Cognitive effects of early life exposure to PCBs: Sex-specific behavioral, hormonal and neuromolecular mechanisms involving the brain dopamine system.

Endocrine-disrupting chemicals (EDCs) are environmental toxicants that disrupt hormonal and neurodevelopmental processes. Among these chemicals, polychlorinated biphenyls (PCBs) are particularly concerning due to their resistance to biodegradation and tendency to bioaccumulate. PCBs affect neurodevelopmental function and disrupt the brain's dopamine (DA) system, which is crucial for attentional, affective, and reward processing. These disruptions may contribute to the rising prevalence of DA-mediated neuropsychiatric disorders such as ADHD, depression, and substance use disorders. Notably, these behaviors are sexually dimorphic, in part due to differences in sex hormones and their receptors, which are targets of estrogenic PCBs. Therefore, this study determined effects of early life PCB exposure on behaviors and neurochemistry related to potential disruption of dopaminergic signaling. Male and female Sprague Dawley rats were exposed to PCBs or vehicle perinatally and then underwent a series of behavioral tests, including the sucrose preference test to measure affect, conditioned orienting to assess incentive-motivational phenotype, and attentional set-shifting to evaluate cognitive flexibility and response latency. Following these tests, rats were euthanized, and we measured serum estradiol (E2), midbrain DA cells, and gene expression in the midbrain. Female rats exposed perinatally to A1221 exhibited decreased sucrose preference, and both male and female A1221 rats had reduced response latency in the attentional set-shifting task compared to vehicle counterparts. Conditioned orienting, serum estradiol (E2), and midbrain DA cell numbers were not affected in either sex; however, A1221-exposed male rats displayed higher expression of estrogen receptor alpha ( Esr1 ) in the midbrain and non-significant effects on other DA-signaling genes. Additionally, E2 uniquely predicted behavioral outcomes and DAergic cell numbers in A1221-exposed female rats, whereas DA signaling genes were predictive of behavioral outcomes in males. These data highlight sex-specific effects of A1221 on neuromolecular and behavioral phenotypes.

Usability of a Web-Based App for Increasing Adolescent Vaccination in Primary Care Settings: Think-Aloud and Survey Assessment.

BACKGROUND: In the United States, only 58% of teens receive the recommended 2 doses of the human papillomavirus vaccine by 15 years of age. Overcoming vaccine hesitancy often requires effective communication between clinicians and parents to address specific concerns. To support this, we developed ProtectMe4, a multilevel, theory-informed web-based intervention designed to address parents' vaccine-related questions and assist clinicians in discussing vaccine concerns for 4 adolescent vaccines. OBJECTIVE: This study aims to evaluate the usability of ProtectMe4 in routine care settings across 3 pediatric primary care clinics. Specifically, the study aims to (1) observe the proposed workflow in practice, (2) identify usability issues experienced by parents and clinicians, and (3) assess the perceptions of both parents and clinicians regarding the app's usability. METHODS: On designated days in 2020 and 2021, the study team recruited parents of 11- to 12-year-old patients attending appointments with participating clinicians. We conducted think-aloud assessments during routine care visits and administered a usability survey after participants used the app. For parents, we simultaneously video-recorded the app screens and audio-recorded their commentary. For clinicians, observational notes were taken regarding their actions and comments. Timings recorded within the app provided data on the length of use. We reviewed the recordings and notes to compile a list of identified issues and calculated the frequencies of survey responses. RESULTS: Out of 12 parents invited to use the app, 9 (75%) participated. Two parents who were invited outside of the planned workflow, after seeing the clinician, refused to participate. For the parents whose child's vaccination record was identified by the app, the median time spent using the app was 9 (range 6-28) minutes. Think-aloud assessment results for parents were categorized into 2 themes: (1) troubleshooting vaccine record identification and (2) clarifying the app content and purpose. Among the 8 parents who completed the survey, at least 75% (6/8) agreed with each acceptability measure related to user satisfaction, perceived usefulness, and acceptance. These parents' children were patients of 4 of the 7 participating clinicians. Consistent with the planned workflow, clinicians viewed the app before seeing the patient in 4 of 9 (44%) instances. The median time spent on the app per patient was 95 (range 5-240) seconds. Think-aloud assessment results for clinicians were grouped into 2 themes: (1) trust of app vaccine results and (2) clarifying the app content. On the survey, clinicians were unanimously positive about the app, with an average System Usability Scale score of 87.5 (SE 2.5). CONCLUSIONS: This mixed methods evaluation demonstrated that ProtectMe4 was usable and acceptable to both parents and clinicians in real-world pediatric primary care. Improved coordination among clinic staff is needed to ensure the app is consistently offered to patients and reviewed by clinicians before seeing the patient.

