Fifteen-year trajectories of multimorbidity and polypharmacy in Dutch primary care-A longitudinal analysis of age and sex patterns.

OBJECTIVE: After stratifying for age, sex and multimorbidity at baseline, our aim is to analyse time trends in incident multimorbidity and polypharmacy in the 15-year clinical trajectories of individual patients in a family medicine setting. METHODS: This study was carried out using data from the Registration Network Family Medicine in the South of the Netherlands. The clinical trajectories of 10037 subjects during the 15-year period (2000-2014) were analyzed in a repeated measurement of using a generalized estimating equations model as well as a multilevel random intercept model with repeated measurements to determine patterns of incident multimorbidity and polypharmacy. Hierarchical age-period-cohort models were used to generate age and cohort trajectories for comparison with prevalence trends in multimorbidity literature. RESULTS: Multimorbidity was more common in females than in males throughout the duration of the 15-year trajectory (females: 39.6%; males: 33.5%). With respective ratios of 11.7 and 5.9 between the end and the beginning of the 15-year period, the youngest female and male groups showed a substantial increase in multimorbidity prevalence. Ratios in the oldest female and male groups were 2.2 and 1.9 respectively. Females had higher levels of multimorbidity than males in the 0-24-year and 25-44-year age groups, but the levels converged to a prevalence of 92.2% in the oldest male and 90.7% in the oldest female group. Similar, albeit, moderate differences were found in polypharmacy patterns. CONCLUSIONS: We sought to specify the progression of multimorbidity from an early age. As a result, our study adds to the multimorbidity literature by specifying changes in chronic disease accumulation with relation to polypharmacy, and by tracking differences in patient trajectories according to age and sex. Multimorbidity and polypharmacy are common and their prevalence is accelerating, with a relatively rapid increase in younger groups. From the point of view of family medicine, this underlines the need for a longitudinal approach and a life course perspective in patient care.

Genotoxicity assessment of chemical mixtures.

The EFSA Scientific Committee addressed in this document the peculiarities related to the genotoxicity assessment of chemical mixtures. The EFSA Scientific Committee suggests that first a mixture should be chemically characterised as far as possible. Although the characterisation of mixtures is relevant also for other toxicity aspects, it is particularly significant for the assessment of genotoxicity. If a mixture contains one or more chemical substances that are individually assessed to be genotoxic in vivo via a relevant route of administration, the mixture raises concern for genotoxicity. If a fully chemically defined mixture does not contain genotoxic chemical substances, the mixture is of no concern with respect to genotoxicity. If a mixture contains a fraction of chemical substances that have not been chemically identified, experimental testing of the unidentified fraction should be considered as the first option or, if this is not feasible, testing of the whole mixture should be undertaken. If testing of these fraction(s) or of the whole mixture in an adequately performed set of in vitro assays provides clearly negative results, the mixture does not raise concern for genotoxicity. If in vitro testing provides one or more positive results, an in vivo follow-up study should be considered. For negative results in the in vivo follow-up test(s), the possible limitations of in vivo testing should be weighed in an uncertainty analysis before reaching a conclusion of no concern with respect to genotoxicity. For positive results in the in vivo follow-up test(s), it can be concluded that the mixture does raise a concern about genotoxicity.

Conceptual considerations on exposure assessment goals for aquatic pesticide risks at EU level.

Assessment of the risk to aquatic organisms is an important aspect of pesticide registration. This assessment must be based on well-defined exposure assessment goals (EAGs). However, these goals have not yet been defined for the EU authorization procedure. The definition of an aquatic EAG has seven elements, including: type of water body, spatial dimension of this body, spatial population of water bodies, multi-year temporal population of concentrations for a single water body, and the space-time percentile combination to be selected from the spatio-temporal population of concentrations. The seven elements are split into 16 items, three which are within the risk-management domain. The remaining 13 scientific items should preferably be based on consistency with landscape-level approaches. Subdivision of the spatial population of water bodies on the occurrence of exposure routes should be avoided (although this is current practice). The multi-year temporal population of concentrations should be based on all years in rotational crops (including years without applications). Risk managers should be offered a suite of coherent packages of EAGs and effect assessment goals from which they can select the package corresponding to the desired overall level of protection. © 2017 Society of Chemical Industry.

The effect of the runoff size on the pesticide concentration in runoff water and in FOCUS streams simulated by PRZM and TOXSWA.

