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Highlights Following in vitro ischemia, the nerve growth factor receptor TrkB is activated in the presence of the TrkB agonist 7,8-DHF only in female and not in male cultured hippocampal neurons, leading to increased neuronal survival. Expression of ERα is increased following in vitro ischemia in female but not male hippocampal neurons. The female hippocampal neuronal specific responses to in vitro ischemia are blocked by pre-treatment with testosterone. The data support a model for a female-specific a neuroprotective pathway in hippocampal neurons. The pathway is activated by a TrkB agonist, dependent on ERα and blocked by testosterone.

Abstract Background Neonatal hypoxia ischemia (HI) related brain injury is one of the major causes of life-long neurological morbidities that result in learning and memory impairments. Evidence suggests that male neonates are more susceptible to the detrimental effects of HI, yet the mechanisms mediating these sex-specific responses to neural injury in neonates remain poorly understood. We previously tested the effects of treatment with a small molecule agonist of the tyrosine kinase B receptor (TrkB), 7,8-dihydroxyflavone (DHF) following neonatal HI and determined that females, but not males exhibit increased phosphorylation of TrkB and reduced apoptosis in their hippocampi. Moreover, these female-specific effects of the TrkB agonist were found to be dependent upon the expression of $$\text{ER}\alpha$$ ER α . These findings demonstrated that TrkB activation in the presence of $$\text{ER}\alpha$$ ER α comprises one pathway by which neuroprotection may be conferred in a female-specific manner. The goal of this study was to determine the role of $$\text{ER}\alpha$$ ER α -dependent TrkB-mediated neuroprotection in memory and anxiety in young adult mice exposed to HI during the neonatal period. Methods In this study, we used a unilateral hypoxic ischemic (HI) mouse model. $$\text{ER}\alpha$$ ER α +/+ or $$\text{ER}\alpha$$ ER α −/− mice were subjected to HI on postnatal day (P) 9 and mice were treated with either vehicle control or the TrkB agonist, DHF, for 7 days following HI. When mice reached young adulthood, we used the novel object recognition, novel object location and open field tests to assess long-term memory and anxiety-like behavior. The brains were then assessed for tissue damage using immunohistochemistry. Results Neonatal DHF treatment prevented HI-induced decrements in recognition and location memory in adulthood in females, but not in males. This protective effect was absent in female mice lacking $$\text{ER}\alpha$$ ER α . The female-specific improved recognition and location memory outcomes in adulthood conferred by DHF therapy after neonatal HI tended to be or were $$\text{ER}\alpha$$ ER α -dependent, respectively. Interestingly, DHF triggered anxiety-like behavior in both sexes only in the mice that lacked $$\text{ER}\alpha$$ ER α . When we assessed the severity of injury, we found that DHF therapy did not decrease the percent tissue loss in proportion to functional recovery. We additionally observed that the presence of $$\text{ER}\alpha$$ ER α significantly reduced overall HI-associated mortality in both sexes. Conclusions These observations provide evidence for a therapeutic role for DHF in which TrkB-mediated sustained recovery of recognition and location memories in females are $$\text{ER}\alpha$$ ER α -associated and dependent, respectively. However, the beneficial effects of DHF therapy did not include reduction of gross tissue loss but may be derived from the enhanced functioning of residual tissues in a cell-specific manner.

BackgroundClinical experience and progressive autonomy are essential components of medical education and must be balanced with patient comfort. While previous studies have suggested that most patients accept trainee involvement in their care, few studies have focused specifically on the views of parents of pediatric patients or examined groups who may not report acceptance. ObjectiveThis study aims to understand parental profiles of resident and medical student involvement in pediatric care and to use latent class analysis (LCA) methodology to identify classes of responses associated with parent demographic characteristics. MethodsWe used data from a national cross-sectional web-based survey of 3000 parents. The survey used a 5-point Likert scale to assess 8 measures of parent perceptions of residents and medical students. We included participants who indicated prior experience with residents or medical students. We compared responses about resident involvement in pediatric care with responses about student involvement, used LCA to identify latent classes of parent responses, and compared demographic features between the latent classes. ResultsOf the 3000 parents who completed the survey, 1543 met the inclusion criteria for our study. Participants reported higher mean scores for residents than for medical students for perceived quality of care, comfort with autonomously performing an examination, and comfort with autonomously giving medical advice. LCA identified 3 latent classes of parent responses: Trainee-Hesitant, Trainee-Neutral, and Trainee-Supportive. Compared with the Trainee-Supportive and Trainee-Neutral classes, the Trainee-Hesitant class had significantly more members reporting age

ObjectivePediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal infection (PANDAS) and Pediatric Acute-Onset Neuropsychiatric syndrome (PANS) are presumed autoimmune complications of infection or other instigating events. To determine the incidence of these disorders, we performed a retrospective review for the years 2017–2019 at three academic medical centers.MethodsWe identified the population of children receiving well-child care at each institution. Potential cases of PANS and PANDAS were identified by including children age 3–12 years at the time they received one of five new diagnoses: avoidant/restrictive food intake disorder, other specified eating disorder, separation anxiety disorder of childhood, obsessive-compulsive disorder, or other specified disorders involving an immune mechanism, not elsewhere classified. Tic disorders was not used as a diagnostic code to identify cases. Data were abstracted; cases were classified as PANDAS or PANS if standard definitions were met.ResultsThe combined study population consisted of 95,498 individuals. The majority were non-Hispanic Caucasian (85%), 48% were female and the mean age was 7.1 (SD 3.1) years. Of 357 potential cases, there were 13 actual cases [mean age was 6.0 (SD 1.8) years, 46% female and 100% non-Hispanic Caucasian]. The estimated annual incidence of PANDAS/PANS was 1/11,765 for children between 3 and 12 years with some variation between different geographic areas.ConclusionOur results indicate that PANDAS/PANS is a rare disorder with substantial heterogeneity across geography and time. A prospective investigation of the same question is warranted.

Abstract Background Inhibitors of poly(ADP‐ribose) polymerase (PARP) proteins potentiate antitumor activity of platinum chemotherapy. This study sought to determine the safety and tolerability of PARP inhibitor talazoparib with carboplatin and paclitaxel. Methods We conducted a phase I study of talazoparib with carboplatin AUC5‐6 and paclitaxel 80 mg/m2 days 1, 8, 15 of 21‐day cycles in patients with advanced solid tumors. Patients enrolled using a 3 + 3 design in two cohorts with talazoparib for 7 (schedule A) or 3 days (schedule B). After induction with 4–6 cycles of triplet therapy, patients received one of three maintenance options: (a) continuation of triplet (b) carboplatin/talazoparib, or (c) talazoparib monotherapy. Results Forty‐three patients were treated. The MTD for both schedules was talazoparib 250mcg daily. The main toxicity was myelosuppression including grade 3/4 hematologic treatment‐related adverse events (TRAEs). Dose modification occurred in 87% and 100% of patients for schedules A and B, respectively. Discontinuation due to TRAEs was 13% in schedule A and 10% in B. Ten out of 22 evaluable patients in schedule A and 5/16 patients in schedule B had a complete or partial response. Twelve out of 43 patients received ≥6 cycles of talazoparib after induction, with a 13‐month median duration of maintenance. Conclusion We have established the recommended phase II dose of Talazoparib at 250mcg on a 3‐ or 7‐day schedule with carboplatin AUC6 and paclitaxel 80 mg/m2 on days 1, 8, 15 of 21‐day cycles. This regimen is associated with significant myelosuppression, and in addition to maximizing supportive care, modification of the chemotherapy component would be a consideration for further development of this combination with the schedules investigated in this study.

The SARS-CoV-2 Delta Variant of Concern is highly transmissible and contains mutations that confer partial immune escape. The emergence of Delta in North America caused the first surge in COVID-19 cases after SARS-CoV-2 vaccines became widely available. To determine whether individuals infected despite vaccination might be capable of transmitting SARS-CoV-2, we compared RT-PCR cycle threshold (Ct) data from 20,431 test-positive anterior nasal swab specimens from fully vaccinated (n = 9,347) or unvaccinated (n = 11,084) individuals tested at a single commercial laboratory during the interval 28 June- 1 December 2021 when Delta variants were predominant. We observed no significant effect of vaccine status alone on Ct value, nor when controlling for vaccine product or sex. Testing a subset of low-Ct (

