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PURPOSE: To compare fertility outcomes of obese patients (body mass index [BMI] ≥ 30 kg/m2) undergoing superovulation and intrauterine insemination (SO-IUI) using gonadotropins versus letrozole. METHODS: A single centre retrospective cohort study of obese patients undergoing SO-IUI using gonadotropins or letrozole between January/2019 and June/2022. Primary outcome was clinical pregnancy rate (intrauterine pregnancy with positive fetal heart rate). Secondary outcomes included rates of multifollicular development, multiple pregnancy, spontaneous abortion and cycle cancellation. Subgroup analysis was done stratifying by obesity class. A multivariate logistic regression model was used for primary/secondary outcomes, adjusting for clinically determined covariates. RESULTS: Out of 802 total identified SO-IUI cycles, 715 cycles were completed (518-gonadotropins and 197-letrozole cycles). The clinical pregnancy rates were not significantly different in obese patients undergoing SO-IUI with gonadotropins versus letrozole when adjusted for age, gravidity, parity, cause of infertility, IUI cycle number, endometrial thickness, sperm source and post-wash motile sperm count (adjusted odds ratio [aOR] 1.37, 95% confidence interval [CI] 0.72-2.59). Similarly, no significant associations were found in spontaneous abortion (aOR1.46, 95%CI 0.42-5.08), multiple pregnancy (aOR1.33, 95%CI 0.20-8.88) or cancellation rates (OR0.89, 95%CI 0.55-1.45) between the two groups. The rates of multifollicular development were also comparable between the two groups (aOR0.51, 95% CI 0.19-1.38). For cycles involving gonadotropins, higher BMI classes required higher total gonadotropin dose (p < 0.001). CONCLUSION: After adjusting for patient and cycle factors, gonadotropins and letrozole led to comparable odds of achieving pregnancy in obese patients undergoing SO-IUI. Future research in the obese population will help to better understand how to optimize fertility treatments for this growing population.

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Vasa previa occurs when fetal vessels lie above the cervical os. A novel type of vasa previa, known as type III, is characterized by an abnormal branching of fetal vessels from the placenta in the absence of velamentous cord insertion (as seen in type I) or multilobed placenta (as seen in type II). Here, we present a case of a type III vasa previa after a resolution of a low-lying placenta. The presence of any known risk factors of vasa previa, including low-lying placenta, should prompt screening for vasa previa in the third trimester. Accurate and timely diagnosis of vasa previa will confer significant survival benefit for the neonate.

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Chimeric antigen receptor (CAR) T cell therapy is a medical breakthrough in the treatment of B cell malignancies. There is intensive focus on developing solid tumor-targeted CAR-T cell therapies. Although clinically approved CAR-T cell therapies target B cell lineage antigens, solid tumor targets include neoantigens and tumor-associated antigens (TAAs) with diverse roles in tumor biology. Multiple early-stage clinical trials now report encouraging signs of efficacy for CAR-T cell therapies that target solid tumors. We review the landscape of solid tumor target antigens from the perspective of cancer biology and gene regulation, together with emerging clinical data for CAR-T cells targeting these antigens. We then discuss emerging synthetic biology strategies and their application in the clinical development of novel cellular immunotherapies.

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Chimeric antigen receptor (CAR) T cell therapies are medical breakthroughs in cancer treatment. However, treatment failure is often caused by CAR T cell dysfunction. Additional approaches are needed to overcome inhibitory signals that limit anti-tumor potency. Here, we developed bifunctional fusion "degrader" proteins that bridge one or more target proteins and an E3 ligase complex to enforce target ubiquitination and degradation. Conditional degradation strategies were developed using inducible degrader transgene expression or small molecule-dependent E3 recruitment. We further engineered degraders to block SMAD-dependent TGFß signaling using a domain from the SARA protein to target both SMAD2 and SMAD3. SMAD degrader CAR T cells were less susceptible to suppression by TGFß and demonstrated enhanced anti-tumor potency in vivo. These results demonstrate a clinically suitable synthetic biology platform to reprogram E3 ligase target specificity for conditional, multi-specific endogenous protein degradation, with promising applications including enhancing the potency of CAR T cell therapy.