Within the European Union the exposure of aquatic organisms to pesticides is assessed by simulations with the so-called FOCUS Surface Water Scenarios. Runoff plays an important role in these scenarios. As little is known about the effect of runoff size on the exposure, we investigated the effect of runoff size on the concentration in the runoff water and in streams simulated with the PRZM and TOXSWA models for two FOCUS runoff scenarios. For weakly sorbing pesticides (KF,oc<100Lkg-1) the pesticide concentration in the runoff water decreased exponentially with increasing daily runoff size. The runoff size hardly affected the pesticide concentration in the runoff water of strongly sorbing pesticides (KF,oc≥1000Lkg-1). For weakly sorbing pesticides the concentration in the FOCUS stream reached a maximum at runoff sizes of about 0.3 to 1mm. The concentration increased rapidly when the runoff size increased from 0 to 0.1mm and gradually decreased when runoff exceeded 1mm. For strongly sorbing pesticides the occurrence of the maximum concentration in the stream is clearly less pronounced and lies approximately between 1 and 20mm runoff. So, this work indicates that preventing small runoff events (e.g. by vegetated buffer strips) reduces exposure concentrations strongly for weakly sorbing pesticides. A simple metamodel was developed for the ratio between the concentrations in the stream and in the runoff water. This model predicted the ratios simulated by TOXSWA very well and it demonstrated that (in addition to runoff size and concentration in runoff) the size of the pesticide-free base flow and pesticide treatment ratio of the catchment determine the stream concentration to a large extent.

Effects of aged sorption on pesticide leaching to groundwater simulated with PEARL.

Leaching to groundwater is an important element of the regulatory risk assessment of pesticides in western countries. Including aged sorption in this assessment is relevant because there is ample evidence of this process and because it leads to a decrease in simulated leaching. This work assesses the likely magnitude of this decrease for four groundwater scenarios used for regulatory purpose in the EU (from the UK, Portugal, Austria and Greece) and for ranges of aged-sorption parameters and substance properties using the PEARL model. Three aged-sorption parameters sets were derived from literature, representing approximately 5th, 50th and 95th percentile cases for the magnitude of the effect of aged sorption on leaching concentrations (called S, M and L, respectively). The selection of these percentile cases was based only on the fNE parameter (i.e. the ratio of the aged sorption and the equilibrium sorption coefficients) because leaching was much more affected by the uncertainty in this parameter than by the uncertainty in the desorption rate coefficient of these sites (kd). For the UK scenario, the annual flux concentration of pesticide leaching at 1m depth decreased by typically a factor of 5, 30 and >1000 for the S, M and L parameter sets, respectively. This decrease by a factor of 30 for the M parameter set appeared to be approximately valid also for the other three scenarios. Decreasing the Freundlich exponent N from 0.9 into 0.7 for the M parameter set, increased this factor of 30 into a factor of typically 1000, considering all four scenarios. The aged-sorption sites were close to their equilibrium conditions during the leaching simulations for two of the four scenarios (for all substances considered and the M parameter set), but this was not the case for the other two scenarios.

An energetics-based honeybee nectar-foraging model used to assess the potential for landscape-level pesticide exposure dilution.

Estimating the exposure of honeybees to pesticides on a landscape scale requires models of their spatial foraging behaviour. For this purpose, we developed a mechanistic, energetics-based model for a single day of nectar foraging in complex landscape mosaics. Net energetic efficiency determined resource patch choice. In one version of the model a single optimal patch was selected each hour. In another version, recruitment of foragers was simulated and several patches could be exploited simultaneously. Resource availability changed during the day due to depletion and/or intrinsic properties of the resource (anthesis). The model accounted for the impact of patch distance and size, resource depletion and replenishment, competition with other nectar foragers, and seasonal and diurnal patterns in availability of nectar-providing crops and wild flowers. From the model we derived simple rules for resource patch selection, e.g., for landscapes with mass-flowering crops only, net energetic efficiency would be proportional to the ratio of the energetic content of the nectar divided by distance to the hive. We also determined maximum distances at which resources like oilseed rape and clover were still energetically attractive. We used the model to assess the potential for pesticide exposure dilution in landscapes of different composition and complexity. Dilution means a lower concentration in nectar arriving at the hive compared to the concentration in nectar at a treated field and can result from foraging effort being diverted away from treated fields. Applying the model for all possible hive locations over a large area, distributions of dilution factors were obtained that were characterised by their 90-percentile value. For an area for which detailed spatial data on crops and off-field semi-natural habitats were available, we tested three landscape management scenarios that were expected to lead to exposure dilution: providing alternative resources than the target crop (oilseed rape) in the form of (i) other untreated crop fields, (ii) flower strips of different widths at field edges (off-crop in-field resources), and (iii) resources on off-field (semi-natural) habitats. For both model versions, significant dilution occurred only when alternative resource patches were equal or more attractive than oilseed rape, nearby and numerous and only in case of flower strips and off-field habitats. On an area-base, flower strips were more than one order of magnitude more effective than off-field habitats, the main reason being that flower strips had an optimal location. The two model versions differed in the predicted number of resource patches exploited over the day, but mainly in landscapes with numerous small resource patches. In landscapes consisting of few large resource patches (crop fields) both versions predicted the use of a small number of patches.

