Genetic Implication of Prenatal GABAergic and Cholinergic Neuron Development in Susceptibility to Schizophrenia.

BACKGROUND: The ganglionic eminences (GE) are fetal-specific structures that give rise to gamma-aminobutyric acid (GABA)- and acetylcholine-releasing neurons of the forebrain. Given the evidence for GABAergic, cholinergic, and neurodevelopmental disturbances in schizophrenia, we tested the potential involvement of GE neuron development in mediating genetic risk for the condition. STUDY DESIGN: We combined data from a recent large-scale genome-wide association study of schizophrenia with single-cell RNA sequencing data from the human GE to test the enrichment of schizophrenia risk variation in genes with high expression specificity for developing GE cell populations. We additionally performed the single nuclei Assay for Transposase-Accessible Chromatin with Sequencing (snATAC-Seq) to map potential regulatory genomic regions operating in individual cell populations of the human GE, using these to test for enrichment of schizophrenia common genetic variant liability and to functionally annotate non-coding variants-associated with the disorder. STUDY RESULTS: Schizophrenia common variant liability was enriched in genes with high expression specificity for developing neuron populations that are predicted to form dopamine D1 and D2 receptor-expressing GABAergic medium spiny neurons of the striatum, cortical somatostatin-positive GABAergic interneurons, calretinin-positive GABAergic neurons, and cholinergic neurons. Consistent with these findings, schizophrenia genetic risk was concentrated in predicted regulatory genomic sequence mapped in developing neuronal populations of the GE. CONCLUSIONS: Our study implicates prenatal development of specific populations of GABAergic and cholinergic neurons in later susceptibility to schizophrenia, and provides a map of predicted regulatory genomic elements operating in cells of the GE.

The diagnosis and management of systemic autoimmune rheumatic disease-related interstitial lung disease: British Society for Rheumatology guideline scope.

Interstitial lung disease (ILD) is a significant complication of many systemic autoimmune rheumatic diseases (SARDs), although the clinical presentation, severity and outlook may vary widely between individuals. Despite the prevalence, there are no specific guidelines addressing the issue of screening, diagnosis and management of ILD across this diverse group. Guidelines from the ACR and EULAR are expected, but there is a need for UK-specific guidelines that consider the framework of the UK National Health Service, local licensing and funding strategies. This article outlines the intended scope for the British Society for Rheumatology guideline on the diagnosis and management of SARD-ILD developed by the guideline working group. It specifically identifies the SARDs for consideration, alongside the overarching principles for which systematic review will be conducted. Expert consensus will be produced based on the most up-to-date available evidence for inclusion within the final guideline. Key issues to be addressed include recommendations for screening of ILD, identifying the methodology and frequency of monitoring and pharmacological and non-pharmacological management. The guideline will be developed according to methods and processes outlined in Creating Clinical Guidelines: British Society for Rheumatology Protocol version 5.1.

Violence Exposure, Self-Reported Mental Health Concerns and Use of Alcohol and Drugs for Coping among Youth in the Slums of Kampala, Uganda.

This study aimed to a) compute the prevalence of violence exposure types, polyvictimization, and self-reported depression, anxiety, and using substances to cope among youth ages 12 to 18 years living on the streets or in the slums of Kampala, Uganda, (b) examine the independent associations among orphan status, violence exposure types, and self-reported mental health concerns, and c) explore the association between polyvictimization and mental health concerns. Data are from a 2014 cross-sectional survey of service-seeking youth ages 12 to 18 years (N = 1134) in Kampala, Uganda. Violence exposure types explored in this study were: witnessing family physical violence, direct physical abuse by a parent, any rape history, and physical dating violence. We used descriptive statistics and multivariable logistic regression to test study objectives. Over half of the sample (60.5%) reported experiencing at least one type of violence exposure; many youth endorsed self-reported depression (57.8%), anxiety (76.8%), and substance use to cope (37.0%). Exposure to violence was associated with higher odds for self-reported depression, anxiety, and using substances to cope. These findings underscore the urgent need to implement evidence-based interventions among this young, underserved population and their families to prevent violence, improve mental health outcomes, and promote resilience.

