Profiling mechanisms that drive acute oral toxicity in mammals and its prediction via machine learning.

We present a mechanistic machine-learning quantitative structure-activity relationship (QSAR) model to predict mammalian acute oral toxicity. We trained our model using a rat acute toxicity database compiled by the US National Toxicology Program. We profiled the database using new and published profilers and identified the most plausible mechanisms that drive high acute toxicity (LD50 ≤ 50 mg/kg; GHS categories 1 or 2). Our QSAR model assigns primary mechanisms to compounds, followed by predicting their acute oral LD50 using a random-forest machine-learning model. These predictions were further refined based on structural and mechanistic read-across to substances within the training set. Our model is optimized for sensitivity and aims to minimize the likelihood of underpredicting the toxicity of assessed compounds. It displays high sensitivity (76.1% or 76.6% for compounds in GHS 1-2 or GHS 1-3 categories, respectively), coupled with ≥73.7% balanced accuracy. We further demonstrate the utility of undertaking a mechanistic approach when predicting the toxicity of compounds acting via a rare mode of action (MOA) (aconitase inhibition). The mechanistic profilers and framework of our QSAR model are route- and toxicity endpoint-agnostic, allowing for future applications to other endpoints and routes of administration. Furthermore, we present a preliminary exploration of the potential role of metabolic clearance in acute toxicity. To the best of our knowledge, this effort represents the first accurate mechanistic QSAR model for acute oral toxicity that combines machine learning with MOA assignment, while also seeking to minimize underprediction of more highly potent substances.

Lessons Learned Recruiting and Retaining Pregnant and Postpartum Individuals in Digital Trials: Viewpoint.

In an increasingly connected world and in the midst of a global pandemic, digital trials offer numerous advantages over traditional trials that rely on physical study sites. Digital trials have the potential to improve access to research and clinical treatments for the most vulnerable and minoritized, including pregnant and postpartum individuals. However, digital trials are underutilized in maternal and child health research, and there is limited evidence to inform the design and conduct of digital trials. Our research collaborative, consisting of 5 research teams in the U.S. and Australia, aimed to address this gap. We collaborated to share lessons learned from our experiences recruiting and retaining pregnant and postpartum individuals in digital trials of social and behavioral interventions. We first discuss the promise of digital trials in improving participation in research during the perinatal period, as well as the unique challenges they pose. Second, we present lessons learned from 12 completed and ongoing digital trials that have used platforms such as Ovia, Facebook, and Instagram for recruitment. Our trials evaluated interventions for breastfeeding, prenatal and postpartum depression, insomnia, decision making, and chronic pain. We focus on challenges and lessons learned in 3 key areas: (1) rapid recruitment of large samples with a diversity of minoritized identities, (2) retention of study participants in longitudinal studies, and (3) prevention of fraudulent enrollment. We offer concrete strategies that we pilot-tested to address these challenges. Strategies presented in this commentary can be incorporated, as well as formally evaluated, in future studies.

Impact of telelactation services on breastfeeding outcomes among Black and Latinx parents: protocol for the Tele-MILC randomized controlled trial.

