In Silico Assessment of Biomolecule Reactivity with Leachables.

Leachables in pharmaceutical products may react with biomolecule active pharmaceutical ingredients (APIs), for example, monoclonal antibodies (mAb), peptides, and ribonucleic acids (RNA), potentially compromising product safety and efficacy or impacting quality attributes. This investigation explored a series of in silico models to screen extractables and leachables to assess their possible reactivity with biomolecules. These in silico models were applied to collections of known leachables to identify functional and structural chemical classes likely to be flagged by these in silico approaches. Flagged leachable functional classes included antimicrobials, colorants, and film-forming agents, whereas specific chemical classes included epoxides, acrylates, and quinones. In addition, a dataset of 22 leachables with experimental data indicating their interaction with insulin glargine was used to evaluate whether one or more in silico methods are fit-for-purpose as a preliminary screen for assessing this biomolecule reactivity. Analysis of the data showed that the sensitivity of an in silico screen using multiple methodologies was 80%-90% and the specificity was 58%-92%. A workflow supporting the use of in silico methods in this field is proposed based on both the results from this assessment and best practices in the field of computational modeling and quality risk management.

Characterizing Extractables and Leachables Chemical Space to Support In Silico Toxicological Hazard Assessments.

This article describes the development of a representative dataset of extractables and leachables (E&L) from the combined Extractables and Leachables Safety Information Exchange (ELSIE) Consortium and the Product Quality Research Institute (PQRI) published datasets, representing a total of 783 chemicals. A chemical structure-based clustering of the combined dataset identified 142 distinct chemical classes with two or more chemicals across the combined dataset. The majority of these classes (105 chemical classes out of 142) contained chemicals from both datasets, whereas 8 classes contained only chemicals from the ELSIE dataset and 29 classes contain only chemicals from the PQRI dataset. This evaluation also identified classes containing chemicals that were flagged as potentially mutagenic as well as potent (strong or extreme) dermal sensitizers by in silico tools. The prevalence of alerting structures in the E&L datasets was approximately 9% (69 examples) for mutagens and 3% (25 examples) for potent sensitizers. This analysis showed that most (80%; 20 of 25) E&L predicted to be strong or extreme dermal sensitizers were also flagged as potential mutagens. Only two chemical classes, each containing three chemicals (alkyl bromides and isothiocyanates), were uniquely identified in the PQRI dataset and contained chemicals predicted to be potential mutagens and/or potent dermal sensitizers.

Prevalence and correlates of workplace violence: descriptive results from the National Transgender Discrimination Survey.

OBJECTIVE: To describe the lifetime prevalence of workplace harassment, physical violence and sexual assault against transgender and non-binary workers targeted due to their gender identity and to identify correlates of this workplace violence. METHODS: This descriptive cross-sectional study used data from 4597 transgender or non-binary respondents from the 2008-2009 National Transgender Discrimination Survey. Respondents reported if they had ever experienced harassment, physical violence or sexual assault at work specifically because of their gender identity. We estimated the prevalence of each type of violence stratified by gender identity, race/ethnicity, age, educational attainment, history of working in the street economy (eg, sex industry, drug sales) and if people at work knew their gender identity. RESULTS: Workplace violence was prevalent, with 50% of transgender and non-binary workers having ever experienced harassment, 7% physical violence and 6% sexual assault at work because of their gender identity. Harassment was common among all of these workers, but physical violence and sexual assault were more than twice as common among transfeminine and non-binary workers assigned male at birth, workers of colour, workers with low educational attainment and those who had ever worked in the street economy. CONCLUSIONS: Transgender and non-binary workers commonly face violence at work because of their gender identity. Workplace violence prevention programmes should incorporate ways to prevent gender identity-based violence and facilitate channels for workers to report the occurrence of discrimination and violence.

Asking MultiCrit Questions: A Reflexive and Critical Framework to Promote Health Data Equity for the Multiracial Population.