A Review of an Interfacility Transport Program Pediatric Stroke Clinical Practice Guideline.

BACKGROUND: Pediatric acute ischemic stroke is a rare diagnosis that requires timely recognition and definitive management to prevent morbidity and mortality. Children often present to primary care offices, urgent care clinics, and adult emergency departments for evaluation of symptoms that may be signs and symptoms of stroke. Currently, there are no published prehospital or transport protocols specific to pediatric acute ischemic stroke. The Children's Mercy Hospital Critical Care Transport Team (CMCCT) created a pediatric-specific clinical practice guideline (CPG) for suspected acute ischemic stroke. METHODS: This retrospective, descriptive study reports pediatric patients aged younger than 18 years who met criteria for the pediatric stroke CPG and required interfacility transport by CMCCT over a 4- year period. Large vessel occlusion (LVO) scores used in adults were calculated retrospectively. RESULTS: Seventeen patients met inclusion criteria. Four (24%) of 17 had radiographic evidence of acute thrombus, 3 of whom received alteplase and/or endovascular clot retrieval. Median age of confirmed stroke was 83 months (interquartile range, 65-148) compared with 177 months for nonstroke (interquartile range, 169-191), P = 0.126. The most common presenting symptom was hemiplegia in the confirmed stroke group. The confirmed stroke group scored significantly lower on the Glasgow Coma Scale (median of 8 vs 15, P = 0.014), significantly higher on the Los Angeles Motor Scale LVO score (median 4 vs 0, P = 0.021), and significantly higher on the Rapid Arterial Occlusion Evaluation LVO (median 4 vs 0, P = 0.036). CONCLUSIONS: To our knowledge, the CMCCT CPG is the first pediatric transport protocol aimed at recognition and management of pediatric stroke described in the literature. Retrospective calculation of LVO scores show that they may be helpful in application to pediatric patients.

Orphanhood vulnerabilities for violence and HIV by education, sex, and orphan type among 18-24-year-old youth: findings from the 2018 Lesotho violence against children and youth survey.

HIV and violence among orphans are key measures of vulnerability in low-resource settings. Although Lesotho has the second highest HIV adult prevalence rate (21.1%) in the world, and the prevalence of orphanhood (44.2%) and violence exposure (67.0%) is high, little research exist on orphanhood vulnerabilities for violence and HIV in Lesotho. Using data from 4,408 youth (18-24 years old) from Lesotho's 2018 Violence Against Children and Youth survey, a nationally representative cross-sectional household survey, the study examined associations among orphan status, violence, and HIV and assessed how associations differed by education, sex, and orphan type, using logistic regression. Orphans had higher odds of violence (aOR, 1.21; 95% CI, 1.01-1.46) and HIV (aOR, 1.69; 95% CI, 1.24-2.29). Having primary education or less (aOR, 1.43; 95% CI, 1.02-2.02), male sex (aOR, 1.74; 95% CI, 1.27-2.36), and being a paternal orphan (aOR, 1.43; 95% CI, 1.14-1.80) were significant interaction terms for violence. Orphans who completed primary school or less (aOR, 1.61; 95% CI, 1.09-2.39), female (aOR, 3.08; 95% CI, 2.14-4.42) and double orphans (aOR, 2.54; 95% CI, 1.56-4.13) had higher odds of HIV. These relationships highlight the importance of comprehensive strategies to support education and family strengthening for orphans as core violence and HIV prevention efforts.

Tetracyclines activate mitoribosome quality control and reduce ER stress to promote cell survival.

