Feasibility study of a telehealth school-based behavioral parent training group program for attention-deficit/hyperactivity disorder.

OBJECTIVE: To evaluate the feasibility and preliminary efficacy of Telehealth Behavioral Parent Training (T-BPT), a school telehealth group intervention for attention-deficit/hyperactivity disorder (ADHD) with a companion training program for school clinicians. METHODS: T-BPT was developed in an iterative three-phase design in partnership with community stakeholders during the COVID-19 pandemic. School clinicians (N = 4) delivered T-BPT over 8 weeks to parents (N = 21, groups of 5-6 per school) of children (Grades 2-5) with ADHD while simultaneously receiving training and consultation from PhD-level study trainers. A single-arm open trial was used to assess feasibility, engagement, and preliminary efficacy. RESULTS: Parents and school clinicians endorsed high feasibility, acceptability, and usability of T-BPT. Parent attendance was high (M = 94.6%) and a majority of parents (66.7%) attended all eight sessions. Preliminary outcomes indicate moderate to large reductions in parent-reported ADHD symptoms (ω2 = .36), functional and clinical global impairment (ω2s= .21 and .19, respectively), and distance learning challenges (ω2 = .22). CONCLUSIONS: Results were in line with in-person delivery, indicating promising feasibility of school telehealth BPT groups. This study also provided further support for the feasibility of the remote training model for school clinicians. Implications of the commonly endorsed barriers and benefits beyond COVID-19 and relevance to under resourced communities are also discussed.

Emotion Regulation and Organizational Skills in Children With ADHD Symptoms Are Associated With Behavioral Parent Training Adherence.

OBJECTIVE: Behavioral parent training (BPT) is a well-established treatment for ADHD; however, treatment response is variable. Consistency in parent skill use during BPT is known to influence child outcomes post-treatment, while less research has focused on specific child factors that may be impacting parent skill utilization during treatment. The current study examined associations between child organizational skills and emotion dysregulation (ED) with parent treatment adherence during BPT and post-treatment child impairment. METHOD: Parents of 72 children (Mage = 8.31) with ADHD symptoms and impairment participated in BPT which was embedded in a 12-week, multicomponent, school-based intervention for children delivered by school mental health clinicians. Outcomes included parent treatment adherence and child improvements in global impairment post-treatment. RESULTS: Greater pre-treatment child organizational problems were associated with less parent treatment adherence regardless of ADHD symptom severity. Worse pre-treatment child ED was associated with more impairment post-treatment regardless of ADHD symptom severity whereas the effects of child ED on parent treatment adherence were moderated by child ADHD symptom severity. CONCLUSION: The current study suggests that pre-treatment child ED and organizational difficulties impact parent treatment adherence to behavioral interventions targeting ADHD symptoms, potentially in unique ways, and should be considered in future BPT treatment studies.

Parental Cognitions, Treatment Engagement, and Child Outcomes of ADHD Behavioral Treatment among Asian American Families.

Asian American (AA) families remain critically underrepresented in clinical trials for ADHD interventions. Little is known about AA families' engagement in and outcomes of behavioral treatment (BT). Comparing AA families to other minoritized (OM) families and White families, this study examined parental cognitions, treatment engagement, and child outcomes of BT for ADHD inattentive type (ADHD-I). Path analyses were conducted utilizing data from a randomized controlled trial of BT for ADHD-I (N = 199 children, ages 7-11). Racial/ethnic differences in pretreatment parental self-competence and treatment expectations were examined for AA (n = 29) compared to OM (n = 35) and White (n = 135) parents. Two additional path models were conducted to examine the relations among race/ethnicity, pretreatment parental cognitions, treatment engagement, and posttreatment child outcomes. Direct effects of race/ethnicity and parental cognitions on posttreatment child outcomes as well as their indirect effects via treatment engagement were estimated. At pretreatment, AA parents endorsed lower parental self-competence and treatment expectations compared to OM and White parents. At posttreatment, AA parents reported fewer improvements in ADHD symptoms than White parents and lower global psychosocial improvement than OM parents. For all parents, treatment expectations positively predicted parent- and observer-rated treatment engagement, which in turn predicted child global psychosocial improvement. Path analyses indicated that the relationship between treatment expectations and posttreatment child global improvement was fully mediated by treatment engagement. These findings suggest that treatment expectations impede AA parents' engagement and success in BT. Implications for cultural adaptations of BT to improve AA families' treatment experience are discussed.