Policy Points Health equity work primarily centers monoracial populations; however, the rapid growth of the Multiracial population and increasingly clear health disparities affecting the people in that population complicate our understanding of racial health equity. Limited resources exist for health researchers and professionals grappling with this complexity, likely contributing to the relative dearth of health literature describing the Multiracial population. We introduce a question-based framework built on core principles from Critical Multiracial Theory (MultiCrit) and Critical Race Public Health Praxis, designed for researchers, clinicians, and policymakers to encourage health data equity for the Multiracial population.

Occupational physical demands and menstrual cycle irregularities in flight attendants and teachers.

OBJECTIVES: Flight attendants perform physically demanding work such as lifting baggage, pushing service carts and spending the workday on their feet. We examined if more frequent exposure to occupational physical demands could explain why previous studies have found that flight attendants have a higher reported prevalence of menstrual cycle irregularities than other workers. METHODS: We conducted a cross-sectional analysis of 694 flight attendants and 120 teachers aged 18-44 years from three US cities. Eligible participants were married, had not had a hysterectomy or tubal ligation, were not using hormonal contraception and were not recently pregnant. Participants reported menstrual cycle characteristics (cramps, pain, irregular cycles, flow, bleed length, cycle length) and occupational physical demands (standing, lifting, pushing/pulling, bending/twisting, overall effort). We used modified Poisson regression to examine associations between occupation (flight attendant, teacher) and menstrual irregularities; among flight attendants, we further examined associations between occupational physical demands and menstrual irregularities. RESULTS: All occupational physical demands were more commonly reported by flight attendants than teachers. Flight attendants reported more frequent menstrual cramps than teachers, and most occupational physical demands were associated with more frequent or painful menstrual cramps. Lifting heavy loads was also associated with irregular cycles. CONCLUSIONS: Occupational physical demands were associated with more frequent and worse menstrual pain among flight attendants. The physical demands experienced by these workers may contribute to the high burden of menstrual irregularities reported by flight attendants compared with other occupational groups, such as teachers.

Fever and antibiotic use in maternal urinary tract infections during pregnancy and risk of congenital heart defects: Findings from the National Birth Defects Prevention Study.

BACKGROUND: Previous studies report an association between prenatal maternal urinary tract infections (UTI) and specific congenital heart defects (CHDs); however, the role of fever and antibiotic use on this association is poorly understood. Using data from the National Birth Defects Prevention Study, we examined whether the relationship between maternal UTIs during the periconceptional period and occurrence of CHDs is modified by the presence of fever due to UTI and corresponding antibiotic use among 11,704 CHD case infants and 11,636 live-born control infants. METHODS: Information on UTIs, fever associated with UTI and antibiotic use (sulfonamides, nitrofurantoin, cephalosporins, penicillin, macrolides, and quinolones) during pregnancy were obtained using a computer-assisted telephone interview. Using unconditional multivariable logistic regression, we calculated adjusted odds ratios (ORs) to determine the association between maternal UTIs and subtypes of CHDs. Analyses were stratified by the presence of fever and medication use associated with UTI. RESULTS: The prevalence of UTIs during the periconceptional period was 7.6% in control mothers, and 8.7% in case mothers. In the absence of fever, UTI was associated with secundum atrial septal defects (ASD) (OR 1.3; 95% confidence interval [CI] 1.1-1.5) and in the absence of antibiotics, UTI was associated with conotruncal defects as a group and for four specific CHDs. When fever and UTI occurred concomitantly, no significantly elevated odds ratios were noticed for any subtypes of CHD. Among women with UTIs who used antibiotics, an elevated but statistically non-significant estimate was observed for secundum ASD (OR 1.4; 95% CI 1.0-2.0). CONCLUSION: Findings in the present study suggest that fever due to UTI and corresponding maternal antibiotic use do not substantially modify the association between maternal UTIs and specific CHDs in offspring. Further studies with larger sample sizes are warranted to guide clinical management of UTIs during the periconceptional period.

Physical job demands in pregnancy and associated musculoskeletal health and employment outcomes: a systematic review.

