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

OBJECTIVES: 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, multi-year 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% versus 7.7% with and without obesity, and 14.4% versus 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 (odds ratio=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.

Decoding of EEG signals reveals non-uniformities in the neural geometry of colour.

The idea of colour opponency maintains that colour vision arises through the comparison of two chromatic mechanisms, red versus green and yellow versus blue. The four unique hues, red, green, blue, and yellow, are assumed to appear at the null points of these the two chromatic systems. Here we hypothesise that, if unique hues represent a tractable cortical state, they should elicit more robust activity compared to other, non-unique hues. We use a spatiotemporal decoding approach to report that electroencephalographic (EEG) responses carry robust information about the tested isoluminant unique hues within a 100-350 ms window from stimulus onset. Decoding is possible in both passive and active viewing tasks, but is compromised when concurrent high luminance contrast is added to the colour signals. For large hue-differences, the efficiency of hue decoding can be predicted by mutual distance in a nominally uniform perceptual colour space. However, for small perceptual neighbourhoods around unique hues, the encoding space shows pivotal non-uniformities which suggest that anisotropies in neurometric hue-spaces may reflect perceptual unique hues.

A Pilot Test of a Workshop for Pediatric Clinicians About Communicating with Parents About the HPV Vaccine Using the C-LEAR Approach.

Low HPV vaccinations rates lead to missed opportunities to prevent cancer. Specifically, some parents (12-76%) report never receiving a recommendation for their child to receive the vaccine. Current models for talking about HPV vaccination fall short in that they focus primarily on how to introduce the vaccine with limited guidance on how to follow through with the conversation, particularly with those parents who may be hesitant. We developed the C-LEAR approach, an easy to remember, evidence-informed mnemonic to guide clinicians through the process of introducing and discussing the HPV vaccine with parents. We pilot tested this approach with a total of 20 pediatric clinicians (n = 13 residents; n = 7 attendings) in 60-min Zoom workshops that included a short didactic session, a demonstration of skills, and a small group, facilitator-led role play session. On an immediate post-training survey, all participants stated that the training was helpful and easy to understand. Ninety-four percent responded that they would implement what they had learned in their clinic. Participants reported appreciation for the small group sessions. While not specifically asked or required to incorporate the material into their practice, 1 year following the training, 8/9 (88%) participants reported using the C-LEAR approach in their clinics "most" or "all of the time." We are further testing this model through teaching our workshop in a large, randomized trial across the state of Florida.

Messaging preferences among Florida caregivers participating in focus groups who had not yet accepted the HPV vaccine for their 11- to 12-year-old child.

BACKGROUND: In the United States, human papillomavirus (HPV) vaccination rates remain low. The President's Cancer Panel suggests that effective messaging about the HPV vaccination focus on the vaccine's safety, efficacy, ability to prevent cancer, and recommendation at ages 11- to 12-years. We aimed to develop messages about HPV vaccine that include the President Cancer Panel's suggestions and were acceptable to caregivers of adolescents. METHODS: From August to October 2020, we conducted one-hour, Zoom videoconference focus groups with caregivers who lived in Florida, had an 11- to 12-year-old child, and had not had any of their children receive the HPV vaccine. Focus group moderators asked caregivers to react to three videos of clinician (i.e., MD, DO, APRN, PA) recommendations and three text message reminders. Thematic analysis was conducted using the constant comparative method and led by one author with qualitative analysis expertise. Two additional authors validated findings. RESULTS: Caregivers (n = 25 in six groups) were primarily non-Hispanic white (84%) and educated (64% had at least an Associate's degree). Approximately a third of caregivers had delayed (44%) or decided against a vaccine for their child (36%). Caregivers described six preferred message approaches: recognize caregivers' autonomy, balanced benefits and risks, trustworthy sources, increased feasibility of appointment scheduling, information prior to decision point, and preferred personalized information. Caregivers expressed a desire to have the follow-up doses mentioned in the introduction. CONCLUSIONS: HPV vaccine messages, whether delivered by a clinician or via text message, will be more acceptable to caregivers if they approach HPV vaccination as the caregivers' decision, and include information from trusted sources to help caregivers make an informed choice.