Sensitivity of Medicaid Claims Data for Identifying Opioid Use Disorder in Patients Admitted to 6 New York City Public Hospitals.

OBJECTIVES: Behavioral health diagnoses are frequently underreported in administrative health data. For a pragmatic trial of a hospital addiction consult program, we sought to determine the sensitivity of Medicaid claims data for identifying patients with opioid use disorder (OUD). METHODS: A structured review of electronic health record (EHR) data was conducted to identify patients with OUD in 6 New York City public hospitals. Cases selected for review were adults admitted to medical/surgical inpatient units who received methadone or sublingual buprenorphine in the hospital. For cases with OUD based on EHR review, we searched for the hospitalization in Medicaid claims data and examined International Classification of Diseases, Tenth Revision discharge diagnosis codes to identify opioid diagnoses (OUD, opioid poisoning, or opioid-related adverse events). Sensitivity of Medicaid claims data for capturing OUD hospitalizations was calculated using EHR review findings as the reference standard measure. RESULTS: Among 552 cases with OUD based on EHR review, 465 (84.2%) were found in the Medicaid claims data, of which 418 (89.9%) had an opioid discharge diagnosis. Opioid diagnoses were the primary diagnosis in 49 cases (11.7%), whereas in the remainder, they were secondary diagnoses. CONCLUSION: In this sample of hospitalized patients receiving OUD medications, Medicaid claims seem to have good sensitivity for capturing opioid diagnoses. Although the sensitivity of claims data may vary, it can potentially be a valuable source of information about OUD patients.

The role of feedback and modulation in determining temperature resiliency in the lobster cardiac nervous system.

Changes in ambient temperature affect all biological processes. However, these effects are process specific and often vary non-linearly. It is thus a non-trivial problem for neuronal circuits to maintain coordinated, functional output across a range of temperatures. The cardiac nervous systems in two species of decapod crustaceans, Homarus americanus and Cancer borealis, can maintain function across a wide but physiologically relevant temperature range. However, the processes that underlie temperature resilience in neuronal circuits and muscle systems are not fully understood. Here, we demonstrate that the non-isolated cardiac nervous system (i.e., the whole heart: neurons, effector organs, intrinsic feedback systems) in the American lobster, H. americanus, is more sensitive to warm temperatures than the isolated cardiac ganglion (CG) that controls the heartbeat. This was surprising as modulatory processes known to stabilize the output from the CG are absent when the ganglion is isolated. One source of inhibitory feedback in the intact cardiac neuromuscular system is nitric oxide (NO), which is released in response to heart contractions. We hypothesized that the greater temperature tolerance observed in the isolated CG is due to the absence of NO feedback. Here, we demonstrate that applying an NO donor to the isolated CG reduces its temperature tolerance. Similarly, we show that the NO synthase inhibitor L-nitroarginine (LNA) increases the temperature tolerance of the non-isolated nervous system. This is sufficient to explain differences in temperature tolerance between the isolated CG and the whole heart. However, in an intact lobster, the heart and CG are modulated by an array of endogenous peptides and hormones, many of which are positive regulators of the heartbeat. Many studies have demonstrated that excitatory modulators increase temperature resilience. However, this neuromuscular system is regulated by both excitatory and inhibitory peptide modulators. Perfusing SGRNFLRFamide, a FLRFamide-like peptide, through the heart increases the non-isolated nervous system's tolerance to high temperatures. In contrast, perfusing myosuppressin, a peptide that negatively regulates the heartbeat frequency, decreases the temperature tolerance. Our data suggest that, in this nervous system, positive regulators of neural output increase temperature tolerance of the neuromuscular system, while modulators that decrease neural output decrease temperature tolerance.

Identifying xenobiotic metabolites with in silico prediction tools and LCMS suspect screening analysis.