Effect of Harsh or Mild Extraction of Soil on Pesticide Leaching to Groundwater.

Assessment of leaching to groundwater is an important aspect of pesticide risk assessment. The first leaching tier usually consists of simulations with leaching scenarios based on pesticide-soil properties derived from laboratory studies. Because the extractability of pesticide residues in such studies decreases with time, the harshness of the extraction method influences these pesticide-soil properties. This study investigates the effect of using a mild or harsh extraction method on simulated leaching to groundwater with consideration of substances with a range of half-lives and organic matter sorption coefficient values for selected leaching scenarios. The model for linking the concentrations of the mild and the harsh systems was based on laboratory studies with two pesticides and a Dutch sandy soil and was tested against Canadian field studies with atrazine (6-chloro-2-ethyl-4-isopropyl-1,3,5-triazine-2,4-diamine). The degradation rate and the aged-sorption parameters of each "mild" soil-substance system were derived from a hypothetical laboratory incubation study using prescribed parameter values for the corresponding "harsh" soil-substance system. Simulations were performed for three European leaching scenarios (United Kingdom, France, Portugal). For the best-guess parameter set, the leaching concentrations of the harsh system were approximately equal to those of the mild system at leaching concentrations greater than 1 µg L and were at most approximately a factor of two higher than those of the mild systems at mild leaching concentrations between 0.01 and 0.1 µg L. However, an extreme parameter set led to harsh leaching concentrations that were at most approximately 10 times higher than the mild leaching concentrations at levels between 0.01 and 0.1 µg L.

Trajectories of multimorbidity: exploring patterns of multimorbidity in patients with more than ten chronic health problems in life course.

BACKGROUND: Physicians are frequently confronted with complex health situations of patients, but knowledge of intensive forms of multimorbidity and their development during life is lacking. This study explores patterns and trajectories of chronic health problems of patients with multimorbidity particularly those with more than ten conditions and type and variety of organ systems involved in these patterns during life. METHOD: Life time prevalence patterns of chronic health problems were determined in patients with illness trajectories accumulating more than ten chronic health problems during life as registered by general practitioners in the South of the Netherlands in the Registration Network Family Practices (RNH). RESULTS: Overall 4,560 subjects (5%) were registered with more than ten chronic health problems during their life (MM11+), accounting for 61,653 (20%) of the 302,808 registered health problems in the population (N = 87,837 subjects). More than 30% accumulates 4 or more chronic health conditions (MM4-5: 4-5 conditions (N = 14,199; 16.2%); MM6-10: 6-10 conditions (N = 14,365; 16.4%). Gastro-intestinal, cardiovascular, locomotor, respiratory and metabolic conditions occur more frequently in the MM11+ patients than in the other patients, while the nature and variety of body systems involved in lifetime accumulation of chronic health problem clusters is both generic and specific. Regarding chronic conditions afflicting multiple sites throughout the body, the number of neoplasms seems low (N = 3,592; 5.8%), but 2,461 (49%) of the 4,560 subjects have registered at least one neoplasm condition during life. A similar pattern is noted for inflammation (N = 3,537, 78%), infection (N = 2,451, 54%) and injury (N = 3,401, 75%). CONCLUSION: There are many challenges facing multimorbidity research, including the implementation of a longitudinal, life-time approach from a family practice perspective. The present study, although exploratory by nature, shows that both general and specific mechanisms characterize the development of multimorbidity trajectories. A small proportion of patients has a high number of chronic health problems (MM11+) and keeps adding health problems during life. However, GP's need to realise that more than one third of their patients accumulate four or more chronic health problems (MM4-5 and MM6-10) during life.

