Evaluation of a standardised protocol to measure the disease burden of respiratory syncytial virus infection in young children in primary care.

BACKGROUND: A better understanding of the burden of respiratory syncytial virus (RSV) infections in primary care is needed for policymakers to make informed decisions regarding new preventive measures and treatments. The aim of this study was to develop and evaluate a protocol for the standardised measurement of the disease burden of RSV infection in primary care in children aged < 5 years. METHODS: The standardised protocol was evaluated in Italy and the Netherlands during the 2019/20 winter. Children aged < 5 years who consulted their primary care physician, met the WHO acute respiratory infections (ARI) case definition, and had a laboratory confirmed positive test for RSV (RT-PCR) were included. RSV symptoms were collected at the time of swabbing. Health care use, duration of symptoms and socio-economic impact was measured 14 days after swabbing. Health related Quality of life (HRQoL) was measured using the parent-proxy report of the PedsQL™4.0 generic core scales (2-4 years) and PedsQL™4.0 infant scales (0-2 years) 30 days after swabbing. The standardised protocol was evaluated in terms of the feasibility of patient recruitment, data collection procedures and whether parents understood the questions. RESULTS: Children were recruited via a network of paediatricians in Italy and a sentinel influenza surveillance network of general practitioners in the Netherlands. In Italy and the Netherlands, 293 and 152 children were swabbed respectively, 119 and 32 tested RSV positive; for 119 and 12 children the Day-14 questionnaire was completed and for 116 and 11 the Day-30 questionnaire. In Italy, 33% of the children had persistent symptoms after 14 days and in the Netherlands this figure was 67%. Parents had no problems completing questions concerning health care use, duration of symptoms and socio-economic impact, however, they had some difficulties scoring the HRQoL of their young children. CONCLUSION: RSV symptoms are common after 14 days, and therefore, measuring disease burden outcomes like health care use, duration of symptoms, and socio-economic impact is also recommended at Day-30. The standardised protocol is suitable to measure the clinical and socio-economic disease burden of RSV in young children in primary care.

The relation between modeled odor exposure from livestock farming and odor annoyance among neighboring residents.

PURPOSE: Odor annoyance is an important environmental stressor for neighboring residents of livestock farms and may affect their quality of life and health. However, little is known about the relation between odor exposure due to livestock farming and odor annoyance. Even more, the relation between odor exposure and odor annoyance is rather complicated due to variable responses among individuals to comparable exposure levels and a large number of factors (such as age, gender, education) that may affect the relation. In this study, we (1) investigated the relation between modeled odor exposure and odor annoyance; (2) investigated whether other factors can affect this relation; and (3) compared our dose-response relation to a dose-response relation established in a previous study carried out in the Netherlands, more than 10 years ago, in order to investigate changes in odor perception and appreciation over time. METHODS: We used data from 582 respondents who participated in a questionnaire survey among neighboring residents of livestock farms in the south of the Netherlands. Odor annoyance was established by two close-ended questions in a questionnaire; odor exposure was estimated using the Stacks dispersion model. RESULTS: The results of our study indicate a statistically significant and positive relation between modeled odor exposure and reported odor annoyance from livestock farming (OR 1.92; 95 % CI 1.53-2.41). Furthermore, age, asthma, education and perceived air pollution in the environment are all related to odor annoyance, although they hardly affect the relation between estimated livestock odor exposure and reported odor annoyance. We also found relatively more odor annoyance reported among neighboring residents than in a previous study conducted in the Netherlands. CONCLUSIONS: We found a strong relation between modeled odor exposure and odor annoyance. However, due to some uncertainties and small number of studies on this topic, further research and replication of results is recommended.

Real world cost of human epidermal receptor 2-positive metastatic breast cancer patients: a longitudinal incidence-based observational costing study in the Netherlands and Belgium.