OBJECTIVE: A decline in musculoskeletal health during pregnancy is an underappreciated adverse outcome of pregnancy that can have immediate and long-term health consequences. High physical job demands are known risk factors for nontraumatic musculoskeletal disorders in the general working population. Evidence from meta-analyses suggest that occupational lifting and prolonged standing during pregnancy may increase risk of adverse pregnancy outcomes. This systematic review examined associations between occupational lifting or postural load in pregnancy and associated musculoskeletal disorders and related sequalae. DATA SOURCES: Five electronic databases (Medline, Embase, CINAHL, NIOSHTIC-2, and Ergonomic Abstracts) were searched from 1990 to July 2022 for studies in any language. A Web of Science snowball search was performed in December 2022. Reference lists were manually reviewed. STUDY ELIGIBILITY CRITERIA: Eligible studies reported associations between occupational lifting or postural load and musculoskeletal health or sequelae (eg, employment outcomes) among pregnant and postpartum workers. METHODS: Data were extracted using a customized form to document study and sample characteristics; and details of exposures, outcomes, covariates, and analyses. Investigators independently assessed study quality for 7 risk-of-bias domains and overall utility, with discrepant ratings resolved through discussion. A narrative synthesis was conducted due to heterogeneity. RESULTS: Sixteen studies (11 cohort studies, 2 nested case-control studies, and 3 cross-sectional studies) from 8 countries were included (N=142,320 pregnant and N=1744 postpartum workers). Limited but consistent evidence with variable quality ratings, ranging from critical concern to high, suggests that pregnant workers exposed to heavy lifting (usually defined as ≥22 lbs or ≥10 kg) may be at increased risk of functionally limiting pelvic girdle pain and antenatal leave. Moreover, reports of dose-response relationships suggest graded risk levels according to lifting frequency, ranging from 21% to 45% for pelvic girdle pain and 58% to 202% for antenatal leave. Limited but consistent evidence also suggests that postural load increases the risk of employment cessation. CONCLUSION: Limited but consistent evidence suggests that pregnant workers exposed to heavy lifting and postural load are at increased risk of pelvic girdle pain and employment cessation. Job accommodations to reduce exposure levels may promote safe sustainable employment for pregnant workers.

Understanding the roles of state demographics and state policies in epidemiologic studies of maternal-child health disparities.

Disparities in maternal-child health outcomes by race and ethnicity highlight structural differences in the opportunity for optimal health in the United States. Examples of these differences include access to state-level social policies that promote maternal-child health. States vary in their racial and ethnic composition as a result of the complex history of policies and laws related to slavery, Indigenous genocide and relocation, segregation, immigration, and settlement in the United States. States also vary in the social policies they enact. As a result, correlations exist between the demographic makeup of a state's population and the presence or absence of social policies in that state. These correlations become a mechanism by which racial and ethnic disparities in maternal-child health outcomes can operate. In this commentary, we use the example of three labor-related policies actively under consideration at state and federal levels (paid parental leave, paid sick leave, and reasonable accommodations during pregnancy) to demonstrate how correlations between state demographics and presence of these state policies could cause or exacerbate racial and ethnic disparities in maternal-child health outcomes. We conclude with a call for researchers to consider how the geographic distribution of racialized populations and state policies could contribute to maternal-child health disparities.

Identifying occupational health inequities in the absence of suitable data: are there inequities in access to adequate bathrooms in US workplaces?

OBJECTIVES: Our research questions are often chosen based on the existence of suitable data for analysis or prior research in the area. For new interdisciplinary research areas, such as occupational health equity, suitable data might not yet exist. In this manuscript, we describe how we approached a research question in the absence of suitable data using the example of identifying inequities in adequate bathrooms in US workplaces. METHODS: We created a conceptual model that hypothesises causal mechanisms for occupational health inequities, and from this model we identified a series of questions that could be answered using separate data sets to better understand inequities in adequate workplace bathrooms. Breaking up the analysis into multiple steps allowed us to use multiple data sources and analysis methods, which helped compensate for limitations in each data set. RESULTS: Using the conceptual model as a guide, we were able to identify some jobs that likely have inadequate bathrooms as well as subpopulations potentially at higher risk for inadequate bathrooms. We also identified specific data gaps by reflecting on the challenges we faced in our multistep analysis. These gaps, which indicated future data collection needs, included difficulty finding data sources for some predictors of inadequate bathrooms that prevented us from fully investigating potential inequities. CONCLUSIONS: We share our conceptual model and our example analysis to motivate researchers to avoid letting availability of data limit the research questions they pursue.