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Though differences in informant perceptions of family processes are associated with poorer health, few studies have examined discrepancies between father- and adolescent-report of family phenomena and their impact on adolescent mental health. This study examined how father and adolescent-reported parenting and the differences in their perceptions is related to adolescent mental health. Participants were 326 father-adolescent dyads (Fathers: Mage = 41.2; Adolescents: 7th grade students, Mage = 12.0, 48.5% female). Overall, analyses revealed significant main effects of father and/or adolescent report of father-adolescent conflict and harsh parenting on adolescent internalizing and externalizing symptoms. Analyses revealed two instances in which discrepancies between father- and adolescent-report of family phenomena was related to adolescent mental health. Given the mixed nature of the findings based on the outcome reporter, the current study discusses implications for discrepancy research and future directions to better understand discrepant perceptions as useful information on their own. The parent clinical trial is registered at ClinicalTrials.gov (Identifier: NCT03125291, Registration date: 4/13/2017).

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OBJECTIVE: This observational study characterizes youth and caregiver behaviors that may pose challenges to engagement within a system-driven implementation of multiple evidence-based practices (EBPs). We examined links between Engagement Challenges and therapist EBP implementation outcomes. METHOD: Community therapists (N = 102) provided audio recordings of EBP sessions (N = 666) for youth (N = 267; 71.54%, Latinx; 51.69%, female; Mage = 9.85, Range: 1-18). Observers rated the extent to which youth and/or caregivers engaged in the following behaviors: Caregiver and/or Youth Expressed Concerns about interventions, and Youth Disruptive Behaviors. Multilevel modeling was used to identify predictors of observable Engagement Challenges, and examine associations between Engagement Challenges, and therapist-reported ability to deliver planned activities, and observer-rated extensiveness of EBP strategy delivery. RESULTS: At least one Engagement Challenge was observed in 43.99% of sessions. Youth Engagement Challenges were not associated with outcomes. Caregiver Expressed Concerns were negatively associated with therapist-reported ability to carry out planned session activities (B = -.21, 95% CI[-.39-(-.02)], p < .05). However, Caregiver Expressed Concerns were positively associated with extensiveness of EBP Content strategy delivery (B = .08, 95% CI[.01-.15], p < .05). CONCLUSIONS: Results suggest that Youth Engagement Challenges have little observed impact on EBP delivery. In contrast, although therapists perceive that Caregiver Expressed Concerns derail their planned activities, Caregiver Expressed Concerns are associated with more extensive delivery of content about therapeutic interventions. Community therapists' implementation of EBPs appear unaffected by common youth in-session behavioral challenges, but future research is needed to clarify whether caregivers' concerns about interventions prompt, or are prompted by, more intensive therapist EBP content instruction.

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Septins in endothelial cells (ECs) have important roles supporting the integrity of the endothelial monolayer. Cell-cell junctions in EC monolayers are highly dynamic, with continuous retractions and protrusions. Depletion of septins in ECs leads to disruption of cell-cell junctions, which are composed of VE-cadherin and other junctional proteins. In EC monolayers, septins are concentrated at the plasma membrane at sites of cell-cell contact, in curved- and scallop-shaped patterns. These membrane-associated septin accumulations are located in regions of positive membrane curvature, and those regions are often associated with and immediately adjacent to actin-rich protrusions with negative membrane curvature. EC septins associate directly with plasma membrane lipids, based on findings with site-specific mutations of septins in ECs, which is consistent with biochemical and cell biological studies in other systems. Loss of septins leads to disruption of the EC monolayer, and gaps form between cells. The number and breadth of cell-cell contacts and junctions decreases, and the number and frequency of retractions, ruffles, and protrusions at cell edges also decreases. In addition, loss of septins leads to decreased amounts of F-actin at the cortical membrane, along with increased amounts of F-actin in stress fibers of the cytoplasm. Endothelial monolayer disruption from loss of septins is also associated with decreased transendothelial electric resistance (TEER) and increased levels of transendothelial migration (TEM) by immune and cancer cells, owing to the gaps in the monolayer. A current working model is that assembly of septin filaments at regions of positive membrane curvature contributes to a mechanical footing or base for actin-based protrusive forces generated at adjoining regions of the membrane. Specific molecular interactions between the septin and actin components of the cytoskeleton may also be important contributors. Regulators of actin assembly may promote and support the assembly of septin filaments at the membrane, as part of a molecular feedback loop between the assembly of septin and actin filaments.

