Kp4 , ICE Kp2 , ICE Kp5 , ICE Kp12 , ICE Kp10 , and ICE Kp22 , respectively. Multidrug-resistant lineages-ST11, ST101, and ST405-were associated with ybt  10/ICE Kp4 , ybt  9/ICE Kp3 , and ybt  27/ICE Kp22 , respectively. The fimbrial adhesin kpi operon ( kpiABCDEFG ) was predominant among ST14, ST15, and ST405 isolates, as well as the ferric uptake system kfuABC , which was also predominant among ST101 isolates. No convergence of hypervirulence and resistance was observed in this collection of OXA-48-producing K. pneumoniae clinical isolates. Nevertheless, two isolates, ST133 and ST792, were positive for the genotoxin colibactin gene cluster (ICE Kp10 ). In this study, the integrative conjugative element, ICE Kp , was the major vehicle for yersiniabactin and colibactin gene clusters spreading. IMPORTANCE Convergence of multidrug resistance and hypervirulence in Klebsiella pneumoniae isolates has been reported mostly related to sporadic cases or small outbreaks. Nevertheless, little is known about the real prevalence of carbapenem-resistant hypervirulent K. pneumoniae since these two phenomena are often separately studied. In this study, we gathered information on the virulent content of nonoutbreak, high-risk clones (i.e., ST11, ST15, and ST405) and other less common STs associated with the spread of OXA-48-producing K. pneumoniae clinical isolates. The study of virulence content in nonoutbreak isolates can help us to expand information on the genomic landscape of virulence factors in K. pneumoniae population by identifying virulence markers and their mechanisms of spread. Surveillance should focus not only on antimicrobial resistance but also on virulence characteristics to avoid the spread of multidrug and (hyper)virulent K. pneumoniae that may cause untreatable and more severe infections., Competing Interests: The authors declare a conflict of interest. J.W.A.R. was employed by IDbyDNA and is currently consulting for ARES-genetics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Carriage of Neisseria meningitidisis an accepted endpoint in monitoring meningococcal vaccine effects. We applied molecular methods to assess the impact of menACWY vaccine implementation on meningococcal carriage and genogroup-specific prevalence in young adults in Fall of 2022, four years after the introduction of the tetravalent vaccine in the Netherlands. The overall carriage rate of genogroupable meningococci was not significantly different compared to a pre-menACWY cohort investigated in 2018 (20.8 % or 125 of 601 versus 17.4 % or 52 of 299 individuals, p = 0.25). Of 125 carriers of genogroupable meningococci, 122 (97.6 %) were positive for either vaccine-types menC, menW, menY or genogroups, menB, menE, and menX, which are not targeted by the menACWY vaccine. Compared with a pre-vaccine-implementation cohort, there was 3.8-fold reduction (p < 0.001) in vaccine-type carriage rates and 9.0-fold increase (p < 0.0001) in non-vaccine type menE prevalence. We observe a reduction in menW and menY and an increase in menE, which suggest that implementation of menACWY vaccine affected carriage., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Carbapenem-resistant Klebsiella pneumoniae (CRKP) strains are of particular concern, especially strains with mobilizable carbapenemase genes such as blaKPC, blaNDM or blaOXA-48, given that carbapenems are usually the last line drugs in the β-lactam class and, resistance to this sub-class is associated with increased mortality and frequently co-occurs with resistance to other antimicrobial classes., Objectives: To characterize the genomic diversity and international dissemination of CRKP strains from tertiary care hospitals in Lisbon, Portugal., Methods: Twenty CRKP isolates obtained from different patients were subjected to WGS for species confirmation, typing, drug resistance gene detection and phylogenetic reconstruction. Two additional genomic datasets were included for comparative purposes: 26 isolates (ST13, ST17 and ST231) from our collection and 64 internationally available genomic assemblies (ST13)., Results: By imposing a 21 SNP cut-off on pairwise comparisons we identified two genomic clusters (GCs): ST13/GC1 (n = 11), all bearing blaKPC-3, and ST17/GC2 (n = 4) harbouring blaOXA-181 and blaCTX-M-15 genes. The inclusion of the additional datasets allowed the expansion of GC1/ST13/KPC-3 to 23 isolates, all exclusively from Portugal, France and the Netherlands. The phylogenetic tree reinforced the importance of the GC1/KPC-3-producing clones along with their rapid emergence and expansion across these countries. The data obtained suggest that the ST13 branch emerged over a decade ago and only more recently did it underpin a stronger pulse of transmission in the studied population., Conclusions: This study identifies an emerging OXA-181/ST17-producing strain in Portugal and highlights the ongoing international dissemination of a KPC-3/ST13-producing clone from Portugal., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Recent insights supporting the safety of live-attenuated vaccines and novel studies on the immunogenicity of vaccinations in the era of biological disease-modifying antirheumatic drugs in paediatric patients with autoimmune/inflammatory rheumatic diseases (pedAIIRD) necessitated updating the EULAR recommendations., Methods: Recommendations were developed using the EULAR standard operating procedures. Two international expert committees were formed to update the vaccination recommendations for both paediatric and adult patients with AIIRD. After a systematic literature review, separate recommendations were formulated for paediatric and adult patients. For pedAIIRD, six overarching principles and seven recommendations were formulated and provided with the level of evidence, strength of recommendation and Task Force level of agreement., Results: In general, the National Immunisation Programmes (NIP) should be followed and assessed yearly by the treating specialist. If possible, vaccinations should be administered prior to immunosuppressive drugs, but necessary treatment should never be postponed. Non-live vaccines can be safely given to immunosuppressed pedAIIRD patients. Mainly, seroprotection is preserved in patients receiving vaccinations on immunosuppression, except for high-dose glucocorticoids and B-cell depleting therapies. Live-attenuated vaccines should be avoided in immunosuppressed patients. However, it is safe to administer the measles-mumps-rubella booster and varicella zoster virus vaccine to immunosuppressed patients under specific conditions. In addition to the NIP, the non-live seasonal influenza vaccination should be strongly considered for immunosuppressed pedAIIRD patients., Conclusions: These recommendations are intended for paediatricians, paediatric rheumatologists, national immunisation agencies, general practitioners, patients and national rheumatology societies to attain safe and effective vaccination and optimal infection prevention in immunocompromised pedAIIRD patients., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background. Scarlet fever, an infectious disease caused by Streptococcus pyogenes , largely disappeared in developed countries during the twentieth century. In recent years, scarlet fever is on the rise again, and there is a need for a better understanding of possible factors driving transmission. Methods. Using historical case notification data from the three largest cities in The Netherlands (Amsterdam, Rotterdam and The Hague) from 1906 to 1920, we inferred the transmission rate for scarlet fever using time-series susceptible-infected-recovered (TSIR) methods. Through additive regression modelling, we investigated the contributions of meteorological variables and school term times to transmission rates. Results. Estimated transmission rates varied by city, and were highest overall for Rotterdam, the most densely populated city at that time. High temperature, seasonal precipitation levels and school term timing were associated with transmission rates, but the roles of these factors were limited and not consistent over all three cities. Conclusions. While weather factors alone can only explain a small portion of the variability in transmission rates, these results help understand the historical dynamics of scarlet fever infection in an era with less advanced sanitation and no antibiotic treatment and may offer insights into the driving factors associated with its recent resurgence., (© 2022 The Authors.)