Streamlining Universal Prenatal Screening for Risk for Adverse Birth Outcomes.

OBJECTIVE: Many of the medical risk factors for adverse birth outcomes (e.g., preeclampsia) are regularly monitored in prenatal care. However, many of the psychosocial risk factors associated with adverse birth outcomes (e.g., maternal stress, anxiety, depression, intimate partner violence) are not regularly addressed during routine prenatal care. Comprehensive prenatal screening for psychosocial risk factors for adverse birth outcomes can improve maternal and neonatal outcomes. In this study, we examine an existing tool for opportunities to streamline and improve screening. METHODS: We reviewed medical records for 528 mother-infant dyads, recording maternal responses to a 21-item prenatal risk screening tool, and gestational age/birth weight of infants. Multiple approaches to scoring were used to predict likelihood of adverse birth outcome. RESULTS: Women who answered yes to any of the top four interrelated items were 3.32 times more likely to have an adverse birth outcome. Sensitivity and specificity were 68% and 65%, respectively. CONCLUSION FOR PRACTICE: We identified a short surveillance tool to identify women who are at highest risk and require more in-depth screening, and to rule out women who are at very low risk of an adverse birth outcome.

Transgenerational effects of polychlorinated biphenyls: 2. Hypothalamic gene expression in rats†.

Polychlorinated biphenyls (PCBs) are endocrine-disrupting chemicals (EDCs) with well-established effects on reproduction and behavior in developmentally-exposed (F1) individuals. Because of evidence for transgenerational effects of EDCs on the neuroendocrine control of reproductive physiology, we tested the hypothesis that prenatal PCB exposure leads to unique hypothalamic gene-expression profiles in three generations. Pregnant Sprague-Dawley rats were treated on gestational days 16 and 18 with the PCB mixture Aroclor 1221 (A1221), vehicle (3% DMSO in sesame oil), or estradiol benzoate (EB, 50 µg/kg), the latter a positive control for estrogenic effects of A1221. Maternal- and paternal-lineage F2 and F3 generations were bred using untreated partners. The anteroventral periventricular nucleus (AVPV) and arcuate nucleus (ARC), involved in the hypothalamic control of reproduction, were dissected from F1 to F3 females and males, RNA extracted, and gene expression measured in a qPCR array. We detected unique gene-expression profiles in each generation, which were sex- and lineage-specific. In the AVPV, treatment significantly changed 10, 25, and 11 transcripts in F1, F2, and F3 generations, whereas 10, 1, and 12 transcripts were changed in these generations in the ARC. In the F1 AVPV and ARC, most affected transcripts were decreased by A1221. In the F2 AVPV, most effects of A1221 were observed in females of the maternal lineage, whereas only Pomc expression changed in the F2 ARC (by EB). The F3 AVPV and ARC were mainly affected by EB. It is notable that results in one generation do not predict results in another, and that lineage was a major determinant in results. Thus, transient prenatal exposure of F1 rats to A1221 or EB can alter hypothalamic gene expression across three generations in a sex- and lineage-dependent manner, leading to the conclusion that the legacy of PCBs continues for generations.

Adverse Childhood Experiences Are Associated with Cardiometabolic Risk among Hispanic American Adolescents.