Understanding the metabolic fate of a xenobiotic substance can help inform its potential health risks and allow for the identification of signature metabolites associated with exposure. The need to characterize metabolites of poorly studied or novel substances has shifted exposure studies towards non-targeted analysis (NTA), which often aims to profile many compounds within a sample using high-resolution liquid-chromatography mass-spectrometry (LCMS). Here we evaluate the suitability of suspect screening analysis (SSA) liquid-chromatography mass-spectrometry to inform xenobiotic chemical metabolism. Given a lack of knowledge of true metabolites for most chemicals, predictive tools were used to generate potential metabolites as suspect screening lists to guide the identification of selected xenobiotic substances and their associated metabolites. Thirty-three substances were selected to represent a diverse array of pharmaceutical, agrochemical, and industrial chemicals from Environmental Protection Agency's ToxCast chemical library. The compounds were incubated in a metabolically-active in vitro assay using primary hepatocytes and the resulting supernatant and lysate fractions were analyzed with high-resolution LCMS. Metabolites were simulated for each compound structure using software and then combined to serve as the suspect screening list. The exact masses of the predicted metabolites were then used to select LCMS features for fragmentation via tandem mass spectrometry (MS/MS). Of the starting chemicals, 12 were measured in at least one sample in either positive or negative ion mode and a subset of these were used to develop the analysis workflow. We implemented a screening level workflow for background subtraction and the incorporation of time-varying kinetics into the identification of likely metabolites. We used haloperidol as a case study to perform an in-depth analysis, which resulted in identifying five known metabolites and five molecular features that represent potential novel metabolites, two of which were assigned discrete structures based on in silico predictions. This workflow was applied to five additional test chemicals, and 15 molecular features were selected as either reported metabolites, predicted metabolites, or potential metabolites without a structural assignment. This study demonstrates that in some-but not all-cases, suspect screening analysis methods provide a means to rapidly identify and characterize metabolites of xenobiotic chemicals.

Patterns of Childhood Adversity among Women with and without Childhood ADHD: Links to Adult Psychopathology and Global Functioning.

We examine the outcomes associated with childhood adversity for women with and without carefully diagnosed childhood ADHD, via an ethnically diverse sample of 140 participants with ADHD (Mage = 9.7) and 88 age- and ethnicity-matched comparisons (Mage = 9.4). At adult follow-up, we retained 211 of the original 228 participants (92.6%; Mage = 25.6). We used latent class analysis to identify patterns of childhood adversity and examine their association with adult global functioning and psychopathology. Key findings: (1) Four childhood adversity classes emerged (Low Exposure, Familial Dysfunction, Emotional Maltreatment, Pervasive Exposure); (2) Childhood ADHD predicted membership in the Emotional Maltreatment class; and (3) Childhood adversity classes were differently associated with adult outcomes, such that membership in both the Emotional Maltreatment and Pervasive Exposure classes predicted significantly higher internalizing and externalizing symptoms as well as significantly lower global functioning than women in the Low Exposure class. Furthermore, compared to the Emotional Maltreatment class, the Familial Dysfunction class had lower externalizing symptoms, whereas the Pervasive Exposure class had lower global functioning and higher internalizing symptoms by adulthood. Findings provide information about girls and women who could be targeted for intervention in terms of ADHD behavior patterns plus adverse experiences in childhood. Beyond limitations, we discuss the need to investigate the confluence of neurodevelopmental conditions and adverse child events with respect to maladaptive outcomes.

Improving Adherence to Behavioral Parent Training for ADHD Using Digital Health Tools.

Behavioral Parent Training (BPT) is a well-established treatment for school-age children with ADHD but lack of parent adherence to prescribed parenting strategies limits treatment gains. Digital Health (dHealth) tools can be leveraged to target barriers to parent adherence but existing tools for parenting interventions are limited. New efforts to develop a dHealth tool to target adherence barriers including limited skill competence, EF processes, and low motivation/negative attitudes, are presented and recommendations for future technology-enhanced treatments are provided.

Dual loss of regulator of G protein signaling 2 and 5 exacerbates ventricular myocyte arrhythmias and disrupts the fine-tuning of Gi/o signaling.