BACKGROUND: Breastfeeding offers many medical and neurodevelopmental advantages for birthing parents and infants; however, the majority of parents stop breastfeeding before it is recommended. Professional lactation support by the International Board Certified Lactation Consultants (IBCLCs) increases breastfeeding rates; however, many communities lack access to IBCLCs. Black and Latinx parents have lower breastfeeding rates, and limited access to professional lactation support may contribute to this disparity. Virtual "telelactation" consults that use two-way video have the potential to increase access to IBCLCs among disadvantaged populations. We present a protocol for the digital Tele-MILC trial, which uses mixed methods to evaluate the impact of telelactation services on breastfeeding outcomes. The objective of this pragmatic, parallel design randomized controlled trial is to assess the impact of telelactation on breastfeeding duration and exclusivity and explore how acceptability of and experiences with telelactation vary across Latinx, Black, and non-Black and non-Latinx parents to guide future improvement of these services. METHODS: 2400 primiparous, pregnant individuals age > 18 who intend to breastfeed and live in the USA underserved by IBCLCs will be recruited. Recruitment will occur via Ovia, a pregnancy tracker mobile phone application (app) used by over one million pregnant individuals in the USA annually. Participants will be randomized to (1) on-demand telelactation video calls on personal devices or (2) ebook on infant care/usual care. Breastfeeding outcomes will be captured via surveys and interviews and compared across racial and ethnic groups. This study will track participants for 8 months (including 6 months postpartum). Primary outcomes include breastfeeding duration and breastfeeding exclusivity. We will quantify differences in these outcomes across racial and ethnic groups. Both intention-to-treat and as-treated (using instrumental variable methods) analyses will be performed. This study will also generate qualitative data on the experiences of different subgroups of parents with the telelactation intervention, including barriers to use, satisfaction, and strengths and limitations of this delivery model. DISCUSSION: This is the first randomized study evaluating the impact of telelactation on breastfeeding outcomes. It will inform the design and implementation of future digital trials among pregnant and postpartum people, including Black and Latinx populations which are historically underrepresented in clinical trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT04856163. Registered on April 23, 2021.

Appropriateness of Telemedicine Versus In-Person Care: A Qualitative Exploration of Psychiatrists' Decision Making.

OBJECTIVE: With widespread adoption of telemedicine in response to the COVID-19 pandemic, psychiatrists must determine which visits are best conducted via telemedicine versus in person. Although some telepsychiatry guidelines and best practices have been developed, the literature has not described how psychiatrists make decisions about offering different care modalities. The authors explored how psychiatrists decide whether telemedicine is appropriate for a given patient. METHODS: From June 25 to August 4, 2021, the authors conducted semistructured interviews with 20 outpatient psychiatrists. The authors used a critical incident technique and clinical vignettes to identify conscious and unconscious factors that influence psychiatrists' decision to offer telemedicine. Using inductive thematic analysis, the authors analyzed interview data. RESULTS: Psychiatrists perceived that most patients are good candidates for telemedicine visits in the context of hybrid care models. Patient preference and situational factors, such as access to private spaces, rather than any particular diagnosis or patient demographic characteristic, drove telemedicine versus in-person care. Psychiatrists described numerous factors affecting their decision to offer telemedicine, and they were driven to try telemedicine and adjust as needed to "meet patients where they are" and to improve engagement in care. Psychiatrists reported using telemedicine as a bargaining chip in negotiations with patients, leveraging the offer of telemedicine to improve treatment attendance and adherence. CONCLUSIONS: This detailed assessment of how psychiatrists choose different care modalities can inform clinical practice guidelines and reimbursement policies that often mandate in-person visits. The results show that psychiatrists did not perceive intermittent in-person visits as essential for high-quality care.

Integrating Tobacco Prevention Skills into an Evidence-Based Intervention for Adolescents with ADHD: Results from a Pilot Efficacy Randomized Controlled Trial.

Adolescents with attention-deficit/hyperactivity disorder (ADHD) are at high risk for tobacco use, but tobacco use prevention strategies are not regularly incorporated into evidence-based ADHD interventions. We conducted a pilot randomized-controlled trial to determine the feasibility of integrating tobacco use prevention skills into a behavioral treatment for ADHD and to provide preliminary efficacy data comparing a combined (ADHD + tobacco) intervention (N = 40) to an ADHD only intervention (N = 23) on tobacco risk outcomes. Sixty-three adolescents (72% male; 13-17 years) with ADHD and their caregivers were randomly assigned to condition and families were masked to condition. Parent and adolescent ratings were collected at baseline, immediate post-intervention, and at 3- and 9-month follow-up assessments. The combined intervention was (1) implemented with high fidelity (94%), (2) well received by parents and adolescents as evidenced by high levels of treatment attendance (82%) and satisfaction with the intervention, and (3) associated with parent- and adolescent-reported reductions in tobacco use risk. Relative to the ADHD intervention, the combined intervention buffered against increases in tobacco risk, including reduced intentions to smoke and maladaptive social normative beliefs, and increased parental control, family cohesion, and family communication about substance use. Effect sizes at post-treatment were in the small to moderate range. Overall, this study provides preliminary support for a parent-adolescent behavioral treatment supplemented with family-based tobacco prevention strategies. This approach targets families already in treatment for ADHD, reducing barriers that occur when families attend multi-session prevention programs in addition to ADHD treatment.