Sensitization Assessment of Extractables and Leachables in Pharmaceuticals: ELSIE Database Analysis.

Quality by design is the foundation of the risk management framework for extractables and leachables (E&Ls) recommended by the Extractables and Leachables Safety Information Exchange (ELSIE). Following these principles during the selection of materials for pharmaceutical product development minimizes the presence of highly toxic substances and decreases the health risk of potential leachables in the drug product. Therefore, in the context of the broad arena of chemicals, it is important to distinguish E&Ls as a subset of chemicals and evaluate this relevant chemical space to derive appropriate analytical and safety thresholds. When considering the health hazards posed by E&Ls, one area presenting a challenge is understanding the sensitization potential and whether it poses a risk to patients. A dataset of E&Ls compiled by ELSIE (n=466) was analysed to determine the prevalence and potency of skin sensitizers in this chemical subset and explore a scientifically justified approach to the sensitization assessment of potential leachables in parenteral drug products. Approximately half of the compounds (56%, 259/466) had sensitization data recorded in the ELSIE database and of these, 20% (52/259) are potential skin sensitizers. Only 3% (8/259) of the E&L dataset with sensitization data were considered potent (strong or extreme) sensitizers following in silico analysis and expert review, illustrating that potent sensitizers are not routinely observed as leachables in pharmaceutical products. Our analysis highlights that in silico potency prediction and expert review are key tools during the sensitization assessment process for E&Ls. The results confirm where material selection is anticipated to mitigate the risk of presence of strong and/or extreme sensitizers (e.g., extractable testing via ISO 10993-10), and that implementing thresholds per ICH M7 and/or Masuda-Herrera et al. provides a reasonably conservative approach for establishing the analytical testing and safety thresholds.

Zika virus knowledge, attitudes and prevention behaviors among pregnant women in the ZEN cohort study, Colombia, 2017-2018.

BACKGROUND: Zika virus (ZIKV) infection during pregnancy can cause severe birth defects in the fetus and is associated with neurodevelopmental abnormalities in childhood. Our objective was to describe ZIKV knowledge and attitudes among pregnant women in Colombia while ZIKV was circulating and whether they predicted the adoption of behaviors to prevent ZIKV mosquito-borne and sexual transmission. METHODS: We used self-reported data from Zika en Embarazadas y Niños (ZEN), a cohort study of women in early pregnancy across three regions of Colombia during 2017-2018. We used Poisson regression to estimate associations between knowledge, attitudes and previous experience with mosquito-borne infection and preventative behaviors. RESULTS: Among 1519 women, knowledge of mosquito-borne transmission was high (1480; 97.8%) and 1275 (85.5%) participants were worried about ZIKV infection during pregnancy. The most common preventive behavior was wearing long pants (1355; 89.4%). Regular mosquito repellent use was uncommon (257; 17.0%). While ZIKV knowledge and attitudes were not associated with the adoption of ZIKV prevention behaviors, previous mosquito-borne infection was associated with increased condom use (prevalence ratio 1.4, 95% CI 1.1 to 1.7). CONCLUSIONS: Participants were well informed about ZIKV transmission and its health consequences. However, whether this knowledge resulted in behavior change is less certain.

Paid sick leave among US private sector employees.

BACKGROUND: Inequities in US employees' access to paid sick leave are known, but it is not clear whether they are increasing or decreasing over time. More than two dozen state and local paid sick leave laws were recently enacted, many with the stated goal of reducing inequities in access to paid sick leave. We examined how inequities in access to paid sick leave have changed over time, focusing on the years when these laws were coming into effect. METHODS: Private sector employees participating in the National Health Interview Survey between 2006 (before laws came into effect) and 2018 (after most came into effect) reported if they had paid sick leave in their main job. We examined how differences in access to paid sick leave by Census region, race/ethnicity, work hours, and educational attainment changed over time. RESULTS: The percentage of employees with access to paid sick leave increased from 56% in 2006 to 61% in 2018, with most of the increases in access occurring in the West. Inequities by race/ethnicity decreased substantially between 2015 and 2018, the years when most paid sick leave laws came into effect. This change was driven by Hispanic and Latino workers rapidly gaining access to paid sick leave during this time. Differences in access to paid sick leave by work hours and education attainment remained stable over time. CONCLUSIONS: Inequities in access to paid sick leave remain. Paid sick leave laws could be effective means to increase access to paid sick leave and equalize access.