Introduction: Influenza vaccination, besides protecting traditional risk groups, can protect employees and reduce illness-related absence, which is especially relevant in sectors with staff shortages. This study describes current knowledge of influenza vaccination in teachers and estimates its potential impact., Methods: We conducted a scoping review of the considerations for and impact of influenza vaccination of schoolteachers (grey and scientific literature up to 2020 March, complemented with interviews). We then estimated the potential impact of teacher vaccination in the Netherlands, with different scenarios of vaccine uptake for 3 influenza seasons (2016-2019). Using published data on multiple input parameters, we calculated potentially averted absenteeism notifications, averted absenteeism duration and averted doctor visits for influenza., Results: Only one scientific paper reported on impact; it showed lower absenteeism in vaccinated teachers, whereas more knowledge of vaccination impact was deemed crucial by 50% of interviewed experts. The impact for the Netherlands of a hypothetical 50% vaccine uptake was subsequently estimated: 74-293 potentially averted physician visits and 11,178-28,896 potentially averted days of influenza absenteeism (on ≈200,000 total teacher population). An estimated 12-32 vaccinations were required to prevent one teacher sick-leave notification, or 3.5-9.1 vaccinations to prevent one day of teacher absenteeism (2016-2019)., Conclusion: Scientific publications on influenza vaccination in teachers are few, while public interest has increased to reduce teacher shortages. However, school boards and public health experts indicate requiring knowledge of impact when considering this vaccination. Estimations of 3.5-9.1 vaccinated teachers preventing one day of influenza-related sick leave suggest a possible substantial vaccination impact on absenteeism. Financial incentives, more accessible on-site vaccinations at workplaces, or both, are expected to increase uptake, but more research is needed on teachers' views and vaccine uptake potential and its cost-effectiveness. Piloting free on-site influenza vaccination in several schools could provide further information on teacher participation., Competing Interests: The authors have declared that no competing interests exist.

The human gut microbiome plays a central role in health and disease. Environmental factors, such as lifestyle and diet, are known to shape the gut microbiome as well as the reservoir of resistance genes that these microbes harbour; the resistome. In this study we assessed whether long-term dietary habits within a single geographical region (the Netherlands) impact the human gut resistome. Faecal samples from Dutch omnivores, pescatarians, vegetarians and vegans were analysed by metagenomic shotgun sequencing (MSS) (n = 149) and resistome capture sequencing approach (ResCap) (n = 64). Among all diet groups, 119 and 145 unique antibiotic resistance genes (ARGs) were detected by MSS or ResCap, respectively. Five or fifteen ARGs were shared between all diet groups, based on MSS and ResCap, respectively. The total number of detected ARGs by MSS or ResCap was not significantly different between the groups. MSS also revealed that vegans have a distinct microbiome composition, compared to other diet groups. Vegans had a lower abundance of Streptococcus thermophilus and Lactococcus lactis compared to pescatarians and a lower abundance of S. thermophilus when compared to omnivores. In summary, our study showed that long-term dietary habits are not associated with a specific resistome signature., (© 2022. The Author(s).)

