Population PK-guided simulation study in children exposed to drugs in human milk

Risks of significant infant drug exposure through human milk arepoorly defined due to lack of large-scale PK data. We propose to useBayesian approach based on population PK (popPK)-guided modelingand simulation for risk prediction. As a proof-of-principle study, weexploited fluoxetine milk concentration data from 25 women. popPKparameters including milk-to-plasma ratio (MP ratio) were estimatedfrom the best model. The dose of fluoxetine the breastfed infant wouldreceive through mother's milk, and infant plasma concentrations wereestimated from 1000 simulated mother-infant pairs, using randomassignment of feeding times and milk volume. A conservative estimateof CYP2D6 activity of 20% of the allometrically-adjusted adult valuewas assumed. Derived model parameters, including MP ratio were consistentwith those reported in the literature. Visual predictive check andother model diagnostics showed no signs of model misspecifications.The model simulation predicted that infant exposure levels to fluoxetinevia mother's milk were below 10% of weight-adjusted maternal therapeuticdoses in >99% of simulated infants. Predicted median ratio ofinfant-mother serum levels at steady state was 0.093 (range 0.033-0.31),consistent with literature reported values (mean=0.07; range 0-0.59).Predicted incidence of relatively high infant-mother ratio (>0.2) ofsteady-state serum fluoxetine concentrations was <1.3%. Overall, ourpredictions are consistent with clinical observations. Our approach maybe valid for other drugs, allowing in silico prediction of infant drugexposure risks through human milk. We will discuss application of thisapproach to another drug used in lactating women.

Bidirectional shifts in colony queen number in a socially polymorphic ant population.

The breeding system of social organisms affects many important aspects of social life. Some species vary greatly in the number of breeders per group, but the mechanisms and selective pressures contributing to the maintenance of this polymorphism in social structure remain poorly understood. Here, we take advantage of a genetic dataset that spans 15 years to investigate the dynamics of colony queen number within a socially polymorphic ant species. Our study population of Formica selysi has single- and multiple-queen colonies. We found that the social structure of this species is somewhat flexible: on average, each year 3.2% of the single-queen colonies became polygynous, and conversely 1.4% of the multiple-queen colonies became monogynous. The annualized queen replacement rates were 10.3% and 11.9% for single- and multiple-queen colonies, respectively. New queens were often but not always related to previous colony members. At the population level, the social polymorphism appeared stable. There was no genetic differentiation between single- and multiple-queen colonies at eight microsatellite loci, suggesting ongoing gene flow between social forms. Overall, the regular and bidirectional changes in queen number indicate that social structure is a labile trait in F. selysi, with neither form being favored within a time-frame of 15 years.

Vitamin D levels and associated factors: a population-based study in Switzerland.

QUESTIONS UNDER STUDY: To update the prevalence of vitamin D insufficiency and to identify factors associated with vitamin D status in the Swiss adult population. METHODS: Data from the 2010-2011 Swiss Study on Salt intake, a population-based study in the Swiss population, was used. Vitamin D concentration in serum was measured by liquid chromatography- tandem mass spectrometry. Major factors that influence vitamin D levels were taken into account. Survey statistical procedures were used to estimate means and prevalences of vitamin D levels and status. Monthly-specific tertiles of vitamin D and ordinal logistic regression were used to determine the associations of covariates of interest with vitamin D status. RESULTS: The prevalences of vitamin D insufficiency (serum 25-hydroxyvitamin D: 20-29.9 ng/ml) and deficiency (<20 ng/ml) were the highest in the January-March period; 26.4% (95%CI: 21.6-31.7) and 61.6% (95%CI: 56.0-67.0), respectively. In the same period, more than 9 of ten men were vitamin D insufficient or deficient. Each unit increase of Body Mass Index was associated with an 8% decreased likelihood of being in a higher vitamin D tertiles. Oral contraceptive, altitude, urinary excretion of calcium, use of vitamin D supplement or treatment, high wine consumption, physical activity were associated with vitamin D tertiles. Compared to the French-speaking region, the Italian-speaking region was independently associated with a higher likelihood of being in higher vitamin D tertiles (OR: 1.66, 95%CI: 1.14-2.43). CONCLUSIONS: Low levels of vitamin D are common among Swiss adults, in particular during winter months and outside the Italian-speaking region.