OBJECTIVE: To assess the relationship between adverse childhood experiences (ACEs) and cardiometabolic risk among Hispanic adolescents. STUDY DESIGN: This cross-sectional study was conducted at an academic research center in Gainesville, Florida. Participants were locally recruited, and data were collected from June 2016 to July 2018. Participants (n = 133, 60.2% female) were healthy adolescents aged 15-21 years who self-identified as Hispanic, were born in the US, and had a body mass index (BMI) between ≥18.5 and ≤40 kg/m2. Primary outcomes were BMI, body fat percentage, waist circumference, and resting blood pressure. Associations between ACEs and cardiometabolic measures were assessed by multivariable logistic regression models, which controlled for sex, age, parental education, and food insecurity. Results were sex-stratified to assess potential variations. RESULTS: Reporting ≥4 ACEs (28.6%) was significantly associated with a greater BMI (P = .004), body fat percentage (P = .02), and diastolic blood pressure (P = .05) compared with reporting <4 ACEs. Female participants reporting ≥4 ACEs were significantly more likely to have a greater BMI (P = .04) and body fat percentage (P = .03) whereas male participants reporting ≥4 ACEs were significantly more likely to have a greater BMI (P = .04), systolic blood pressure (P = .03), and diastolic blood pressure (P = .03). CONCLUSIONS: Hispanic adolescent participants who experienced ≥4 ACEs were more likely to have elevated risk markers of obesity and cardiometabolic disease. Further research is needed to elucidate the physiological mechanisms driving these relationships.

Considerations to Support Use of Patient-Reported Outcomes Measurement Information System Pediatric Measures in Ambulatory Clinics.

OBJECTIVE: To identify challenges to the use of Patient-Reported Outcomes Measurement Information System (PROMIS) Pediatric measures in the ambulatory pediatric setting and possible solutions to these challenges. STUDY DESIGN: Eighteen semistructured telephone interviews of health system leaders, measurement implementers, and ambulatory pediatric clinicians were conducted. Five coders used applied thematic analysis to iteratively identify and refine themes in interview data. RESULTS: Most interviewees had roles in leadership or the implementation of patient-centered outcomes; 39% were clinicians. Some had experience using PROMIS clinically (44%) and 6% were considering this use. Analyses yielded 6 themes: (1) selection of PROMIS measures, (2) method of administration, (3) use of PROMIS Parent Proxy measures, (4) privacy and confidentiality of PROMIS responses, (5) interpretation of PROMIS scores, and (6) using PROMIS scores clinically. Within the themes, interviewees illuminated specific unique considerations for using PROMIS with children, including care transitions and privacy. CONCLUSIONS: Real-world challenges continue to hamper PROMIS use. Ongoing efforts to disseminate information about the integration of PROMIS measures in clinical care is critical to impacting the health of children.

Neoadjuvant Short-Course Radiotherapy for Upper Third Rectal Tumors: Systematic Review and Individual Patient Data Metaanalysis of Randomized Controlled Trials.

BACKGROUND: There is no consensus on the use of neoadjuvant radiotherapy for tumors of the upper third of the rectum. Due to conflicting findings in high-quality trials and significant long-term side effects associated with neoadjuvant radiotherapy, the benefit of neoadjuvant radiotherapy for upper third rectal tumors is less certain than for lower two third rectal tumors. This metaanalysis compares oncological outcomes with neoadjuvant radiotherapy and surgery versus surgery alone for upper third rectal tumors. PATIENTS AND METHODS: PubMed, Embase, and the Cochrane library databases were searched. Randomized controlled trials (RCT) comparing neoadjuvant radiotherapy and surgery versus surgery alone for resectable rectal cancer were included. Individual patient data were sought from the principal investigator of each eligible trial for comparative data on patients with upper third rectal tumors. The main outcomes measured were survival outcomes, oncological outcomes, postoperative morbidity, and late toxicity. RESULTS: Individual patient data from two RCTs examining outcomes in 758 patients were obtained. Published data from one further RCT containing comparable data on upper third rectal tumors were included in analysis of local recurrence. In patients with curative surgery, there was no significant reduction in local recurrence or significant improvement in overall survival or disease-free survival with neoadjuvant radiotherapy (LR RR: 0.38, 95% CI 0.14-1.04, p = 0.06) (OS RR: 1.10, 95% CI 0.98-1.24, p = 0.11) (DFS RR: 1.11, 95% CI 0.97-1.26, p = 0.13). CONCLUSIONS: The benefit of neoadjuvant radiotherapy for upper third rectal tumors is not certain, and surgery alone for patients with potentially curative disease at preoperative staging may be sufficient.