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The current study aimed to assess the measurement equivalence and functional equivalence of the UPPS (Urgency, Premeditation, Perseverance, Sensation Seeking) Impulsivity Scale among three ethnoracial adolescent samples in the U.S. seventh-grade students who self-identified as Hispanic (n = 472), non-Hispanic Black (n = 89), or non-Hispanic White (n = 90), and completed an English-language version of the Child version of the UPPS, which was shortened and modified to include positive urgency items. Through a series of confirmatory factor analyses, the UPPS demonstrated configural, metric, and partial threshold invariance. Fisher's r-to-z transformations were used to assess the functional equivalence of the UPPS against well-validated measures of self-regulation and mental health commonly associated with impulsivity. We found some group differences in the magnitude of associations. Yet, overall, this study provides evidence that the UPPS can be used to measure distinct factors of impulsivity among Hispanic, non-Hispanic Black, and non-Hispanic White adolescents.

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Prevention programs are a key method to reduce the prevalence and impact of mental health disorders in childhood and adolescence. Caregiver participation engagement (CPE), which includes caregiver participation in sessions as well as follow-through with homework plans, is theorized to be an important component in the effectiveness of these programs. This systematic review aims to (1) describe the terms used to operationalize CPE and the measurement of CPE in prevention programs, (2) identify factors associated with CPE, (3) examine associations between CPE and outcomes, and (4) explore the effects of strategies used to enhance CPE. Thirty-nine articles representing 27 unique projects were reviewed. Articles were included if they examined CPE in a program that focused to some extent on preventing child mental health disorders. There was heterogeneity in both the terms used to describe CPE and the measurement of CPE. The majority of projects focused on assessment of caregiver home practice. There were no clear findings regarding determinants of CPE. With regard to the impact of CPE on program outcomes, higher levels of CPE predicted greater improvements in child and caregiver outcomes, as well as caregiver-child relationship quality. Finally, a small number of studies found that motivational and behavioral strategies (e.g., reinforcement, appointment reminders) were successful in promoting CPE. This review highlights the importance of considering CPE when developing, testing, and implementing prevention programs for child mental health disorders. Increased uniformity is needed in the measurement of CPE to facilitate a better understanding of determinants of CPE. In addition, the field would benefit from further evaluating strategies to increase CPE as a method of increasing the potency of prevention programs.

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OBJECTIVE: Community therapists inevitably adapt evidence-based practices (EBPs) to meet the needs of their clients and practice settings. Yet, the implications of spontaneous, therapist-driven adaptations for EBP implementation outcomes are not well understood. We used a sequential QUAN → qual mixed-methods design to examine how different types of therapist-described adaptations were associated with observer-rated extensiveness of therapist delivery of EBP content and technique strategies at the session level. METHOD: Data were drawn from an observational study of a system-driven implementation of multiple EBPs into public children's mental health services. Community therapists (n = 103) described adaptations they made in 680 sessions with 273 clients (50.92% female, 49.08% male, Mage = 9.72 years, 70.70% Hispanic/Latinx). Coders classified therapist-described adaptations into five types: (a) Modifying Presentation, (b) Integrating, (c) Extending, (d) Reducing, and (e) Generalizing. Independent observers rated the extensiveness of EBP strategy delivery from session recordings using the EBP Concordant Care Assessment (ECCA) Observational Coding System. RESULTS: Quantitative analyses using multilevel regression revealed that Modifying Presentation adaptations were associated with higher extensiveness of EBP technique delivery, whereas Extending adaptations were associated with lower extensiveness of EBP content and technique delivery. Qualitative analysis of adaptation descriptions identified explanations for the quantitative findings. CONCLUSIONS: Findings suggest that Modifying Presentation adaptations, associated with higher extensiveness, involved creative use of activities and materials, language modification, and personalization of EBP content to meet clients' diverse needs, whereas Extending adaptations, associated with lower extensiveness, involved slowing EBP pacing in response to client challenges. Implications for provider training are discussed. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