Evaluating Confidence in Toxicity Assessments Based on Experimental Data and In Silico Predictions.

Understanding the reliability and relevance of a toxicological assessment is important for gauging the overall confidence and communicating the degree of uncertainty related to it. The process involved in assessing reliability and relevance is well defined for experimental data. Similar criteria need to be established for in silico predictions, as they become increasingly more important to fill data gaps and need to be reasonably integrated as additional lines of evidence. Thus, in silico assessments could be communicated with greater confidence and in a more harmonized manner. The current work expands on previous definitions of reliability, relevance, and confidence and establishes a conceptional framework to apply those to in silico data. The approach is used in two case studies: 1) phthalic anhydride, where experimental data are readily available and 2) 4-hydroxy-3-propoxybenzaldehyde, a data poor case which relies predominantly on in silico methods, showing that reliability, relevance, and confidence of in silico assessments can be effectively communicated within Integrated approaches to testing and assessment (IATA).

Implementation of In Silico Toxicology Protocols in Leadscope.

In silico toxicology protocols help ensure the results from computational toxicology models are performed and documented in a standardized, consistent, transparent, and accepted manner. In silico toxicology protocols for skin sensitization and genetic toxicology have been previously published and have been implemented within the Leadscope software. The following chapter outlines how such protocols have been deployed in the Leadscope platform including integration with toxicology databases and a battery of computational toxicology models.

Implementation of in silico toxicology protocols within a visual and interactive hazard assessment platform.

Mechanistically-driven alternative approaches to hazard assessment invariably require a battery of tests, including both in silico models and experimental data. The decision-making process, from selection of the methods to combining the information based on the weight-of-evidence, is ideally described in published guidelines or protocols. This ensures that the application of such approaches is defendable to reviewers within regulatory agencies and across the industry. Examples include the ICH M7 pharmaceutical impurities guideline and the published in silico toxicology protocols. To support an efficient, transparent, consistent and fully documented implementation of these protocols, a new and novel interactive software solution is described to perform such an integrated hazard assessment based on public and proprietary information.

Maternal occupation as a nail technician or hairdresser during pregnancy and birth defects, National Birth Defects Prevention Study, 1997-2011.

OBJECTIVE: Nail technicians and hairdressers may be exposed to chemicals with potential reproductive effects. While studies have examined birth defects in children of hairdressers, those in children of nail technicians have not been evaluated. We investigated associations between selected birth defects and maternal occupation as a nail technician or hairdresser versus a non-cosmetology occupation during pregnancy. METHODS: We analysed population-based case-control data from the multisite National Birth Defects Prevention Study, 1997-2011. Cases were fetuses or infants with major structural birth defects; controls were live-born infants without major birth defects. Expert raters classified self-reported maternal jobs as nail technician, combination nail technician-hairdresser, hairdresser, other cosmetology work or non-cosmetology work. We used logistic regression to calculate adjusted ORs and 95% CIs for associations between occupation during pregnancy and birth defects, controlling for age, smoking, education and race/ethnicity. RESULTS: Sixty-one mothers worked as nail technicians, 196 as hairdressers, 39 as combination nail technician-hairdressers and 42 810 as non-cosmetologists. The strongest associations among nail technicians included seven congenital heart defect (CHD) groups (ORs ranging from 2.7 to 3.5) and neural tube defects (OR=2.6, CI=0.8 to 8.4). Birth defects most strongly associated with hairdressing included anotia/microtia (OR=2.1, CI=0.6 to 6.9) and cleft lip with cleft palate (OR=2.0, CI=1.1 to 3.7). All oral cleft groups were associated with combination nail technician-hairdresser work (ORs ranging from 4.2 to 5.3). CONCLUSIONS: Small samples resulted in wide CIs. Still, results suggest associations between maternal nail technician work during pregnancy and CHDs and between hairdressing work and oral clefts.

