Predictors Of Variation Research Articles

An Investigational Study on the Role of CYP2D6, CYP3A4 and UGTs Genetic Variation on Fesoterodine Pharmacokinetics in Young Healthy Volunteers.

Introduction: Fesoterodine is one of the most widely used antimuscarinic drugs to treat an overactive bladder. Fesoterodine is extensively hydrolyzed by esterases to 5-hydroxymethyl tolterodine (5-HMT), the major active metabolite. CYP2D6 and CYP3A4 mainly metabolize 5-HMT and are, therefore, the primary pharmacogenetic candidate biomarkers. Materials and Methods: This is a candidate gene study designed to investigate the effects of 120 polymorphisms in 33 genes (including the CYP, COMT, UGT, NAT2, and CES enzymes, ABC and SLC transporters, and 5-HT receptors) on fesoterodine pharmacokinetics and their safety in 39 healthy volunteers from three bioequivalence trials. Results: An association between 5-HMT exposure (dose/weight corrected area under the curve (AUC/DW) and dose/weight corrected maximum plasma concentration (Cmax/DW)), elimination (terminal half-life (T1/2) and the total drug clearance adjusted for bioavailability (Cl/F)), and CYP2D6 activity was observed. Poor/intermediate metabolizers (PMs/IMs) had higher 5-HMT AUC/DW (1.5-fold) and Cmax/DW (1.4-fold) values than the normal metabolizers (NMs); in addition, the normal metabolizers (NMs) had higher 5-HMT AUC/DW (1.7-fold) and Cmax/DW (1.3-fold) values than the ultrarapid metabolizers (UMs). Lower 5-HMT exposure and higher T1/2 were observed for the CYP3A4 IMs compared to the NMs, contrary to our expectations. Conclusions: CYP2D6 might have a more important role than CYP3A4 in fesoterodine pharmacokinetics, and its phenotype might be a better predictor of variation in its pharmacokinetics. An association was observed between different genetic variants of different genes of the UGT family and AUC, Cmax, and CL/F of 5-HMT, which should be confirmed in other studies.

Did the entry of the corn ethanol industry in Brazil affect the relationship between domestic and international corn prices?

AbstractThis study investigates the relationship between corn prices in Brazil and the international market, considering a rise in corn ethanol production in Brazil's Midwest region since 2017. Did the entry of the corn ethanol industry in Brazil affect the relationship between domestic and international corn prices? A cointegration analysis was made with a monthly time series from May 2005 to August 2023 controlling for different exogenous events or shocks that may have affected global agricultural markets. The study's findings indicate a stable long‐term relationship between the international and Brazilian corn prices, with changes in international prices being predictors of variations in Brazilian domestic prices, while the opposite was not statistically supported. The study also found no evidence to support the claim that the entry of the corn ethanol industry into Mato Grosso state in 2017 impacted the prices paid to local producers. Therefore, the increase in Brazilian corn prices cannot be attributed to additional demand for corn by local mills, an important result that contributes to discussions such as food versus fuel and indirect land use change.

Feeding practices and anthropometric classification of nutritional status in low-birth-weight infants at term. A prospective cohort study

BackgroundAbout 50 % of LBW occurs in term newborns, which is associated with higher infant mortality rates compared to infants of average birth weight. Analysis of feeding practices in at-risk groups is essential to address malnutrition and stunting in infancy. AimTo identify feeding practices and anthropometric classification of nutritional status in a cohort of low-birth-weight term infants. MethodsMethods: Cohort study. A prospective follow-up of 73 term newborns with low birth weight up to six months of age was performed. Feeding practices and anthropometric classification of nutritional were analysed. Data were processed by univariate analysis and multivariate linear regression. ResultsThe most common feeding practice was exclusive breastfeeding. Breast milk substitutes are frequent in this population group. The risk of undernutrition ranged from 2.7 % to 19.2 % and of overweight from 4.1 % to 11.0 % during the first six months of life. Low height-for-age risk was the most frequent anthropometric classification during the follow-up period. Average head circumference was consistent in infants with low birth weight. Gestational risk classification, breastfeeding during the first hour of life, and sex of the newborn were predictors of variations in anthropometric indicators. ConclusionsExclusive breastfeeding is the most common feeding practice in the population group studied, but using breast milk substitutes is also prevalent. Low height-for-age is the most frequent anthropometric classification. The weight growth rate seems reasonable, but further studies are needed based on gender differences, analysis of the composition of breast milk, and socio-environmental factors involved in growth.