Currently, no country-specific metastatic breast cancer (MBC) observational costing data are available for the Netherlands and Belgium. Our aim is to describe country-specific resource use and costs of human epidermal receptor 2 (HER-2)-positive MBC in the Netherlands and Belgium, making use of real-world data. The eligibility period for patient selection was from April 2004 to April 2010. Inclusion and retrospective data collection begins at the time of first diagnosis of HER-2-positive MBC during the eligibility period and ends 24 months post-index diagnosis of MBC or at patient death. We identified 88 eligible patients in the Netherlands and 44 patients in Belgium. The total costs of medical treatment and other resource use utilisation per patient was €48,301 in the Netherlands and €37,431 in Belgium. Majority of costs was related to the use of trastuzumab in both countries, which was 50% of the total costs in the Netherlands and 56% in Belgium respectively. Our study provides estimates of resource use and costs for HER-2-positive MBC in the Netherlands and Belgium. We noticed various differences in resource use patterns between both countries demonstrating caution is needed when transferring cost estimates between countries.

Exceptionally low rotavirus incidence in the Netherlands in 2013/14 in the absence of rotavirus vaccination.

An unexpected drop in rotavirus (RV) detections was observed in the Netherlands in 2014, without RV vaccination. The estimated decrease in RV detections and gastroenteritis consultations in under five year-olds, in January-April 2014, compared to the same months in previous years, was 72% and 36%, respectively. The low birth rate, mild winter, high RV incidence in the previous year and the introduction of RV vaccination in neighbouring countries may have contributed to this decrease.

Calponin modulates the exclusion of Otx-expressing cells from convergence extension movements.

Otx2, a vertebrate homologue of the Drosophila orthodenticle gene, coordinates two processes in early embryonic development. Not only does it specify cell fate in the anterior regions of the embryo, it also prevents the cells that express it from participating in the convergence extension movements that shape the rest of the body axis. Here we show that, in Xenopus, this latter function is mediated by XclpH3, transcription of which is directly stimulated by Xotx2. XclpH3 is a Xenopus homologue of the mammalian calponin gene, the product of which binds both actin and myosin and prevents the generation of contractile force by actin filaments.

Impact of the 2009 influenza A(H1N1) pandemic on public health workers in the Netherlands.

A cross-sectional study was undertaken to analyse the impact of the 2009 influenza A(H1N1) pandemic on frontline public health workers in the Netherlands and to consider its implications for future pandemics. A structured, self-administered questionnaire was made available online (26 March to 26 May 2010) for frontline public health workers employed by the communicable disease departments of the public health services in the Netherlands (n=302). A total of 166 questionnaires (55%) were completed. The majority of respondents reported an increased workload, perceived as too busy (117 respondents, 70.5%) or extreme (13 respondents, 7.8%). Most respondents were not anxious about becoming infected (only seven were regularly concerned). The overall compliance with the control measures was good. The case definition was strictly applied by 110 of the 166 respondents (66%); 56 of 141 (39.7%) consistently consulted the Preparedness and Response Unit within a centralised assessment system, while 68 of 141 (48.2%) consulted the unit only at the beginning of the pandemic. Of 145 respondents with available data, 128 (88.3%) always used personal protective equipment. Reported adherence to the advice to discuss the various isolation measures with patients and their contacts was between 71% and 98.7%. Our study shows that the surveyed frontline public health workers considered the workload to be high during the first 3.5 months of the pandemic and their level of anxiety about becoming infected was reported to be low. During the pandemic, these workers were able to accommodate what they considered to be an excessive workload, even though initially their assignments were unfamiliar to them.

Maternal occupation and the risk of birth defects: an overview from the National Birth Defects Prevention Study.

OBJECTIVES: To examine the association between a spectrum of 24 maternal occupations and 45 birth defects for hypothesis generating purposes. METHODS: Cases of isolated and multiple birth defects (n = 8977) and all non-malformed live-born control births (n = 3833) included in the National Birth Defects Prevention Study (NBDPS) with estimated dates of delivery from 1 October 1997 through 31 December 2003 were included. A computer-assisted telephone interview with mothers was conducted. Occupational coding using the 2000 Standard Occupational Classification System and the 1997 North American Industry Classification System was completed for all jobs held by mothers. Jobs held from 1 month before pregnancy to the end of the third pregnancy month were considered exposures. Logistic regression models were run, adjusted for potential confounders. We also used a Bayesian approach to logistic regression. RESULTS: Approximately 72% of case mothers and 72% of control mothers in the NBDPS were employed. Several occupational groups were positively associated with one or more birth defects, including janitors/cleaners, scientists and electronic equipment operators. Using standard logistic regression, we found 42 (26 for Bayesian) significantly elevated risks of birth defects in offspring of working mothers. In addition, several other occupational groups were found to be negatively associated with one or more birth defects, including teachers and healthcare workers. Using standard logistic regression, we found 12 (11 for Bayesian) significantly reduced risks of birth defects among offspring of working women. CONCLUSIONS: Results from these analyses can be used for hypothesis generating purposes and guiding future investigations of occupational exposures and birth defects.