European scenarios for exposure of soil organisms to pesticides.

Standardised exposure scenarios play an important role in European pesticide authorisation procedures (a scenario is a combination of climate, weather and crop data to be used in exposure models). The European Food Safety Authority developed such scenarios for the assessment of exposure of soil organisms to pesticides. Scenarios were needed for both the concentration in total soil and for the concentration in the liquid phase. The goal of the exposure assessment is the 90th percentile of the exposure concentration in the area of agricultural use of a pesticide in each of three regulatory European zones (North, Centre and South). A statistical approach was adopted to find scenarios that are consistent with this exposure goal. Scenario development began with the simulation of the concentration distribution in the entire area of use by means of a simple analytical model. In the subsequent two steps, procedures were applied to account for parameter uncertainty and scenario uncertainty (i.e. the likelihood that a scenario that is derived for one pesticide is not conservative enough for another pesticide). In the final step, the six scenarios were selected by defining their average air temperature, soil organic-matter content and their soil textural class. Organic matter of the selected scenarios decreased in the order North-Centre-South. Because organic matter has a different effect on the concentration in total soil than it has on the concentration in the liquid phase, the concentration in total soil decreased in the order North-Centre-South whereas the concentration in the liquid phase decreased in the opposite order. The concentration differences between the three regulatory zones appeared to be no more than a factor of two. These differences were comparatively small in view of the considerable differences in climate and soil properties between the three zones.

Estimating degradation rates in outdoor stagnant water by inverse modelling with TOXSWA: a case study with prosulfocarb.

BACKGROUND: The regulatory risk assessment of pesticides requires the assessment of exposure of aquatic ecosystems in small surface waters adjacent to agricultural fields. This exposure is predicted using simulation models, for which an important input parameter is the degradation rate in water. In regulatory dossiers, the decline rate in water from outdoor mesocosms is often available, but this rate encompasses more processes than degradation. Therefore, a procedure was designed for estimating the degradation rate in water that was suitable for mesocosm studies with limited datasets, e.g. datasets lacking site-specific sorption coefficients and relevant sediment properties. The procedure, based upon inverse modelling with TOXSWA, has been tested on a dataset for prosulfocarb in stagnant ditches. RESULTS: A degradation half-life in the ditch water of 2.9 days (20 °C) was found. This short half-life was to a significant extent accounted for by biodegradation rather than hydrolysis or photolysis. This half-life was considerably shorter than the half-life in the water layer of two laboratory water-sediment system experiments. CONCLUSION: The estimation procedure resulted in a unique half-life for the degradation rate in water. Such outdoor mesocosm studies seem to be better suited to assessing the degradation rate in water in ditches than the conventional water-sediment studies.

Simulation of movement of pesticides towards drains with a preferential flow version of PEARL.

BACKGROUND: As part of the Dutch authorisation procedure for pesticides, an assessment of the effects on aquatic organisms in surface waters adjacent to agricultural fields is required. The peak concentration is considered to be the most important exposure endpoint for the ecotoxicological effect assessment. Macropore flow is an important driver for the peak concentration, so the leaching model PEARL was extended with a macropore module. The new model has two macropore domains: a bypass domain and an internal catchment domain. The model was tested against data from a field leaching study on a cracking clay soil in the Netherlands. RESULTS: Most parameters of the model could be obtained from site-specific measurements, pedotransfer functions and general soil structural knowledge; only three macropore-flow-related parameters needed calibration. The flow-related macropore parameters could not be calibrated without using the concentration in drain water. Sequential calibration strategies, in which firstly the water flow model and then the pesticide fate model are calibrated, may therefore be less suitable for preferential flow models. CONCLUSION: After calibration, PEARL could simulate well the observed rapid movement towards drains of two pesticides with contrasting sorption and degradation rate properties. The calibrated value for the fraction of the internal catchment domain was high (90%). This means that a large fraction of water entering the macropores infiltrates into the soil matrix, thus reducing the fraction of rapid flow.

Development of a framework based on an ecosystem services approach for deriving specific protection goals for environmental risk assessment of pesticides.