Assembly structures of coastal woody species of eastern South America: Patterns and drivers

Tropical regions have provided new insights into how ecological communities are assembled. In dry coastal communities, water stress has been hypothesized to determine plant assembly structure by favoring preadapted lineages from neighboring ecosystems, consistent with functional clustering. However, it is unclear whether this hypothesis is sufficient to explain how coastal communities in tropical ecosystems are assembled. Here, we test whether water stress or other factors drive community assembly in woody plant communities across the coastal zone of Brazil, a tropical ecosystem. We characterized functional and phylogenetic structures of these communities and determined the underlying environmental factors (e.g., water stress, historical climate stability, edaphic constraints, and habitat heterogeneity) that drive their community assembly. Assemblages of coastal woody species show geographically varied patterns, including stochastic arrangements, clustering, and overdispersion of species relative to their traits and phylogenetic relatedness. Topographic complexity, water vapor pressure, and soil nutrient availability best explained the gradient in the functional structure. Water deficit, water vapor pressure, and soil organic carbon were the best predictors of variation in phylogenetic structure. Our results support the water-stress conservatism hypothesis on functional and phylogenetic structure, as well as the effect of habitat heterogeneity on functional structure and edaphic constraints on functional and phylogenetic structure. These effects are associated with increased phenotypic and phylogenetic divergence of woody plant assemblages, which is likely mediated by abiotic filtering and niche opportunities, suggesting a complex pattern of ecological assembly.

Predictors of Variation in the Cognitive Function Trajectories among Older Adults Living Alone: A Growth Mixture Modeling Approach.

Considering the global aging population, this study investigates changes in cognitive function and predictive factors among older adults living alone. Using data collected from the Korean Longitudinal Study of Aging (KLoSA), the study examines 1217 participants to identify distinct cognitive change patterns and the variables affecting them. Two primary cognitive function change types emerged: "High-Level Declining Type" and "Low-Level Stable Type." Although the former initially displayed normal cognitive function, it gradually declined over a period of 14 years until it reached mild cognitive impairment (MCI) levels by the year 2020. While the latter group had lower cognitive function from the beginning and remained stable throughout the study. Older age, female gender, rural residence, lower education, lower income, unemployment, and higher levels of depression were linked to a higher likelihood of belonging to the "Low-Level Stable Type". The findings of these studies emphasize the need for proactive interventions and regular cognitive assessments for older individuals living alone, as cognitive impairment can develop even in individuals whose cognitive abilities are initially good. Also, tailored interventions should target specific demographic and socioeconomic groups to mitigate cognitive decline effectively.

Satellite‐derived prefire vegetation predicts variation in field‐based invasive annual grass cover after fire

AbstractAimsInvasion by annual grasses (IAGs) and concomitant increases in wildfire are impacting many drylands globally, and an understanding of factors that contribute to or detract from community resistance to IAGs is needed to inform postfire restoration interventions. Prefire vegetation condition is often unknown in rangelands but it likely affects variation in postfire invasion resistance across large burned scars. Whether satellite‐derived products like the Rangeland Analysis Platform (RAP) can fulfill prefire information needs and be used to parametrize models of fire recovery to inform postfire management of IAGs is a key question.MethodsWe used random forests to ask how IAG abundances in 669 field plots measured in the 2‐3 years following megafires in sagebrush steppe rangelands of western USA responded to RAP estimates of annual:perennial prefire vegetation cover, the effects of elevation, heat load, postfire treatments, soil moisture–temperature regimes, and land‐agency ratings of ecosystem resistance to invasion and resilience to disturbance.ResultsPostfire IAG cover measured in the field was % and RAP‐estimated prefire annual herbaceous cover was %. The random forest model had an R2 of 0.36 and a root‐mean‐squared error (RMSE) of 4.41. Elevation, postfire herbicide treatment, and prefire estimates from RAP for the ratio of annual:perennial and shrub cover were the most important predictors of postfire IAG cover. Threshold‐like relationships between postfire IAG cover and the predictors indicate that maintaining annual:perennial cover below 0.4 and shrub cover below <10% prior to wildfire would decrease invasion, at low elevations below 1400 m above sea level.ConclusionDespite known differences between RAP and field‐based estimates of vegetation cover, RAP was still a useful predictor of variation in IAG abundances after fire. IAG management is oftentimes reactive, but our findings indicate impactful roles for more inclusively addressing the exotic annual community, and focusing on prefire maintenance of annual:perennial herbaceous and shrub cover at low elevations.