Mitochondrial diseases are a group of disorders defined by defects in oxidative phosphorylation caused by nuclear- or mitochondrial-encoded gene mutations. A main cellular phenotype of mitochondrial disease mutations is redox imbalances and inflammatory signaling underlying pathogenic signatures of these patients. One method to rescue this cell death vulnerability is the inhibition of mitochondrial translation using tetracyclines. However, the mechanisms whereby tetracyclines promote cell survival are unknown. Here, we show that tetracyclines inhibit the mitochondrial ribosome and promote survival through suppression of endoplasmic reticulum (ER) stress. Tetracyclines increase mitochondrial levels of the mitoribosome quality control factor MALSU1 (Mitochondrial Assembly of Ribosomal Large Subunit 1) and promote its recruitment to the mitoribosome large subunit, where MALSU1 is necessary for tetracycline-induced survival and suppression of ER stress. Glucose starvation induces ER stress to activate the unfolded protein response and IRE1α-mediated cell death that is inhibited by tetracyclines. These studies establish a new interorganelle communication whereby inhibition of the mitoribosome signals to the ER to promote survival, implicating basic mechanisms of cell survival and treatment of mitochondrial diseases.

The Design and Impact of a Clinic-Based Community Program on Food Insecurity, Healthy Eating Behaviors, and Mood.

Food insecurity is a national issue that disproportionately impacts Louisiana citizens, contributing to the state's poor health outcomes. We know that the Supplemental Nutrition Assistance Program (SNAP) and food pantries improve access to food, but we have limited data on what interventions improve food insecurity. The Geaux Get Healthy Clinical Program at Our Lady of the Lake (GGHOLOL) is a clinic-based community program that leverages community partnerships and a clinical setting to provide education and access to resources for individuals with food insecurity. This prospective study examines the impact of GGHOLOL on food insecurity as a pre-post survey evaluation over a two-year period. A total of 57 research participants with food insecurity completed the program. Mean food security scores improved at completion of GGHOLOL, and these scores further improved 6 months after enrollment. Furthermore, participants demonstrated sustainable improvements in healthy eating, cooking, and shopping behaviors. Lastly, participants improved their overall depression scores at the completion of the program with sustainable improvement at 6 months. With the improvement in GGHOLOL on food insecurity and nutrition behaviors, GGHOLOL may serve as a model for other programs addressing food insecurity in the future.

Use of technology in evidence-based programs for child maltreatment and its impact on parent and child outcomes.

Introduction: Technology has been used in evidence-based child maltreatment (CM) programs for over a decade. Although advancements have been made, the extent of the application of technology in these programs, and its influence on parental and child outcomes, remains unclear within the context of changes that emerged because of the COVID-19 pandemic. This scoping review provides a contextualized overview and summary of the use of technology in evidence-based parenting and child programs serving families impacted by child maltreatment and the effects of technology-enhanced programs on target outcomes. Materials and methods: Using Arksey and O'Malley's methodological framework, we searched seven databases to identify peer-reviewed and grey literature published in English from 2000 to 2023 on evidence-based programs, according to the California Evidence-Based Clearinghouse (CEBC), that included technological supports for two populations: at-risk parents for child maltreatment prevention, and children and youth 0-18 years exposed to child maltreatment. All study designs were included. Results: Eight evidence-based parenting programs and one evidence-based child trauma program were identified as using technology across a total of 25 peer-reviewed articles and 2 peer-reviewed abstracts meeting inclusion criteria (n = 19 on parent-level programs; n = 8 on child-level programs). Four studies were published in the context of COVID-19. Two main uses of technology emerged: (1) remote programmatic delivery (i.e., delivering all or part of the program virtually using technology) and (2) programmatic enhancement (i.e., augmenting program content with technology). Improvements across parenting and child mental health and behavioral outcomes were generally observed. Discussion: Technology use in evidence-based child maltreatment programs is not new; however, the small sample since the start of the COVID-19 pandemic in this review that met inclusion criteria highlight the dearth of research published on the topic. Findings also suggest the need for the inclusion of implementation outcomes related to adoption and engagement, which could inform equitable dissemination and implementation of these programs. Additional considerations for research and practice are discussed.

Reprint of: COVID-19 messaging in U.S. state parks: Extensions of the outdoor recreation strategies and practices framework unmasked by the pandemic.

U.S. state parks are a considerable part of the nation's recreation landscape. Understanding their management concerns, including impacts from pandemics, is imperative for sustainably achieving park objectives. Our study aimed to 1) examine park managers' responses to a novel stressor (COVID-19); 2) aid managers in communicating these strategies to visitors in their pre-visit phase; and 3) test a park management framework's ability to adapt to this novel stressor in this pre-visit phase. Manning and colleagues' outdoor recreation strategies and practices framework provides parks with up to 24 response options to an issue: four strategies intersecting with six practices. This framework has been limited to common in-park concerns and visitors. We examined how park systems communicate with potential visitors about COVID-19, to advance the framework toward broader concerns and scales. We analyzed the 50 U.S. state park systems' official COVID-19 communications at the traditional start of the peak use season (summer 2020). We qualitatively coded these for reference to the framework's components and mentions of scale. This highlighted that while "limit use" and "reduce impact of use" were the only strategies used, different practices and recognitions of beyond-park and beyond-visit scales were acknowledged (e.g., "please recreate close to home"). We suggest the data reveal a seventh practice in use and for framework inclusion: "influence pre-visit decisions." The pandemic provided an opportunity for parks to communicate their managerial responses with consistency and creativity, as well as an opportunity for researchers and managers to advance the strategies and practices framework. Management implications: The temporal issue of COVID-19 as a stressor and the spatial nature of its impact across whole social landscapes implores park managers to pay special attention to the critical time in a potential visitor's visit-cycle: the planning and anticipation stages. It is here that effective messaging about the park's integration of expert authority data, detailed communication about park-level responses, and awareness of beyond-park contexts can help potential visitors decide how to safely recreate. This examination highlights the importance of pre-visit safety messaging and provides specific examples of how the outdoor recreation strategies and practices framework can assist park managers in targeting visitor use management communications and actions. Given this strategies and practices framework's usefulness to park managers and ubiquity across parks, we examine ways to expand it to consider broader and emergent contexts.

The impact of time to amiodarone administration on survival from out-of-hospital cardiac arrest.

Aim: To examine the impact of time to amiodarone administration on survival from shock-refractory Ventricular Fibrillation/pulseless Ventricular Tachycardia (VF/pVT) following out-of-hospital cardiac arrest (OHCA). Methods: A retrospective cohort study of adult (≥16 years) OHCA patients in shock-refractory VF/pVT (after 3 consecutive defibrillation attempts) of medical aetiology who arrested between January 2010 and December 2019. Time-dependent propensity score matching was used to sequentially match patients who received amiodarone at any given minute of resuscitation with patients eligible to receive amiodarone during the same minute. Log-binomial regression models were used to assess the association between time of amiodarone administration (by quartiles of time-to-matching) and survival outcomes. Results: A total of 2,026 patients were included, 1,393 (68.8%) of whom received amiodarone with a median (interquartile range) time to administration of 22.0 (18.0-27.0) minutes. Propensity score matching yielded 1,360 matched pairs. Amiodarone administration within 28 minutes of the emergency call was associated with a higher likelihood of return of spontaneous circulation (ROSC) (≤18minutes: RR = 1.03 (95%CI 1.02, 1.04); 19-22minutes: RR = 1.02 (95%CI 1.01, 1.03); 23-27minutes: RR = 1.01 (95%CI 1.00, 1.02)) and event survival (pulse on hospital arrival) (≤18 minutes: RR = 1.05 (95%CI 1.03, 1.07); 19-22 minutes: RR = 1.03 (95%CI 1.01, 1.05); 23-27 minutes: RR = 1.02 (95%CI 1.00, 1.03). Amiodarone administration within 23 minutes of the emergency call was associated with a higher likelihood of survival to hospital discharge (≤18minutes: RR = 1.17 (95%CI 1.09, 1.24; 19-22 minutes: RR = 1.10 (95%CI 1.04, 1.17). Conclusion: Amiodarone administered within 23 minutes of the emergency call is associated with improved survival outcomes in shock-refractory VF/pVT, although prospective trials are required to confirm these findings.

Multiple myeloma presenting as blepharitis in a horse.