General protection goals for the environmental risk assessment (ERA) of plant protection products are stated in European legislation but specific protection goals (SPGs) are often not precisely defined. These are however crucial for designing appropriate risk assessment schemes. The process followed by the Panel on Plant Protection Products and their Residues (PPR) of the European Food Safety Authority (EFSA) as well as examples of resulting SPGs obtained so far for environmental risk assessment (ERA) of pesticides is presented. The ecosystem services approach was used as an overarching concept for the development of SPGs, which will likely facilitate communication with stakeholders in general and risk managers in particular. It is proposed to develop SPG options for 7 key drivers for ecosystem services (microbes, algae, non target plants (aquatic and terrestrial), aquatic invertebrates, terrestrial non target arthropods including honeybees, terrestrial non-arthropod invertebrates, and vertebrates), covering the ecosystem services that could potentially be affected by the use of pesticides. These SPGs need to be defined in 6 dimensions: biological entity, attribute, magnitude, temporal and geographical scale of the effect, and the degree of certainty that the specified level of effect will not be exceeded. In general, to ensure ecosystem services, taxa representative for the key drivers identified need to be protected at the population level. However, for some vertebrates and species that have a protection status in legislation, protection may be at the individual level. To protect the provisioning and supporting services provided by microbes it may be sufficient to protect them at the functional group level. To protect biodiversity impacts need to be assessed at least at the scale of the watershed/landscape.

Effect of pesticide fate parameters and their uncertainty on the selection of 'worst-case' scenarios of pesticide leaching to groundwater.

BACKGROUND: For the registration of pesticides in the European Union, model simulations for worst-case scenarios are used to demonstrate that leaching concentrations to groundwater do not exceed a critical threshold. A worst-case scenario is a combination of soil and climate properties for which predicted leaching concentrations are higher than a certain percentile of the spatial concentration distribution within a region. The derivation of scenarios is complicated by uncertainty about soil and pesticide fate parameters. As the ranking of climate and soil property combinations according to predicted leaching concentrations is different for different pesticides, the worst-case scenario for one pesticide may misrepresent the worst case for another pesticide, which leads to 'scenario uncertainty'. RESULTS: Pesticide fate parameter uncertainty led to higher concentrations in the higher percentiles of spatial concentration distributions, especially for distributions in smaller and more homogeneous regions. The effect of pesticide fate parameter uncertainty on the spatial concentration distribution was small when compared with the uncertainty of local concentration predictions and with the scenario uncertainty. CONCLUSION: Uncertainty in pesticide fate parameters and scenario uncertainty can be accounted for using higher percentiles of spatial concentration distributions and considering a range of pesticides for the scenario selection.

Defining antimicrobial prescribing quality indicators: what is a new prescription?

UNLABELLED: : Since guidelines on antibiotic drug treatment often focus on appropriate first choice drugs, assessment of guideline adherence should only concentrate on the first drug prescribed, and not on subsequent antibiotics prescribed after failure of the first one. PURPOSE: To determine a valid cut-off point for a definition of "first" or "new" prescription in indicators for the assessment of the quality of antibiotic drug treatment on the basis of pharmaceutical data. METHODS: Three possible definitions for the term "new prescription" were compared, based on three different periods of time, viz. more than 35, 28, or 21 days after starting a previous antibiotic. In an observational study, 1,225 antimicrobial prescriptions from the medical files of five family practices were audited ("clinical classification") and compared with a classification based on the three definitions ("technical classification"). Agreement between these clinical and technical classifications was determined by calculating Cohen's kappa. The technical classification was analyzed as a diagnostic test, using the clinical classification as the gold standard, and sensitivity, specificity, likelihood ratios, and post-test probabilities were calculated. RESULTS: Defining "new prescription" as "more than 35 days after a previous prescription was issued" resulted in a Cohen's kappa of 0.93 (95% CI 0.92-0.98). The diagnostic value of this definition was extremely high, with a sensitivity of 0.976, specificity of 0.987, positive likelihood ratio of 77.7, and negative likelihood ratio of 0.02. CONCLUSION: We recommend using a cut-off value of 35 days since the last antimicrobial prescription as the definition of a "new prescription" when no diagnostic information is available, i.e., when using pharmaceutical data to assess the quality of antibiotic prescribing behavior.

Pesticide Leaching from Agricultural Fields with Ridges and Furrows.