Time-to-pregnancy among male greenhouse workers.

OBJECTIVES: Fertility problems are an increasing public health issue in industrialised countries. Exposure to exogenous agents with endocrine disrupting properties, such as some pesticides, are potential risk factors for subfertility. The aim of this study was to determine whether time-to-pregnancy (TTP) is prolonged in male greenhouse workers exposed to pesticides in comparison with a non-exposed reference group. METHODS: Data were collected through self-administrated questionnaires with detailed questions on TTP, as well as on lifestyle (for example, smoking habits, coffee and alcohol consumption), work tasks, and occupational exposures of the men and their partners in the six months before conception of the most recent pregnancy. TTP was compared between male greenhouse workers (n = 694) and a non-exposed reference group (n = 613) by means of discrete proportional hazards regression analysis. RESULTS: The crude analyses did not show a decreased overall fecundability among greenhouse workers compared to the non-exposed reference group. However, when fecundability was assessed for primigravidous couples, duogravidous couples, and multigravidous couples separately, greenhouse workers were found to be less fecund when trying to conceive their first pregnancy (FR = 0.65; 95% CI 0.46 to 0.92), which is also the most valid analysis in which pregnancy planning issues were avoided. Among couples who already experienced one or more pregnancies, no association was seen between pesticide exposure and TTP after adjustment for confounders. CONCLUSION: A prolonged time-to-pregnancy was observed in male greenhouse workers exposed to pesticides before conception of their first pregnancy.

Adverse reproductive outcomes among male painters with occupational exposure to organic solvents.

OBJECTIVES: To assess the risks of reproductive disorders and birth defects in offspring of male painters with exposure to organic solvents, and to determine the shape of the dose-response relationship. METHODS: Random samples of painters and carpenters were drawn from workers affiliated with the Dutch Trade Union for Construction Workers, the Netherlands, 2001. Information on reproductive outcomes, occupational exposures, and lifestyle habits was retrospectively obtained through self-administered questionnaires filled in by 398 painters exposed to organic solvents in paints, thinners, and cleansers in the period of three months before the last pregnancy, and 302 carpenters with little or no exposure to solvents. A statistical model was used to estimate quantitative exposure measures. RESULTS: Workers employed as painters at three months before pregnancy had an increased risk (odds ratio 6.2, 95% CI 1.4 to 27.9) of congenital malformations in offspring compared to carpenters. There was a positive exposure-response trend with increasing exposure to organic solvents based on quantitative model predicted exposure estimates using toluene as a marker. There was some indication of an increased risk of functional developmental disorders in offspring among painters with intermediate and high model predicted exposure. The risk of low birth weight children seemed to be slightly increased among painters as well. Results for other reproductive outcomes (time to pregnancy, spontaneous abortion, and preterm birth) did not show increased risks. CONCLUSION: This study showed a positive association between paternal occupational exposure to organic solvents and congenital malformations in offspring. However, the small numbers of cases, especially when examining different exposure levels, as well as the self-reported nature of exposure and outcome variables, may hamper interpretation of the results.

[Physicians and scientific research: slight decline of the numbers of physicians with a doctoral degree]. / Artsen en wetenschappelijk onderzoek: lichte teruggang van het aantal gepromoveerde artsen.