A feasibility trial of parent HPV vaccine reminders and phone-based motivational interviewing.

BACKGROUND: We assessed the feasibility and acceptability of a sequential approach of parent-targeted HPV vaccine reminders and phone-based Motivation Interviewing (MI). METHODS: In 2016, we selected all 11- to 12-year-old boys and girls seen in one clinic whose vaccine records did not include the HPV vaccine (n=286). By gender, we individually randomized parents of adolescents to an interactive text message (74 girls and 45 boys), postcard reminder (46 boys and no girls because of previously demonstrated efficacy), or standard care group (75 girls and 46 boys). Reminders were sent with medical director permission and a HIPAA waiver. Two months after reminders, among the adolescents whose vaccine records still did not include the HPV vaccine, we selected a gender-stratified random sample of 20 parents for phone-based MI. We assessed the percentage of deliverable messages, the percentage of parents' responding to the interactive text message, parent acceptability of receiving a text message, and MI parent responsiveness and interviewer competence (MI Treatment Integrity Coding system). RESULTS: Nearly all messages were deliverable (98% of postcards and 74% of text messages). Six of the 88 parents (7%) receiving text messages scheduled an appointment through our interactive system. The acceptability survey response rate was 37% (38/102). Respondents were favorable toward vaccine reminders for all parents (82%). Among 20 sampled parents, 17 were reached by phone of whom 7 completed MI, 4 had or were getting the HPV vaccine for their child, and 5 expressed disinterest. Across the 7 MI calls, the interviewer was rated 100% MI adherent and scored an average 4.19 rating for Global Spirit. CONCLUSION: Without providing explicit consent to receive vaccine-related messages, parents nonetheless found postcards and interactive text messages acceptable. Centralizing MI to phone calls with trained staff was acceptable to parents and resulted in highly MI-adherent interviews.

Identifying adverse childhood experiences in pediatrics to prevent chronic health conditions.

Despite evidence that over 40% of youth in the United States have one or more adverse childhood experiences (ACEs), and that ACEs have cumulative, pernicious effects on lifelong health, few primary care clinicians routinely ask about ACEs. Lack of standardized and accurate clinical assessments for ACEs, combined with no point-of-care biomarkers of the "toxic stress" caused by ACEs, hampers prevention of the health consequences of ACEs. Thus, there is no consensus regarding how to identify, screen, and track ACEs, and whether early identification of toxic stress can prevent disease. In this review, we aim to clarify why, for whom, when, and how to identify ACEs in pediatric clinical care. To do so, we examine the evidence for such identification; describe the efficacy and accuracy of potential screening instruments; discuss current trends in, and potential barriers to, the identification of ACEs and the prevention of downstream effects; and recommend next steps for research, practice, and policy.

Specific adverse childhood experiences and their association with other adverse childhood experiences, asthma and emotional, developmental and behavioral problems in childhood.

BACKGROUND: Adverse childhood experiences (ACEs) have lifelong health consequences, yet screening remains challenging. Particularly in clinical settings, brief screeners that could lead to comprehensive assessments may be more feasible. We explore how two ACEs (economic hardship, parental/caregiver divorce/separation) are associated with other ACEs, asthma, and emotional, developmental, or behavioral (EDB) problems. METHODS: Using the 2016 National Survey of Children's Health, we assessed the associations between ACEs and asthma and EDB problems and calculated sensitivities, specificities and predictive values. RESULTS: Parents frequently reported 1+ ACEs for their child (50.3%). Individual ACE frequency ranged from 4.2 to 29.6%; all were significantly associated with EDB problems (adjusted odds ratios (aORs): 2.2-5.1) and more ACEs confirmed higher odds. Two ACES (economic hardship, parental/caregiver divorce/separation) co-occurred frequently with other ACEs, having either predicted EDB problems similarly to other ACEs (aORs 1.8; 95% CI 1.4, 2.3) and having both greatly increased odds (aOR 3.8; 95% CI 2.8, 5.2). The negative predictive value of EDB problems associated with citing neither ACE was high (95.7%). Similar trends with asthma were observed. CONCLUSIONS: Economic hardship and caregiver separation are strongly associated with other ACEs, EDB problems and asthma. A brief screener including these ACEs may reduce clinical barriers to broader ACEs screening.