BackgroundDigital technology and media use is integral to adolescents’ lives and has been associated with both positive and negative health consequences. Previous studies have largely focused on understanding technology behaviors and outcomes within adolescent populations, which can promote assumptions about adolescent technology use as homogeneous. Furthermore, many studies on adolescent technology use have focused on risks and negative outcomes. To better understand adolescent digital technology use, we need new approaches that can assess distinct profiles within study populations and take a balanced approach to understanding the risks and benefits of digital technology use. ObjectiveThe purpose of this study was to identify profiles of adolescent technology use within a large study population focusing on four evidence-based constructs: technology ownership and use, parental involvement, health outcomes, and well-being indicators. MethodsAdolescent-parent dyads were recruited for a cross-sectional web-based survey using the Qualtrics (Qualtrics International, Inc) platform and panels. Technology use measures included ownership of devices, social media use frequency, and the Adolescents’ Digital Technology Interactions and Importance scale. Parent involvement measures included household media rules, technology-related parenting practices, parent social media use frequency, and the parent-child relationship. Health outcome measures included physical activity, sleep, problematic internet use, and mental health assessments. Well-being indicators included mental wellness, communication, and empathy. We used latent class analysis (LCA) to identify distinct profile groups across the aforementioned 4 critical constructs. ResultsAmong the 3981 adolescent-parent dyads recruited, adolescent participants had a mean age of 15.0 (SD 1.43) years; a total of 46.3% (1842/3981) were female, 67.8% (2701/3981) were White, and 75% (2986/3981) lived in a household with an income above the poverty line. The LCA identified 2 discrete classes. Class 1 was made up of 62.8% (2501/3981) of the participants. Class 1 participants were more likely than Class 2 participants to report family-owned devices, have lower technology importance scores, have household technology rules often centered on content, have positive parent relationships and lower parent social media use, and report better health outcomes and well-being indicators. ConclusionsFindings from this national cross-sectional survey using LCA led to 2 distinct profile groups of adolescent media use and their association with technology use and parent involvement as well as health and well-being outcomes. The two classes included a larger Class 1 (Family-Engaged Adolescents) and a smaller Class 2 (At-Risk Adolescents). The findings of this study can inform interventions to reinforce positive technology use and family support.

BackgroundDigital technology use is nearly ubiquitous among young adults; this use provides both benefits and risks. The risks of technology use include maladaptive technology use or technology addiction. Several conceptualizations of these addictions have emerged, each with its own assessment tools. These conditions include problematic internet use (PIU), internet gaming disorder (IGD), and social media addiction (SMA). These conditions have been associated with health outcomes such as problematic alcohol use, sleep disorders, and mental illness. These maladaptive technology conditions have been most commonly studied in isolation from each other. ObjectiveThe aim of this study is to examine PIU, IGD, and SMA together to better inform future research approaches and provider screening practices for young adults. MethodsThis cross-sectional survey study was conducted using Qualtrics panel-based recruitment and survey hosting. We recruited US young adults aged 18-25 years. The survey assessed PIU, IGD, and SMA. Survey measures also included assessments of problematic alcohol use, sleep, depression, and anxiety. We evaluated the frequency of and overlap in positive screening scores among PIU, IGD, and SMA and modeled each condition using multivariate logistic regression. Finally, we calculated sensitivity and specificity, as well as the positive predictive value and negative predictive value of the screening tools using the most prevalent maladaptive technology type. ResultsOur 6000 participants had an average age of 21.7 (SD 2.5) years. Of these 6000 participants, 3062 (51.03%) were female, 3431 (57.18%) were Caucasian, 1686 (28.1%) were in a 4-year college program, and 2319 (38.65%) worked full time. The mean PIU score was 3.5 (SD 3.1), and 53.58% (3215/6000) of participants met the criteria for PIU. The mean IGD score was 2.7 (SD 2.6), and 24.33% (1460/6000) of participants met the criteria for IGD. The mean SMA score was 7.5 (SD 5.7), and 3.42% (205/6000) met the criteria for SMA. Across all 3 maladaptive technology use diagnoses, there were varied associations with demographic variables and similar overlap with health outcomes. The sensitivity of PIU screening to detect IGD was 82% and to detect SMA was 93%, whereas the specificity and positive predictive value were much lower (37%-54% specificity; 6%-37% positive predictive value). ConclusionsThis cross-sectional survey screened a large national sample of adolescents and young adults for PIU, IGD, and SMA to determine prevalence and overlap, demographic associations with each, and associations between these technology-related conditions and health outcomes. There was overlap across PIU, IGD, and SMA in some associated demographic variables and health outcomes. However, the patterns in the associated variables demonstrated unique qualities of each of these conditions.