OBJECTIVE: To establish whether the number of physicians interested in a career in academia (i.e. research) is declining. DESIGN: Descriptive. METHOD: The researchers analysed the pre- and post-doctoral careers of PhD students at 3 university medical centres (VU Amsterdam, Nijmegen and Maastricht) in 4 separate reference years (1989, 1994, 1999 and 2003), using information from doctoral dissertations and the Dutch medical address book. The researchers recorded the gender of the students and the timing of the doctorate in relation to specialist training, university education and employment, as applicable. RESULTS: The total number of dissertations produced at the 3 medical faculties in the 4 reference years increased gradually by nearly a factor of 2 (1989: 112; 1994: 152; 1999: 198; 2003: 213). In terms of absolute numbers, the number of dissertations authored by physicians increased from 1989 to 1994 and again in 1999 (64, 90 and 105), but decreased slightly in 2003 (96). The percentage of female physicians obtaining a doctorate doubled during this period (1989: 9/64 (14); 2003: 28/96 (29)). Increasingly, physicians prepared their dissertation before or during their training as specialists or general practitioners (1989: 15/64 (23%); 2003: 51/96 (53%)). Ofthe clinical specialists who had received their doctorate, approximately half continued to work in an academic setting after obtaining their degree. This percentage remained approximately the same in all reference years (1989: 13/26 (50); 1994:19/35 (54); 1999: 21/45 (47); 2003: 21/40 (53)). CONCLUSION: Although the number of physicians performing scientific research as part of their doctoral degree project declined slightly in 2003 following an initial rise, our data indicate no cause for major concern. One reason may be increased interest in Clinical Research Fellow programmes. However, the future of medical research would look brighter if young physicians with doctorates had better career prospects within academic centres. To follow the academic careers of clinicians in The Netherlands, a national registry is needed to collect the type of data analysed in this study continually.

[Trends in suicidal behaviour in Dutch general practice, 1983-2013]. / Suïcidepreventie in de huisartsenpraktijk, 1983-2013* * Dit onderzoek werd eerder gepubliceerd in BMJ Open (2016;6:e010868) met als titel 'Trends in suicidal behaviour in Dutch general practice 1983-2013: a retrospective observational study'. Afgedrukt met toestemming. NIVEL Nederlands instituut voor onderzoek van de gezondheidszorg, Utrecht.Dr. D.P. de Beurs, klinisch psycholoog; dr.ir. M. Hooiveld, epidemioloog; dr.ir. J.C. Korevaar, epidemioloog; dr. G.A. Donker, huisarts-epidemioloog. Vrije Universiteit, afd. Klinische Psychologie, Amsterdam.Prof.dr. A.J.F.M. Kerkhof, klinisch psycholoog.Contactpersoon: dr. G.A. Donker (g.donker@nivel.nl).

OBJECTIVE: We investigated trends in suicidal behaviour as reported by Dutch general practices from 1983 to 2013. Also, we analysed the relationship with patient characteristics and with the financial crisis of 2008. DESIGN: Retrospective observational study. METHOD: We estimated age-adjusted and gender-specific trends in suicides (342) and attempted suicides (1614), as registered in 1983-2013 under ICPC code P77 by 40 Dutch general practices participating in the NIVEL Primary Care Database sentinel station. Secondary outcomes, on the basis of supplementary questions in the GP Information System (Huisartsen Informatie Systeem), were the relationship between suicidal behaviour, earlier treatments and patient characteristics. Also, we analysed separate frequencies for the periods 1983-2007 and 2008-2013. RESULTS: Join-point analyses revealed a significant rise in male suicides from 2008 (b = 0.32, SE = 0.1, p = 0.008), and an increase in male suicide attempts since 2009 (b = 0.19, SE = 0.04, p < 0.001). Female suicidal behaviour showed a steady decrease in 1989-2013: b = -0.03, SE = 0.007, p < 0.0001 for female suicide, b = -0.02, SE = 0.002, p < 0.001 for female attempts. Almost half of the suicidal patients had visited their GP one month before the event. In 31% of these patients, the GP had recognized suicidal behaviour. CONCLUSIONS: Since 2008, there was a rise in the male suicide rate while female suicide behaviour has continued to decline. Training in the early recognition of suicide ideation in depressive patients might improve suicide prevention in primary care.

A novel guanine exchange factor increases the competence of early ectoderm to respond to neural induction.

Inductive interactions between different cell layers have an extremely important role in early embryogenesis. One of the most intensively studied and best characterised of these is the induction of neural tissue from ectodermal cells by the dorsal mesoderm. The competence of ectodermal cells to respond to neural induction varies according to dorsal-ventral position; with dorsal ectoderm (much of which forms the neural plate) having a far higher competence. Here we show that overexpression of the nucleotide exchange factor lfc increases ectodermal competence for neural induction as well as the amount of neural tissue in the whole embryo. Lfc is expressed pan ectodermally soon after gastrulation and may respond to an early determinant of dorsal ectoderm.