Carriage of Neisseria meningitidis is an accepted endpoint in monitoring meningococcal vaccines effects. We have assessed N. meningitidis and vaccine-type genogroup carriage prevalence in college students at the time of MenACWY vaccine introduction in the Netherlands, and evaluated the feasibility of saliva sampling for the surveillance of carriage. For this, paired saliva and oropharyngeal samples collected from 299 students were cultured for meningococcus. The DNA extracted from all bacterial growth was subjected to qPCRs quantifying meningococcal and genogroup-specific genes presence. Samples negative by culture yet positive for qPCR were cultured again for meningococcus. Altogether 74 (25%) of students were identified as meningococcal carrier by any method. Sixty-one students (20%) were identified as carriers with qPCR. The difference between number of qPCR-positive oropharyngeal (n = 59) and saliva (n = 52) samples was not significant (McNemar's test, p = 0.07). Meningococci were cultured from 72 students (24%), with a significantly higher (p < 0.001) number of oropharyngeal (n = 70) compared with saliva (n = 54) samples. The prevalence of genogroups A, B, C, W, and Y was none, 9%, 1%, 1% and 6%, respectively, and 8% of students carried MenACWY vaccine-type genogroup meningococci. Saliva is easy to collect and when combined with qPCR detection can be considered for meningococcal carriage studies., (© 2021. The Author(s).)

Background: Scabies outbreaks are common in nursing homes in the Netherlands. In October 2018, a local public health service (PHS) in The Hague was notified of a new scabies outbreak in a nursing home in that region. The PHS initiated an outbreak investigation. Cases were defined as: possible (reported symptoms), probable (scabies-like lesions) and confirmed (PCR or microscopy in skin flakes). Head-to-toe examinations were performed of all residents and those staff members who reported symptoms suggestive of scabies. Skin scrapings of lesions were tested either with microscopy or by PCR. Experimentally for case finding, skin flakes from bed linens of residents who reported symptoms of itchiness but did not have primary lesions were sent for PCR testing., Principal Findings: All residents (41) and 37/44 staff were included in this outbreak investigation. We identified 30 possible, four probable and six confirmed cases. The overall attack rate for probable/confirmed cases was 10/78 (13%). Of the six confirmed cases, two were confirmed by PCR, three by microscopy, and one showed positive findings with both techniques. Two out of the three bed-linen specimens were PCR-positive., Conclusions: In this outbreak of scabies in a nursing home, PCR was used on skin flakes from bed linens, which led to the detection of two additional cases. This illustrates the potential of PCR during the investigation of scabies outbreaks., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: BW works at Microvida which has Scabies PCR commercially available. The rest of the authors have no conflict of interest.

During the first wave of the severe acute respiratory syndrome-coronavirus-2 epidemic in the Netherlands, notifications consisted mostly of patients with relatively severe disease. To enable real-time monitoring of the incidence of mild coronavirus disease 2019 (COVID-19) - for which medical consultation might not be required - the Infectieradar web-based syndromic surveillance system was launched in mid-March 2020. Our aim was to quantify associations between Infectieradar participant characteristics and the incidence of self-reported COVID-19-like illness. Recruitment for this cohort study was via a web announcement. After registering, participants completed weekly questionnaires, reporting the occurrence of a set of symptoms. The incidence rate of COVID-19-like illness was estimated and multivariable Poisson regression used to estimate the relative risks associated with sociodemographic variables, lifestyle factors and pre-existing medical conditions. Between 17 March and 24 May 2020, 25 663 active participants were identified, who reported 7060 episodes of COVID-19-like illness over 131 404 person-weeks of follow-up. The incidence rate declined over the analysis period, consistent with the decline in notified cases. Male sex, age 65+ years and higher education were associated with a significantly lower COVID-19-like illness incidence rate (adjusted rate ratios (RRs) of 0.80 (95% CI 0.76-0.84), 0.77 (0.70-0.85), 0.84 (0.80-0.88), respectively) and the baseline characteristics ever-smoker, asthma, allergies, diabetes, chronic lung disease, cardiovascular disease and children in the household were associated with a higher incidence (RRs of 1.11 (1.04-1.19) to 1.69 (1.50-1.90)). Web-based syndromic surveillance has proven useful for monitoring the temporal trends in, and risk factors associated with, the incidence of mild disease. Increased relative risks observed for several patient factors could reflect a combination of exposure risk, susceptibility to infection and propensity to report symptoms.

Objectives: To determine the risk of invasive pneumococcal disease (IPD) in adult cancer patients stratified by type of underlying malignancy, age, and capsular serotype and to assess herd effects of childhood pneumococcal vaccination., Methods: All adult IPD cases reported to the Dutch pneumococcal surveillance system between 2004 and 2016 were included in this study. IPD incidence rates (IR) stratified by subtype of malignancy were calculated per 100 000 patient-years of follow-up. Incidence rate ratios (IRR) were calculated to compare IRs between groups., Results: A total of 7167 IPD cases were included, of which 1453 were in patients with malignancies. For patients with hematological malignancies (HM) and solid organ malignancies (SOM), IRs were 482/100 000 and 79/100 000, respectively, compared with 15/100 000 in controls. The highest incidence was observed among patients with multiple myeloma, non-Hodgkin lymphoma, chronic lymphocytic leukemia, pancreatic cancer, and lung cancer (3299/100 000, 2717/100 000, 538/100 000, 559/100 000, and 393/100 000, respectively), and in patients ≥50 years old. Among HM patients, the incidence of IPD declined significantly after the implementation of infant pneumococcal vaccination (IRR 0.65, 95% confidence interval 0.51-0.84); among SOM patients, the decline was not statistically significant (IRR 0.88, 95% confidence interval 0.72-1.07)., Conclusions: The IPD disease burden in cancer patients remains high. Large differences in IPD incidence between the different types of cancer demand tailored guidance regarding pneumococcal vaccination., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