The cost of buying land for protected areas in the United States

Buying land to establish protected areas is a common conservation strategy, particularly in countries with strong private property rights. Accurately accounting for spatial heterogeneity in land cost could lead to large efficiency savings when planning future acquisitions. However, lack of data regarding actual acquisition costs faced by conservation organizations has led planners to rely on more readily available proxies, such as agricultural land value. Using data on nearly 36,000 parcels acquired for conservation by public agencies and land trusts in the continental U.S., we built a model predicting protected area acquisition costs. While costs of land for agriculture or development are useful predictors of variation in protected area acquisition costs, they are not, by themselves, good approximations of those costs. For example, using a more comprehensive combination of variables, our model explained almost four times as much variation in actual acquisition costs as those. We found that agricultural land value loses most of its explanatory power once other predictors are used, confirming that it acts as a partial proxy for actual acquisition costs. We then used an optimization model to compare prioritization recommendations with our new cost estimates to those suggested when relying on agricultural land values alone. Locations of highest conservation return on investment shifted from coastal regions toward the country's center, when using actual cost data. Cost estimates used in conservation planning should be based on actual protected area acquisitions, because the type of properties and motivations of buyers and sellers differ from those of other land transactions.

Microbial carbon use efficiency promotes global soil carbon storage

Soils store more carbon than other terrestrial ecosystems1,2. How soil organic carbon (SOC) forms and persists remains uncertain1,3, which makes it challenging to understand how it will respond to climatic change3,4. It has been suggested that soil microorganisms play an important role in SOC formation, preservation and loss5–7. Although microorganisms affect the accumulation and loss of soil organic matter through many pathways4,6,8–11, microbial carbon use efficiency (CUE) is an integrative metric that can capture the balance of these processes12,13. Although CUE has the potential to act as a predictor of variation in SOC storage, the role of CUE in SOC persistence remains unresolved7,14,15. Here we examine the relationship between CUE and the preservation of SOC, and interactions with climate, vegetation and edaphic properties, using a combination of global-scale datasets, a microbial-process explicit model, data assimilation, deep learning and meta-analysis. We find that CUE is at least four times as important as other evaluated factors, such as carbon input, decomposition or vertical transport, in determining SOC storage and its spatial variation across the globe. In addition, CUE shows a positive correlation with SOC content. Our findings point to microbial CUE as a major determinant of global SOC storage. Understanding the microbial processes underlying CUE and their environmental dependence may help the prediction of SOC feedback to a changing climate.

The hare and the tortoise: A comparative study of Vietnam's and Kenya's pathways to local enterprise development through foreign direct investment

ABSTRACT Almost simultaneously, two developing countries – Kenya and Vietnam – set out to promote industrial development through FDI. Vietnam embarked on a targeted strategy aimed at selecting FDI that could specifically aid the country’s strategic export sectors through linkages to local industry. In contrast, Kenya embarked on a cross-the-board FDI attraction policy with no specific sector orientation and with few specific linkage policies. This paper asks how FDI has contributed to local industry development in the two countries. Based on an analysis of firm level data from the World Bank Enterprise Survey, the paper compares the two countries’ ability to generate spillovers from FDI spillovers and discusses what explains differences and similarities. The paper finds that in spite of the obvious differences between the two countries in terms of local industrial development and policy, firm and industry factors appeared to be better predictors of variations in spillovers than country level factors. Among the policy implications drawn are that developing countries should focus their FDI policies on firms and industries that have high linkage and hence spillover potential rather than adopting cross-the-board policies.

Impact of the built, social, and food environment on long-term weight loss within a behavioral weight loss intervention.

