• High prevalence of multidrug resistant Enterobacteriaceae among residents of long term care facilities in Amsterdam, the Netherlands.

      van Dulm, Eline; Tholen, Aletta T R; Pettersson, Annika; van Rooijen, Martijn S; Willemsen, Ina; Molenaar, Peter; Damen, Marjolein; Gruteke, Paul; Oostvogel, Paul; Kuijper, Ed J; et al. (2019-01-01)
    • High resolution annual average air pollution concentration maps for the Netherlands.

      Schmitz, Oliver; Beelen, Rob; Strak, Maciej; Hoek, Gerard; Soenario, Ivan; Brunekreef, Bert; Vaartjes, Ilonca; Dijst, Martin J; Grobbee, Diederick E; Karssenberg, Derek (2019-03-12)
      Long-term exposure to air pollution is considered a major public health concern and has been related to overall mortality and various diseases such as respiratory and cardiovascular disease. Due to the spatial variability of air pollution concentrations, assessment of individual exposure to air pollution requires spatial datasets at high resolution. Combining detailed air pollution maps with personal mobility and activity patterns allows for an improved exposure assessment. We present high-resolution datasets for the Netherlands providing average ambient air pollution concentration values for the year 2009 for NO
    • High seroprevalence of Toxoplasma gondii and probability of detecting tissue cysts in backyard laying hens compared with hens from large free-range farms.

      Schares, G; Bangoura, B; Randau, F; Goroll, T; Ludewig, M; Maksimov, P; Matzkeit, B; Sens, M; Bärwald, A; Conraths, F J; et al. (2017-10)
      Serological assays are commonly used to determine the prevalence of Toxoplasma gondii infection in livestock, but the predictive value of seropositivity with respect to the presence of infective tissue cysts is less clear. The present study aimed at the identification of seropositive and seronegative free-range laying hens from organic and backyard farms, and the relationship with the presence of viable tissue cysts. In addition, potential risk and protective factors on the selected farms were investigated. An in-house T. gondii surface antigen (TgSAG1, p30, SRS29B) ELISA was validated with sera from experimentally infected chickens and used to examine 470 serum samples collected from laying hens from large organic and small backyard farms at the end of their laying period. A total of 11.7% (55/470) of all chickens tested positive, and another 18.9% (89/470) of test results were inconclusive. The highest seroprevalences were observed on small backyard farms with 47.7% (41/86) of chickens being seropositive while another 20.9% (18/86) of test results were inconclusive. Twenty-nine seropositive, 20 seronegative and 12 laying hens which yielded inconclusive ELISA results, were selected for further examination. Hearts and limb muscles of these hens were examined for T. gondii tissue cysts in a bioassay with IFNɣ-knockout or IFNɣ-receptor-knockout mice. Viable T. gondii was isolated from 75.9% (22/29) of the seropositive, 25.0% (3/12) of the inconclusive, and 5.0% (1/20) of the seronegative chickens. All 26 chickens tested positive in heart samples, while drumstick muscles (i.e. limb muscles) tested positive only in three. Data on putative risk and protective factors were collected on the farms using a standard questionnaire. Generalised multilevel modelling revealed farm size, cat related factors ('cats on the premise', 'cats used for rodent control'), hen house/hall related factors ('size category of hen house/hall', 'frequency category of cleaning hen house/hall', 'service period') as significantly associated with seropositivity to T. gondii in hens. The final model, which included the age of the birds as an effect modifier and farm as a random effect variable, revealed that the use of cats for rodent control and an area available per hen in the chicken run of ≥10sqm were statistically significant risk factors for T. gondii seropositivity. Overall this study showed that exposure to T. gondii is common in small backyard farms but is rare on large organic farms with a high density of free-range hens, even when cats were present on the premises.
    • High throughput cultivation-based screening on porous aluminum oxide chips allows targeted isolation of antibiotic resistant human gut bacteria.