Myeloma-related disorders, including multiple myeloma, extramedullary plasmacytoma, and solid osseous plasmacytoma, are rare in horses. Clinical complaints for myeloma-related disorders are nonspecific, and when present, M-protein location is more variable on protein electrophoresis in horses relative to dogs and cats. Here, we describe a case of a 15-year-old Thoroughbred mare who presented with recurrent blepharitis. Marked hyperglobulinemia was an incidental finding on routine hematologic and biochemical testing. Bone marrow aspiration consisted of >30% plasma cells, and serum protein electrophoresis demonstrated a monoclonal gammopathy in the alpha 2 fraction leading to a diagnosis of multiple myeloma. Immunofixation and radial immunodiffusion confirmed the presence of an IgG M-protein. Based on a restricted peak in the alpha 2 location, the specific M-protein is suspected to be IgG(T), an IgG isotype unique to horses. M-protein migration in horses is variable relative to dogs and cats, yet immunofixation can still be used to identify equine IgG M-protein isotypes. The unique clinical presentation in this case also serves as a reminder to consider neoplasia in horses with unusual or nonspecific clinical signs.

Systematic braiding of Smoke-Free Home SafeCare to address child maltreatment risk and secondhand smoke exposure: findings from a pilot study.

BACKGROUND: Exposure to secondhand tobacco smoke (SHS) and child maltreatment are preventable threats to child health. Few evidence-based interventions target both SHS and child maltreatment risk. The purpose of this paper is to describe the systematic braiding process of two evidence-based programs to address child SHS in the home and maltreatment perpetration risk, and present results from the formative work and pilot study. METHODS: The first 4 steps of the systematic braiding process were completed, including the following: (1) the identification of core elements of both programs, (2) the development of an initial draft of the braided curriculum (Smoke-Free Home SafeCare - SFH-SC), (3) an acceptability and feasibility pilot of SFH-SC with caregivers of young children who reported a smoker living in the home (N = 8), and (4) feedback collection on the braided curriculum from SafeCare Providers (N = 9). RESULTS: Experts identified common pedagogical and theoretical underpinnings for the two programs and braided Smoke-Free Homes: Some Things Are Better Outside into two SafeCare modules. Caregiver feedback from the pilot demonstrated that participants were engaged with SFH-SC and felt supported and comfortable discussing SHS intervention content with the SFH-SC Provider. Caregiver self-reports indicated a slight increase in smoke-free home rules from baseline to follow-up and a notable reduction in parent stress on the Parent Stress Index of 5.9 points (SD = 10.2). SafeCare Provider feedback following intensive review of the curriculum indicated high feasibility for SFH-SC delivery. CONCLUSIONS: Parent and Provider findings suggest SFH-SC is a viable intervention that has potential to reduce the public health impact of SHS and child maltreatment for at-risk families. PROTOCOL: The protocol for the pilot is not published elsewhere; however, the full protocol for the hybrid trial can be found here: https://clinicaltrials.gov/ct2/show/NCT05000632 . TRIAL REGISTRATION: NCT, NCT05000632. Registered 14 July 2021, there is not a separate registration number for the pilot.

Sigma 1 receptor activation improves retinal structure and function in the RhoP23H/+ mouse model of autosomal dominant retinitis pigmentosa.