Behavioral weight loss interventions can lead to an average weight loss of 5%-10% of initial body weight, however there is wide individual variability in treatment response. Although built, social, and community food environments can have potential direct and indirect influences on body weight (through their influence on physical activity and energy intake), these environmental factors are rarely considered as predictors of variation in weight loss. Evaluate the association between built, social, and community food environments and changes in weight, moderate-to-vigorous physical activity (MVPA), and dietary intake among adults who completed an 18-month behavioral weight loss intervention. Participants included 93 adults (mean±SD; 41.5±8.3years, 34.4±4.2kg/m2, 82% female, 75% white). Environmental variables included urbanicity, walkability, crime, Neighborhood Deprivation Index (includes 13 social economic status factors), and density of convenience stores, grocery stores, and limited-service restaurants at the tract level. Linear regressions examined associations between environment and changes in body weight, waist circumference (WC), MVPA (SenseWear device), and dietary intake (3-day diet records) from baseline to 18months. Grocery store density was inversely associated with change in weight (β=-0.95; p=0.02; R 2=0.062) and WC (β=-1.23; p<0.01; R 2=0.109). Participants living in tracts with lower walkability demonstrated lower baseline MVPA and greater increases in MVPA versus participants with higher walkability (interaction p=0.03). Participants living in tracts with the most deprivation demonstrated greater increases in average daily steps (β=2048.27; p=0.02; R 2=0.039) versus participants with the least deprivation. Limited-service restaurant density was associated with change in % protein intake (β=0.39; p=0.046; R 2=0.051). Environmental factors accounted for some of the variability (<11%) in response to a behavioral weight loss intervention. Grocery store density was positively associated with weight loss at 18months. Additional studies and/or pooled analyses, encompassing greater environmental variation, are required to further evaluate whether environment contributes to weight loss variability.

Variation in Response to Pharmacological Intervention with Risperidone and the Role of Adjuvant Medications in the Treatment of Autism Spectrum Disorders: A Systematic Review and Meta-analysis

Non-genetic traits as predictors of variation in response to pharmacological interventions in ASD need to be identified for better management. This review aims to identify these non-genetic traits and the role of adjuvant medications in ASD. Electronic database searches in PUBMED and Cochrane libraries were conducted using MeSH search terms "Autism" and "Risperidone." Randomized or cross-over trials comparing the efficacy of ‘risperidone plus placebo’ vs. ‘risperidone plus adjuvant medications’ using Aberrant Behavior Checklist-Community Version (ABC-CV) scores in ASD patients of any age group were included in the analysis. The quantity of reduced irritability (ABC-I) sub-score was the primary outcome measure analyzed.In contrast, the reduction in remaining ABC-CV sub-scores at the end of 10 weeks were the secondary outcome measures analyzed. All the outcome measures were estimated by calculating the Mean Difference (MD) values and their 95% Confidence Intervals (CI) by both fixed and random effect models using Revman 5.4.1 software. A total of 13 trials were found to be eligible and included in the quantitative synthesis of efficacy. A small but significant decrease in the ABC irritability sub-score was evident in the ‘risperidone plus adjuvants’ group (MD: -3.19, 95% CI:-3.82, -2.56, N=658). The meta-analysis results attributed the highest decrease in ABC-irritability sub-scores to adjuvant topiramate. There is a possibility of bias and minimal impact of adjuvants in alleviating irritability symptoms of ASD. Baseline severity of irritability symptoms and the dose/medication regimen appear to be possible non-genetic traits responsible for variation in response to pharmacological intervention.

Predictors of Variations in Residential Water Consumption in Central Texas

Background: The 100th Meridian in Texas aligns with a corridor of large and rapidly growing urban areas with a growing water demand and limited supply. Understanding the variations in residential water consumption may assist with identifying the characteristics associated with disproportionate water consumption that may be responsive to policy changes and enforcement. Methods: Data from the San Antonio Water System, the Bexar County Appraisal District, and the American Community Survey were utilized. The average daily water consumption was estimated for the seasons and a total year for more than 300,000 single-family residences between 2009 and 2015. The presence of a swimming pool, residential parcel hectares, size of the living space, and per capita income were examined as predictors of the variations in residential water consumption using hierarchal modeling. Results: The presence of swimming pools and a residential property’s value were the strongest predictors of water consumption. Parcel hectares and household income were positively associated with water consumption. A quartile analysis of select independent variables identified the disproportionate variations of water consumption of units with large yards, swimming pools, and high values. Conclusions: The findings indicate a strong association between variations in residential water consumption and both irrigation and swimming pool water used, which emphasize a need to focus conservation efforts on higher-valued housing and residences with swimming pools and the consideration of tiered pricing.