COVID-19, although a respiratory illness, has been clinically associated with non-respiratory symptoms. We conducted a negative case-control study to identify the symptoms associated with SARS-CoV-2-positive results in Portugal. Twelve symptoms and signs included in the clinical notification of COVID-19 were selected as predictors, and the dependent variable was the RT-PCR test result. The χ2 tests were used to compare notified cases on sex, age group, health region and presence of comorbidities. The best-fit prediction model was selected using a backward stepwise method with an unconditional logistic regression. General and gastrointestinal symptoms were strongly associated with a positive test (P < 0.001). In this sense, the inclusion of general symptoms such as myalgia, headache and fatigue, as well as diarrhoea, together with actual clinical criteria for suspected cases, already updated and included in COVID-19 case definition, can lead to increased identification of cases and represent an effective strength for transmission control.

Background: Older persons may suffer more from travel-related health problems because of ageing and underlying chronic disorders. Knowledge on who is more likely to have these health problems helps to tailor travel health advice more specifically. This study aimed to determine predictors of travel-related morbidity in older travellers by assessing their pre-travel characteristics and performance using physical and cognitive functioning tests., Methods: Multicentre prospective cohort study among older travellers (≥60 years) who consulted one of the participating Dutch travel clinics. Handgrip strength and cognitive performance were measured pre-travel. Participants completed questionnaires before departure and 1 and 4 weeks after return. A diary recorded health complaints during travel until 2-week post-travel., Results: In total, 477 travellers completed the study (follow-up rate of 97%). Participants' median age was 66 years. The most visited regions were South-East Asia (34%) and South Asia (14%). Median travel duration was 19 days. Polypharmacy (≥5 medications per day) was not uncommon (16%). The median Charlson Comorbidity Index (CCI) score was 0. Self-reported travel-related infectious diseases concerned primarily respiratory tract infections (21%) and gastroenteritis (10%) whereas non-infectious complaints were injuries (13%), peripheral edema (12%) and dehydration (3%). Medical assistance was sought by 18%, mostly post-travel from their general practitioner (87%). Self-reported physical and mental health-related quality of life significantly improved during and after travel. Predictors for an increased risk of travel-related morbidity were higher CCI score, more travel experience, longer travel duration, higher number of daily medications, visiting northern Africa or South-East and East Asia, and phone and social media use., Conclusion: Older Dutch travellers are generally fit, well-prepared and suffer not only from common infectious health problems, but also from injuries. Travel improved their self-perceived health. The predictors could be used to identify the more at-risk older traveller and to decrease travel-related morbidity by optimizing pre-travel advice., (© International Society of Travel Medicine 2020.)

Tolerogenic dendritic cells (tolDCs) are central players in the maintenance of immune tolerance and thereby have been identified as the most favourable candidates for cell therapy of autoimmune diseases. We have recently shown that excretory-secretory products (ES L1) released by Trichinella spiralis larvae induce stable human tolDCs in vitro via Toll-like receptor 2 (TLR2) and TLR4. However, engagement of these receptors did not fully explain the tolerogenic profile of DCs. Here, we observed for the first time that dendritic cell-specific ICAM-3 grabbing non-integrin (DC-SIGN) interacts with highly glycosylated ES L1 and contributes to the generation of ES L1-induced tolDCs. Blocking DC-SIGN interfered with the ES L1-induced higher expression of CD40 and CCR7 and the production of IL-10 and TGF-β by DCs. The cooperation of TLR2, TLR4 and DC-SIGN receptors is of importance for the capacity of DCs to prime T cell response toward Th2 and to induce expansion of CD4+CD25+Foxp3+ T cells, as well as for the production of IL-10 and TGF-β by these cells. Overall, these results indicate that induction of tolDCs by ES L1 involves engagement of multiple pattern recognition receptors namely, TLR2, TLR4 and DC-SIGN.

