Human variability in influx and efflux transporters in relation to uncertainty factors for chemical risk assessment

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Bayesian meta-analysis of inter-phenotypic differences in human serum paraoxonase-1 activity for chemical risk assessment

Human variability in paraoxonase-1 (PON1) activities is driven by genetic polymorphisms that affect the internal dose of active oxons of organophosphorus (OP) insecticides. Here, an extensive literature search has been performed to collect human genotypic frequencies (i.e. L55M, Q192R, and C-108T) in subgroups from a range of geographical ancestry and PON1 activities in three probe substrates (paraoxon, diazoxon and phenyl acetate). Bayesian meta-analyses were performed to estimate variability distributions for PON1 activities and PON1-related uncertainty factors (UFs), while integrating quantifiable sources of inter-study, inter-phenotypic and inter-individual differences. Inter-phenotypic differences were quantified using the population with high PON1 activity as the reference group. Results from the meta-analyses provided PON1 variability distributions and these can be implemented in generic physiologically based kinetic models to develop quantitative in vitro in vivo extrapolation models. PON1-related UFs in the Caucasian population were above the default toxicokinetic UF of 3.16 for two specific genotypes namely −108CC using diazoxon as probe substrate and, −108CT, −108TT, 55MM and 192QQ using paraoxon as probe substrate. However, integration of PON1 genotypic frequencies and activity distributions showed that all UFs were within the default toxicokinetic UF. Quantitative inter-individual differences in PON1 activity are important for chemical risk assessment particularly with regards to the potential sensitivity to organophosphates' toxicity. Keywords: Human variability, PON1 activity, Polymorphism, Uncertainty facto

Evaluation of the London Measure of Unplanned Pregnancy in a United States population of women

Copyright @ 2012 Morof et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Objective: To evaluate the reliability and validity of the London Measure of Unplanned Pregnancy (a U.K.-developed measure of pregnancy intention), in English and Spanish translation, in a U.S. population of women. Methods: A psychometric evaluation study of the London Measure of Unplanned Pregnancy (LMUP), a six-item, self-completion paper measure was conducted with 346 women aged 15–45 who presented to San Francisco General Hospital for termination of pregnancy or antenatal care. Analyses of the two language versions were carried out separately. Reliability (internal consistency) was assessed using Cronbach’s alpha and item-total correlations. Test-retest reliability (stability) was assessed using weighted Kappa. Construct validity was assessed using principal components analysis and hypothesis testing. Results: Psychometric testing demonstrated that the LMUP was reliable and valid in both U.S. English (alpha = 0.78, all item-total correlations .0.20, weighted Kappa = 0.72, unidimensionality confirmed, hypotheses met) and Spanish translation (alpha = 0.84, all item-total correlations .0.20, weighted Kappa = 0.77, unidimensionality confirmed, hypotheses met). Conclusion: The LMUP was reliable and valid in U.S. English and Spanish translation and therefore may now be used with U.S. women.The study was funded by an anonymous donation

Mesenchymal Stem Cell Responses to Bone-Mimetic Electrospun Matrices Composed of Polycaprolactone, Collagen I and Nanoparticulate Hydroxyapatite

The performance of biomaterials designed for bone repair depends, in part, on the ability of the material to support the adhesion and survival of mesenchymal stem cells (MSCs). In this study, a nanofibrous bone-mimicking scaffold was electrospun from a mixture of polycaprolactone (PCL), collagen I, and hydroxyapatite (HA) nanoparticles with a dry weight ratio of 50/30/20 respectively (PCL/col/HA). The cytocompatibility of this tri-component scaffold was compared with three other scaffold formulations: 100% PCL (PCL), 100% collagen I (col), and a bi-component scaffold containing 80% PCL/20% HA (PCL/HA). Scanning electron microscopy, fluorescent live cell imaging, and MTS assays showed that MSCs adhered to the PCL, PCL/HA and PCL/col/HA scaffolds, however more rapid cell spreading and significantly greater cell proliferation was observed for MSCs on the tri-component bone-mimetic scaffolds. In contrast, the col scaffolds did not support cell spreading or survival, possibly due to the low tensile modulus of this material. PCL/col/HA scaffolds adsorbed a substantially greater quantity of the adhesive proteins, fibronectin and vitronectin, than PCL or PCL/HA following in vitro exposure to serum, or placement into rat tibiae, which may have contributed to the favorable cell responses to the tri-component substrates. In addition, cells seeded onto PCL/col/HA scaffolds showed markedly increased levels of phosphorylated FAK, a marker of integrin activation and a signaling molecule known to be important for directing cell survival and osteoblastic differentiation. Collectively these results suggest that electrospun bone-mimetic matrices serve as promising degradable substrates for bone regenerative applications

Standards in semen examination: publishing reproducible and reliable data based on high-quality methodology