PREDICTING THE ONSET, EVOLUTION, AND POSTGRADUATE IMPACT OF COLLEGE ACTIVISM

The topics of differential recruitment to activism and its longer-term impacts have generated substantial empirical research. Yet, the lack of longitudinal studies of movement participation have limited our understanding of individual activism’s dynamics over time. Here, we use six years of longitudinal survey data and two waves of interview data from a class of college students before, throughout, and after college to examine predictors of variation in college activism, the ebb and flow of activism over the course of college, and the effect of college activism on activism two years post-graduation. Our findings dispute one consistent empirical claim in social movement studies and confirm another. Counter to the scholarly finding on the weak impact of predisposition on recruitment, we find that predisposition powerfully predicts variation in college activism. Consistent with the claim that significant early activism is linked with future activism, we find that students’ activism at the end of college significantly predicts their engagement in activism after graduation.

Simultaneous bilingualism and speech style as predictors of variation in allophone production: Evidence from Finland-Swedish

This study investigates cross-linguistic transfer in the production of long mid front vowels [øː] and [œː] by simultaneous bilingual Finnish and Finland-Swedish speakers in Finland. In Swedish, the phoneme /ø/ can be realised as the allophones [ø] and [œ], while in Finnish, only [ø] is used. Combining approaches from sociophonetic and bilingual transfer research, the study used acoustic analysis to compare the height and fronting of [øː] and [œː] produced by bilingual and monolingual Finland-Swedish speakers in three different speech styles on a continuum of formality. The data from 115 participants are stratified according to language background, speech style, region, and age. The statistical analysis indicates increased overlap of [øː] and [œː] in the vowel spaces of bilingual speakers, particularly in informal speech. The results suggest a potential effect of Finnish transfer on the distinction of the phonetic variants in simultaneous Finland-Swedish bilinguals, as well as demonstrate the importance of considering speech style in bilingual transfer research.

Antisocial personality traits transcend species.

Antisocial personality is generally used to describe people who treat other people with callous disregard and disrespect. Although animal cruelty is diagnostic of conduct disorder, a precursor of antisocial personality in children, it is unclear whether the term antisocial also encompasses disregard and disrespect toward nonhuman animals among adults. In this study, we examined associations between three antianimal attitudes and behaviors-speciesism, hunting/fishing, and lack of sympathy for animal rights-and traits that underlie adult antisocial behavior. We found consistent links between antisocial personality traits and antianimal attitudes and behaviors in 2 samples. These effects were generally specific to traits linked to antisociality (although we also found associations with low openness), and these traits were stronger as predictors of variation among meat eaters than as predictors of differences between vegetarians and meat eaters. These results suggest that the term antisocial applies to negative attitudes and behaviors toward both humans and nonhuman animals and imply the potential value of considering antianimal attitudes and behaviors in the clinical assessment of antisocial personality. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Urban Growth and Heat in Tropical Climates

This research describes the change in temperatures across approximately 270 tropical cities from 1960 to 2020 with a focus on urban warming. It associates urban growth indicators with temperature variations in tropical climate zones (tropical rainforest, tropical monsoon, and tropical wet-dry savanna). Our findings demonstrate that over time while temperatures have increased across the tropics, urban residents have experienced higher temperatures (minimum and maximum) than those living outside of cities. Moreover, in certain tropical zones, over the study period, temperatures have risen faster in urban areas than the background (non-urban) temperatures. The results also suggest that with continuing climate change and urban growth, temperatures will continue to rise at higher than background levels in tropical cities unless mitigation measures are implemented. Several fundamental characteristics of urban growth including population size, population density, infrastructure and urban land use patterns are factors associated with variations in temperatures. We find evidence that dense urban forms (compact residential and industrial developments) are associated with higher temperatures and population density is a better predictor of variation in temperatures than either urban population size or infrastructure in most tropic climate zones. Infrastructure, however, is a better predictor of temperature increases in wet-dry savanna tropical climates than population density. There are a number of potential mitigation measures available to urban managers to address heat. We focus on ecological services, but whether these services can address the projected increasing heat levels is unclear. More local research is necessary to untangle the various contributions to increasing heat in cities and evaluate whether these applications can be effective to cool tropical cities as temperature continue to rise. Our methods include combining several different datasets to identify differences in daily, seasonal, and annual maximum and minimum temperatures.