Neisseria meningitidis serogroup B is a major cause of invasive meningococcal disease in Europe. In the absence of a conjugate serogroup B vaccine, a subcapsular 4CMenB vaccine was developed. Data on 4CMenB vaccine efficacy is still limited. Recently, genomic MATS (Meningococcal Antigen Typing System) was developed as a tool to predict strain coverage, using vaccine antigens sequence data. We characterized all invasive meningococcal isolates received by the Netherlands Reference Laboratory for Bacterial Meningitis (NRLBM) in two epidemiological years 2017-2019 using whole-genome sequencing and determined serogroup, clonal complex (cc) and estimated 4CMenB vaccine coverage by gMATS. Of 396 cases of invasive meningococcal disease, corresponding to an incidence of 1.22 cases/10 5 inhabitants, 180 (45%) were serogroup W, 155 (39%) serogroup B, 46 (12%) serogroup Y, 10 (3%) serogroup C, 2 non-groupable (0.5%) and 3 (0.7%) unknown. The incidence was the highest among 0-4 years olds (4 cases/10 5 inhabitants), and 57/72 (79%) of these cases were serogroup B. Serogroup W predominated among persons 45 years of age or older with 110/187 (59%) cases. Serogroup B isolates comprised 11 different clonal complexes, with 103/122 (84%) isolates belonging to 4 clonal complexes: cc32, cc41/44, cc269 and cc213. In contrast, serogroup W isolates were genetically similar with 95% belonging to cc11. Of 122 serogroup B isolates, 89 (73%; 95% CI: 64-80%) were estimated to be covered by 4CMenB and the degree of coverage varied largely by clonal complex and age. Among the 0-4 year olds, 25 of 43 (58%; 95% CI: 43-72%) MenB isolates were estimated to be covered. Since the coverage of the 4CMenB vaccine is dependent on circulating clonal complexes, our findings emphasize the need for surveillance of circulating meningococcal strains. In addition, estimation of age specific coverage is relevant to determine the right target age group for vaccination., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Climate change may contribute to higher incidence and wider geographic spread of vector borne diseases (VBDs). Effective monitoring and surveillance of VBDs is of paramount importance for the prevention of and timely response to outbreaks. Although international regulations exist to support this, barriers and operational challenges within countries hamper efficient monitoring. As a first step to optimise VBD surveillance and monitoring, it is important to gain a deeper understanding of system characteristics and experiences in to date non-endemic regions at risk of becoming endemic in the future. Therefore, this study qualitatively analyses the nature and flexibility of VBD surveillance and response in Beijing., Methods: In this qualitative study, eleven experts working in Beijing's vector-borne diseases surveillance and response system were interviewed about vector-borne disease surveillance, early warning, response, and strengths and weaknesses of the current approach., Results: Vector-borne disease surveillance occurs using passive syndromic surveillance and separate vector surveillance. Public health authorities use internet reporting networks to determine vector-borne disease risk across Beijing. Response toward a vector-borne disease outbreak is uncommon in this setting due to the currently low occurrence of outbreaks., Conclusions: A robust network of centralised institutions provides the continuity and flexibility needed to adapt and manage possible vector-borne disease threats. Opportunities exist for population-based health promotion and the integration of environment and climate monitoring in vector-borne disease surveillance.

Background: The burden of severe influenza virus infections is poorly known, for which surveillance of severe acute respiratory infection (SARI) is encouraged. Hospitalized SARI patients are however not always tested for influenza virus infection. Thus, to estimate the impact of influenza circulation we studied how influenza in primary care relates to intensive care unit (ICU) admissions using a modelling approach., Methods: We used time-series regression modelling to estimate a) the number of SARI admissions to ICU associated with medically attended influenza infections in primary care; b) how this varies by season; and c) the time lag between SARI and influenza time series. We analysed weekly adult ICU admissions (registry data) and adult influenza incidence (primary care surveillance data) from July 2007 through June 2016., Results: Depending on the year, 0% to 12% of annual SARI admissions were associated with influenza (0-554 in absolute numbers; population rate: 0/10 000-0.39/10 000 inhabitants), up to 27% during influenza epidemics. The average optimal fitting lag was +1 week (SARI trend preceding influenza by 1 week), varying between seasons (-1 to +4) with most seasons showing positive lags., Conclusion: Up to 12% of yearly SARI admissions to adult ICU are associated with influenza, but with large year-to-year variation and higher during influenza epidemics. In most years, SARI increases earlier than medically attended influenza infections in the general population. SARI surveillance could thus complement influenza-like illness surveillance by providing an indication of the season-specific burden of severe influenza infections and potential early warning of influenza activity and severity., (© 2020 The Authors. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

Background: Ambulance dispatches could be useful for syndromic surveillance of severe respiratory infections. We evaluated whether ambulance dispatch calls of highest urgency reflect the circulation of influenza A virus, influenza B virus, respiratory syncytial virus (RSV), rhinovirus, adenovirus, coronavirus, parainfluenzavirus and human metapneumovirus (hMPV)., Methods: We analysed calls from four ambulance call centres serving 25% of the population in the Netherlands (2014-2016). The chief symptom and urgency level is recorded during triage; we restricted our analysis to calls with the highest urgency and identified those compatible with a respiratory syndrome. We modelled the relation between respiratory syndrome calls (RSC) and respiratory virus trends using binomial regression with identity link function., Results: We included 211 739 calls, of which 15 385 (7.3%) were RSC. Proportion of RSC showed periodicity with winter peaks and smaller interseasonal increases. Overall, 15% of RSC were attributable to respiratory viruses (20% in out-of-office hour calls). There was large variation by age group: in <15 years, only RSV was associated and explained 11% of RSC; in 15-64 years, only influenza A (explained 3% of RSC); and in ≥65 years adenovirus explained 9% of RSC, distributed throughout the year, and hMPV (4%) and influenza A (1%) mainly during the winter peaks. Additionally, rhinovirus was associated with total RSC., Conclusion: High urgency ambulance dispatches reflect the burden of different respiratory viruses and might be useful to monitor the respiratory season overall. Influenza plays a smaller role than other viruses: RSV is important in children while adenovirus and hMPV are the biggest contributors to emergency calls in the elderly., (© 2020 The Authors. Influenza and Other Respiratory Viruses Published by John Wiley & Sons Ltd.)