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Initiatives to scale up evidence-based practices (EBPs) in routine care are likely to have myriad impacts on community providers, but these impacts have not yet been examined in depth. This is especially true within the context of simultaneous implementation of multiple evidence-based practices. The aim of this study was to characterize the multifaceted impacts on community mental health therapists within a system-driven implementation of multiple EBPs for youth and families. Semistructured interview and survey data were gathered from 60 therapists at 11 agencies contracted with the Los Angeles County Department of Mental Health to deliver EBPs within the Prevention and Early Intervention initiative. Therapists' accounts of impacts varied, and were either predominately negative, predominantly positive, or mixed-valence. Mixed-methods analyses using Kruskal-Wallis tests showed therapist valence groups varied on mean levels of self-reported burnout on surveys. Themes from qualitative data revealed several favorable (e.g., increased EBP knowledge, structure) and unfavorable (e.g., distress, feeling constrained by EBPs) impacts of county-contracted EBP implementation. These findings inform the development and implementation of future system-driven EBP initiatives that consider therapist perspective to optimize positive impacts and minimize negative impacts on therapists.

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Mindful parenting is linked to positive youth emotion regulation, mental health, and parent-child relationship quality. We examined bidirectional relations between adolescent mental health and mindful parenting among a diverse sample of 249 7th grade students and their female (N = 232) and male caregivers (N = 120). We conducted multiple-group cross-lagged models (grouped by adolescent sex). Female adolescents' externalizing symptoms predicted decreased female caregiver mindful parenting six months later, but male and female adolescent externalizing behaviors were negatively associated with male caregivers' mindful parenting one year later. Findings suggest mindful parenting capacities are vulnerable to disruption via adolescent problem behavior. Mindful parenting's potential benefits, caveats, and need to support parent efforts to sustain mindful parenting amidst adolescents' externalizing behaviors are discussed.

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Background: Evidence-based intervention (EBI) effectiveness is hindered by low rates of caregiver home practice, or caregiver rehearsal of intervention skills at home. Although home practice is essential to intervention success, we know little about what makes home practice difficult to complete. We sought to identify the challenges caregivers face when attempting home practice assignments within the context of community implementation of a family-based preventative EBI. We also aimed to identify barriers, perceived need, and implementation-related factors that may contribute to frequency of home practice challenges. Methods: The family-based preventative intervention Bridges was delivered to caregivers and adolescents in three public middle schools in North America within a randomized efficacy-effectiveness hybrid trial. Caregivers (N = 233) completed worksheets in which they reported challenges to home practice of intervention skills. Caregiver-endorsed challenges were coded for emergent themes and categorized into higher-order home practice challenge domains. Additional data was gathered through multiple methods. In addition to descriptive analyses, multilevel linear regressions were conducted to identify factors associated with frequency of home practice challenge domains. Results: Over 85% of caregivers reported one or more home practice challenges. Challenges fell into six domains: daily stresses, cognitions/beliefs about the intervention/practice, caregiver wellness/regulation, adolescent responsiveness, relevance/acceptability of intervention or assignment, and external barriers to practice. Adolescent externalizing symptoms, academic performance, and caregiver participation in the English-language intervention group (compared to Spanish-language delivery) were associated with greater frequency of reported challenges. Conclusions: Among caregivers already attending intervention sessions, specific support to overcome challenges in daily stresses and beliefs about the intervention/practice can support greater home practice compliance, which in turn may impact overall intervention effectiveness. Findings suggest that providing services in caregivers' preferred language may avert potential challenges. Further research into home practice challenges is necessary to identify appropriate home practice implementation supports. Plain Language Summary: Low rates and poor quality of caregiver home practice of intervention skills hampers intervention effectiveness, but no prior studies have identified the difficulties caregivers face when attempting home practice of intervention skills and their rates of occurrence. Within a community implementation of a family-based preventative intervention, we found that difficulties were common and largely fell in the domains theorized to impact engagement, such as daily stresses and beliefs about the intervention/practice. Findings also suggest that providing services and materials in caregivers' preferred language may avert potential home practice challenges. By identifying common home practice challenges and correlates of different challenges, our findings point to a need to develop appropriate and effective home practice implementation support.

