This study described the complexity of service need co-occurrence among foster care-involved families and identified prevalent patterns of needs to inform future evidence-based service planning ...research. We utilized state administrative child maltreatment records, and restricted data to cases where the child entered foster care in 2019 and the caseworker indicated the presence of at least one need from the Family Assessment of Needs and Strengths (FANS; n = 1631). We extracted all unique combinations of needs (i.e., needs profiles), and we used association rule mining to identify patterns within these profiles. A total of 780 unique needs profiles emerged among the 1631 cases, which we condensed into 78 patterns. Although the variability and complexity of needs profiles makes evidence-based service planning difficult, the present analysis mapped prevalent needs patterns to guide future research intended to assist caseworkers in this task. Identification of maltreatment determinants among families involved in foster care, and future research into the needs within different needs patterns that might undermine treatment effectiveness, may result in a better balance between parsimonious service plans and a full consideration of co-occurring service needs.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Abstract
To address concerns around age-related sensitivity to pyrethroids, a life-stage physiologically based pharmacokinetic (PBPK) model, supported by in vitro to in vivo extrapolation (IVIVE) was ...developed. The model was used to predict age-dependent changes in target tissue exposure of 8 pyrethroids; deltamethrin (DLM), cis-permethrin (CPM), trans-permethrin, esfenvalerate, cyphenothrin, cyhalothrin, cyfluthrin, and bifenthrin. A single model structure was used based on previous work in the rat. Intrinsic clearance (CLint) of each individual cytochrome P450 or carboxylesterase (CES) enzyme that are active for a given pyrethroid were measured in vitro, then biologically scaled to obtain in vivo age-specific total hepatic CLint. These IVIVE results indicate that, except for bifenthrin, CES enzymes are largely responsible for human hepatic metabolism (>50% contribution). Given the high efficiency and rapid maturation of CESs, clearance of the pyrethroids is very efficient across ages, leading to a blood flow-limited metabolism. Together with age-specific physiological parameters, in particular liver blood flow, the efficient metabolic clearance of pyrethroids across ages results in comparable to or even lower internal exposure in the target tissue (brain) in children than that in adults in response to the same level of exposure to a given pyrethroid (Cmax ratio in brain between 1- and 25-year old = 0.69, 0.93, and 0.94 for DLM, bifenthrin, and CPM, respectively). Our study demonstrated that a life-stage PBPK modeling approach, coupled with IVIVE, provides a robust framework for evaluating age-related differences in pharmacokinetics and internal target tissue exposure in humans for the pyrethroid class of chemicals.
Neighborhood environment has been linked to behavioral outcomes in adolescence. The current study examined two potential mediators (i.e., perceived social capital, perceived neighborhood disorder) in ...the association between neighborhood structural characteristics (i.e., neighborhood disorganization) and problem behaviors (i.e., externalizing behavior, substance use) among at‐risk adolescents with prenatal substance exposure. The study sample included 350 15‐year‐old adolescents recruited at birth. Adolescents' addresses were linked to census tract data. Neighborhood structural characteristics were not directly associated with adolescent problem behaviors in the presence of perceived social capital and neighborhood disorder. Greater neighborhood disorganization was associated with lower levels of perceived social capital, which was related to greater perceived neighborhood disorder, and then problem behaviors. The findings suggest that community practice needs to focus on subjective perceptions of neighborhoods when developing intervention programs on problem behaviors among at‐risk adolescents.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Concerns for potential vulnerability to manganese (Mn) neurotoxicity during fetal and neonatal development have been raised due to increased needs for Mn for normal growth, different sources of ...exposure to Mn, and pharmacokinetic differences between the young and adults. A physiologically based pharmacokinetic (PBPK) model for Mn during human gestation and lactation was developed to predict Mn in fetal and neonatal brain using a parallelogram approach based upon extrapolation across life stages in rats and cross-species extrapolation to humans. Based on the rodent modeling, key physiological processes controlling Mn kinetics during gestation and lactation were incorporated, including alterations in Mn uptake, excretion, tissue-specific distributions, and placental and lactational transfer of Mn. Parameters for Mn kinetics were estimated based on human Mn data for milk, placenta, and fetal/neonatal tissues, along with allometric scaling from the human adult model. The model was evaluated by comparison with published Mn levels in cord blood, milk, and infant blood. Maternal Mn homeostasis during pregnancy and lactation, placenta and milk Mn, and fetal/neonatal tissue Mn were simulated for normal dietary intake and with inhalation exposure to environmental Mn. Model predictions indicate similar or lower internal exposures to Mn in the brains of fetus/neonate compared with the adult at or above typical environmental air Mn concentrations. This PBPK approach can assess expected Mn tissue concentration during early life and compares contributions of different Mn sources, such as breast or cow milk, formula, food, drinking water, and inhalation, with tissue concentration.