      Versluis, Dennis; de J Bello González, Teresita; Zoetendal, Erwin G; Passel, Mark W J van; Smidt, Hauke (2019-01-01)
      The emergence of bacterial pathogens that are resistant to clinical antibiotics poses an increasing risk to human health. An important reservoir from which bacterial pathogens can acquire resistance is the human gut microbiota. However, thus far, a substantial fraction of the gut microbiota remains uncultivated and has been little-studied with respect to its resistance reservoir-function. Here, we aimed to isolate yet uncultivated resistant gut bacteria by a targeted approach. Therefore, faecal samples from 20 intensive care patients who had received the prophylactic antibiotic treatment selective digestive decontamination (SDD), i.e. tobramycin, polymyxin E, amphotericin B and cefotaxime, were inoculated anaerobically on porous aluminium oxide chips placed on top of poor and rich agar media, including media supplemented with the SDD antibiotics. Biomass growing on the chips was analysed by 16S rRNA gene amplicon sequencing, showing large inter-individual differences in bacterial cultivability, and enrichment of a range of taxonomically diverse operational taxonomic units (OTUs). Furthermore, growth of Ruminococcaceae (2 OTUs), Enterobacteriaceae (6 OTUs) and Lachnospiraceae (4 OTUs) was significantly inhibited by the SDD antibiotics. Strains belonging to 16 OTUs were candidates for cultivation to pure culture as they shared ≤95% sequence identity with the closest type strain and had a relative abundance of ≥2%. Six of these OTUs were detected on media containing SDD antibiotics, and as such were prime candidates to be studied regarding antibiotic resistance. One of these six OTUs was obtained in pure culture using targeted isolation. This novel strain was resistant to the antibiotics metrodinazole and imipenem. It was initially classified as member of the Ruminococcaceae, though later it was found to share 99% nucleotide identity with the recently published Sellimonas intestinalis BR72T. In conclusion, we show that high-throughput cultivation-based screening of microbial communities can guide targeted isolation of bacteria that serve as reservoirs of antibiotic resistance.
    • High Whole-Genome Sequence Diversity of Human Papillomavirus Type 18 Isolates.

      Weele, Pascal van der; Meijer, Chris J L M; King, Audrey J (2018-02-07)
      The most commonly found human papillomavirus (HPV) types in cervical cancer are HPV16 and HPV18. Genome variants of these types have been associated with differential carcinogenic potential. To date, only a handful of studies have described HPV18 whole genome sequencing results. Here we describe HPV18 variant diversity and conservation of persistent infections in a longitudinal retrospective cohort study.
    • Historical greenhouse gas concentrations for climate modelling (CMIP6)

      Meinshausen, Malte; Vogel, Elisabeth; Nauels, Alexander; Lorbacher, Katja; Meinshausen, Nicolai; Etheridge, David M.; Fraser, Paul J.; Montzka, Stephen A.; Rayner, Peter J.; Trudinger, Cathy M.; et al. (2017-05-31)
      Atmospheric greenhouse gas (GHG) concentrations are at unprecedented, record-high levels compared to the last 800 000 years. Those elevated GHG concentrations warm the planet and – partially offset by net cooling effects by aerosols – are largely responsible for the observed warming over the past 150 years. An accurate representation of GHG concentrations is hence important to understand and model recent climate change. So far, community efforts to create composite datasets of GHG concentrations with seasonal and latitudinal information have focused on marine boundary layer conditions and recent trends since the 1980s. Here, we provide consolidated datasets of historical atmospheric concentrations (mole fractions) of 43 GHGs to be used in the Climate Model Intercomparison Project – Phase 6 (CMIP6) experiments. The presented datasets are based on AGAGE and NOAA networks, firn and ice core data, and archived air data, and a large set of published studies. In contrast to previous intercomparisons, the new datasets are latitudinally resolved and include seasonality. We focus on the period 1850–2014 for historical CMIP6 runs, but data are also provided for the last 2000 years. We provide consolidated datasets in various spatiotemporal resolutions for carbon dioxide (CO2), methane (CH4) and nitrous oxide (N2O), as well as 40 other GHGs, namely 17 ozone-depleting substances, 11 hydrofluorocarbons (HFCs), 9 perfluorocarbons (PFCs), sulfur hexafluoride (SF6), nitrogen trifluoride (NF3) and sulfuryl fluoride (SO2F2). In addition, we provide three equivalence species that aggregate concentrations of GHGs other than CO2, CH4 and N2O, weighted by their radiative forcing efficiencies. For the year 1850, which is used for pre-industrial control runs, we estimate annual global-mean surface concentrations of CO2 at 284.3 ppm, CH4 at 808.2 ppb and N2O at 273.0 ppb. The data are available at https://esgf-node.llnl.gov/search/input4mips/ and http://www.climatecollege.unimelb.edu.au/cmip6. While the minimum CMIP6 recommendation is to use the global- and annual-mean time series, modelling groups can also choose our monthly and latitudinally resolved concentrations, which imply a stronger radiative forcing in the Northern Hemisphere winter (due to the latitudinal gradient and seasonality).
    • HIV and risk of cardiovascular disease in sub-Saharan Africa: Rationale and design of the Ndlovu Cohort Study.