Background: An increase in invasive meningococcal disease (IMD) serogroup W (IMD-W) cases caused by sequence type-11 clonal complex (cc11) was observed from October 2015 in the Netherlands. We compared the clinical picture and disease outcome of IMD-W cases with other serogroups, adjusting for host characteristics., Methods: We included IMD cases reported from January 2015 to June 2018 in the Netherlands and assessed clinical manifestation and symptoms at disease onset and calculated case fatality rates (CFRs). We used logistic regression to compare clinical manifestations and mortality of IMD-W with IMD caused by meningococci serogroup B, Y, or C, adjusting for age, gender, and comorbidities., Results: A total of 565 IMD cases were reported, of which 204 were IMD-W, 270 IMD-B, 63 IMD-Y, and 26 IMD-C. Most IMD-W isolates belonged to cc11 (93%; 175/188). Compared with other serogroups, IMD-W patients were diagnosed more often with septicemia (46%) or pneumonia (12%) and less often with meningitis (17%, P < .001). IMD-W cases presented more often with respiratory symptoms (45%, P < .001); 16% of IMD-W patients presented with diarrhea without IMD-specific symptoms (P = .061). The CFR for IMD-W was 16% (32/199, P < .001). The differences between IMD-W and other serogroups remained after adjusting for age, gender, and comorbidities., Conclusions: The atypical presentation and severe outcome among IMD-W cases could not be explained by age, gender, and comorbidities. Almost all our IMD-W cases were caused by cc11. More research is needed to identify the bacterial factors involved in clinical presentation and severity of IMD-W cc11., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)

To assess correlates of protection against measles and against subclinical measles virus (MV) infection, we recruited once-vaccinated children from geographic regions associated with increased MV circulation and/or at schools with low vaccination coverage in the Netherlands. Paired blood samples were collected shortly after onset of the measles outbreak and after the outbreak. A questionnaire was used to document the likelihood of exposure to MV and occurrence of measles-like symptoms. All blood samples were tested for MV-specific antibodies with five different assays. Correlates of protection were assessed by considering the lowest neutralizing antibody levels in children without MV infection, and by ROC analyses. Among 91 participants, two seronegative children (2%) developed measles, and an additional 19 (23%) experienced subclinical MV infection. The correlate of protection against measles was lower than 0.345 IU/mL. We observed a decreasing attack rate of subclinical MV infection with increasing levels of specific antibodies until 2.1 IU/mL, above which no subclinical MV infections were detected. The ROC analyses found a correlate of protection of 1.71 IU/mL (95% CI 1.01-2.11) for subclinical MV infection. Our correlates of protection were consistent with previous estimates. This information supports the analyses of serosurveys to detect immunity gaps that require targeted intervention strategies.

Introduction: In 2006, the Netherlands introduced the 7-valent pneumococcal conjugate vaccine (PCV7) in their national immunisation programme. In 2011, PCV7 was replaced by the 10-valent vaccine (PCV10). We report on the impact of PCV on invasive pneumococcal disease (IPD) incidence, clinical syndromes and patient outcomes., Methods: Pneumococcal isolates of hospitalised IPD patients between June 2004 and May 2018 were obtained from nine sentinel laboratories, covering 25% of the Dutch population. All isolates were serotyped. IPD incidence and clinical outcome were determined before and after introduction of PCV7 and after the switch to PCV10, stratified by age and serotype., Results: Compared to before PCV7 introduction, significant declines in IPD incidence were observed in 2016-2018 in children <5 years (69%), 18-49 year olds (31%) and ≥65 year olds (19%). Compared to before PCV10 introduction, the IPD incidence in 2016-2018 declined in children <5 years (RR:0.68, 95%CI:0.42-1.11), 5-17 year olds (RR:0.58, 95%CI:0.29-1.14) and 18-49 year olds (RR:0.72, 95%CI:0.57-0.90), but not in 50-64 year olds (RR:0.94, 95%CI:0.81-1.10) and ≥65 year olds (RR:1.04, 95%CI:0.0.93-1.15). While the case fatality rate (CFR) decreased from 16.2% pre-PCV to 13.4% post-PCV10 (RR:0.83, 95%CI:0.70-0.99), the switch to PCV10 had no further impact on CFR (RR:1.14, 95%CI:0.96-1.36)., Conclusion: Twelve years of PCV in the Netherlands has resulted in a sustained reduction of IPD incidence in children and younger adults. The switch from PCV7 to PCV10 did not have additional impact on the IPD incidence in older adults and CFR due to emerging non-vaccine serotypes., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The presence of intensive livestock farms in close vicinity to residential areas in the Netherlands is a complex problem characterised by knowledge uncertainty about the effects on residential health, overlapping value-driven concerns and stakeholder diversity. In order to address concerns about the health effects and effectively manage the debate about intensive livestock farming, constructive stakeholder dialogues are encouraged, informed by current scientific insights. We explored the current knowledge, beliefs and concerns of scientific experts, following the mental models approach. A summary expert model was derived from scanning the relevant literature and informed by interviews with 20 scientific experts. The study shows imprecise use of terminology by experts. Moreover, they appear to perceive intensive livestock farming not as a major health problem at least at this moment for neighbouring residents in the Netherlands. Broader themes such as (environmental) unsustainability and biodiversity loss seem a more prominent concern among the experts. Our study questions whether dialogues should only focus on residential health or cover broader values and concerns. However, mental models about risk may differ with other stakeholders, impeding communication. Hence, we will identify other stakeholders' knowledge, beliefs and value-based concerns in the light of facilitating constructed dialogues between stakeholders.