According to the interviews the CRCG conducted with the generic drug industry, industry is strongly interested in applying MIE approaches as an alternative to conventional end point BE studies for ...inhalation and LAI products to their product development programs. The annual GDUFA science and research reports are another resource to check out the progress in MIE, which include a summary of research activities, research highlights, comprehensive lists of new, ongoing, and completed grants and contracts, and outcomes generated from the GDUFA-funded science and research program in each fiscal year. ...the value of artificial intelligence (AI) and machine learning (ML), potentially combined with real-world evidence/data, in advancing the development of complex generics has been well-recognized by industry, regulatory agency, and other stakeholders, thus the need for further research has been emphasized. Specifically, AI and ML may demonstrate their utility in optimizing the program design and reduce study duration; in utilizing public domain information (e.g., drug labeling) to facilitate unique study designs for complex generic drug product or exploratory studies on related compounds in support of generic development.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Rising obesity rates worldwide have socio-economic ramifications. While genetics, diet, and lack of exercise are major contributors to obesity, environmental factors may enhance susceptibility ...through disruption of hormone homeostasis and metabolic processes. The obesogen hypothesis contends that chemical exposure early in development may enhance adipocyte differentiation, thereby increasing the number of adipocytes and predisposing for obesity and metabolic disease. We previously developed a primary human adipose stem cell (hASC) assay to evaluate the effect of environmental chemicals on PPARG-dependent adipogenesis. Here, the assay was modified to determine the effects of chemicals on the glucocorticoid receptor (GR) pathway. In differentiation cocktail lacking the glucocorticoid agonist dexamethasone (DEX), hASCs do not differentiate into adipocytes. In the presence of GR agonists, adipocyte maturation was observed using phenotypic makers for lipid accumulation, adipokine secretion, and expression of key genes. To evaluate the role of environmental compounds on adipocyte differentiation, progenitor cells were treated with 19 prioritized compounds previously identified by ToxPi as having GR-dependent bioactivity, and multiplexed assays were used to confirm a GR-dependent mode of action. Five chemicals were found to be strong agonists. The assay was also modified to evaluate GR-antagonists, and 8/10 of the hypothesized antagonists inhibited adipogenesis. The in vitro bioactivity data was put into context with extrapolated human steady state concentrations (Css) and clinical exposure data (Cmax). These data support using a human adipose-derived stem cell differentiation assay to test the potential of chemicals to alter human GR-dependent adipogenesis.
•A biological pathway approach to testing chemicals for GR-dependent adipogenesis•ToxCast GR assays were used to prioritize chemicals for phenotypic in vitro testing.•Fit-for-purpose assays can be used for comparing in vitro potency to human exposure.•Testing prioritized chemicals in vitro can help provide context for human risk.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
We propose a Bayesian population modeling and virtual bioequivalence assessment approach to establishing dissolution specifications for oral dosage forms. A generalizable semi-physiologically based ...pharmacokinetic absorption model with six gut segments and liver, connected to a two-compartment model of systemic disposition for bupropion hydrochloride oral dosage forms was developed. Prior information on model parameters for gut physiology, bupropion physicochemical properties, and drug product properties were obtained from the literature. The release of bupropion hydrochloride from immediate-, sustained- and extended-release oral dosage forms was described by a Weibull function. In vitro dissolution data were used to assign priors to the in vivo release properties of the three bupropion formulations. We applied global sensitivity analysis to identify the influential parameters for plasma bupropion concentrations and calibrated them. To quantify inter- and intra-individual variability, plasma concentration profiles in healthy volunteers that received the three dosage forms, each at two doses, were used. The calibrated model was in good agreement with both in vitro dissolution and in vivo exposure data. Markov Chain Monte Carlo samples from the joint posterior parameter distribution were used to simulate virtual crossover clinical trials for each formulation with distinct drug dissolution profiles. For each trial, an allowable range of dissolution parameters (“safe space”) in which bioequivalence can be anticipated was established. These findings can be used to assure consistent product performance throughout the drug product life-cycle and to support manufacturing changes. Our framework provides a comprehensive approach to support decision-making in drug product development.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
•Examined opioid prescribing and opioid-overdose death rates in Michigan counties.•Conducted urban-rural county comparisons and tested for changes across 2013–2017.•Higher rates of overdose deaths in ...urban, and higher rates of prescribing in rural.•Opioid-overdose death rates rose in both urban and rural counties across 2013–2017.•Opioid prescribing rates did not change in urban or rural counties across 2013–2017.