Variation in Tdap and Influenza Vaccination Coverage Among Pregnant Women by Insurance Type - Florida, 2016-2018.

Infants are at increased risk for pertussis-associated morbidity and mortality, and pregnant women and their infants are more likely than other patient populations to experience severe influenza-related illness (1,2). The Advisory Committee on Immunization Practices (ACIP) recommends that all women receive the tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine during each pregnancy, preferably during the early part of gestational weeks 27-36 (3). ACIP also recommends that women who are or might be pregnant during the influenza season receive the inactivated influenza vaccine at any time during pregnancy (4). Despite these recommendations, coverage with Tdap and influenza vaccines during pregnancy has been low, with approximately one half of women receiving each vaccine and only one third receiving both, based on a survey during March-April 2019 (5). Data obtained through a retrospective chart review of randomly selected pregnant women who delivered at the University of Florida Health Shands Hospital in Gainesville, Florida, from January 1, 2016, to December 31, 2018, were analyzed to assess vaccination coverage by insurance type. Because the Florida Medicaid policy at that time did not cover these vaccines during pregnancy, the hospital system offered Tdap and influenza vaccines at no additional cost to mothers during the immediate postpartum hospital stay. Among 341 women, 68.6% of privately insured and 13.4% with Medicaid received Tdap during pregnancy, and among 316 women, 70.4% of privately insured and 35.6% with Medicaid received influenza vaccine during pregnancy. Many women, especially those with Medicaid, were vaccinated in the immediate postpartum period, when vaccination was available at no cost, increasing Tdap vaccination rates to 79.3% for privately insured and 51.7% for women with Medicaid; influenza vaccination rates rose to 72.0% for privately insured and 43.5% for women with Medicaid. These data suggest that the state Medicaid policy to not cover these vaccines during pregnancy might have significantly reduced coverage among its enrollees.

Tobacco-Related Counseling and Documentation in Adolescent Primary Care Practice: Challenges and Opportunities.

INTRODUCTION: Primary care visits present an opportunity to reduce tobacco use and tobacco smoke exposure (TSE) among adolescents. To date, few studies have examined tobacco-related electronic health record (EHR) documentation in adolescent visits. The purpose of this study was to (1) describe tobacco-related EHR documentation practices in adolescent care clinics, including whether alternative tobacco products, parental use, and TSE were addressed; and (2) identify aspects of adolescent tobacco use that may inform EHR updates and counseling and documentation practices. METHODS: Following a convergent mixed-methods design, we conducted an EHR review of 508 adolescent well-child visits, performed focus groups with pediatric providers and staff, and conducted in-depth interviews with adolescent patients. Record review data and interview transcripts were analyzed and interpreted concurrently. RESULTS: In the EHR review, cigarette screening was documented in 92.3% of visits, smokeless tobacco screening in 51.4%, parental tobacco use in 23.2%, and home TSE in 33.1% of visits. Smoking status options were not mutually exclusive and did not include noncigarette products. No records documented assessment of e-cigarette use, despite nearly half of adolescent interview respondents citing these as the most popular products among adolescents. In interviews, adolescents discussed their experiences with alternative tobacco/nicotine products more than cigarettes. CONCLUSIONS: Tobacco use status prompts should be revised for clarity and include noncigarette tobacco products and TSE. Provider education on noncigarette products and TSE assessment is needed. Improvements in EHR systems, resources, and tools can lead to better tobacco screening, prevention, and treatment practices among primary care providers. IMPLICATIONS: Clinical guidelines call for pediatricians to assess and treat adolescent and parental tobacco use during primary care visits. The use of electronic health records (EHRs) can improve screening and counseling practices; however, few studies have examined tobacco-related EHR documentation practices in adolescent care settings. This mixed-methods study found low rates of EHR documentation related to noncigarette nicotine/tobacco products, parental tobacco use, and tobacco smoke exposure. These results demonstrate the need for increased provider training and EHR modifications to facilitate comprehensive tobacco control efforts in the adolescent population.