Natural variation in yolk fatty acids, but not androgens, predicts offspring fitness in a wild bird

BackgroundIn egg-laying animals, mothers can influence the developmental environment and thus the phenotype of their offspring by secreting various substances into the egg yolk. In birds, recent studies have demonstrated that different yolk substances can interactively affect offspring phenotype, but the implications of such effects for offspring fitness and phenotype in natural populations have remained unclear. We measured natural variation in the content of 31 yolk components known to shape offspring phenotypes including steroid hormones, antioxidants and fatty acids in eggs of free-living great tits (Parus major) during two breeding seasons. We tested for relationships between yolk component groupings and offspring fitness and phenotypes.ResultsVariation in hatchling and fledgling numbers was primarily explained by yolk fatty acids (including saturated, mono- and polyunsaturated fatty acids) - but not by androgen hormones and carotenoids, components previously considered to be major determinants of offspring phenotype. Fatty acids were also better predictors of variation in nestling oxidative status and size than androgens and carotenoids.ConclusionsOur results suggest that fatty acids are important yolk substances that contribute to shaping offspring fitness and phenotype in free-living populations. Since polyunsaturated fatty acids cannot be produced de novo by the mother, but have to be obtained from the diet, these findings highlight potential mechanisms (e.g., weather, habitat quality, foraging ability) through which environmental variation may shape maternal effects and consequences for offspring. Our study represents an important first step towards unraveling interactive effects of multiple yolk substances on offspring fitness and phenotypes in free-living populations. It provides the basis for future experiments that will establish the pathways by which yolk components, singly and/or interactively, mediate maternal effects in natural populations.

Health system influences on potentially avoidable hospital admissions by secondary mental health service use: A national ecological study

ObjectivesPotentially avoidable hospital admissions (PAAs) are costly to health services and potentially harmful for patients. This study aimed to compare area-level PAA rates among people using and not using secondary mental health services in England and to identify health system features that may influence between-area PAA variation.MethodsNational ecological study using linked English hospital admissions and secondary mental health services data (2016–2018). We calculated two-year average age-sex standardised area-level PAA rates according to primary admission diagnoses for 12 physical conditions, among, first, secondary mental health service users with any non-organic diagnosis, and, second, people not in contact with secondary mental health services. We used penalised regression analyses to identify predictors of area-level variation in PAA rates.ResultsArea-level PAA rates were over four times greater in the mental health group, at 7,594 per 100,000 population compared to 1,819 per 100,000 in the comparator group. Common predictors of variation were greater density of older age groups (lower PAA rates), higher underlying population morbidity of chronic obstructive pulmonary disease and, to a lesser extent, urbanity (higher PAA rates). For both groups, health system factors such as the number of general practitioners per capita or ambulance despatch rates were significant but weak predictors of variation. Mental health diagnosis data were available for half of secondary mental health care records only and sensitivity analyses found that urbanity remained the sole significant predictor for PAAs in this group.ConclusionsFindings support the need for improved management of physical conditions for secondary mental health service users. Understanding and predicting variation in PAAs among mental health service users is constrained by availability of data on mental health diagnosis, physical health care and needs.