Retinitis pigmentosa (RP) is a group of devastating inherited retinal diseases that leads to visual impairment and oftentimes complete blindness. Currently no cure exists for RP thus research into prolonging vision is imperative. Sigma 1 receptor (Sig1R) is a promising small molecule target that has neuroprotective benefits in retinas of rapidly-degenerating mouse models. It is not clear whether Sig1R activation can provide similar neuroprotective benefits in more slowly-progressing RP models. Here, we examined Sig1R-mediated effects in the slowly-progressing RhoP23H/+ mouse, a model of autosomal dominant RP. We characterized the retinal degeneration of the RhoP23H/+ mouse over a 10 month period using three in vivo methods: Optomotor Response (OMR), Electroretinogram (ERG), and Spectral Domain-Optical Coherence Tomography (SD-OCT). A slow retinal degeneration was observed in both male and female RhoP23H/+ mice when compared to wild type. The OMR, which reflects visual acuity, showed a gradual decline through 10 months. Interestingly, female mice had more reduction in visual acuity than males. ERG assessment showed a gradual decline in scotopic and photopic responses in RhoP23H/+ mice. To investigate the neuroprotective benefits of Sig1R activation in the RhoP23H/+ mouse model, mutant mice were treated with a high-specificity Sig1R ligand (+)-pentazocine ((+)-PTZ) 3x/week at 0.5 mg/kg and examined using OMR, ERG, SD-OCT. A significant retention of visual function was observed in males and females at 10 months of age, with treated females retaining ∼50% greater visual acuity than non-treated mutant females. ERG revealed significant retention of scotopic and photopic b-wave amplitudes at 6 months in male and female RhoP23H/+ mice treated with (+)-PTZ. Further, in vivo analysis by SD-OCT revealed a significant retention of outer nuclear layer (ONL) thickness in male and female treated RhoP23H/+ mice. Histological studies showed significant retention of IS/OS length (∼50%), ONL thickness, and number of rows of photoreceptor cell nuclei at 6 months in (+)-PTZ-treated mutant mice. Interestingly, electron microscopy revealed preservation of OS discs in (+)-PTZ treated mutant mice compared to non-treated. Taken collectively, the in vivo and in vitro data provide the first evidence that targeting Sig1R can rescue visual function and structure in the RhoP23H/+ mouse. These results are promising and provide a framework for future studies to investigate Sig1R as a potential therapeutic target in retinal degenerative disease.

Tetracycline-dependent inhibition of mitoribosome protein elongation in mitochondrial disease mutant cells suppresses IRE1α to promote cell survival.

Mitochondrial diseases are a group of disorders defined by defects in oxidative phosphorylation caused by nuclear- or mitochondrial-encoded gene mutations. A main cellular phenotype of mitochondrial disease mutations are redox imbalances and inflammatory signaling underlying pathogenic signatures of these patients. Depending on the type of mitochondrial mutation, certain mechanisms can efficiently rescue cell death vulnerability. One method is the inhibition of mitochondrial translation elongation using tetracyclines, potent suppressors of cell death in mitochondrial disease mutant cells. However, the mechanisms whereby tetracyclines promote cell survival are unknown. Here, we show that in mitochondrial mutant disease cells, tetracycline-mediated inhibition of mitoribosome elongation promotes survival through suppression of the ER stress IRE1α protein. Tetracyclines increased levels of the splitting factor MALSU1 (Mitochondrial Assembly of Ribosomal Large Subunit 1) at the mitochondria with recruitment to the mitochondrial ribosome (mitoribosome) large subunit. MALSU1, but not other quality control factors, was required for tetracycline-induced cell survival in mitochondrial disease mutant cells during glucose starvation. In these cells, nutrient stress induced cell death through IRE1α activation associated with a strong protein loading in the ER lumen. Notably, tetracyclines rescued cell death through suppression of IRE1α oligomerization and activity. Consistent with MALSU1 requirement, MALSU1 deficient mitochondrial mutant cells were sensitive to glucose-deprivation and exhibited increased ER stress and activation of IRE1α that was not reversed by tetracyclines. These studies show that inhibition of mitoribosome elongation signals to the ER to promote survival, establishing a new interorganelle communication between the mitoribosome and ER with implications in basic mechanisms of cell survival and treatment of mitochondrial diseases.

The PTSD Symptom Presentation and the Effect of Polytrauma on PTSD Symptom Clusters Among Young People Who Have Experienced Commercial Sexual Exploitation and Trafficking.