In the evaluation of the risk of pesticide leaching to groundwater, the soil surface is usually assumed to be level, although important crops like potato are grown on ridges. A fraction of the water from rainfall and sprinkler irrigation may flow along the soil surface from the ridges to the furrows, thus bringing about an extra load of water and pesticide on the furrow soil. A survey of the literature reveals that surface-runoff from ridges to furrows is a well-known phenomenon but that hardly any data are available on the quantities of water and pesticide involved. On the basis of a field experiment with additional sprinkler irrigation, computer simulations were carried out with the Pesticide Emission Assessment at Regional and Local scales model for separate ridge and furrow systems in a humic sandy potato field. Breakthrough curves of bromide ion (as a tracer for water flow) and carbofuran (as example pesticide) were calculated for 1-m depth in the field. Bromide ion leached comparatively fast from the furrow system, while leaching from the ridge system was slower showing a maximum concentration of about half of that for the furrow system. Carbofuran breakthrough from the furrow system began about a month after application and increased steadily to substantial concentrations. Because the transport time of carbofuran in the ridge soil was much longer, no breakthrough occurred in the growing season. The maximum concentration of carbofuran leaching from the ridge-furrow field was computed to be a factor of six times as high as that computed for the corresponding level field. The study shows that the risk of leaching of pesticides via the furrow soil can be substantially higher than that via the corresponding level field soil.

Measurement and computation of movement of bromide ions and carbofuran in ridged humic-sandy soil.

Water flow and pesticide transport in the soil of fields with ridges and furrows may be more complex than in the soil of more level fields. Prior to crop emergence, the tracer bromide ion and the insecticide carbofuran were sprayed on the humic-sandy soil of a potato field with ridges and furrows. Rainfall was supplemented by sprinkler irrigation. The distribution of the substances in the soil profile of the ridges and furrows was measured on three dates in the potato growing season. Separate ridge and furrow systems were simulated by using the pesticide emission assessment at regional and local scales (PEARL) model for pesticide behavior in soil-plant systems. The substances travelled deeper in the furrow soil than in the ridge soil, because of runoff from the ridges to the furrows. At 19 days after application, the peak of the bromide distribution was measured to be in the 0.1-0.2 m layer of the ridges, while it was in the 0.3-0.5 m layer of the furrows. After 65 days, the peak of the carbofuran distribution in the ridge soil was still in the 0.1 m top layer, while the pesticide was rather evenly distributed in the top 0.6 m of the furrow soil. The wide ranges in concentration measured with depth showed that preferential water flow and substance transport occurred in the sandy soil. Part of the bromide ion distribution was measured to move faster in soil than the computed wave. The runoff of water and pesticide from the ridges to the furrows, and the thinner root zone in the furrows, are expected to increase the risk of leaching to groundwater in ridged fields, in comparison with more level fields.

What factors explain the differences in morbidity estimations among general practice registration networks in the Netherlands? A first analysis.

BACKGROUND: Information on the incidence and prevalence of diseases is a core indicator for public health. There are several ways to estimate morbidity in a population (e.g., surveys, healthcare registers). In this paper, we focus on one particular source: general practice based registers. Dutch general practice is a potentially valid source because nearly all non-institutionalized inhabitants are registered with a general practitioner (GP), and the GP fulfils the role as "gatekeeper". However, there are some unexplained differences among morbidity estimations calculated from the data of various general practice registration networks (GPRNs). OBJECTIVE: To describe and categorize factors that may explain the differences in morbidity rates from different GPRNs, and to provide an overview of these factors in Dutch GPRNs. RESULTS: Four categories of factors are distinguished: "healthcare system", "methodological characteristics", "general practitioner", and "patient". The overview of 11 Dutch GPRNs reveals considerable differences in factors. CONCLUSION: Differences in morbidity estimation depend on factors in the four categories. Most attention is dedicated to the factors in the "methodology characteristics" category, mainly because these factors can be directly influenced by the GPRN.

Symptoms of preclinical dementia in general practice up to five years before dementia diagnosis.