      Vos, Alinda; Tempelman, Hugo; Devillé, Walter; Barth, Roos; Wensing, Annemarie; Kretzschmar, Mirjam; Klipstein-Grobusch, Kerstin; Hoepelman, Andy; Tesselaar, Kiki; Aitken, Sue; et al. (2017-07)
      Background The largest proportion of people living with HIV resides in sub-Saharan Africa (SSA). Evidence from developed countries suggests that HIV infection increases the relative risk of cardiovascular disease (CVD) by up to 50%. Differences in lifestyle, gender distribution, routes of HIV transmission and HIV subtype preclude generalisation of data from Western countries to the SSA situation. The Ndlovu Cohort Study aims to provide insight into the burden of cardiovascular risk factors and disease, the mechanisms driving CVD risk and the contribution of HIV infection and its treatment to the development of CVD in a rural area of SSA. Design The Ndlovu Cohort Study is a prospective study in the Moutse area, Limpopo Province, South Africa. Methods A total of 1000 HIV-positive and 1000 HIV-negative participants aged 18 years and older with a male to female ratio of 1:1 will be recruited. Measurements of CVD risk factors and HIV-related characteristics will be performed at baseline, and participants will be followed-up over time at 6-month intervals. The burden of CVD will be assessed with repeated carotid intima-media thickness and pulse wave velocity measurements, as well as by recording clinical cardiovascular events that occur during the follow-up period. Conclusion This project will contribute to the understanding of the epidemiology and pathogenesis of CVD in the context of HIV infection in a rural area of SSA. The ultimate goal is to improve cardiovascular risk prediction and to indicate preventive approaches in the HIV-infected population and, potentially, for non-infected high-risk populations in a low-resource setting.
    • HIV care cost in England: a cross-sectional analysis of antiretroviral treatment and the impact of generic introduction.

      Ong, K J; van Hoek, A J; Harris, R J; Figueroa, J; Waters, L; Chau, C; Croxford, S; Kirwan, P; Brown, A; Postma, M J; et al. (2019-07-01)
    • HIV testing week 2015: lowering barriers for HIV testing among high-risk groups in Amsterdam.

      Bartelsman, M; Joore, I K; van Bergen, J E; Hogewoning, A A; Zuure, F R; van Veen, M G (2017-08-01)
      Evaluation of the HIV Testing Week (HTW) 2015 in Amsterdam: the number of (positive) tested persons, characteristics and testing history of the tested population, the differences in attendance per location and the healthcare workers' experiences and opinions concerning the HTW.
    • Hiv-bestrijding begint met GIS-werk

      Op de Coul, E L M; Joore, I K; van Sighem, A; Bom, B C J; Hillebregt, M; Prins, J M; Geerlings, S E; van Bergen, J E A M (2017)
      To map regions of the Netherlands with high HIV prevalence for surveillance and prevention purposes.
    • Hoeveel klinische geneesmiddelenstudies worden uiteindelijk gepubliceerd?