AIMS: Cardiac contractility, essential to maintaining proper cardiac output and circulation, is regulated by G protein-coupled receptor (GPCR) signaling. Previously, the absence of regulator of G protein signaling (RGS) 2 and 5, separately, was shown to cause G protein dysregulation, contributing to modest blood pressure elevation and exaggerated cardiac hypertrophic response to pressure-overload. Whether RGS2 and 5 redundantly control G protein signaling to maintain cardiovascular homeostasis is unknown. Here we examined how the dual absence of RGS2 and 5 (Rgs2/5 dbKO) affects blood pressure and cardiac structure and function. METHODS AND RESULTS: We found that Rgs2/5 dbKO mice showed left ventricular dilatation at baseline by echocardiography. Cardiac contractile response to dobutamine stress test was sex-dependently reduced in male Rgs2/5 dbKO relative to WT mice. When subjected to surgery-induced stress, male Rgs2/5 dbKO mice had 75% mortality within 72-96 h after surgery, accompanied by elevated baseline blood pressure and decreased cardiac contractile function. At the cellular level, cardiomyocytes (CM) from Rgs2/5 dbKO mice showed augmented Ca2+ transients and increased incidence of arrhythmia without augmented contractile response to electrical field stimulation (EFS) and activation of ß-adrenergic receptors (ßAR) with isoproterenol. Dual loss of Rgs2 and 5 suppressed forskolin-induced cAMP production, which was restored by Gi/o inactivation with pertussis toxin that also reduced arrhythmogenesis during EFS or ßAR stimulation. Cardiomyocyte NCX and PMCA mRNA expression was unaffected in Rgs2/5 dbKO male mice. However, there was an exaggerated elevation of EFS-induced cytoplasmic Ca2+ in the presence of SERCA blockade with thapsigargin. CONCLUSIONS: We conclude that RGS2 and 5 promote normal ventricular rhythm by coordinating their regulatory activity towards Gi/o signaling and facilitating cardiomyocyte calcium handling.

Review: Adult Outcome as Seen Through Controlled Prospective Follow-up Studies of Children With Attention-Deficit/Hyperactivity Disorder Followed Into Adulthood.

OBJECTIVE: To describe adult outcome of people with attention-deficit/hyperactivity disorder (ADHD) diagnosed in childhood and its several key predictors via a review of 7 North American controlled prospective follow-up studies: Montreal, New York, Milwaukee, Pittsburgh, Massachusetts General Hospital (MGH), Berkeley, and 7-site Multimodal Treatment Study of Children With ADHD (MTA). METHOD: All studies were prospective and followed children with a diagnosis of ADHD and an age- and gender-matched control group at regular intervals from childhood (6-12 years of age) through adolescence into adulthood (20-40 years of age), evaluating symptom and syndrome persistence, functional outcomes, and predictors of these outcomes. RESULTS: The rates of ADHD syndrome persistence ranged from 5.7% to 77%, likely owing to varying diagnostic criteria and the source of information (self-report vs informant report) across the studies. However, all studies observed high rates of symptomatic persistence ranging from 60% to 86%. The 7 studies were largely consistent in finding that relative to control groups, research participants with childhood-diagnosed ADHD had significant impairments in the areas of educational functioning, occupational functioning, mental health, and physical health as well as higher rates of substance misuse, antisocial behavior, and unsafe driving. The most consistently observed predictors of functional outcomes included ADHD persistence and comorbidity, especially with disruptive behavior disorders. CONCLUSION: Childhood ADHD has high rates of symptomatic persistence, which is associated with negative functional outcomes. Characteristics that predict these negative outcomes, such as comorbid disruptive behavior disorders, may be important targets for intervention.

Variable Patterns of Remission From ADHD in the Multimodal Treatment Study of ADHD.

OBJECTIVE: It is estimated that childhood attention deficit hyperactivity disorder (ADHD) remits by adulthood in approximately 50% of cases; however, this conclusion is typically based on single endpoints, failing to consider longitudinal patterns of ADHD expression. The authors investigated the extent to which children with ADHD experience recovery and variable patterns of remission by adulthood. METHODS: Children with ADHD (N=558) in the Multimodal Treatment Study of ADHD (MTA) underwent eight assessments over follow-ups ranging from 2 years (mean age, 10.44 years) to 16 years (mean age, 25.12 years) after baseline. The authors identified participants with fully remitted, partially remitted, and persistent ADHD at each time point on the basis of parent, teacher, and self-reports of ADHD symptoms and impairment, treatment utilization, and substance use and mental disorders. Longitudinal patterns of remission and persistence were identified that considered context and timing. RESULTS: Approximately 30% of children with ADHD experienced full remission at some point during the follow-up period; however, a majority of them (60%) experienced recurrence of ADHD after the initial period of remission. Only 9.1% of the sample demonstrated recovery (sustained remission) by study endpoint, and only 10.8% demonstrated stable ADHD persistence across study time points. Most participants with ADHD (63.8%) had fluctuating periods of remission and recurrence over time. CONCLUSIONS: The MTA findings challenge the notion that approximately 50% of children with ADHD outgrow the disorder by adulthood. Most cases demonstrated fluctuating symptoms between childhood and young adulthood. Although intermittent periods of remission can be expected in most cases, 90% of children with ADHD in MTA continued to experience residual symptoms into young adulthood.