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OBJECTIVE: Septin 2 is localized at junctions in human microvascular endothelial monolayers. The junctional localization of septin 2 is necessary for organization of cell-cell adhesion proteins of endothelial cells. Approach and Results: Septin 2 was depleted at junctions by suppression of expression using shRNA, treatment with inflammatory cytokine, TNF (tumor necrosis factor)-α, and ectopic overexpression of septin 2 phosphatidylinositol 4,5-bisphosphate binding mutant defect in interaction with plasma membrane. Under those conditions, organizations and expression levels of various junctional proteins were analyzed. Confocal images of immunofluorescence staining showed substantial disorganization of adherens junctional proteins, nectin-2 and afadin, TJP (tight junction protein), ZO (zonula occludens)-1, and intercellular adhesion protein, PECAM-1 (platelet-endothelial cell adhesion molecule-1). Immunoblots for those proteins did not show significant changes in expression except for nectin-2 that highly increased in expression. Significant differential gene expression profiles and biological pathway analysis by septin 2 suppression and by TNF-α treatment using RNA-seq showed common overlapping pathways. The commonalities in expression may be consistent with the similar effects on the overall organization of cell-cell adhesion proteins. CONCLUSIONS: Localization of septin 2 at cell junctions are required for the arrangement of junctional proteins and the integrity of the barrier formed by endothelial monolayers.

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The current study examined adolescent psychological reactivity to daily family experiences, an important feature of emotion regulation that could have significant implications for psychopathology. A total of 428 Mexican-heritage adolescents (Mage  = 15.02 years, range: 13-18 years) completed daily diary checklists for 14 days and again 1 year later. Results revealed that adolescents' family experiences were associated with negative mood, positive mood, and role fulfillment on a daily basis. Only role fulfillment reactivity was stable across 1 year, suggesting instability in individual differences in positive and negative mood reactivity. Sex moderated the relation between positive and negative mood reactivity during the second year of study, with males exhibiting broad psychological reactivity to daily family experiences. However, females who experienced higher negative mood reactivity exhibited less positive mood reactivity. Implications for possible sex differences in depression risk during the high school years are discussed.

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BACKGROUND: Operating room (OR) costs are a large portion of healthcare expenses. This study evaluates the impact of a surgeon-targeted surgical receipt cost feedback system on OR supply costs in sinonasal surgery and individual components contributing to procedural cost. METHODS: Itemized weekly surgical receipts detailing individual case supply costs were analyzed before and after the implementation of a non-incentivized surgeon cost feedback system between January 2017 and June 2019. Supply cost data collected 15 months prior to intervention was compared to cost data 15 months after implementation of the weekly automated receipt dissemination to surgeons. Chi square test was used for categorical data and the Wilcoxon test was used to compare change in cost. Univariate and mediation analyses were performed to assess variables impacting cost. RESULTS: Of 502 sinonasal procedures analyzed, 239 were before and 264 after cost feedback implementation. There were no significant differences in age/gender, or indication for surgery. The median OR supply cost decreased from $1229.64 to $1097.22 (p = 0.02) after receipt implementation. There were effects of procedure type (p = 0.02), circulating nurse specialization (p < 0.001), steroid eluting stent (p = 0.002), and sinus drill (p < 0.001) on cost. Mediation analysis confirmed full mediation by decreasing use of steroid-eluting stents. CONCLUSION: Surgeon cost feedback in the form of individualized OR surgical receipts is an effective model to reduce supply cost per case in sinonasal surgery.

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The study sought to (a) characterize the types and frequency of session-level adaptations made to multiple evidence-based practices (EBPs) and (b) identify therapist-, client-, and session-level predictors of adaptations. Within the community implementation of multiple EBPs, 103 community mental health therapists reported on 731 therapy sessions for 280 clients. Therapists indicated whether they adapted EBPs in specific sessions and described adaptations in open-ended responses. Responses were coded using the Augmenting and Reducing adaptations framework. Therapists reported making adaptations in 59% of sessions. Augmenting adaptations were reported more frequently than Reducing adaptations. Multilevel logistic regression analyses revealed that greater therapist openness to EBPs, younger child age, and presenting problems was associated with Augmenting adaptations. Child presenting problem of externalizing problems predicted fewer Reducing adaptations compared with internalizing problems. This study extends the growing research examining adaptations within the context of the system-driven implementation of multiple EBPs by applying the Augmenting and Reducing adaptation framework to the session-level.