      van den Bogert, C A; Souverein, P C; Brekelmans, C T M; Janssen, S W J; Koëter, G H; Leufkens, H G M; Bouter, L M (2017)
      The objective of this study was to investigate the occurrence and determinants of non-publication of clinical drug trials in the Netherlands. All clinical drug trials reviewed by the 28 Institutional Review Boards (IRBs) in the Netherlands in 2007 were followed-up from approval to publication. Candidate determinants were the sponsor, phase, applicant, centers, therapeutic effect expected, type of trial, approval status of the drug(s), drug type, participant category, oncology or other disease area, prospective registration, and early termination. The main outcome was publication as peer reviewed article. The percentage of trials that were published, crude and adjusted odds ratio (OR), and 95% confidence interval (CI) were used to quantify the associations between determinants and publication. In 2007, 622 clinical drug trials were reviewed by IRBs in the Netherlands. By the end of follow-up, 19 of these were rejected by the IRB, another 19 never started inclusion, and 10 were still running. Of the 574 trials remaining in the analysis, 334 (58%) were published as peer-reviewed article. The multivariable logistic regression model identified the following determinants with a robust, statistically significant association with publication: phase 2 (60% published; adjusted OR 2.6, 95% CI 1.1-5.9), phase 3 (73% published; adjusted OR 4.1, 95% CI 1.7-10.0), and trials not belonging to phase 1-4 (60% published; adjusted OR 3.2, 95% CI 1.5 to 6.5) compared to phase 1 trials (35% published); trials with a company or investigator as applicant (63% published) compared to trials with a Contract Research Organization (CRO) as applicant (50% published; adjusted OR 1.7; 95% CI 1.1-2.8); and multicenter trials also conducted in other EU countries (68% published; adjusted OR 2.2, 95% CI 1.1-4.4) or also outside the European Union (72% published; adjusted OR 2.0, 95% CI 1.0-4.0) compared to single-center trials (45% published). Trials that were not prospectively registered (48% published) had a lower likelihood of publication compared to prospectively registered trials (75% published; adjusted OR 0.5, 95% CI 0.3-0.8), as well as trials that were terminated early (33% published) compared to trials that were completed as planned (64% published; adjusted OR 0.2, 95% CI 0.1-0.3). The non-publication rate of clinical trials seems to have improved compared to previous inception cohorts, but is still far from optimal, in particular among phase 1, single-center, not prospectively registered, and early terminated trials.
    • Hormonal and reproductive factors are associated with chronic low back pain and chronic upper extremity pain in women--the MORGEN study.

      Wijnhoven, Hanneke A H; Vet, Henrica C W de; Smit, Henriëtte A; Picavet, H Susan J (2006-06-01)
      STUDY DESIGN: Cross-sectional study of 11,428 women aged 20-59 years who were included in a postal questionnaire survey in the Dutch general population. OBJECTIVE: To examine how hormonal and reproductive factors are associated with chronic low back pain (LBP) and chronic upper extremity pain (UEP) in women. SUMMARY OF BACKGROUND DATA: Although LBP is suggested to be linked to hormonal and reproductive factors in women, results from previous studies are inconclusive. In addition, the association with chronic UEP is unknown. METHODS: Multivariate logistic regression models were used to examine associations between hormonal and reproductive factors (independent variables) and, respectively, chronic LBP, chronic UEP and combined chronic LBP/UEP. Associations were adjusted for age, level of education, working status, smoking, and overweight. RESULTS: Past pregnancy, young maternal age at first birth, duration of oral contraceptive use, and use of estrogens during menopause were associated with chronic LBP, while young age at menarche was associated with chronic UEP. Irregular or prolonged menstruation and hysterectomy were associated both with chronic LBP and chronic UEP. No positive associations were found for current pregnancy and number of children. CONCLUSIONS: In adult women, hormonal and reproductive factors are associated with chronic musculoskeletal pain in general. Factors related to increased estrogen levels may specifically increase the risk of chronic LBP.
    • Host gene expression kinetics during treatment of tuberculosis in HIV-coinfected individuals is independent of HAART therapy.

      Gebremicael, Gebremedhin; Kassa, Desta; Quinten, Edwin; Alemayehu, Yodit; Gebreegziaxier, Atsbeha; Belay, Yohannes; van Baarle, Debbie; Ottenhoff, Tom H M; Cliff, Jacqueline M; Haks, Mariëlle C (2018-07-02)
      Limitations in diagnostic tools to discriminate between active and latent tuberculosis (TB) and for monitoring TB treatment responses are major challenges in TB control, especially in HIV-coinfected individuals.
    • Host genetics of Bordetella pertussis infection in mice: significance of Toll-like receptor 4 in genetic susceptibility and pathobiology.