Background: Antimicrobial usage (AMU) in livestock plays a key role in the emergence and spread of antimicrobial resistance. Analysis of AMU data in livestock is therefore relevant for both animal and public health., Objectives: To assess AMU in 470 broiler and 252 turkey farms of one of Italy's largest poultry companies, accounting for around 30% of national poultry production, to identify trends and risk factors for AMU., Methods: Antimicrobial treatments administered to 5827 broiler and 1264 turkey grow-out cycles in 2015-17 were expressed as DDDs for animals per population correction unit (DDDvet/PCU). A retrospective analysis was conducted to examine the effect of geographical area, season and prescribing veterinarian on AMU. Management and structural interventions implemented by the company were also assessed., Results: AMU showed a 71% reduction in broilers (from 14 to 4 DDDvet/PCU) and a 56% reduction in turkeys (from 41 to 18 DDDvet/PCU) during the study period. Quinolones, macrolides and polymyxins decreased from 33% to 6% of total AMU in broilers, and from 56% to 32% in turkeys. Broiler cycles during spring and winter showed significantly higher AMU, as well as those in densely populated poultry areas. Different antimicrobial prescribing behaviour was identified among veterinarians., Conclusions: This study evidenced a decreasing trend in AMU and identified several correlates of AMU in broilers and turkeys. These factors will inform the design of interventions to further reduce AMU and therefore counteract antimicrobial resistance in these poultry sectors., (© The Author(s) 2019. 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.)

Background: From 2007 through 2010, a large epidemic of acute Q fever occurred in the Netherlands. Patients with cardiac valvulopathy are at high risk to develop chronic Q fever after an acute infection. This patient group was not routinely screened, so it is unknown whether all their chronic infections were diagnosed. This study aims to investigate how many chronic Q fever patients can be identified by routinely screening patients with valvulopathy and to establish whether the policy of not screening should be changed., Methods: In a cross-sectional study (2016-2017) in a hospital at the epicentre of the Q fever epidemic, a blood sample was taken from patients 18 years and older who presented with cardiac valvulopathy. The sample was tested for IgG antibodies against phase I and II of Coxiella burnetii using an immunofluorescence assay. An IgG phase II titre of ≥1:64 was considered serological evidence of a previous Q fever infection. An IgG phase I titre of ≥1:512 was considered suspicious for a chronic infection, and these patients were referred for medical examination., Results: Of the 904 included patients, 133 (15%) had evidence of a previous C. burnetii infection, of whom 6 (5%) had a chronic infection on medical examination., Conclusions: In a group of high-risk patients with a heart valve defect, we diagnosed new chronic Q fever infections seven years after the epidemic, emphasizing the need for screening of this group to prevent complications in those not yet diagnosed in epidemic areas., Competing Interests: The authors have declared that no competing interests exist.

This national study characterized invasive Haemophilus influenzae serotype b infections. Vaccinated (n = 41) and nonvaccinated (n = 10) cases were similar regarding presentation as meningitis (68.8% vs 90.0%; P = .25), predisposing factors (29.3% vs 20.0%; P = .76), admission to intensive care unit or death (22.0% vs 10.0%; P = 1.00), or sequelae (21.6% vs 10.0%; P = .81). Haemophilus influenzae serotype b occurred in vaccinated, healthy children with comparable disease course., (© The Author(s) 2018. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Vaccines have revolutionized public health, preventing millions of deaths each year, particularly in childhood. Yet, there is considerable variability in the magnitude and persistence of vaccine-induced immunity. Maintenance of specific antibody is essential for continuity of vaccine-induced serological protection. We conducted a genome-wide association study into the persistence of immunity to three childhood vaccines: capsular group C meningococcal (MenC), Haemophilus influenzae type b, and tetanus toxoid (TT) vaccines. We detail associations between variants in a locus containing a family of signal-regulatory proteins and the persistence MenC immunity. We postulate a regulatory role for the lead SNP, with supporting epigenetic and expression quantitative trait loci data. Furthermore, we define associations between SNPs in the human leukocyte antigen (HLA) locus and the persistence of TT-specific immunity. Moreover, we describe four classical HLA alleles, HLA DRB1 ∗ 0301, HLA DQB1 ∗ 0201, HLA DQB1 ∗ 0602, and HLA DRB1 ∗ 1501, associated with TT-specific immunity, independent of the lead SNP association., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Burden of disease (BoD) estimations are increasingly used to prioritize public health interventions. Previous Cryptosporidium BoD models accounted only for acute episodes, while there is increasing evidence of long-term manifestations. Our objective was to update Cryptosporidium BoD and cost-of-illness (COI) models and to estimate BoD and COI for the Netherlands in years 2013-2017., Methods: We performed a scoping literature review and drew an outcome tree including long-term manifestations for which sufficient evidence was found, such as recurrent diarrhea and joint pain. We chose the Disability-Adjusted Life Year (DALY) metric to synthesize years of life lost due mortality (YLLs) and years lived with disability due to non-fatal outcomes (YLDs). For the costs, we adopted a societal perspective accounting for direct healthcare costs, patient costs and productivity losses. Uncertainty was managed using Latin Hypercube sampling (30,000 iterations)., Results: In the Netherlands in 2017, we estimated 50,000 Cryptosporidium cases (95% uncertainty interval (UI): 15,000-102,000), 7,000 GP visits, 300 hospitalizations and 3 deaths, resulting in 137 DALYs (95%UI: 54-255) and €19.2 million COI (95%UI: €7.2 million- €36.2 million). Estimates were highest for 2016 (218 DALYs and €31.1 million in COI), and lowest in 2013 (100 DALYs and €13.8 million in COI). Most of the BoD was attributable to YLD (≈80% of DALYs). The most important cost was productivity losses (≈90% of total COI). Long-term manifestations, including recurring diarrhea and joint pain, accounted for 9% of the total DALYs and 7% of the total COI., Conclusion: Current evidence supports the inclusion of long-term manifestations in Cryptosporidium models, which contribute close to 10% of the total DALYs and costs. This may be an underestimation, as we were conservative in our assumptions. Cryptosporidium should be considered a priority organism with respect to public health surveillance, even in industrialized countries with high hygiene standards., Competing Interests: The authors have declared that no competing interests exist.