Maternal care modulates transgenerational effects of endocrine-disrupting chemicals on offspring pup vocalizations and adult behaviors.

Endocrine-disrupting chemicals (EDCs) can act upon a developing organism to change its endocrine health and behavior in adulthood. Beyond actions on the exposed individuals, transgenerational effects of several EDCs have been reported. This study assessed the combinatorial impact of EDC-altered maternal care and transgenerational inheritance on F3 male and female offspring. Pregnant rats were exposed to EDCs with different modes of action: the weakly estrogenic polychlorinated biphenyl (PCB) mixture Aroclor 1221, the anti-androgenic fungicide vinclozolin (VIN), or the vehicle (6% dimethylsulfoxide in sesame oil; VEH) during embryonic development. The F1 male and female offspring were bred through the paternal- or maternal-lineage with untreated partners to generate F2 offspring. This process was repeated through both maternal and paternal lineages to create the F3 generation. Maternal care of F2 dams towards their F3 offspring was altered in a lineage-dependent manner, particularly in PCB paternal-lineage animals. When F3 pups were recorded for ultrasonic vocalizations (USVs) following separation from the mother, the rate of neonatal USVs in F3 offspring were decreased in PCB paternal-lineage pups. In adulthood, anxiety-like behaviors of the F3 rats were tested, with only small effects of EDCs detected. These interactions of maternal behaviors and EDC effects across generations, especially via the paternal lineage, has implications for health and environmental responses in wildlife and humans.

Self-harm in young people with perinatal HIV and HIV negative young people in England: cross sectional analysis.

BACKGROUND: Self-harm in adolescents is of growing concern internationally but limited evidence exists on the prevalence of self-harm in those living with HIV, who may be at higher risk of poor mental health outcomes. Therefore our aim was to determine the prevalence and predictors of self-harm among young people with perinatally-acquired HIV (PHIV) and HIV negative (with sibling or mother living with HIV) young people living in England. METHODS: 303 PHIV and 100 HIV negative young people (aged 12-23 years) participating in the Adolescents and Adults Living with Perinatal HIV cohort study completed an anonymous self-harm questionnaire, as well as a number of standardised mental-health assessments. Logistic regression investigated predictors of self-harm. RESULTS: The median age was 16.7 years in both groups, and 40.9% of the PHIV and 31.0% of the HIV negative groups were male. In total 13.9% (56/403) reported having ever self-harmed, with no difference by HIV status (p = 0.089). Multivariable predictors of self-harm were female sex (adjusted odds ratio (AOR) 5.3, (95% confidence interval 1.9, 14.1), p = 0.001), lower self-esteem (AOR 0.9 (0.8, 0.9) per 1 point increase, p < 0.001) and having ever used alcohol (AOR 3.8 (1.8, 7.8), p < 0.001). Self-esteem z-scores for both PHIV and HIV negative participants were 1.9 standard deviations below the mean for population norms. CONCLUSIONS: Self-harm is common among PHIV and HIV negative adolescents in England. Reassuringly however, they do not appear to be at an increased risk compared to the general adolescent population (15-19% lifetime prevalence). The low level of self-esteem (compared to available normative data) in both groups is worrying and warrants further attention.

Transgenerational effects of polychlorinated biphenyls: 1. Development and physiology across 3 generations of rats.