OBJECTIVES: To investigate which symptoms are indicative of preclinical dementia in general practice and whether subjects with preclinical dementia have an increased contact frequency with their general practitioner (GP). METHODS: Individuals with preclinical dementia (n = 75) and non-demented controls (n = 125) were selected from the Dutch GP registration network (RNH). Number of visits and odds ratio for the risk of subsequent dementia of various symptoms were analysed. Analyses were done separately for each 12-month period, in the 5 years prior to the diagnosis of dementia. RESULTS: In the 5 years prior to diagnosis, subjects with preclinical dementia visited their GP more often than controls. Gait disturbances were the earliest predictor. Cognitive complaints were predictive for dementia in the 3 years before diagnosis. All other symptoms, except vascular symptoms, were predictive in the year prior to diagnosis. Sensitivity was highest for cognitive symptoms (0.58) and gait disturbances (0.47) in the year before diagnosis. CONCLUSION: Preclinical dementia is associated with an increased contact frequency between patient and GP at least 5 years prior to the diagnosis of dementia. Gait disturbances and cognitive complaints are the earliest symptoms of preclinical dementia.

Testing MACRO (version 5.1) for pesticide leaching in a Dutch clay soil.

Testing of pesticide leaching models against comprehensive field-scale measurements is necessary to increase confidence in their predictive ability when used as regulatory tools. Version 5.1 of the MACRO model was tested against measurements of water flow and the behaviour of bromide, bentazone [3-isopropyl-1H-2,1,3-benzothiadiazin-4(3H)-one-2,2-dioxide] and imidacloprid [1-(6-chloro-3-pyridylmethyl)-N-nitroimidazolidin-2-ylideneamine] in a cracked clay soil. In keeping with EU (FOCUS) procedures, the model was first calibrated against the measured moisture profiles and bromide concentrations in soil and in drain water. Uncalibrated pesticide simulations based on laboratory measurements of sorption and degradation were then compared with field data on the leaching of bentazone and imidacloprid. Calibrated parameter values indicated that a high degree of physical non-equilibrium (i.e. strong macropore flow) was necessary to describe solute transport in this soil. Comparison of measured and simulated bentazone concentration profiles revealed that the bulk of the bentazone movement in this soil was underestimated by MACRO. Nevertheless, the model simulated the dynamics of the bentazone breakthrough in drain water rather well and, in particular, accurately simulated the timing and the concentration level of the early bentazone breakthrough in drain water. The imidacloprid concentration profiles and its persistence in soil were simulated well. Moreover, the timing of the early imidacloprid breakthrough in the drain water was simulated well, although the simulated concentrations were about 2-3 times larger than measured. Deep groundwater concentrations for all substances were underestimated by MACRO, although it simulated concentrations in the shallow groundwater reasonably well. It is concluded that, in the context of ecotoxicological risk assessments for surface water, MACRO can give reasonably good simulations of pesticide concentrations in water draining from cracking clay soils, but that prior calibration against hydrologic and tracer data is desirable to reduce uncertainty and improve accuracy.

Simulation of pesticide leaching in a cracking clay soil with the PEARL model.

Testing of pesticide leaching models is important to increase confidence in their use in pesticide registration procedures world-wide. The chromatographic PEARL model was tested against the results of a field leaching study on a cracking clay soil with a tracer (bromide), a mobile pesticide (bentazone) and a moderately sorbing, persistent pesticide (imidacloprid). Input parameters for water flow and solute transport were obtained from site-specific measurements and from literature. The model was tested using a stepwise approach in which each sub-model was sequentially and separately tested. Uncalibrated simulations for the water flow resulted in moisture profiles that were too wet. Calibration of the hydraulic relationships resulted in a good description of the moisture profiles. Calibration of the dispersion length was necessary to obtain a good description of bromide leaching. The calibrated dispersion length was 61 cm, which is very long and indicates a large non-uniformity of solute transport. The half-life of bentazone had to be calibrated to obtain a good description of its field persistence. The calibrated half-life was 2.5 times shorter than the half-life derived from the laboratory studies. Concentrations of bentazone in drain water and groundwater were described reasonably well by PEARL. Although measured and simulated persistence of imidacloprid in soil corresponded well, the bulk of the imidacloprid movement was overestimated by PEARL. However, imidacloprid concentrations in drain water were underestimated. In spite of the extensive calibration of water flow and tracer movement, the behaviour of the moderately sorbing pesticide imidacloprid could not be simulated. This indicates that the convection-dispersion equation cannot be used for accurate simulation of pesticide transport in cracking clay soils (even if extremely long dispersion length is used). Comparison of the model results from a poorly sorbed chemical (bentazone) and a moderately sorbed chemical (imidacloprid) were useful in defining the limitations of using a chromatographic flow model to simulate the effects of preferential flow.