Hepatitis A virus (HAV) and norovirus are important agents of food-borne human viral illness, with common vehicles including bivalve molluscan shellfish, soft fruit and various vegetables. Outbreaks of viral illness due to contamination of the surfaces of foods, or food preparation surfaces by for example infected food handlers are also common. Virus analysis of food matrices can contribute towards risk management for these hazards and a two-part technical specification for determination of Hepatitis A virus and norovirus in food matrices (ISO/TS 15216:2013) was published jointly by the European Committee for Standardisation and the International Organization for Standardization in 2013. As part of the European Mandate No. M381 to validate 15 standards in the field of food microbiology, an international validation study involving 18 laboratories from 11 countries in Europe was conducted between 2012 and 2014. This study aimed to generate method characteristics including limit of detection, limit of quantification, repeatability and reproducibility for ISO 15216 - Part 1, the method for quantification, in seven food matrices. The organization and results of this study, including observations that led to improvements in the standard method are presented here. After its conclusion, the method characteristics generated were added to the revised international standard, ISO 15216-1:2017, published in March 2017., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: While influenza-like-illness (ILI) surveillance is well-organized at primary care level in Europe, few data are available on more severe cases. With retrospective data from intensive care units (ICU) we aim to fill this current knowledge gap. Using multiple parameters proposed by the World Health Organization we estimate the burden of severe acute respiratory infections (SARI) in the ICU and how this varies between influenza epidemics., Methods: We analyzed weekly ICU admissions in the Netherlands (2007-2016) from the National Intensive Care Evaluation (NICE) quality registry (100% coverage of adult ICUs in 2016; population size 14 million) to calculate SARI incidence, SARI peak levels, ICU SARI mortality, SARI mean Acute Physiology and Chronic Health Evaluation (APACHE) IV score, and the ICU SARI/ILI ratio. These parameters were calculated both yearly and per separate influenza epidemic (defined epidemic weeks). A SARI syndrome was defined as admission diagnosis being any of six pneumonia or pulmonary sepsis codes in the APACHE IV prognostic model. Influenza epidemic periods were retrieved from primary care sentinel influenza surveillance data., Results: Annually, an average of 13% of medical admissions to adult ICUs were for a SARI but varied widely between weeks (minimum 5% to maximum 25% per week). Admissions for bacterial pneumonia (59%) and pulmonary sepsis (25%) contributed most to ICU SARI. Between the eight different influenza epidemics under study, the value of each of the severity parameters varied. Per parameter the minimum and maximum of those eight values were as follows: ICU SARI incidence 558-2400 cumulated admissions nationwide, rate 0.40-1.71/10,000 inhabitants; average APACHE score 71-78; ICU SARI mortality 13-20%; ICU SARI/ILI ratio 8-17 cases per 1000 expected medically attended ILI in primary care); peak-incidence 101-188 ICU SARI admissions in highest-incidence week, rate 0.07-0.13/10,000 population)., Conclusions: In the ICU there is great variation between the yearly influenza epidemic periods in terms of different influenza severity parameters. The parameters also complement each other by reflecting different aspects of severity. Prospective syndromic ICU SARI surveillance, as proposed by the World Health Organization, thereby would provide insight into the severity of ongoing influenza epidemics, which differ from season to season.

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.

Cystic echinococcosis (CE), a zoonotic disease caused by tapeworms of the species complex Echinococcus granulosus sensu lato, represents a substantial global health and economic burden. Within this complex, E. granulosus sensu stricto (genotypes G1 and G3) is the most frequent causative agent of human CE. Currently, there is no fully reliable method for assigning samples to genotypes G1 and G3, as the commonly used mitochondrial cox1 and nad1 genes are not sufficiently consistent for the identification and differentiation of these genotypes. Thus, a new genetic assay is required for the accurate assignment of G1 and G3. Here we use a large dataset of near-complete mtDNA sequences (n = 303) to reveal the extent of genetic variation of G1 and G3 on a broad geographical scale and to identify reliable informative positions for G1 and G3. Based on extensive sampling and sequencing data, we developed a new method, that is simple and cost-effective, to designate samples to genotypes G1 and G3. We found that the nad5 is the best gene in mtDNA to differentiate between G1 and G3, and developed new primers for the analysis. Our results also highlight problems related to the commonly used cox1 and nad1. To guarantee consistent identification of G1 and G3, we suggest using the sequencing of the nad5 gene region (680 bp). This region contains six informative positions within a relatively short fragment of the mtDNA, allowing the differentiation of G1 and G3 with confidence. Our method offers clear advantages over the previous ones, providing a significantly more consistent means to distinguish G1 and G3 than the commonly used cox1 and nad1., (Copyright © 2018 Elsevier B.V. All rights reserved.)