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Patient-centered care includes efforts to align treatment with patient preferences to improve outcomes and has not been studied in adolescent depression prevention. Within a school-based randomized trial, we examined the effects of offering a preference between two evidence-based preventive interventions for youth at risk of depression, Learning to BREATHE (L2B) and Interpersonal Therapy-Adolescent Skills Training. We examined the effects of 3 preference factors (assignment condition [preference vs. random], receipt of preferred program, and baseline program preference) on outcomes in a diverse sample of 111 adolescents (M age = 15.18 years, SD = .86): 81 (73%) girls, 45 (41%) White, 40 (36%) Asian American, 8 (7%) Latinx, 1 (1%) African American, and 17 (15%) multiracial or other race/ethnicity. Findings revealed little evidence that receiving a preferred intervention or being given a choice of interventions was linked to greater improvement or initial engagement. Further, analyses did not indicate that adolescents with baseline indications for a specific intervention would benefit more from that intervention; rather, adolescents with generally lower baseline functioning improved more regardless of the intervention received. However, receipt of L2B and a baseline preference for L2B were associated with greater improvements in about half of the outcomes examined, with effect sizes ranging from R 2 = 0.04 to 0.14. There was little support for the need to match interventions to adolescent preferences in school-based prevention efforts. Rather, the more scalable mindfulness-based intervention had stronger effects than the interpersonal intervention and may hold promise for diverse adolescents.

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Research on the health benefits and consequences of close relationships has suggested the linkage in daily emotions (i.e., coregulation) between close partners is an important relationship dynamic. While the coupling of daily emotions among family members (parent-child and marital dyads) has been widely documented, research examining emotional coregulation among ethnic minority youth during adolescence, a period marked by heightened emotion and risk for psychopathology, remains an important area in need of exploration. This study examined correlates of emotional coregulation in a sample of Mexican-origin adolescents (Mage = 15.02, SD = .83) and their parents (Mage = 41.93, SD = 6.70). Dyads reported on daily levels of distress and happiness for 14 consecutive days across two waves of data collection a year apart (nwave1 = 428 dyads, nwave2 = 336 dyads). Dyads who reported getting along were more likely to coregulate their daily happiness. Importantly, coregulation of distress was only present in older adolescents who reported above average levels of internalizing symptoms. The results suggest coregulation of distress may shape or be shaped by poor mental health during the later years of adolescence, a time when youth may be establishing a degree of emotional autonomy from parents.

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The study examined the efficacy of a school-based mindfulness intervention on mental health and emotion regulation outcomes among adolescents in a wait-list controlled trial. The study also explored mediators and moderators of intervention effects. A total of 145 predominantly ethnic minority (Asian and Latino) 9th grade students with elevated mood symptoms were randomized to receive a 12-week mindfulness intervention at the start of the academic year, or in the second semester of the year. Students completed measures of emotion regulation and mental health symptoms at baseline, post-intervention, and 3-month follow-up. Intent-to-treat analyses revealed significant treatment effects of the mindfulness intervention for internalizing symptoms and perceived stress at post-treatment. Pooled pre-to-post treatment analyses of the entire sample revealed a small effect size for attention problems, medium for internalizing and externalizing problems, and large for perceived stress. We also found a small effect size for cognitive reappraisal, medium for expressive suppression, emotional processing, emotional expression, and rumination and large for avoidance fusion. Mediation analyses showed that treatment effects on internalizing symptoms and perceived stress were mediated by reductions in expressive suppression and rumination. Moderation analyses revealed that treatment effects were larger among youth with more severe problems at baseline for internalizing problems, externalizing problems, and perceived stress. However, for attention problems, students with lower severity at baseline appeared to have larger treatment gains. The study provided evidence that mindfulness intervention was beneficial for low-income ethnic minority youth in reducing perceived stress and internalizing problems, and improving emotion regulation outcomes. Furthermore, mindfulness training was associated with reduced mental health symptoms via improvements in emotion regulation.

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