Recruitment and retention of participants with obesity into a longitudinal birth cohort: the Breastfeeding and Early Child Health (BEACH) study.

BACKGROUND: The study aimed to evaluate how maternal pre-pregnant body mass index (BMI) impacts participant recruitment and retention. METHODS: Participants were enrolled in a longitudinal study between 30 and 36 weeks of pregnancy as having normal weight (pre-pregnant BMI ≥ 18.5 and <25 kg/m2) or obesity (pre-pregnant BMI ≥ 30.0 kg/m2). Recruitment channels included Facebook, email, newspaper, phone calls, radio advertisements, flyers, and word-of-mouth. The stages of recruitment included eligibility, consent, and completion. Pearson's chi-square tests were used to evaluate the relationship between BMI and enrollment outcomes. RESULTS: Recruitment yielded 2770 total prospective participants. After screening, 141 individuals were eligible, 83 consented, and 60 completed the study. Facebook was the most successful method for identifying eligible pregnant patients with obesity, while a higher percentage of participants recruited through word-of-mouth and flyers consented to the study. Pre-pregnant BMI was significantly associated with the stage of recruitment completed by the participant (p = 0.04), whereby individuals eligible for the study with obesity were less likely to consent and complete study visits. CONCLUSION: We demonstrated that maternal obesity was significantly associated with enrollment outcomes in a longitudinal birth cohort study. This study showed that pre-pregnancy BMI influenced study participation. Therefore, tailored recruitment strategies to enhance the recruitment and enrollment of individuals with obesity in maternal-infant health research may be necessary.

What Teens Should Know About Choosing Contraception.

This JAMA Pediatrics Patient Page describes what teens should consider when choosing contraception methods.

What Parents Need to Know About Autism Screening and Early Treatment.

This JAMA Pediatrics Patient Page describes autism screening for children and how to access therapies.

Lipid Testing among Youth in Medicaid: The Role of Social Determinants of Health and Providers.

OBJECTIVE: To assess recent temporal trends in guideline-compliant pediatric lipid testing, and to examine the influence of social determinants of health (SDoH) and provider characteristics on the likelihood of testing in youth. STUDY DESIGN: In this observational, multiyear cross-sectional study, we calculated lipid testing prevalence by year among 268 627 12-year olds from 2015 through 2019 who were enrolled in Florida Medicaid and eligible for universal lipid screening during age 9 to 11, and 11 437 22-year olds (2017-2019) who were eligible for screening during age 17-21. We compared trends in testing prevalence by SDoH and health risk factors at two recommended ages and modeled the associations between patient characteristics and provider type on lipid testing using generalized estimating equations. RESULTS: Testing among 12-year olds remained low between 2015 through 2019 with the highest prevalence in 2015 (8.0%) and lowest in 2017 (6.7%). Screening compliance among 22-year olds was highest in 2017 (21.1%) and fell to 17.8% in 2019. Hispanics and non-Hispanic Blacks in both age groups had about 2%-3% lower testing prevalence than non-Hispanic Whites. Testing in 12-year olds was 12.3% vs 7.7% with and without obesity, and 14.4% vs 7.6% with and without antipsychotic use. Participants who saw providers who were more likely to prescribe lipid testing were more likely to receive testing (OR = 2.3, 95% CI 2.0-2.8, P < .001). CONCLUSIONS: Although lipid testing prevalence was greatest among high-risk children, overall prevalence of lipid testing in youth remains very low. Provider specialty and choices by individual providers play important roles in improving guideline-compliant pediatric lipid testing.