A conserved 30 base pair element in the Wnt-5a promoter is sufficient both to drive its' early embryonic expression and to mediate its' repression by otx2.

We have characterised a short (30 base pair) element from the Xenopus Wnt-5a promoter which is nearly identical to one located in the human Wnt-5a promoter, and has the same position relative to the transcription start site. When placed in front of a LacZ gene, this element can reproduce the same expression pattern observed for Wnt-5a at the late gastrula stage. Further we show that gastrula stage Wnt-5a expression is repressed by otx2, something which is reflected by the mutually exclusive expression patterns of these two genes. The isolated promoter sequence contains an OTX- consensus binding site and its' activity in embryos is repressed by ectopically expressed otx2.

Novel interactions between vertebrate Hox genes.

Understanding why metazoan Hox/HOM-C genes are expressed in spatiotemporal sequences showing colinearity with their genomic sequence is a central challenge in developmental biology. Here, we studied the consequences of ectopically expressing Hox genes to investigate whether Hox-Hox interactions might help to order gene expression during very early vertebrate embryogenesis. Our study revealed conserved autoregulatory loops for the Hox4 and Hox7 paralogue groups, detected following ectopic expression Hoxb-4 or HOXD4, and Hoxa-7, respectively. We also detected specific induction of 5' posterior Hox genes; Hoxb-5 to Hoxb-9, following ectopic expression of Hoxb-4/HOXD4; Hoxb-8 and Hoxb-9 following ectopic expression of Hoxa-7. Additionally, we observed specific repression of 3' anterior genes, following ectopic expression of Hox4 and Hox7 paralogues. We found that induction of Hoxb-4 and Hoxb-5 by Hoxb-4 can be direct, whereas induction of Hoxb-7 is indirect, suggesting the possibility of an activating cascade. Finally, we found that activation of Hoxb-4 itself and of posterior Hox genes by Hoxb-4 can be both non-cell-autonomous, as well as direct. We believe that our findings could be important for understanding how a highly ordered Hox expression sequence is set up in the early vertebrate embryo.

Alpha-MSH stimulates neurite outgrowth of neonatal rat corticospinal neurons in vitro.

Peptides related to melanocortin (alpha MSH) and corticotropin (ACTH), collectively termed melanocortins, exert trophic effects on the outgrowth of neurites from peripheral and central nervous system in vitro. Here we study the neurite outgrowth promoting effect of alpha-MSH on corticospinal (CS) neurons in vitro. Corticospinal neurons were identified in cell culture of neonatal rat cortex by immunostaining of cholera toxin subunit B (CTB), retrogradely transported from the cervical parts of the spinal cord. The CTB-immunoreactive neurons represent a small percentage (3-5%) of the total cell population after 72 h in vitro. The axons or dendrites of cortical and CTB-labelled layer V neurons were visualized using antibodies against axon- or dendrite-specific markers and measured using a semi-automatic quantification device. Here we report that alpha-MSH stimulates axonal as well as dendrite outgrowth from both total and CTB-labelled neurons with a bell-shape response curve. Axonal outgrowth of CTB-labelled neurons was dose-dependently stimulated with a maximal effect of 50% at 10(-10) M alpha-MSH. The maximal effect for stimulation of axon outgrowth for the total cortex population was observed at 10(-8) M alpha-MSH. In addition dendrite outgrowth of both total and CTB-labelled neurons is stimulated in a dose-dependent manner with maximal effects (varying between 46 and 48%) at 10(-8) M alpha-MSH. Explanations in the shift for the optimal alpha-MSH concentration for stimulation of axonal outgrowth of CTB-labelled layer V neurons as compared to total cortex neurons are discussed.

Induction of corticospinal target finding by release of a diffusible, chemotropic factor in cervical spinal grey matter.