BACKGROUND: Polychlorinated biphenyls (PCBs) are persistent organic environmental contaminants and known endocrine-disrupting chemicals (EDCs). Previous studies demonstrated that developmental exposure to the weakly estrogenic PCB mixture Aroclor 1221 (A1221) in Sprague-Dawley rats altered sexual development, adult reproductive physiology and body weight. The current study tested the hypothesis that prenatal A1221 exposure not only disrupts these endpoints within an exposed individual's (F1 generation) lifespan, but may also affect subsequent generations (F2-F3). METHODS: We treated pregnant female rats on embryonic days (E) 16 and E18 with A1221 (1 mg/kg), estradiol benzoate (50 µg/kg, positive estrogenic control), or vehicle (3% DMSO in sesame oil, negative control). Endpoints related to sexually dimorphic developmental trajectories of reproductive and developmental physiology were measured, and as adults, reproductive endocrine status was assessed, in the F1, F2, and F3 generations. RESULTS: Significant effects of transgenerational EDCs were found for body weight and serum hormones. The A1221 descendants had significantly higher body weight in the F2-maternal lineage throughout postnatal development, and in F3-maternal lineage animals after weaning. In females, generation- and lineage-specific effects of exposure were found for serum progesterone and estradiol. Specifically, serum progesterone concentrations were lower in F2-A1221 females, and higher in F3-A1221 females, compared to their respective F2- and F3-vehicle counterparts. Serum estradiol concentrations were higher in F3-A1221 than F3-vehicle females. Reproductive and adrenal organ weights, birth outcomes, sex ratio, and estrous cycles, were unaffected. It is notable that effects of A1221 were only sometimes mirrored by the estrogenic control, EB, indicating that the mechanism of action of A1221 was likely via non-estrogenic pathways. CONCLUSIONS: PCBs caused body weight and hormonal effects in rats that were not observed in the directly exposed F1 offspring, but emerged in F2 and F3 generations. Furthermore, most effects were in the maternal lineage; this may relate to the timing of exposure of the F1 fetuses at E16 and 18, when germline (the future F2 generation) epigenetic changes diverge in the sexes. These results showing transgenerational effects of EDCs have implications for humans, as we are now in the 3rd generation since the Chemical Revolution of the mid-twentieth century, and even banned chemicals such as PCBs have a persistent imprint on the health of our descendants.

Novel Interventions and Assessments Using Patient Portals in Adolescent Research: Confidential Survey Study.

BACKGROUND: While adolescents can receive confidential health care without parental or guardian notification, they are rarely asked about their experiences and opinions regarding their care because participation in research often requires parental consent. Anonymous research with adolescents via confidential patient portals may ameliorate this research gap. OBJECTIVE: Because use of a confidential online adolescent patient portal is high at our academic institution, we hypothesized that adolescents would also respond to survey-based research via the portal, especially if asked anonymously and without parental consent. We used a clinical scenario of needing to better understanding adolescent and young adults' views about their health and health care, including information on a long-acting reversible contraceptive (LARC) to test if and how they will use a portal for research. METHODS: Upon receiving Institutional Review Board approval, we sent 2 portal-based surveys about confidential services to 2 groups of females, ages 14 to 25 years, who had attended an adolescent clinic in the past 3 years. This clinic mostly serves Medicaid recipients (80%) and is racially and ethnically diverse with half of patients identifying as African American and roughly 10% Hispanic. The control group was a random sample of female patients who never received a LARC (n=150) and the intervention group included all female adolescents who had received a LARC from the same clinic (n=107). This second sample was manually cross-checked to confirm they had an office visit for this reason. Consenting for themselves, the control group received an email through the patient portal with a link and a request to perform an assessment. The survey for the control group included items assessing health literacy and health communication preferences. The survey for the intervention group included health literacy items as well as items to assess their opinions and perceptions regarding LARCs. We tracked click-through rates and opened messages; each participant received 4 reminders. RESULTS: While only 3 participants fully completed either survey, email read rates (29/107 [27.1%] of LARC recipients and 39/150 [26.0%] of controls) were encouraging. Additionally, of those who opened the messages, almost twice as many of the LARC recipients (10/107 [9.3%]) read through the entire survey, while less than half read the entire survey as compared to those who received the survey asking about health literacy and health care preferences (6/150 [4.0%]). CONCLUSIONS: The methodology of using adolescent portals for online surveys provides a new avenue for research even though the study did not yield sufficient participation to understand these adolescents' preferences. Future studies need to test if a different survey topic would engage adolescents or if other methods like text-based reminders would improve participation.