Bedaquiline-pretomanid-moxifloxacin-pyrazinamide for drug-sensitive and drug-resistant pulmonary tuberculosis treatment: a phase 2c, open-label, multicentre, partially randomised controlled trial.

BACKGROUND: The current tuberculosis (TB) drug development pipeline is being re-populated with candidates, including nitroimidazoles such as pretomanid, that exhibit a potential to shorten TB therapy by exerting a bactericidal effect on non-replicating bacilli. Based on results from preclinical and early clinical studies, a four-drug combination of bedaquiline, pretomanid, moxifloxacin, and pyrazinamide (BPaMZ) regimen was identified with treatment-shortening potential for both drug-susceptible (DS) and drug-resistant (DR) TB. This trial aimed to determine the safety and efficacy of BPaMZ. We compared 4 months of BPaMZ to the standard 6 months of isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE) in DS-TB. 6 months of BPaMZ was assessed in DR-TB. METHODS: SimpliciTB was a partially randomised, phase 2c, open-label, clinical trial, recruiting participants at 26 sites in eight countries. Participants aged 18 years or older with pulmonary TB who were sputum smear positive for acid-fast bacilli were eligible for enrolment. Participants with DS-TB had Mycobacterium tuberculosis with sensitivity to rifampicin and isoniazid. Participants with DR-TB had M tuberculosis with resistance to rifampicin, isoniazid, or both. Participants with DS-TB were randomly allocated in a 1:1 ratio, stratified by HIV status and cavitation on chest radiograph, using balanced block randomisation with a fixed block size of four. The primary efficacy endpoint was time to sputum culture-negative status by 8 weeks; the key secondary endpoint was unfavourable outcome at week 52. A non-inferiority margin of 12% was chosen for the key secondary outcome. Safety and tolerability outcomes are presented as descriptive analyses. The efficacy analysis population contained patients who received at least one dose of medication and who had efficacy data available and had no major protocol violations. The safety population contained patients who received at least one dose of medication. This study is registered with ClinicalTrials.gov (NCT03338621) and is completed. FINDINGS: Between July 30, 2018, and March 2, 2020, 455 participants were enrolled and received at least one dose of study treatment. 324 (71%) participants were male and 131 (29%) participants were female. 303 participants with DS-TB were randomly assigned to 4 months of BPaMZ (n=150) or HRZE (n=153). In a modified intention-to-treat (mITT) analysis, by week 8, 122 (84%) of 145 and 70 (47%) of 148 participants were culture-negative on 4 months of BPaMZ and HRZE, respectively, with a hazard ratio for earlier negative status of 2·93 (95% CI 2·17-3·96; p<0·0001). Median time to negative culture (TTN) was 6 weeks (IQR 4-8) on 4 months of BPaMZ and 11 weeks (6-12) on HRZE. 86% of participants with DR-TB receiving 6 months of BPaMZ (n=152) reached culture-negative status by week 8, with a median TTN of 5 weeks (IQR 3-7). At week 52, 120 (83%) of 144, 134 (93%) of 144, and 111 (83%) of 133 on 4 months of BPaMZ, HRZE, and 6 months of BPaMZ had favourable outcomes, respectively. Despite bacteriological efficacy, 4 months of BPaMZ did not meet the non-inferiority margin for the key secondary endpoint in the pre-defined mITT population due to higher withdrawal rates for adverse hepatic events. Non-inferiority was demonstrated in the per-protocol population confirming the effect of withdrawals with 4 months of BPaMZ. At least one liver-related treatment-emergent adverse effect (TEAE) occurred among 45 (30%) participants on 4 months of BPaMZ, 38 (25%) on HRZE, and 33 (22%) on 6 months of BPaMZ. Serious liver-related TEAEs were reported by 20 participants overall; 11 (7%) among those on 4 months of BPaMZ, one (1%) on HRZE, and eight (5%) on 6 months of BPaMZ. The most common reasons for discontinuation of trial treatment were hepatotoxicity (ten participants [2%]), increased hepatic enzymes (nine participants [2%]), QTcF prolongation (three participants [1%]), and hypersensitivity (two participants [<1%]). INTERPRETATION: For DS-TB, BPaMZ successfully met the primary efficacy endpoint of sputum culture conversion. The regimen did not meet the key secondary efficacy endpoint due to adverse events resulting in treatment withdrawal. Our study demonstrated the potential for treatment-shortening efficacy of the BPaMZ regimen for DS-TB and DR-TB, providing clinical validation of a murine model widely used to identify such regimens. It also highlights that novel, treatment-shortening TB treatment regimens require an acceptable toxicity and tolerability profile with minimal monitoring in low-resource and high-burden settings. The increased risk of unpredictable severe hepatic adverse events with 4 months of BPaMZ would be a considerable obstacle to implementation of this regimen in settings with high burdens of TB with limited infrastructure for close surveillance of liver biochemistry. Future research should focus on improving the preclinical and early clinical detection and mitigation of safety issues together and further efforts to optimise shorter treatments. FUNDING: TB Alliance.