Little effect of seasonal constraints on population genetic structure in eusocial paper wasps.

Climate has long been suggested to affect population genetic structures of eusocial insect societies. For instance, Hamilton [Journal of Theoretical Biology7 (1964) 17] discusses whether temperate and tropical eusocial insects may show differences in population-level genetic structure and viscosity, and how this might relate to differences in the degree of synchrony in their life cycles or modes of nest founding. Despite the importance of Hamilton's 1964 papers, this specific idea has not been tested in actual populations of wasps, probably due to the paucity of studies on tropical species. Here, we compare colony and population genetic structures in two species of primitively eusocial paper wasps with contrasting ecologies: the tropical species Polistes canadensis and the temperate species P. dominulus. Our results provide important clarifications of Hamilton's discussion. Specifically, we show that the genetic structures of the temperate and tropical species were very similar, indicating that seasonality does not greatly affect population viscosity or inbreeding. For both species, the high genetic differentiation between nests suggests strong selection at the nest level to live with relatives, whereas low population viscosity and low genetic differentiation between nest aggregations might reflect balancing selection to disperse, avoiding competition with relatives. Overall, our study suggests no prevalence of seasonal constraints of the life cycle in affecting the population genetic structure of eusocial paper wasps. These conclusions are likely to apply also to other primitively eusocial insects, such as halictine bees. They also highlight how selection for a kin structure that promotes altruism can override potential effects of ecology in eusocial insects.

Do youths gamble? You bet! A Swiss population-based study.

OBJECTIVES: To establish the gambling prevalence among Swiss resident youths, to estimate the associations between gambling frequency and substance use, poor mental health and social support and to determine the correlation between gambling pattern and gambling frequency. METHODS: Cross-sectional population-based survey conducted in 2007. From 1233 eligible participants aged 15-24 years, adequate information was available for 1116 (582 males), distributed into: non- (n=577), occasional (n=388) and frequent gamblers (n=151). Outcome measures: Substance use, social activities, presence of a reliable person among friends or family, psychological distress, major depression and gambling pattern. RESULTS: Overall, the 48.3% (n=539) of youths who had gambled during the previous year; were older and more likely to be male than non-gamblers. 13.5% (n=151) gambled at least weekly and could be differentiated from occasional gamblers on the basis of their gambling pattern. After controlling for gender, age and language area, occasional gamblers were significantly more likely to be occasional binge drinkers, whereas frequent gamblers were more likely to be daily smokers. CONCLUSION: Almost half of Swiss resident youths are involved in gambling. Both occasional and frequent gambling are associated with further health compromising behaviour. Practitioners dealing with young people should be aware that gambling is a behaviour that might be part of a more global risky behaviour framework.

Prediction of infant drug exposure through breastfeeding: population PK modeling and simulation of fluoxetine