Opioid-overdose deaths and opioid prescriptions have increased substantially within the past decade, leading to examinations of urban-rural differences for these opioid-related outcomes, and whether annual trends differ by urban-rural status. Most investigations have examined differences using national data, whereas few studies have identified patterns in hard-hit regions. Therefore, we examined urban-rural differences for opioid-related outcomes in Michigan, a state with overdose death and prescribing rates above the national average.
This study used county-level public data on opioid prescribing and opioid-overdose death rates in Michigan. Bivariate and joinpoint regression analyses tested for annual differences and annual changes in opioid-related outcomes across 2013–2017. Rural Urban Continuum Codes classified urban-rural county status.
Bivariate analyses demonstrated that urban counties had consistently higher opioid-overdose death rates than rural, whereas rural counties had consistently higher opioid prescribing rates than urban. Joinpoint regression (2013–2017) revealed opioid-overdose death rates increased in urban (Annual Percent Change = 25.0%, p = .001) and rural counties (Annual Percent Change = 21.7%, p = .002), though no changes for opioid prescribing rates were observed among urban or rural counties.
Our study highlights nuanced urban-rural patterns in Michigan, a hard-hit state, compared to trends in national data. Both urban and rural counties experienced rising rates of opioid-overdose deaths, and rural counties experienced higher opioid prescribing rates than urban. Though urban counties experienced higher opioid-overdose death rates than rural, the rise in both county types was similar. Future research directions, implications for public health, and healthcare policy recommendations are discussed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
On September 30 and October 1, 2021, the US Food and Drug Administration (FDA) and the Center for Research on Complex Generics cosponsored a live virtual workshop titled “Regulatory Utility of ...Mechanistic Modeling to Support Alternative Bioequivalence Approaches.” The overall aims of the workshop included (i) engaging the generic drug industry and other involved stakeholders regarding how mechanistic modeling and simulation can support their product development and regulatory submissions; (ii) sharing the current state of mechanistic modeling for bioequivalence (BE) assessment through case studies; (iii) establishing a consensus on best practices for using mechanistic modeling approaches, such as physiologically based pharmacokinetic modeling and computational fluid dynamics modeling, for BE assessment; and (iv) introducing the concept of a Model Master File to improve model sharing between model developers, industry, and the FDA. More than 1500 people registered for the workshop. Based on a postworkshop survey, the majority of participants reported that their fundamental scientific understanding of mechanistic models was enhanced, there was greater consensus on model validation and verification, and regulatory expectations for mechanistic modeling submitted in abbreviated new drug applications were clarified by the workshop.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Current computational technologies hold promise for prioritizing the testing of the thousands of chemicals in commerce. Here, a case study is presented demonstrating comparative risk-prioritization ...approaches based on the ratio of surrogate hazard and exposure data, called margins of exposure (MoEs). Exposures were estimated using a U.S. EPA’s ExpoCast predictive model (SEEM3) results and estimates of bioactivity were predicted using: 1) Oral equivalent doses (OEDs) derived from U.S. EPA’s ToxCast high-throughput screening program, together with
in vitro
to
in vivo
extrapolation and 2) thresholds of toxicological concern (TTCs) determined using a structure-based decision-tree using the Toxtree open source software. To ground-truth these computational approaches, we compared the MoEs based on predicted noncancer TTC and OED values to those derived using the traditional method of deriving points of departure from no-observed adverse effect levels (NOAELs) from
in vivo
oral exposures in rodents. TTC-based MoEs were lower than NOAEL-based MoEs for 520 out of 522 (99.6%) compounds in this smaller overlapping dataset, but were relatively well correlated with the same (
r
2
= 0.59). TTC-based MoEs were also lower than OED-based MoEs for 590 (83.2%) of the 709 evaluated chemicals, indicating that TTCs may serve as a conservative surrogate in the absence of chemical-specific experimental data. The TTC-based MoE prioritization process was then applied to over 45,000 curated environmental chemical structures as a proof-of-concept for high-throughput prioritization using TTC-based MoEs. This study demonstrates the utility of exploiting existing computational methods at the pre-assessment phase of a tiered risk-based approach to quickly, and conservatively, prioritize thousands of untested chemicals for further study.
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