What Parents Need to Know About Peanut Allergy.

This JAMA Pediatrics Patient Page describes peanut allergy guidelines and the importance of giving peanut protein to young children to prevent development of an allergy.

Artificial Intelligence Chatbots and Their Influence on Learning.

This JAMA Pediatrics Patient Page describes what artificial intelligence chatbots are and how they may influence learning among children.

Classifying early infant feeding status from clinical notes using natural language processing and machine learning.

The objective of this study is to develop and evaluate natural language processing (NLP) and machine learning models to predict infant feeding status from clinical notes in the Epic electronic health records system. The primary outcome was the classification of infant feeding status from clinical notes using Medical Subject Headings (MeSH) terms. Annotation of notes was completed using TeamTat to uniquely classify clinical notes according to infant feeding status. We trained 6 machine learning models to classify infant feeding status: logistic regression, random forest, XGBoost gradient descent, k-nearest neighbors, and support-vector classifier. Model comparison was evaluated based on overall accuracy, precision, recall, and F1 score. Our modeling corpus included an even number of clinical notes that was a balanced sample across each class. We manually reviewed 999 notes that represented 746 mother-infant dyads with a mean gestational age of 38.9 weeks and a mean maternal age of 26.6 years. The most frequent feeding status classification present for this study was exclusive breastfeeding [n = 183 (18.3%)], followed by exclusive formula bottle feeding [n = 146 (14.6%)], and exclusive feeding of expressed mother's milk [n = 102 (10.2%)], with mixed feeding being the least frequent [n = 23 (2.3%)]. Our final analysis evaluated the classification of clinical notes as breast, formula/bottle, and missing. The machine learning models were trained on these three classes after performing balancing and down sampling. The XGBoost model outperformed all others by achieving an accuracy of 90.1%, a macro-averaged precision of 90.3%, a macro-averaged recall of 90.1%, and a macro-averaged F1 score of 90.1%. Our results demonstrate that natural language processing can be applied to clinical notes stored in the electronic health records to classify infant feeding status. Early identification of breastfeeding status using NLP on unstructured electronic health records data can be used to inform precision public health interventions focused on improving lactation support for postpartum patients.

Eating Family Meals Together at Home.

This JAMA Pediatrics Patient Page describes the benefits of eating family meals together at home.

Why Is the Pediatrician Asking Me About Social Drivers of Health?

This JAMA Pediatrics Patient Page describes why pediatric clinics ask families about social drivers of health.

What Parents Need to Know About Penicillin Allergy Labels.

This JAMA Pediatrics Patient Page describes why it is important for children to see their pediatrician for any concern about a reaction to penicillin before a child is considered to have a penicillin allergy.

What Parents Should Know About Gun Safety in the Home and Vehicle.

This Patient Page describes safety measures parents can take to protect children from gun violence.

Untargeted Metabolomic Analysis of Lactation-Stage-Matched Human and Bovine Milk Samples at 2 Weeks Postnatal.

