Pharmaceuticals and personal care products in the environment: What are the big questions?

Background: Over the past 10-15 years, a substantial amount of work has been done by the scientific, regulatory, and business communities to elucidate the effects and risks of pharmaceuticals and personal care products (PPCPs) in the environment. Objective: This review was undertaken to identify key outstanding issues regarding the effects of PPCPs on human and ecological health in order to ensure that future resources will be focused on the most important areas. Data sources: To better understand and manage the risks of PPCPs in the environment, we used the "key question" approach to identify the principle issues that need to be addressed. Initially, questions were solicited from academic, government, and business communities around the world. A list of 101 questions was then discussed at an international expert workshop, and a top-20 list was developed. Following the workshop, workshop attendees ranked the 20 questions by importance. Data synthesis: The top 20 priority questions fell into seven categories: a) prioritization of substances for assessment, b) pathways of exposure, c) bioavailability and uptake, d) effects characterization, e) risk and relative risk, f) antibiotic resistance, and g) risk management. Conclusions: A large body of information is now available on PPCPs in the environment. This exercise prioritized the most critical questions to aid in development of future research programs on the topic.Centro de Investigaciones del Medioambient

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Worldwide trends in underweight and obesity from 1990 to 2022: a pooled analysis of 3663 population-representative studies with 222 million children, adolescents, and adults

Background Underweight and obesity are associated with adverse health outcomes throughout the life course. We estimated the individual and combined prevalence of underweight or thinness and obesity, and their changes, from 1990 to 2022 for adults and school-aged children and adolescents in 200 countries and territories. Methods We used data from 3663 population-based studies with 222 million participants that measured height and weight in representative samples of the general population. We used a Bayesian hierarchical model to estimate trends in the prevalence of different BMI categories, separately for adults (age ≥20 years) and school-aged children and adolescents (age 5–19 years), from 1990 to 2022 for 200 countries and territories. For adults, we report the individual and combined prevalence of underweight (BMI &lt;18·5 kg/m2) and obesity (BMI ≥30 kg/m2). For school&#x2;aged children and adolescents, we report thinness (BMI &lt;2 SD below the median of the WHO growth reference) and obesity (BMI &gt;2 SD above the median). Findings From 1990 to 2022, the combined prevalence of underweight and obesity in adults decreased in 11 countries (6%) for women and 17 (9%) for men with a posterior probability of at least 0·80 that the observed changes were true decreases. The combined prevalence increased in 162 countries (81%) for women and 140 countries (70%) for men with a posterior probability of at least 0·80. In 2022, the combined prevalence of underweight and obesity was highest in island nations in the Caribbean and Polynesia and Micronesia, and countries in the Middle East and north Africa. Obesity prevalence was higher than underweight with posterior probability of at least 0·80 in 177 countries (89%) for women and 145 (73%) for men in 2022, whereas the converse was true in 16 countries (8%) for women, and 39 (20%) for men. From 1990 to 2022, the combined prevalence of thinness and obesity decreased among girls in five countries (3%) and among boys in 15 countries (8%) with a posterior probability of at least 0·80, and increased among girls in 140 countries (70%) and boys in 137 countries (69%) with a posterior probability of at least 0·80. The countries with highest combined prevalence of thinness and obesity in school-aged children and adolescents in 2022 were in Polynesia and Micronesia and the Caribbean for both sexes, and Chile and Qatar for boys. Combined prevalence was also high in some countries in south Asia, such as India and Pakistan, where thinness remained prevalent despite having declined. In 2022, obesity in school-aged children and adolescents was more prevalent than thinness with a posterior probability of at least 0·80 among girls in 133 countries (67%) and boys in 125 countries (63%), whereas the converse was true in 35 countries (18%) and 42 countries (21%), respectively. In almost all countries for both adults and school-aged children and adolescents, the increases in double burden were driven by increases in obesity, and decreases in double burden by declining underweight or thinness. Interpretation The combined burden of underweight and obesity has increased in most countries, driven by an increase in obesity, while underweight and thinness remain prevalent in south Asia and parts of Africa. A healthy nutrition transition that enhances access to nutritious foods is needed to address the remaining burden of underweight while curbing and reversing the increase in obesit

Increase in transmitted resistance to non-nucleoside reverse transcriptase inhibitors among newly diagnosed HIV-1 infections in Europe