BACKGROUND: Risks of significant infant drug exposurethrough breastmilk are poorly defined for many drugs, and largescalepopulation data are lacking. We used population pharmacokinetics(PK) modeling to predict fluoxetine exposure levels ofinfants via mother's milk in a simulated population of 1000 motherinfantpairs.METHODS: Using our original data on fluoxetine PK of 25breastfeeding women, a population PK model was developed withNONMEM and parameters, including milk concentrations, wereestimated. An exponential distribution model was used to account forindividual variation. Simulation random and distribution-constrainedassignment of doses, dosing time, feeding intervals and milk volumewas conducted to generate 1000 mother-infant pairs with characteristicssuch as the steady-state serum concentrations (Css) and infantdose relative to the maternal weight-adjusted dose (relative infantdose: RID). Full bioavailability and a conservative point estimate of1-month-old infant CYP2D6 activity to be 20% of the adult value(adjusted by weigth) according to a recent study, were assumed forinfant Css calculations.RESULTS: A linear 2-compartment model was selected as thebest model. Derived parameters, including milk-to-plasma ratios(mean: 0.66; SD: 0.34; range, 0 - 1.1) were consistent with the valuesreported in the literature. The estimated RID was below 10% in >95%of infants. The model predicted median infant-mother Css ratio was0.096 (range 0.035 - 0.25); literature reported mean was 0.07 (range0-0.59). Moreover, the predicted incidence of infant-mother Css ratioof >0.2 was less than 1%.CONCLUSION: Our in silico model prediction is consistent withclinical observations, suggesting that substantial systemic fluoxetineexposure in infants through human milk is rare, but further analysisshould include active metabolites. Our approach may be valid forother drugs. [supported by CIHR and Swiss National Science Foundation(SNSF)]

Population pharmacokinetic study of memantine: effects of clinical and genetic factors.

BACKGROUND AND OBJECTIVE: Memantine, a frequently prescribed anti-dementia drug, is mainly eliminated unchanged by the kidneys, partly via tubular secretion. Considerable inter-individual variability in plasma concentrations has been reported. We aimed to investigate clinical and genetic factors influencing memantine disposition. METHODS: A population pharmacokinetic study was performed including data from 108 patients recruited in a naturalistic setting. Patients were genotyped for common polymorphisms in renal cation transporters (SLC22A1/2/5, SLC47A1, ABCB1) and nuclear receptors (NR1I2, NR1I3, RXR, PPAR) involved in transporter expression. RESULTS: The average clearance was 5.2 L/h with a 27 % inter-individual variability (percentage coefficient of variation). Glomerular filtration rate (p = 0.007) and sex (p = 0.001) markedly influenced memantine clearance. NR1I2 rs1523130 was identified as the unique significant genetic covariate for memantine clearance (p = 0.006), with carriers of the NR1I2 rs1523130 CT/TT genotypes presenting a 16 % slower memantine elimination than carriers of the CC genotype. CONCLUSION: The better understanding of inter-individual variability of memantine disposition might be beneficial in the context of individual dose optimization.

Réduction de la consommation de sel: opportunité, impact et stratégies. [Population reduction of salt consumption: opportunities, impact and strategies].

A national survey showed that Swiss people eat high quantity of salt (9.1 g per day on average). The Swiss Federal Office of Public Health (FOPH) has launched a strategy to reduce salt intake in the population in order to decrease cardiovascular morbidity and mortality, mainly via blood pressure reduction. The most effective public health measures are to reduce the salt content of processed food rich in salt because they do not need to change consumers' eating behaviours. The FOPH has chosen to collaborate with the food industry on a voluntary basis. Regular population-based surveys will be needed to monitor the impact of current measures on salt consumption, hypertension prevalence as well as cardiovascular morbidity and mortality in the years to come.