Estrogen profile- and pharmacogenetics-based lamotrigine dosing regimen optimization: Recommendations for pregnant women with epilepsy

During pregnancy, various physiological changes occur that can alter the pharmacokinetics of antiepileptic drugs, such as lamotrigine (LTG). Anticipating the change in LTG dose required to achieve a pre-pregnancy target concentration is challenging. This study aimed to develop a refined population pharmacokinetic (PopPK) model of LTG in pregnant women with epilepsy (WWE) to identify factors explaining the variability in pharmacokinetics and to establish a model-informed individualized dosing regimen. On that basis, a coarsened model containing only clinical variables was also developed to examine its predictive performance compared to the refined model. In total, 322 concentration-time points from 51 pregnant WWE treated with LTG were employed to establish a refined PopPK model that included endogenous estrogen profiles, variants of candidate genes encoding LTG-metabolizing enzymes and -transporter proteins, and other clinical variables and a coarsened model that included only clinical variables, respectively. Data from an additional 11 patients were used for external validation of these two models. A nonlinear mixed-effect modeling approach was used for PopPK analysis of LTG. The standard goodness-of-fit method, bootstrap, normalized prediction distribution errors and external evaluation were adopted to estimate the stability and predictive performance of the candidate models. Akaike information criterion (AIC) was used to compare the goodness of fit between these two models. A lower AIC indicates a better fit of the data and the preferred model. Recommended dosing regimens for pregnant WWE were selected using Monte Carlo simulation based on the established optimal model. In the refined PopPK model, the population mean of apparent LTG clearance (CL/F) in pregnant WWE was estimated to be 2.82 L/h, with an inter-individual variability of 23.6%. PopPK analysis indicated that changes in estrogen profile during pregnancy were the predominant reason for the significant variations in LTG-CL/F. Up to the 3rd trimester, the concentration accumulation effect of E2 increased LTG-CL/F by 5.109 L/h from baseline levels. Contrary to effect of E2, E3 as the main circulating estrogen in pregnancy with a peak value of 34.41 ng/mL is 1000-fold higher than that in non-pregnancy reduced LTG-CL/F by 1.413 L/h. In addition, the UGT2B7 rs4356975 C > T and ABCB1 rs1128503 A > G variants may contribute to a better understanding of the inter-individual variability in LTG-CL/F. LTG-CL/F was 1.66-fold higher in UGT2B7 rs4356975 CT or TT genotype carriers than in CC genotype carriers. In contrast, ABCB1 rs1128503 GG genotype carriers had only 71.9% of the LTG-CL/F of AA or AG genotype carriers. In the coarsened PopPK model, the gestational age was a promising predictor of changes in LTG-CL/F. When comparing these two models, the refined PopPK model was favored over the coarsened PopPK model (AIC = −30.899 vs. −20.017). Monte Carlo simulation based on optimal PopPK model revealed that the LTG dosage administered to carriers of the UGT2B7 rs4356975 CT or TT genotype required a 33–50% increase to reach the pre-pregnancy target concentration, and carriers of the ABCB1 rs1128503 GG genotype required a 33–66% lower dose of LTG than carriers of the ABCB1 rs1128503 AA or AG genotype. Changes in estrogen profile during pregnancy was a better predictor of variations in LTG-CL/F than gestational age. The developed model based on estrogen profile and pharmacogenetics can serve as a foundation for further optimization of dosing regimens of LTG in pregnant WWE.

The long-term response of lake nutrient and chlorophyll concentrations to changes in nutrient loading in Ireland's largest lake, Lough Neagh

The long-term response of chlorophyll-a (chl-a) to changing lake water nutrient concentrations and increasing water temperature was investigated in Lough Neagh, a large, hypereutrophic lake in Northern Ireland. Trends in external and internal nutrient loading and their relation to lake nutrient concentrations were also established. Lake water concentrations of total P (TP) have increased since the 1990s but were not correlated with catchment inputs, which showed no trend. The characteristics of internal loading of P have changed since the mid-1990s, with an earlier and larger mass of P released from the sediments each summer. Catchment inputs of total oxidised N (NOx) decreased from the peak value of 10,186T/yr in 1995 to 5,396T/yr in 2011, coinciding with a reduction in lake water concentrations. External inputs and lake concentrations of NOx were highly correlated (R=0.88). Water temperature increased approximately 1C and was a predictor of variation in chl-a from 1974 to 2012. After the peak chl-a concentration in 1993, dissolved inorganic N (DIN) also became an important predictor, accounting for almost half of the 44% variance explained by a hierarchical partition model. Decreasing log (DIN:TP) ratios suggest that N limitation of chl-a has become more important in the lake recently.