Hyperlipidemia May Synergize with Hypomethylation in Establishing Trained Immunity and Promoting Inflammation in NASH and NAFLD.

We performed a panoramic analysis on both human nonalcoholic steatohepatitis (NASH) microarray data and microarray/RNA-seq data from various mouse models of nonalcoholic fatty liver disease NASH/NAFLD with total 4249 genes examined and made the following findings: (i) human NASH and NAFLD mouse models upregulate both cytokines and chemokines; (ii) pathway analysis indicated that human NASH can be classified into metabolic and immune NASH; methionine- and choline-deficient (MCD)+high-fat diet (HFD), glycine N-methyltransferase deficient (GNMT-KO), methionine adenosyltransferase 1A deficient (MAT1A-KO), and HFCD (high-fat-cholesterol diet) can be classified into inflammatory, SAM accumulation, cholesterol/mevalonate, and LXR/RXR-fatty acid ß-oxidation NAFLD, respectively; (iii) canonical and noncanonical inflammasomes play differential roles in the pathogenesis of NASH/NAFLD; (iv) trained immunity (TI) enzymes are significantly upregulated in NASH/NAFLD; HFCD upregulates TI enzymes more than cytokines, chemokines, and inflammasome regulators; (v) the MCD+HFD is a model with the upregulation of proinflammatory cytokines and canonical and noncanonical inflammasomes; however, the HFCD is a model with upregulation of TI enzymes and lipid peroxidation enzymes; and (vi) caspase-11 and caspase-1 act as upstream master regulators, which partially upregulate the expressions of cytokines, chemokines, canonical and noncanonical inflammasome pathway regulators, TI enzymes, and lipid peroxidation enzymes. Our findings provide novel insights on the synergies between hyperlipidemia and hypomethylation in establishing TI and promoting inflammation in NASH and NAFLD progression and novel targets for future therapeutic interventions for NASH and NAFLD, metabolic diseases, transplantation, and cancers.

Reply to Comment on Shen H, et al. "Co-signaling receptors regulate T-cell plasticity and immune tolerance". Frontiers in Bioscience-Landmark. 2019; 24: 96-132.

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Characteristics of Women with Urinary Tract Infection in Pregnancy.

Background: Urinary tract infection (UTI) is the most common bacterial infection in pregnancy. Known risk factors for UTI in pregnancy include diabetes and certain urologic conditions. Other maternal characteristics might also be associated with risk and could provide clues to the etiology of UTI in pregnancy. Our objective was to identify maternal characteristics associated with UTI in pregnancy. Materials and Methods: We used data from pregnant women participating in the National Birth Defects Prevention Study, a population-based study of risk factors for major structural birth defects in 10 U.S. sites, from 1997 to 2011. In cross-sectional analyses, we used multivariable log-binomial regression to estimate prevalence ratios (PRs) and 95% confidence intervals (CIs) for associations between self-reported maternal characteristics and UTI in pregnancy. Results: In our sample of 41,869 women, the overall prevalence of reported UTI in pregnancy was 18%, but ranged from 11% to 26% between study sites. In adjusted models, diabetes was moderately associated with higher UTI prevalence (PR 1.39, 95% CI: 1.24-1.57). Higher UTI prevalence was associated even more strongly with low educational attainment (PR 2.06, 95% CI: 1.77-2.40 for some high school vs. graduate school), low household income (PR 1.64, 95% CI: 1.46-1.84 for <$10,000 vs. ≥$50,000), and race/ethnicity (PR 1.45, 95% CI: 1.13-1.80 for American Indian or Alaska Native vs. White women). Conclusions: About one in six women reported UTI in pregnancy but the prevalence varied markedly by geography and maternal characteristics. This variability could provide clues to the causes of UTI in pregnancy.