Attention-Deficit/Hyperactivity Disorder Symptoms, Depression Risk, and Quality of Life in Black Pregnant Women.

BACKGROUND: Experiencing mental health difficulties during pregnancy predicts a variety of quality-of-life (QoL) outcomes for Black women. However, one area of prenatal mental health remains underresearched: attention-deficit/hyperactivity disorder (ADHD). Given the impairments reported by adults with significant symptoms of ADHD and the linkages between depression and ADHD in nonpregnant samples, the current study aimed to examine the relationships among ADHD symptoms, depression, and QoL in Black pregnant women. MATERIALS AND METHODS: Participants for this study were 116 pregnant Black women aged 18-43 years (mean age = 27.14, standard deviation = 5.67) presenting to an urban women's health clinic. We investigated associations among maternal ADHD symptoms, risk of maternal depression, and different aspects of QoL, including relationships, life outlook, and life productivity. RESULTS: Linear hierarchical regressions were performed to investigate the ability of maternal depression risk to mediate the relationship between maternal ADHD symptoms and QoL. Moderate to large negative correlations were found between maternal ADHD symptoms, depression risk, and quality of life (p's ≤ 0.001). Furthermore, maternal depression risk either partially or fully explained the relationship between ADHD symptoms and the different QoL variables. CONCLUSIONS: This study illustrates that symptoms of both ADHD and depression are important clinical considerations for Black women during pregnancy. As significant ADHD symptoms can lead to the development of depression, future research should investigate the temporal relationship between depression and QoL in pregnant women diagnosed with ADHD, as well as study whether ADHD treatment results in improvements in depressive symptoms.

Attention-deficit/hyperactivity disorder symptom clusters differentially predict prenatal health behaviors in pregnant women.

OBJECTIVE: To date, most investigations of mental health in pregnant women have focused on depression or substance use. This study aimed to (a) delineate the relationships between symptoms of attention-deficit/hyperactivity disorder (ADHD) and prenatal health behaviors and (b) explore whether the symptom clusters of ADHD differentially predict prenatal health behaviors (e.g., physical strain, healthy eating, prenatal vitamin use). METHOD: A total of 198 pregnant women (mean age = 27.94 years) completed measures of ADHD symptoms, prenatal health behaviors, and depression. RESULTS: Inattention, hyperactivity, and impulsivity/emotional lability all evidenced significant relationships with the prenatal health behaviors, each differentially predicting different prenatal health behaviors. CONCLUSION: As decreased engagement in adequate prenatal health behaviors puts both the mother and fetus at risk for negative birth outcomes, future research should work to develop a brief ADHD screen to be used in obstetric clinics and should investigate these relationships within a sample of women with a diagnosis of ADHD.

Evaluation of OASIS QSAR Models Using ToxCast™ in Vitro Estrogen and Androgen Receptor Binding Data and Application in an Integrated Endocrine Screening Approach.