Childhood predictors and moderators of lifetime risk of self-harm in girls with and without attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) is associated with self-harm during adolescence and young adulthood, especially among females. Yet little is known about the developmental trajectories or childhood predictors/moderators of self-harm in women with and without childhood histories of ADHD. We characterized lifetime risk for nonsuicidal self-injury (NSSI), suicidal ideation (SI), and suicide attempts (SA), comparing female participants with (n = 140) and without (n = 88) childhood ADHD. We examined theory-informed childhood predictors and moderators of lifetime risk via baseline measures from childhood. First, regarding developmental patterns, most females with positive histories of lifetime self-harm engaged in such behaviors in adolescence yet desisted by adulthood. Females with positive histories of self-harm by late adolescence emanated largely from the ADHD-C group. Second, we found that predictors of NSSI were early externalizing symptoms, overall executive functioning, and father's negative parenting; predictors of SI were adverse childhood experiences and low self-esteem; and predictors of SA were early externalizing symptoms, adverse childhood experiences, and low self-esteem. Third, receiver operating characteristics analyses helped to ascertain interactive sets of predictors. Findings indicate that pathways to self-harm are multifaceted for females with ADHD. Understanding early childhood predictors and moderators of self-harm can inform both risk assessment and intervention strategies.

A Qualitative Analysis of Contextual Factors Relevant to Suspected Late-Onset ADHD.

Objective: Recent studies suggest attention-deficit/hyperactivity disorder (ADHD) may emerge post-childhood. We integrate qualitative methods to systematically characterize contextual factors that may (a) delay identification of ADHD in childhood and (b) inform why ADHD symptoms emerge post-childhood. Method: Suspected late-onset ADHD cases from the local normative comparison group of the Multimodal Treatment Study of ADHD completed a qualitative interview (14 young adults and 7 caregivers). Interviews were qualitatively analyzed. Results: We identified five themes. Three themes may attenuate or delay identification of childhood ADHD: external factors (e.g., supportive adults), internal factors (e.g., strong intellectual functioning), and other factors (e.g., dismissive attitudes toward ADHD). Two themes may accompany an increase in ADHD symptoms post-childhood: external factors (e.g., increased external demands) and internal factors (e.g., perceived stress). Conclusion: Clinicians should probe these factors in suspected late-onset cases to address (a) whether, how, and to what extent ADHD was attenuated in childhood and (b) why symptoms emerge post-childhood.

Outcomes of Endoscopic Versus Open Spring Assisted Surgery for Sagittal Craniosynostosis.

Spring-assisted surgery (SAS) has been shown to be an effective technique for correction of isolated sagittal craniosynostosis in patients less than 6 months of age. At their institution, the authors adopted a minimally invasive technique in 2010, using a shorter incision and an endoscope. A retrospective chart review of 101 patients with isolated, nonsyndromic, sagittal craniosynostosis, who underwent SAS, was performed in order to compare perioperative and clinical outcomes of the open (n = 51) and minimally-invasive (n = 50) approaches. Surgeries were performed by 2 neurosurgeons and 3 plastic surgeons, between 2005 and 2018. The pre and postoperative cephalic indices were not significantly different in both groups. Minimally-invasive spring placement required a longer operative time than the open approach, with the mean minimally-invasive operative time at 65 minutes, compared to 53 minutes (P < 0.0001). Spring removal operative time was not significantly different, with the minimally-invasive operative time at 31 minutes versus 29 minutes (P = 0.48). There were no significant differences in major or minor complications when comparing the open and minimally-invasive approaches. In conclusion, both the open and the minimally-invasive SAS techniques are effective for early correction of isolated sagittal craniosynostosis, although the minimally-invasive approach requires a longer operative time for spring placement.

Long-Term Outcomes of Spring-Assisted Surgery for Sagittal Craniosynostosis.