Biomedical science is rapidly developing in terms of more transparency, openness and reproducibility of scientific publications. This is even more important for all studies that are based on results from basic semen examination. Recently two concordant documents have been published: the 6th edition of the WHO Laboratory Manual for the Examination and Processing of Human Semen, and the International Standard ISO 23162:2021. With these tools, we propose that authors should be instructed to follow these laboratory methods in order to publish studies in peer-reviewed journals, preferable by using a checklist as suggested in an Appendix to this article

Human variability in isoform-specific UDP-glucuronosyltransferases: markers of acute and chronic exposure, polymorphisms and uncertainty factors

UDP-glucuronosyltransferases (UGTs) are involved in phase II conjugation reactions of xenobiotics and differences in their isoform activities result in interindividual kinetic differences of UGT probe substrates. Here, extensive literature searches were performed to identify probe substrates (14) for various UGT isoforms (UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7 and UGT2B15) and frequencies of human polymorphisms. Chemical-specific pharmacokinetic data were collected in a database to quantify interindividual differences in markers of acute (Cmax) and chronic (area under the curve, clearance) exposure. Using this database, UGT-related uncertainty factors were derived and compared to the default factor (i.e. 3.16) allowing for interindividual differences in kinetics. Overall, results show that pharmacokinetic data are predominantly available for Caucasian populations and scarce for other populations of different geographical ancestry. Furthermore, the relationships between UGT polymorphisms and pharmacokinetic parameters are rarely addressed in the included studies. The data show that UGT-related uncertainty factors were mostly below the default toxicokinetic uncertainty factor of 3.16, with the exception of five probe substrates (1-OH-midazolam, ezetimibe, raltegravir, SN38 and trifluoperazine), with three of these substrates being metabolised by the polymorphic isoform 1A1. Data gaps and future work to integrate UGT-related variability distributions with in vitro data to develop quantitative in vitro–in vivo extrapolations in chemical risk assessment are discussed

Clinic Factors Associated with Utilization of a Pregnancy Intention Screening Tool in Community Health Centers.

Objective Routine pregnancy-intention screening in the primary care setting is a promising practice to help patients achieve their reproductive goals. We aim to describe the utilization of a pregnancy-intention screening tool integrated in the electronic health record (EHR) of a national network of community health centers (CHCs) and identify clinic-level factors associated with tool use. Study design We conducted a clinic-level retrospective observational study to assess tool utilization during the first 3 years after the tool was made available in the EHR (November 2015 to October 2018). We describe characteristics of clinics with higher tool utilization (≥90th percentile) versus lower utilization (\u3c90th percentile) and the types of providers who used the tool. We then employ negative binomial regression to identify independent clinic-level factors associated with tool utilization. Results Across 194 clinics in our study sample which served 289,754 eligible female patients, the tool was used for 113,116 (39%). Medical assistants performed 60.3% of screenings and clinicians performed 11.2%. CHCs with higher tool utilization rates were more likely to be located in rural settings (RR 1.75, 95% CI 1.07–2.87) and serve patient populations with higher proportions of women (RR 1.32, 95% CI 1.24–1.41) and lower proportions of patients with non-English language preference (RR 0.92, 95% CI 0.89–0.95). Conclusions Many health centers utilized pregnancy-intention screening after an EHR-based tool was made available, though overall screening rates were low. Implications Additional study of implementation strategies and effectiveness of pregnancy-intention screening tools is needed. Implementation of future pregnancy-intention screening interventions must be tailored to address clinic-level barriers and facilitators to screening

Pharmacists expand access to reproductive heaLthcare: PEARL study protocol

Abstract Background In 2016, Oregon became the first of eight states to allow pharmacists to directly prescribe hormonal contraception (HC), including the pill, patch, or ring, without a clinic visit. In the two years following this policy change, the majority of ZIP codes across the state of Oregon had a pharmacist certified to prescribe HC. Methods We will utilize complementary methodologies to evaluate the effect of this policy change on convenient access to contraception (cost, supply dispensed), safety, contraceptive continuation and unintended pregnancy rates. We will conduct a prospective clinical cohort study to directly measure the impact of provider type on contraceptive continuation and to understand who is accessing hormonal contraception directly from pharmacists. We will concurrently conduct a retrospective analysis using medical claims data to evaluate the state-level effect of the policy. We will examine contraceptive continuation rates, incident pregnancy, and safety measures. The combination of these methodologies allows us to examine key woman-level factors, such as pregnancy intention and usual place of care, while also estimating the impact of the pharmacist prescription policy at the state level. Discussion Pharmacist prescription of HC is emerging nationally as a strategy to reduce unintended pregnancy. This study will provide data on the effect of this practice on convenient access to care, contraceptive safety and continuation rates