BACKGROUND: Integrative testing strategies (ITSs) for potential endocrine activity can use tiered in silico and in vitro models. Each component of an ITS should be thoroughly assessed. OBJECTIVES: We used the data from three in vitro ToxCast™ binding assays to assess OASIS, a quantitative structure-activity relationship (QSAR) platform covering both estrogen receptor (ER) and androgen receptor (AR) binding. For stronger binders (described here as AC50 < 1 µM), we also examined the relationship of QSAR predictions of ER or AR binding to the results from 18 ER and 10 AR transactivation assays, 72 ER-binding reference compounds, and the in vivo uterotrophic assay. METHODS: NovaScreen binding assay data for ER (human, bovine, and mouse) and AR (human, chimpanzee, and rat) were used to assess the sensitivity, specificity, concordance, and applicability domain of two OASIS QSAR models. The binding strength relative to the QSAR-predicted binding strength was examined for the ER data. The relationship of QSAR predictions of binding to transactivation- and pathway-based assays, as well as to in vivo uterotrophic responses, was examined. RESULTS: The QSAR models had both high sensitivity (> 75%) and specificity (> 86%) for ER as well as both high sensitivity (92-100%) and specificity (70-81%) for AR. For compounds within the domains of the ER and AR QSAR models that bound with AC50 < 1 µM, the QSAR models accurately predicted the binding for the parent compounds. The parent compounds were active in all transactivation assays where metabolism was incorporated and, except for those compounds known to require metabolism to manifest activity, all assay platforms where metabolism was not incorporated. Compounds in-domain and predicted to bind by the ER QSAR model that were positive in ToxCast™ ER binding at AC50 < 1 µM were active in the uterotrophic assay. CONCLUSIONS: We used the extensive ToxCast™ HTS binding data set to show that OASIS ER and AR QSAR models had high sensitivity and specificity when compounds were in-domain of the models. Based on this research, we recommend a tiered screening approach wherein a) QSAR is used to identify compounds in-domain of the ER or AR binding models and predicted to bind; b) those compounds are screened in vitro to assess binding potency; and c) the stronger binders (AC50 < 1 µM) are screened in vivo. This scheme prioritizes compounds for integrative testing and risk assessment. Importantly, compounds that are not in-domain, that are predicted either not to bind or to bind weakly, that are not active in in vitro, that require metabolism to manifest activity, or for which in vivo AR testing is in order, need to be assessed differently. CITATION: Bhhatarai B, Wilson DM, Price PS, Marty S, Parks AK, Carney E. 2016. Evaluation of OASIS QSAR models using ToxCast™ in vitro estrogen and androgen receptor binding data and application in an integrated endocrine screening approach. Environ Health Perspect 124:1453-1461; http://dx.doi.org/10.1289/EHP184.

Evaluation of TOPKAT, Toxtree, and Derek Nexus in Silico Models for Ocular Irritation and Development of a Knowledge-Based Framework To Improve the Prediction of Severe Irritation.

Assessment of ocular irritation is an essential component of any risk assessment. A number of (Q)SARs and expert systems have been developed and are described in the literature. Here, we focus on three in silico models (TOPKAT, BfR rulebase implemented in Toxtree, and Derek Nexus) and evaluate their performance using 1644 in-house and 123 European Centre for Toxicology and Ecotoxicology of Chemicals (ECETOC) compounds with existing in vivo ocular irritation classification data. Overall, the in silico models performed poorly. The best consensus predictions of severe ocular irritants were 52 and 65% for the in-house and ECETOC compounds, respectively. The prediction performance was improved by designing a knowledge-based chemical profiling framework that incorporated physicochemical properties and electrophilic reactivity mechanisms. The utility of the framework was assessed by applying it to the same test sets and three additional publicly available in vitro irritation data sets. The prediction of severe ocular irritants was improved to 73-77% if compounds were filtered on the basis of AlogP_MR (hydrophobicity with molar refractivity). The predictivity increased to 74-80% for compounds capable of preferentially undergoing hard electrophilic reactions, such as Schiff base formation and acylation. This research highlights the need for reliable ocular irritation models to be developed that take into account mechanisms of action and individual structural classes. It also demonstrates the value of profiling compounds with respect to their chemical reactivity and physicochemical properties that, in combination with existing models, results in better predictions for severe irritants.