Matti A Ristola on SPREAD Programme -työryhmän jäsen.Peer reviewe

UPTAKE OF PHARMACEUTICALS AND PERSONAL CARE PRODUCTS FROM SEDIMENTS INTO AQUATIC ORGANISMS

Over the past fifteen years there has been increasing interest in the environmental occurrence, fate and effects of substances used as pharmaceuticals or personal care products. While the understanding of the environmental fate and ecotoxicity of pharmaceuticals is now well developed, less information is available on the uptake of pharmaceuticals and personal care products into aquatic organisms and, in particular, into sediment-dwelling organisms. This study was therefore performed to develop an understanding of the factors and processes affecting the uptake of pharmaceuticals and personal care products into the sediment dwelling oligochaete worm, Lumbriculus variegatus. The study combined experimental studies into the distribution of a range of pharmaceuticals and personal care products in sediment-water systems and studies into the uptake of the study compounds under a range of conditions. The results were used to parameterize and evaluate a model for estimating uptake of pharmaceuticals and personal care products into benthic organisms. Adsorption of the study compounds from water to sediment solids increased in the order diclofenac < chloramphenicol < salicylic acid < naproxen < caffeine < sulfamethazine < triclosan < fluoxetine. Comparison of the sorption results with estimations from available models for predicting sorption from chemical properties indicated that relationships developed for neutral organic chemicals were not appropriate for use on ionisable pharmaceuticals and personal care products. While predictive models, developed specifically for ionisable chemicals, produced improved predictions of sorption, even these predictions were not perfect. Bioconcentration factors for the study compounds from water into L. variegatus were found to increase in the order chloramphenicol < diclofenac < salicylic acid < fluoxetine < naproxen < triclosan. The differences in bioconcentration factors could not be explained by differences in log Kow and log Dow which are descriptors that have previously been used to predict the uptake of neutral organic substances and ionisable substances in other species of invertebrates. There was also disagreement between the uptake measurements and predictions obtained from models developed for estimating the uptake of ionisable chemicals into aquatic organisms. The uptake of four of the study compounds (caffeine, diclofenac, fluoxetine and triclosan) was further evaluated at different water pH values. For three of these compounds (diclofenac, fluoxetine and triclosan), the potential for metabolism by L. variegatus was also assessed as was the uptake and route of uptake from whole sediments. Uptake of diclofenac and fluoxetine was found to be highly sensitive to changes in pH with bioconcentration factors varying by over two orders of magnitude (diclofenac) and four orders of magnitude (fluoxetine) across three pH units. Tissue analysis indicated that while diclofenac is not metabolized by the worms, fluoxetine and triclosan are heavily metabolized. The whole sediment studies demonstrated that uptake of diclofenac and fluoxetine occurs primarily from the sediment pore-water whereas for triclosan, sediment ingestion provides a small contribution to the uptake. Results from the different components of the study were used to parameterize and evaluate a model for estimating uptake of pharmaceuticals and personal care products from sediments into benthic organisms. Comparison of predictions from this model for diclofenac, fluoxetine and triclosan were compared to measurements from whole sediment studies. While the model was found to under-predict the uptake of triclosan, good predictions were obtained for diclofenac and fluoxetine. With further development and evaluation, the uptake modeling approach could provide a valuable tool for use in the risk assessment of ionisable compounds such as many pharmaceuticals and personal care products

The structure of the second CysD domain of MUC2 and role in mucin organization by transglutaminase-based cross-linking

Summary: The MUC2 mucin protects the colonic epithelium by a two-layered mucus with an inner attached bacteria-free layer and an outer layer harboring commensal bacteria. CysD domains are 100 amino-acid-long sequences containing 10 cysteines that separate highly O-glycosylated proline, threonine, serine (PTS) regions in mucins. The structure of the second CysD, CysD2, of MUC2 is now solved by nuclear magnetic resonance. CysD2 shows a stable stalk region predicted to be partly covered by adjacent O-glycans attached to neighboring PTS sequences, whereas the CysD2 tip with three flexible loops is suggested to be well exposed. It shows transient dimer interactions at acidic pH, weakened at physiological pH. This transient interaction can be stabilized in vitro and in vivo by transglutaminase 3-catalyzed isopeptide bonds, preferring a specific glutamine residue on one flexible loop. This covalent dimer is modeled suggesting that CysD domains act as connecting hubs for covalent stabilization of mucins to form a protective mucus

Transmission of HIV drug resistance and the predicted effect on current first-line regimens in Europe

Numerous studies have shown that baseline drug resistance patterns may influence the outcome of antiretroviral therapy. Therefore, guidelines recommend drug resistance testing to guide the choice of initial regimen. In addition to optimizing individual patient management, these baseline resistance data enable transmitted drug resistance (TDR) to be surveyed for public health purposes. The SPREAD program systematically collects data to gain insight into TDR occurring in Europe since 2001. Demographic, clinical, and virological data from 4140 antiretroviral-naive human immunodeficiency virus (HIV)-infected individuals from 26 countries who were newly diagnosed between 2008 and 2010 were analyzed. Evidence of TDR was defined using the WHO list for surveillance of drug resistance mutations. Prevalence of TDR was assessed over time by comparing the results to SPREAD data from 2002 to 2007. Baseline susceptibility to antiretroviral drugs was predicted using the Stanford HIVdb program version 7.0. The overall prevalence of TDR did not change significantly over time and was 8.3% (95% confidence interval, 7.2%-9.5%) in 2008-2010. The most frequent indicators of TDR were nucleoside reverse transcriptase inhibitor (NRTI) mutations (4.5%), followed by nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations (2.9%) and protease inhibitor mutations (2.0%). Baseline mutations were most predictive of reduced susceptibility to initial NNRTI-based regimens: 4.5% and 6.5% of patient isolates were predicted to have resistance to regimens containing efavirenz or rilpivirine, respectively, independent of current NRTI backbones. Although TDR was highest for NRTIs, the impact of baseline drug resistance patterns on susceptibility was largest for NNRTIs. The prevalence of TDR assessed by epidemiological surveys does not clearly indicate to what degree susceptibility to different drug classes is affected