BACKGROUND: Spring-assisted surgery is an accepted alternative to cranial vault remodeling for treatment of sagittal craniosynostosis. The long-term safety and efficacy profiles of spring-assisted surgery have not been established. METHODS: This study is a retrospective examination of all patients treated with spring-assisted surgery (n = 175) or cranial vault remodeling (n = 50) for sagittal craniosynostosis at the authors' institution from 2003 to 2017. Data collected included demographic and operative parameters, preoperative and postoperative Cephalic Indices, and complications. Whitaker grades were assigned blindly by a craniofacial surgeon not involved in patients' care. RESULTS: The mean age at surgery was significantly lower for the spring-assisted surgery group compared with the cranial vault remodeling group (4.6 months versus 22.2 months; p < 0.001). Even when combining spring placement with spring removal operations, total surgical time (71.1 minutes versus 173.5 minutes), blood loss (25.0 ml versus 111.2 ml), and hospital stays (41.5 hours versus 90.0 hours) were significantly lower for the spring-assisted surgery cohort versus the cranial vault remodeling group (p < 0.001 for all). There were no differences in infection, reoperation rate, or headaches between the groups. The percentage improvement in Cephalic Index was not significantly different at 1 (p = 0.13), 2 (p = 0.99), and 6 (p = 0.86) years postoperatively. At 12 years postoperatively, the spring-assisted surgery group had persistently improved Cephalic Index (75.7 preoperatively versus 70.7 preoperatively). Those undergoing spring-assisted surgery had significantly better Whitaker scores, indicating less need for revision surgery, compared with the cranial vault remodeling group (p = 0.006). CONCLUSION: Compared with the authors' cranial vault remodeling technique, spring-assisted surgery requires less operating room time and is associated with less blood loss, but it has equivalent long-term Cephalic Indices and subjectively better shape outcomes. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Maternal personality traits moderate treatment response in the Multimodal Treatment Study of attention-deficit/hyperactivity disorder.

Some mothers of children with attention-deficit/hyperactivity disorder (ADHD) present with maladaptive personality profiles (high neuroticism, low conscientiousness). The moderating effect of maternal personality traits on treatment outcomes for childhood ADHD has not been examined. We evaluate whether maternal neuroticism and conscientiousness moderated response in the Multimodal Treatment Study of Children with ADHD. This is one of the first studies of this type. In a randomized controlled trial (RCT), 579 children aged 7-10 (M = 8.5); 19.7% female; 60.8% White with combined-type ADHD were randomly assigned to systematic medication management (MedMgt) alone, comprehensive multicomponent behavioral treatment (Beh), their combination (Comb), or community comparison treatment-as-usual (CC). Latent class analysis and linear mixed effects models included 437 children whose biological mothers completed the NEO Five-Factor Inventory at baseline. A 3-class solution demonstrated best fit for the NEO: MN&MC = moderate neuroticism and conscientiousness (n = 284); HN&LC = high neuroticism, low conscientiousness (n = 83); LN&HC = low neuroticism, high conscientiousness (n = 70). Per parent-reported symptoms, children of mothers with HN&LC, but not LN&HC, had a significantly better response to Beh than to CC; children of mothers with MN&MC and LN&HC, but not HN&LC, responded better to Comb&MedMgt than to Beh&CC. Per teacher-reported symptoms, children of mothers with HN&LC, but not LN&HC, responded significantly better to Comb than to MedMgt. Children of mothers with high neuroticism and low conscientiousness benefited more from behavioral treatments (Beh vs. CC; Comb vs. MedMgt) than other children. Evaluation of maternal personality may aid in treatment selection for children with ADHD, though additional research on this topic is needed.

Adolescent Mediators of Unplanned Pregnancy among Women with and without Childhood ADHD.

We aimed to identify adolescent mediators of the significant and sizable link between childhood attention deficit/hyperactivity disorder (ADHD) and later unplanned pregnancy in our prospectively followed, all-female sample. Participants included an ethnically diverse (47% non-White) sample of women with (n = 140) and without (n = 88) childhood ADHD who were assessed 4 times across childhood, adolescence, and adulthood. Potential mediators were measured via self, parent, and teacher report on questionnaires and interviews and by objective testing. We tested 5 early adolescent variables in three domains (personality, behavioral, and academic) as components of serial mediation pathways from (a) childhood ADHD status to (b) the early adolescent putative mediator to (c) risky sexual behavior in late adolescence and finally to (d) unplanned pregnancy by early adulthood. Of these, academic achievement (indirect effect = .1339, SE = .0721), 95% confidence interval (CI) [.0350, .3225] and substance use frequency (indirect effect = .0211, SE = .0167), 95% CI [.0013, .0711] operated through late-adolescent risky sexual behavior to explain rates of unplanned pregnancy, even adjusting for the effects of age, IQ, and family socioeconomic status (SES). When these 2 indirect effects were entered simultaneously, only the pathway from childhood ADHD to low academic achievement to higher rates of risky sexual behavior to unplanned pregnancy was significant (indirect effect = .0295, SE = .0145), 95% CI [.0056, .0620]. We discuss the significance of these early adolescent mediators, particularly academic engagement, as potential intervention targets intended to reduce rates of later unplanned pregnancies among female individuals with ADHD.