Evolution in structured populations

Cet article est un compte-rendu du colloque "Evolution in Structured Population", tenu du 14 au 16 Septembre 1994 à l'Université de Lausanne. Consacré aux causes écologiques et conséquences évolutives d'horizons divers (zoologie, botanique, anthropologie, mathématiques), utilisant des approches variées, aussi bien empiriques que théoriques. Plusieurs exemples concrets de structurations génétiques de populations naturelles ont été documentés, et leurs causes analysées. Celles-ci sont variées, certaines étant extrinsèques à la biologie des espèces concernées (distances géographique, barrières écologiques, etc), d'autres intrinsèques (stratégies de reproduction, mutations chromosomiques). Les outils quantitatifs les plus largement utilisés pour analyser ces structures restent les F-statistiques de Whright; elles ont néanmoins fait l'objet de plusieurs critiques: d'une part, elles n'exploitent pas toute l'information disponible (certains orateurs ont d'ailleurs proposé diverses améliorations dans ce sens); d'autre part, les hypothèses qui sous-tendent leur interprétation conventionelle (en particulier l'hypothèse de populations à l'équilibre) sont régulièrement violées. Plusieurs des travaux présentés se sont précisément intéressés aux situations de déséquilibre et à leurs conséquences sur la dynamique et l'évolution des populations. Parmi celles ci: l'effet d'extinctions démiques sur les stratégies de dispersion des organismes et la structure génétique de leurs métapopulations, l'inadéquation du modèle classique de métapopulation, dit modèle en île (les modèles de diffusion ou de "pas japonais" (stepping stone) semblent généralement préférables), et le rôle de la "viscosité" des populations, en particulier en relation avec la sélection de parentèle et l'évolution de structures sociales. Le rôle important d'événements historiques sur les structures actuelles a été souligné, notamment dans le cadre de contacts secondaires entre populations hautement différenciées, leur introgression possible et la biogéographie de taxons vicariants. Parmi les problèmes récurrents notés: l'identification de l'unité panmictique, l'échelle de mesure spatiale appropriée, et les difficulté d'estimation des taux de migration et de flux de gènes. Plusieurs auteurs ont relevé la nécessité d'études biologiques de détail: les structures génétiques n'ont d'intérêt que dans la mesure où elles peuvent être situées dans un contexte écologique et évolutif précis. Ce point a été largement illustré dans le cadre des realtions entre structures génétiques et stratégies de reproduction/dispersion.

Evaluation of Muscardinus avellanarius population density by nest box and by trap checking

Population densities of marked common dormice Muscardinus avellanarius are generally based on nest box checks. As dormice also use natural cavities and leaf nests, we tried to answer the question "what proportion of the population cannot be monitored by nest boy checks", using parallel trapping sessions. We selected a forest of 1.7ha where a 5-year nest box survey revealed an annual mean of 3.4 ± 1.4 dormice per check. The trap design (permanent grid of 77 hanging platforms) was developed in June. During July and August the traps were set every second week (4 sessions of two nights = 8 nights) resulting in a total of 75 captures with mean of 9.4 dormice per night and the presence of 16 different individuals. The grid of 60 nest boxes was checked weekly (8 times) which allowed the recapture of 19 dormice with a mean of 2.4 dormice, per control day and the presence of 6 different individuals. Population density estimated by calendar of capture and the minimal number of dormice alive methods gave for nest-box checks a value of 2.4 animals/ha and the trap checks 6.6 animals/ha with the conclusion that 63% of the population were not being monitored by nest box checks.

Eradication d'une population d'écrevisses de Louisiane, Procambarus clarkii, à l'étang de Vidy et situation des populations d'écrevisses à Lausanne, Suisse.

En juillet 2007, des écrevisses de Louisiane, Procambarus clarkii, ont été observées, pour la première fois en Suisse romande, dans l'étang artificiel de Vidy à Lausanne. Au printemps 2008, l'étang a été asséché pendant 2 mois pour tenter d'éradiquer les écrevisses. En juillet 2008, et au printemps 2009, des écrevisses de Louisiane furent à nouveau observées dans l'étang: des individus avaient survécu au traitement et/ou des écrevisses avaient à nouveau été introduites. En 2010, une nouvelle campagne d'éradication a été mise en place: l'étang fut asséché, son lit chaulé et les interstices entre les enrochements bétonnés. Lors du suivi 2011, plus aucune écrevisse ne fut capturée. L'opération semble donc finalement avoir été un succès. Les observations effectuées sur 20 plans d'eau dans un rayon de 4.5 km autour de l'étang de Vidy n'ont pas mis en évidence d'autres populations d'écrevisses de Louisiane. Plusieurs populations d'écrevisses américaines, orconectes limosus, et signal ̧ Pacifastacus lenuisculus, ont été localisées, ainsi qu'une population d'écrevisses à pattes rouges, Astacus astacus.