BackgroundThe COVID-19 pandemic has resulted in significant changes to adolescents’ daily lives and, potentially, to their mental health. The pandemic has also disproportionately affected historically marginalized and at-risk communities, including people of color, socioeconomically disadvantaged people, people identifying as female, and youth. ObjectiveThis study aimed to understand differences in depression and anxiety among 2 groups of adolescents in the United States before and during the COVID-19 pandemic, and to examine demographic and daily activity variables associated with depression and anxiety. MethodsOnline surveys were distributed in 2019 and 2020. Demographic questions were asked at the time of enrollment, and included participants’ age, gender, race and ethnicity, and socioeconomic status (SES). The 8-item Patient Health Questionnaire was used to assess symptoms of depression, and the 7-item Generalized Anxiety Disorder scale was used to assess symptoms of anxiety. A total of 4 pandemic-specific daily activity questions were asked only of the pandemic group. Analyses of covariance compared depression and anxiety between prepandemic and pandemic groups. Demographic and lifestyle variables were included as covariates. ResultsThe sample comprised a total of 234 adolescents, with 100 participants in the prepandemic group and 134 participants in the pandemic group. Within the pandemic group, 94% (n=126) of adolescents reported being out of school due to the pandemic, and another 85.8% (n=115) and 57.1% (n=76) were prevented from extracurricular activities and exercise, respectively. Higher depression was seen in the pandemic group, with a least-squares adjusted mean of 7.62 (SD 1.36) compared to 6.28 (SD 1.42) in the prepandemic group, although the difference was not significant (P=.08). There was no significant difference in anxiety scores between the 2 groups (least-squares adjusted means 5.52, SD 1.30 vs 5.01, SD 1.36; P=.48). Within the pandemic group, lower SES was predictive of anxiety, such that those in the pandemic group of lower SES were more anxious than their higher-SES peers (least-squares adjusted means 11.17, SD 2.34 vs 8.66, SD 2.16; P=.02). Within the pandemic group, being out of work or school and not partaking in extracurricular activities or exercise due to the pandemic were not associated with higher depression or anxiety scores. ConclusionsIn this study, neither being in the pandemic group nor experiencing changes in daily activity due to the pandemic was associated with higher depression or anxiety. However, we found that adolescents from lower SES backgrounds experienced significantly more anxiety during the pandemic than their more privileged peers. Both instrumental and mental health interventions for low-income adolescents are imperative.

Background: Public health policies in France and the USA promote health professionals’ collaborative practices in accordance with World Health Organization recommendations emphasizing the need to promote interprofessional education and training. To optimize alignment of health-care policy and education, a scientific evidence-based approach is required. Methods: A French translation (SPICE-R2F) of the Student Perceptions of Interprofessional Clinical Education—Revised instrument, version 2 (SPICE-R2) was generated. SPICE-R2F was then completed by a multicentric cohort of French health students, and confirmatory factor analysis was utilized to evaluate the validity and reliability of this instrument based on response patterns. Results: Translation of SPICE-R2 was validated evaluating psychometric properties and conducting a confirmatory factor analysis (CFA). Adequate model fit was demonstrated using RMSEA (root mean square error of approximation) and CFI (comparative fit index) model fit criteria. Within each factor, however, low to moderate levels of reliability were observed between items. These observations diverge from other countries and highlight a potential French singularity. Conclusion: Our results suggest the need to improve interprofessional clinical practice education in France at early stages in the health-care curricula. The SPICE-R2F instrument may represent a valuable evidence-based tool to characterize perceptions of interprofessional education and training of health-care students and professionals in France.

Infants exposed to Zika virus (ZIKV) prenatally may develop birth defects, developmental deficits, or remain asymptomatic. It is unclear why some infants are more affected than others, although enhancement of maternal ZIKV infection via immunity to an antigenically similar virus, dengue virus (DENV), may play a role. We hypothesized that DENV immunity may worsen prenatal ZIKV infection and developmental deficits in offspring. We utilized a translational macaque model to examine how maternal DENV immunity influences ZIKV-exposed infant macaque neurodevelopment in the first month of life. We inoculated eight macaques with prior DENV infection with ZIKV, five macaques with ZIKV, and four macaques with saline. DENV/ZIKV-exposed infants had significantly worse visual orientation skills than ZIKV-exposed infants whose mothers were DENV-naive, with no differences in motor, sensory or state control development. ZIKV infection characteristics and pregnancy outcomes did not individually differ between dams with and without DENV immunity, but when multiple factors were combined in a multivariate model, maternal DENV immunity combined with ZIKV infection characteristics and pregnancy parameters predicted select developmental outcomes. We demonstrate that maternal DENV immunity exacerbates visual orientation and tracking deficits in ZIKV-exposed infant macaques, suggesting that human studies should evaluate how maternal DENV immunity impacts long-term neurodevelopment.