CAD or MAD? Anger (not disgust) as the predominant response to pathogen-free violations of the divinity code.

The CAD triad hypothesis (Rozin, Lowery, Imada, & Haidt, 1999) stipulates that, cross-culturally, people feel anger for violations of autonomy, contempt for violations of community, and disgust for violations of divinity. Although the disgust-divinity link has received some measure of empirical support, the results have been difficult to interpret in light of several conceptual and design flaws. Taking a revised methodological approach, including use of newly validated (Study 1), pathogen-free violations of the divinity code, we found (Study 2) little evidence of disgust-related phenomenology (nausea, gagging, loss of appetite) or action tendency (desire to move away), but much evidence of anger-linked desire to retaliate, as a major component of individuals' projected response to "pure" (pathogen-free) violations of the divinity code. Study 3 replicated these results using faces in lieu of words as a dependent measure. Concordant findings emerged from an archival study (Study 4) examining the aftermath of a real-life sacred violation-the burning of Korans by U.S. military personnel. Study 5 further corroborated these results using continuous measures based on everyday emotion terms and new variants of the divinity-pure scenarios featuring sacrilegious acts committed by a theologically irreverent member of one's own group rather than an ideologically opposed member of another group. Finally, a supplemental study found the anger-dominant attribution pattern to remain intact when the impious act being judged was the judge's own. Based on these and related results, we posit anger to be the principal emotional response to moral transgressions irrespective of the normative content involved.

Equity in public health standards: a qualitative document analysis of policies from two Canadian provinces.

INTRODUCTION: Promoting health equity is a key goal of many public health systems. However, little is known about how equity is conceptualized in such systems, particularly as standards of public health practice are established. As part of a larger study examining the renewal of public health in two Canadian provinces, Ontario and British Columbia (BC), we undertook an analysis of relevant public health documents related to equity. The aim of this paper is to discuss how equity is considered within documents that outline standards for public health. METHODS: A research team consisting of policymakers and academics identified key documents related to the public health renewal process in each province. The documents were analyzed using constant comparative analysis to identify key themes related to the conceptualization and integration of health equity as part of public health renewal in Ontario and BC. Documents were coded inductively with higher levels of abstraction achieved through multiple readings. Sets of questions were developed to guide the analysis throughout the process. RESULTS: In both sets of provincial documents health inequities were defined in a similar fashion, as the consequence of unfair or unjust structural conditions. Reducing health inequities was an explicit goal of the public health renewal process. In Ontario, addressing "priority populations" was used as a proxy term for health equity and the focus was on existing programs. In BC, the incorporation of an equity lens enhanced the identification of health inequities, with a particular emphasis on the social determinants of health. In both, priority was given to reducing barriers to public health services and to forming partnerships with other sectors to reduce health inequities. Limits to the accountability of public health to reduce health inequities were identified in both provinces. CONCLUSION: This study contributes to understanding how health equity is conceptualized and incorporated into standards for local public health. As reflected in their policies, both provinces have embraced the importance of reducing health inequities. Both concepualized this process as rooted in structural injustices and the social determinants of health. Differences in the conceptualization of health equity likely reflect contextual influences on the public health renewal processes in each jurisdiction.

Interactive agent based modeling of public health decision-making.

Agent-based models have yielded important insights regarding the transmission dynamics of communicable diseases. To better understand how these models can be used to study decision making of public health officials, we developed a computer program that linked an agent-based model of pertussis with an agent-based model of public health management. The program, which we call the Public Health Interactive Model & simulation (PHIMs) encompassed the reporting of cases to public health, case investigation, and public health response. The user directly interacted with the model in the role of the public health decision-maker. In this paper we describe the design of our model, and present the results of a pilot study to assess its usability and potential for future development. Affinity for specific tools was demonstrated. Participants ranked the program high in usability and considered it useful for training. Our ultimate goal is to achieve better public health decisions and outcomes through use of public health decision support tools.