Anxiety-like behaviors in adulthood are altered in male but not female rats exposed to low dosages of polychlorinated biphenyls in utero.

Exposure to polychlorinated biphenyls (PCBs), a class of endocrine-disrupting chemicals, can result in altered reproductive behavior in adulthood, especially when exposure occurs during critical periods of brain sexual differentiation in the fetus. Whether PCBs alter other sexually dimorphic behaviors such as those involved in anxiety is poorly understood. To address this, pregnant rat dams were injected twice, on gestational days 16 and 18, with the weakly estrogenic PCB mixture Aroclor 1221 (A1221) at one of two low dosages (0.5mg/kg or 1.0mg/kg, hereafter 1.0 and 0.5), estradiol benzoate (EB; 50µg/kg) as a positive estrogenic control, or the vehicle (3% DMSO in sesame oil). We also conducted a comprehensive assessment of developmental milestones of the F1 male and female offspring. There were no effects of treatment on sex ratio at birth and age at eye opening. Puberty, assessed by vaginal opening in females and preputial separation in males, was not affected in females but was advanced in males treated with A1221 (1.0). Males and females treated with A1221 (both dosages) were heavier in early adulthood relative to controls. The earliest manifestation of this effect developed in males prior to puberty and in females slightly later, during puberty. Anxiety-like behaviors were tested using the light:dark box and elevated plus maze tests in adulthood. In females, anxiety behaviors were unaffected by treatment. Males treated with A1221 (1.0) showed reduced indices of anxiety and increased activity in the light:dark box but not the elevated plus maze. EB failed to replicate the phenotype produced by A1221 for any of the developmental and behavioral endpoints. Collectively, these results indicate that PCBs increase body weight in both sexes, but their effects on anxiety-like behaviors are specific to males. Furthermore, differences between the results of A1221 and EB suggest that the PCBs are likely acting through mechanisms distinct from their estrogenic activity.

Two-hit exposure to polychlorinated biphenyls at gestational and juvenile life stages: 1. Sexually dimorphic effects on social and anxiety-like behaviors.

Endocrine disrupting chemicals (EDCs) are widespread environmental contaminants that affect many neuroendocrine functions. The brain is particularly vulnerable to EDCs during critical periods of gestational development when gonadal hormones exert organizational effects on sexually dimorphic behaviors later in life. Peripubertal development is also a time of continued neural sensitivity to organizing effects of hormones, yet little is known about EDC actions at these times. We sought to determine effects of prenatal or juvenile exposures to a class of EDCs, polychlorinated biphenyls (PCBs) at human-relevant dosages on development, physiology, and social and anxiety-related behaviors later in life, and the consequences of a second juvenile "hit" following prenatal treatment. We exposed male and female Sprague-Dawley rats to PCBs (Aroclor 1221, 1mg/kg/day, ip injection) and/or vehicle during prenatal development (embryonic days 16, 18, 20), juvenile development (postnatal days 24, 26, 28), or both. These exposures had differential effects on behaviors in sex and age-dependent ways; while prenatal exposure had more effects than juvenile, juvenile exposure often modified or unmasked the effects of the first hit. Additionally, females exhibited altered social and anxiety behavior in adolescence, while males displayed small but significant changes in sociosexual preferences in adulthood. Thus, the brain continues to be sensitive to organizing effects of EDCs through juvenile development. As humans are exposed to EDCs throughout multiple periods in their life, these findings have implications for our understanding of EDC effects on physiology and behavior.