Pharmaceuticals and personal care products in the environment: What are the big questions?

Background: Over the past 10-15 years, a substantial amount of work has been done by the scientific, regulatory, and business communities to elucidate the effects and risks of pharmaceuticals and personal care products (PPCPs) in the environment. Objective: This review was undertaken to identify key outstanding issues regarding the effects of PPCPs on human and ecological health in order to ensure that future resources will be focused on the most important areas. Data sources: To better understand and manage the risks of PPCPs in the environment, we used the "key question" approach to identify the principle issues that need to be addressed. Initially, questions were solicited from academic, government, and business communities around the world. A list of 101 questions was then discussed at an international expert workshop, and a top-20 list was developed. Following the workshop, workshop attendees ranked the 20 questions by importance. Data synthesis: The top 20 priority questions fell into seven categories: a) prioritization of substances for assessment, b) pathways of exposure, c) bioavailability and uptake, d) effects characterization, e) risk and relative risk, f) antibiotic resistance, and g) risk management. Conclusions: A large body of information is now available on PPCPs in the environment. This exercise prioritized the most critical questions to aid in development of future research programs on the topic.Fil: Boxall, Alistair B. A.. University of York; Reino UnidoFil: Rudd, Murray A.. University of York; Reino UnidoFil: Brooks, Bryan W.. Baylor University; Estados UnidosFil: Caldwell, Daniel J.. Johnson & Johnson; Estados UnidosFil: Choi, Kyungho. Seoul National University; Corea del SurFil: Hickmann, Silke. Umweltbundesamt; AlemaniaFil: Innes, Elizabeth. Health Canada; CanadáFil: Ostapyk, Kim. Health Canada; CanadáFil: Staveley, Jane P.. Exponent; Estados UnidosFil: Verslycke, Tim. Gradient; Estados UnidosFil: Ankley, Gerald T.. United States Environmental Protection Agency; Estados UnidosFil: Beazley, Karen F.. Dalhousie University Halifax; CanadáFil: Belanger, Scott E.. Procter And Gamble; Estados UnidosFil: Berninger, Jason P.. Baylor University; Estados UnidosFil: Carriquiriborde, Pedro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Química. Centro de Investigaciones del Medio Ambiente; ArgentinaFil: Coors, Anja. Ect Oekotoxikologie Gmbh; AlemaniaFil: DeLeo, Paul C.. American Cleaning Institute; Estados UnidosFil: Dyer, Scott D.. Procter And Gamble; Estados UnidosFil: Ericson, Jon F.. Pfizer Inc.; Estados UnidosFil: Gagné, François. Environment Canada; CanadáFil: Giesy, John P.. University of Saskatchewan; CanadáFil: Gouin, Todd. Unilever; Reino UnidoFil: Hallstrom, Lars. University of Alberta; CanadáFil: Karlsson, Maja V.. University of York; Reino UnidoFil: Joakim Larsson, D.G.. University of Göteborg; AlemaniaFil: Lazorchak, James M.. United States Environmental Protection Agency; Estados UnidosFil: Mastrocco, Frank. Pfizer Inc.; Estados UnidosFil: McLaughlin, Alison. Health Canada; CanadáFil: McMaster, Mark E.. Environment Canada; CanadáFil: Meyerhoff, Roger D.. Eli Lilly And Company; Estados UnidosFil: Moore, Roberta. Health Canada; CanadáFil: Parrott, Joanne L.. Environment Canada; CanadáFil: Snape, Jason R.. AstraZeneca UK Ltd.; Reino UnidoFil: Murray-Smith, Richard. AstraZeneca UK Ltd.; Reino UnidoFil: Servos, Mark R.. University of Waterloo; CanadáFil: Sibley, Paul K.. University of Guelph; CanadáFil: Straub, Jürg Oliver. F. Hoffmann-La Roche Ltd.; SuizaFil: Szabo, Nora D.. University of Ottawa; CanadáFil: Topp, Edward. Agriculture Et Agroalimentaire Canada; CanadáFil: Tetreault, Gerald R.. University of Waterloo; CanadáFil: Trudeau, Vance L.. University of Ottawa; CanadáFil: Van Der Kraak, Glen. University of Guelph; Canad