Epidemiological data demonstrate that bovine whole milk is often substituted for human milk during the first 12 months of life and may be associated with adverse infant outcomes. The objective of this study is to interrogate the human and bovine milk metabolome at 2 weeks of life to identify unique metabolites that may impact infant health outcomes. Human milk (n = 10) was collected at 2 weeks postpartum from normal-weight mothers (pre-pregnant BMI < 25 kg/m2) that vaginally delivered term infants and were exclusively breastfeeding their infant for at least 2 months. Similarly, bovine milk (n = 10) was collected 2 weeks postpartum from normal-weight primiparous Holstein dairy cows. Untargeted data were acquired on all milk samples using high-resolution liquid chromatography-high-resolution tandem mass spectrometry (HR LC-MS/MS). MS data pre-processing from feature calling to metabolite annotation was performed using MS-DIAL and MS-FLO. Our results revealed that more than 80% of the milk metabolome is shared between human and bovine milk samples during early lactation. Unbiased analysis of identified metabolites revealed that nearly 80% of milk metabolites may contribute to microbial metabolism and microbe-host interactions. Collectively, these results highlight untargeted metabolomics as a potential strategy to identify unique and shared metabolites in bovine and human milk that may relate to and impact infant health outcomes.

What Parents Should Know About Food and Food Insecurity for Their Families.

This Patient Page discusses how families with food insecurity can partner with their child's pediatrician to access nutrition food .

Pediatric primary care provider and staff perspectives on the implementation of electronic health record-based social needs interventions: A mixed-methods study.

Introduction: Interventions to address social needs in clinical settings can improve child and family health outcomes. Electronic health record (EHR) tools are available to support these interventions but are infrequently used. This mixed-methods study sought to identify approaches for implementing social needs interventions using an existing EHR module in pediatric primary care. Methods: We conducted focus groups and interviews with providers and staff (n = 30) and workflow assessments (n = 48) at four pediatric clinics. Providers and staff completed measures assessing the acceptability, appropriateness, and feasibility of social needs interventions. The Consolidated Framework for Implementation Research guided the study. A hybrid deductive-inductive approach was used to analyze qualitative data. Results: Median scores (range 1-5) for acceptability (4.9) and appropriateness (5.0) were higher than feasibility (3.9). Perceived barriers to implementation related to duplicative processes, parent disclosure, and staffing limitations. Facilitators included the relative advantage of the EHR module compared to existing documentation practices, importance of addressing social needs, and compatibility with clinic culture and workflow. Self-administered screening was seen as inappropriate for sensitive topics. Strategies identified included providing resource lists, integrating social needs assessments with existing screening questionnaires, and reducing duplicative documentation. Conclusions: This study offers insight into the implementation of EHR-based social needs interventions and identifies strategies to promote intervention uptake. Findings highlight the need to design interventions that are feasible to implement in real-world settings. Future work should focus on integrating multiple stakeholder perspectives to inform the development of EHR tools and clinical workflows to support social needs interventions.

Prenatal and postnatal exposure to polychlorinated biphenyls alter follicle numbers, gene expression, and a proliferation marker in the rat ovary.

Polychlorinated biphenyls (PCBs) were used in industrial applications until they were banned in the 1970s, but they still persist in the environment. Little is known about the long-term effects of exposure to PCB mixtures on the rat ovary during critical developmental periods. Thus, this study tested whether prenatal and postnatal exposures to PCBs affect follicle numbers and gene expression in the ovaries of F1 offspring. Sprague-Dawley rats were treated with vehicle or Aroclor 1221 (A1221) at 1 mg/kg/day during embryonic days 8-18 and/or postnatal days (PND) 1-21. Ovaries from F1 rats were collected for assessment of follicle numbers and differential expression of estrogen receptor 1 (Esr1), estrogen receptor 2 (Esr2), androgen receptor (Ar), progesterone receptor (Pgr), and Ki-67 (Ki67) at PNDs 8, 32, and 60. Sera were collected for measurement of estradiol concentrations. Prenatal exposure to A1221 significantly decreased the number of primordial follicles and the total number of follicles at PND 32 compared to control. Postnatal PCB exposure borderline increased Ki67 gene expression and significantly increased Ki67 protein levels (PND 60) compared to control. Combined prenatal and postnatal PCB exposure borderline decreased Ar expression (PND 8) compared to control. However, PCB exposure did not significantly affect the expression of Pgr, Esr1, and Esr2 or serum estradiol concentrations compared to control at any time point. In conclusion, these data suggest that PCB exposure affects follicle numbers and levels of the proliferation marker Ki67, but it does not affect expression of some sex steroid hormone receptors in the rat ovary.