Enhancement of oncolytic virotherapy by vanadium(V) dipicolinates.

Oncolytic viruses rewire the immune system and can lead to long-lasting antitumor defenses against primary and metastatic tumors. However, results from clinical studies have shown heterogeneity in responses suggesting that multiplexed approaches may be necessary to consistently generate positive outcomes in patients. To this end, we explored the combination of oncolytic rhabdovirus VSV∆51 with vanadium(V) dipicolinate derivatives, which have already been explored for their antidiabetic properties in animal models. The combination of vanadium-based dipicolinate compounds with VSV∆51 significantly increased viral replication and cytotoxicity in the human renal cell carcinoma cell line 786-0. The effects of three vanadium(V)-dipicolinate coordination complexes ([VO2dipic]-, [VO2dipic-OH]- and [VO2dipic-Cl]- with -OH or -Cl in the para position) were compared to that of the simple salts using spectroscopy and speciation profiles. Like the vanadate salts and the vanadyl cation, all dioxovanadium(V) dipicolinate complexes tested were found to increase viral infection and cytotoxicity when used in combination with VSV∆51. Viral sensitization is dependent on the vanadium since free dipicolinate ligands exerted no effect on viral infection and viability. The ability of these complexes to interact with interfaces and the stability of the complexes were evaluated under physiological conditions. Results indicate that these complexes undergo hydrolysis in cell culture media thereby generating vanadate. The vanadium dipicolinate derivatives in the context of immunovirotherapy shares similarities with previous studies exploring the antidiabetic properties of the compounds. The synergy between vanadium compounds and the oncolytic virus suggests that these compounds may be valuable in the development of novel and effective pharmaco-viral therapies.

Regulator of G Protein Signaling 2 Facilitates Uterine Artery Adaptation During Pregnancy in Mice.

Background Decreased uterine blood flow is known to contribute to pregnancy complications such as gestational hypertension and preeclampsia. Previously, we showed that the loss of regulator of G protein signaling 2 ( RGS 2), a GTP ase activating protein for Gq/11 and Gi/o class G proteins, decreases uterine blood flow in the nonpregnant state in mice. Here, we examined the effects of the absence of RGS 2 and 5 on uterine blood flow and uterine vascular structure and function at early, mid, and late gestation, as well as peripartum period in mice. Methods and Results Abdominal Doppler ultrasonography was performed on adult female wild-type, Rgs2-/-, and Rgs5-/- mice at pre-pregnancy, gestational days 10, 15, and 18, and postpartum day 3. Uterine artery structure and function were also assessed by vessel myograph studies. At mid-pregnancy, uterine blood flow decreased in both Rgs2-/- and Rgs5-/- mice, whereas resistive index increased only in Rgs2-/- mice. In uterine arteries from wild-type mice, mRNA expression of RGS 2 and 4 increased, whereas RGS 5 expression remained elevated at mid-pregnancy. These changes in gene expression were unique to uterine arteries because they were absent in mesenteric arteries and the aorta of wild-type mice. In Rgs2-/- mice, uterine artery medial cross-sectional area and G protein-coupled receptor-mediated vasoconstriction increased in mid-pregnancy, implicating a role for RGS 2 in structural and functional remodeling of uterine arteries during pregnancy. In contrast, RGS 5 absence increased vasoconstriction only in the peripartum period. Conclusions These data together indicate that RGS 2 plays a critical role in the structural and functional remodeling of uterine arteries to impact uterine blood flow during pregnancy. Targeting the signaling pathway regulated by RGS 2 may therefore be a therapeutic strategy for ameliorating utero-placental perfusion disorders during pregnancy.