      Banus, H Alexander; Vandebriel, R J; Ruiter, H de; Dormans, J A M A; Nagelkerke, Nico J D; Mooi, Frits R; Hoebee, Barbara; Kranen, Henk J van; Kimman, Tjeerd G (2006-05-01)
      The susceptibility to and the severity of Bordetella pertussis infections in infants and children varies widely, suggesting that genetic differences between individuals influence the course of infection. We have previously identified three novel loci that influence the severity of whooping cough by using recombinant congenic strains of mice: Bordetella pertussis susceptibility loci 1, 2, and 3 (Bps1, -2, and -3). Because these loci could not account for all genetic differences between mice, we extended our search for additional susceptibility loci. We therefore screened 11 inbred strains of mice for susceptibility to a pertussis infection after intranasal infection. Susceptibility was defined by the number of bacteria in the lungs, being indicative of the effect between the clearance and replication of bacteria. The most resistant (A/J) and the most susceptible (C3H/HeJ) strains were selected for further genetic and phenotypic characterization. The link between bacterial clearance and chromosomal location was investigated with 300 F2 mice, generated by crossing A/J and C3H/HeJ mice. We found a link between the delayed clearance of bacteria from the lung and a large part of chromosome 4 in F2 mice with a maximum log of the odds score of 33.6 at 65.4 Mb, which is the location of Tlr4. C3H/HeJ mice carry a functional mutation in the intracellular domain of Tlr4. This locus accounted for all detectable genetic differences between these strains. Compared to A/J mice, C3H/HeJ mice showed a delayed clearance of bacteria from the lung, a higher relative lung weight, and increased body weight loss. Splenocytes from infected C3H/HeJ mice produced almost no interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha) upon ex vivo restimulation with B. pertussis compared to A/J mice and also showed a delayed gamma interferon (IFN-gamma) production. TNF-alpha expression in the lungs 3 days after infection was increased fivefold compared to uninfected controls in A/J mice and was not affected in C3H/HeJ mice. In conclusion, Tlr4 is a major host factor explaining the differences in the course of infection between these inbred strains of mice. Functional Tlr4 is essential for an efficient IL-1-beta, TNF-alpha, and IFN-gamma response; efficient clearance of bacteria from the lung; and reduced lung pathology.
    • How Adverse Outcome Pathways Can Aid the Development and Use of Computational Prediction Models for Regulatory Toxicology.

      Wittwehr, Clemens; Aladjov, Hristo; Ankley, Gerald; Byrne, Hugh J; de Knecht, Joop; Heinzle, Elmar; Klambauer, Günter; Landesmann, Brigitte; Luijten, Mirjam; MacKay, Cameron; et al. (2017-02)
      Efforts are underway to transform regulatory toxicology and chemical safety assessment from a largely empirical science based on direct observation of apical toxicity outcomes in whole organism toxicity tests to a predictive one in which outcomes and risk are inferred from accumulated mechanistic understanding. The adverse outcome pathway (AOP) framework provides a systematic approach for organizing knowledge that may support such inference. Likewise, computational models of biological systems at various scales provide another means and platform to integrate current biological understanding to facilitate inference and extrapolation. We argue that the systematic organization of knowledge into AOP frameworks can inform and help direct the design and development of computational prediction models that can further enhance the utility of mechanistic and in silico data for chemical safety assessment. This concept was explored as part of a workshop on AOP-Informed Predictive Modeling Approaches for Regulatory Toxicology held September 24-25, 2015. Examples of AOP-informed model development and its application to the assessment of chemicals for skin sensitization and multiple modes of endocrine disruption are provided. The role of problem formulation, not only as a critical phase of risk assessment, but also as guide for both AOP and complementary model development is described. Finally, a proposal for actively engaging the modeling community in AOP-informed computational model development is made. The contents serve as a vision for how AOPs can be leveraged to facilitate development of computational prediction models needed to support the next generation of chemical safety assessment.
    • How Can Autonomy Be Maintained and Informal Care Improved for People With Dementia Living in Residential Care Facilities: A Systematic Literature Review.

      Boumans, Jogé; van Boekel, Leonieke C; Baan, Caroline A; Luijkx, Katrien G (2018-09-15)
      For people with dementia living in residential care facilities, maintaining autonomy and receiving informal care are important. The objective of this review is to understand how caregiving approaches and physical environment, including technologies contribute to the maintenance of autonomy and informal care provision for this population.
    • How lay people understand and make sense of personalized disease risk information.

      Damman, Olga C; Bogaerts, Nina M M; van den Haak, Maaike J; Timmermans, Danielle R M (2017-10)
      Disease risk calculators are increasingly web-based, but previous studies have shown that risk information often poses problems for lay users.