The outgrowth of corticospinal tract axons in rat spinal cord primarily occurs during the first postnatal week. Axons originating from a group of layer V pyramidal cell bodies situated in the anterior part of the cerebral sensorimotor cortex project mainly to the cervical gray matter (Joosten et al., Dev. Brain Res., 36 (1987) 121-130). By co-culturing explants of the anterior part of the sensorimotor cortex and of cervical spinal gray matter in 3-D collagen gels, a target-specific directional growth of cortical axons towards the cervical spinal gray explant could be demonstrated. After retrograde filling with the fluorescent tracer 1,1-dioctadecyl-3,3,3',3'-tetramethyl indocarbocyanine perchlorate (DiI), in vivo as well as in vitro, most of the DiI-labelled cortical neurons were located in layer V of the cortical explant, and were characterized by a pyramidal shape. These data suggest that the cervical spinal gray matter target area becomes innervated by corticospinal axons through the release of a diffusible chemotropic factor.

Risk of fatal industrial accidents and death from other external causes among asphalt workers.

The hypothesis that asphalt workers are at increased risk of mortality from industrial accidents and other external causes was tested. Mortality rates for external and violent causes of death in a cohort of asphalt industry employees from seven European countries and Israel were compared to that of the general population. There was no evidence that mortality from external causes was increased among long term employees in asphalt application and mixing. There was an increased risk for mortality due to external causes among short term workers. However, none of the fatal accidents among short term workers appear to have occurred during employment in the studied asphalt companies. Overall, no evidence was found supporting the hypothesis that asphalt workers are at increased risk of fatal industrial or road accidents. Mortality from other external causes did not increase in this population as a whole, but increased risks among short term workers deserve further attention.

Modelling of 2,3,7,8-tetrachlorodibenzo-p-dioxin levels in a cohort of workers with exposure to phenoxy herbicides and chlorophenols.

Several cohort studies of herbicide manufacturing workers have been conducted over the last years. Most of these studies used simple proxies of exposure in the analysis such as a crude grouping in exposure categories based on job titles, presence in certain production areas over a period of time or during an accident, and duration of exposure. Current serum 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) levels available for a subset of workers can be used to back-extrapolate TCDD levels at the end of exposure using first order kinetic models, and relate TCDD levels to job history using regression models. The regression model obtained can be used to estimate TCDD levels for all cohort members. In this paper, the effect of changes in model assumptions on estimated TCDD levels is explored. TCDD levels are back-extrapolated assuming different values for TCDD half-life. A range of regression models with different sets of exposure determinants is used to relate back-extrapolated TCDD levels to determinants of exposure. These models were used to predict TCDD levels in the epidemiological analysis of data from a Dutch cohort study. The results show that the predicted serum TCDD level is strongly dependent on the assumed half-life. However, the ranking of all individuals on the exposure axis (from low to high) is not affected by changes in the half-life. Predicted serum TCDD levels seem not sensitive to changes in assumption regarding TCDD half-life. Predicted TCDD levels were positively associated with increased (cause specific) mortality.

Interspecific sequence comparison of the muscle-myosin heavy-chain genes from Drosophila hydei and Drosophila melanogaster.

The muscle-myosin heavy-chain (mMHC) gene of Drosophila hydei has been sequenced completely (size 23.3 kb). The sequence comparison with the D. melanogaster mMHC gene revealed that the exon-intron pattern is identical. The protein coding regions show a high degree of conservation (97%). The alternatively spliced exons (3a-b, 7a-d, 9a-c, 11a-e, and 15a-b) display more variations in the number of nonsynonymous and synonymous substitutions than the common exons (2, 4, 5, 6, 8, 10, 12, 13, 14, 16, 17, and 19). The base composition at synonymous sites of fourfold degenerate codons (third position) is not biased in the alternative exons. In the common exons there exists a bias for C and against A. These findings imply that the alternative exons of the Drosophila mMHC gene evolve at a different, in several cases higher, rate than the common ones. The 5' splice junctions and 5' and 3' untranslated regions show a high level of similarity, indicating a functional constraint on these sequences. The intron regions vary considerably in length within one species, but the corresponding introns are very similar in length between the two species and all contain stretches of sequence similarity. A particular example is the first intron, which contains multiple regions of similarity. In the conserved regions of intron 12 (head-tail border) sequences were found which have the potential to direct another smaller mMHC transcript.