Purpose: The purpose of this study was to describe the PTSD symptom presentation (including dissociative symptoms) of PTSD using the Diagnostic and Statistical Manual of Mental Disorders 5 th Edition diagnostic criteria and explore associations between the symptom severity for each of the four PTSD symptom clusters and polytrauma, defined as multiple exposures to different categories of potentially traumatic events. Methods: This is a secondary analysis of cross-sectional program evaluation data among 95 young people (aged 11-19) at therapy initiation in a southeastern state in the U.S. We used descriptive statistics and multivariable linear regression to test study objectives. Results: Eighty-one respondents (90.0%) experienced a potentially traumatic event in ≥ 2 trauma categories, in addition to experiencing CSE/T. Approximately two-thirds of respondents experienced clinically significant PTSD symptoms for each symptom cluster. Of the 31 young people who met full criteria for PTSD, 9 met criteria for the standard PTSD diagnosis, while 22 met criteria for the dissociative subtype of PTSD. On average, experiencing additional trauma categories was associated with substantively higher PTSD symptom cluster scores for each cluster. Conclusions: These findings support the need for a comprehensive assessment of trauma symptoms that includes cluster-specific PTSD symptoms. They also underscore the need to assess the full breadth and chronicity of trauma experiences to guide treatment planning and delivery, targeting specific domains of trauma impact. These findings can also inform the tailoring and adaptation of evidence-based interventions and strategies to better meet the needs of young people who have experienced CSE/T.

VIP152 is a selective CDK9 inhibitor with pre-clinical in vitro and in vivo efficacy in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is effectively treated with targeted therapies including Bruton tyrosine kinase inhibitors and BCL2 antagonists. When these become ineffective, treatment options are limited. Positive transcription elongation factor complex (P-TEFb), a heterodimeric protein complex composed of cyclin dependent kinase 9 (CDK9) and cyclin T1, functions to regulate short half-life transcripts by phosphorylation of RNA Polymerase II (POLII). These transcripts are frequently dysregulated in hematologic malignancies; however, therapies targeting inhibition of P-TEFb have not yet achieved approval for cancer treatment. VIP152 kinome profiling revealed CDK9 as the main enzyme inhibited at 100 nM, with over a 10-fold increase in potency compared with other inhibitors currently in development for this target. VIP152 induced cell death in CLL cell lines and primary patient samples. Transcriptome analysis revealed inhibition of RNA degradation through the AU-Rich Element (ARE) dysregulation. Mechanistically, VIP152 inhibits the assembly of P-TEFb onto the transcription machinery and disturbs binding partners. Finally, immune competent mice engrafted with CLL-like cells of Eµ-MTCP1 over-expressing mice and treated with VIP152 demonstrated reduced disease burden and improvement in overall survival compared to vehicle-treated mice. These data suggest that VIP152 is a highly selective inhibitor of CDK9 that represents an attractive new therapy for CLL.

Genetic implication of prenatal GABAergic and cholinergic neuron development in susceptibility to schizophrenia.

Background: The ganglionic eminences are fetal-specific structures that give rise to gamma-aminobutyric acid (GABA)- and acetylcholine- releasing neurons of the forebrain. Given evidence for GABAergic and cholinergic disturbances in schizophrenia, as well as an early neurodevelopmental component to the disorder, we tested the potential involvement of developing cells of the ganglionic eminences in mediating genetic risk for the condition. Study Design: We combined data from a recent large-scale genome-wide association study of schizophrenia with single cell RNA sequencing data from the human ganglionic eminences to test enrichment of schizophrenia risk variation in genes with high expression specificity for particular developing cell populations within these structures. We additionally performed the single nuclei Assay for Transposase-Accessible Chromatin with Sequencing (snATAC-Seq) to map potential regulatory genomic regions operating in individual cell populations of the human ganglionic eminences, using these to additionally test for enrichment of schizophrenia common genetic variant liability and to functionally annotate non-coding variants associated with the disorder. Study Results: Schizophrenia common variant liability was enriched in genes with high expression specificity for developing neuron populations that are predicted to form dopamine D1 and D2 receptor expressing GABAergic medium spiny neurons of the striatum, cortical somatostatin-positive GABAergic interneurons, calretinin-positive GABAergic neurons and cholinergic neurons. Consistent with these findings, schizophrenia genetic risk was also concentrated in predicted regulatory genomic sequence mapped in developing neuronal populations of the ganglionic eminences. Conclusions: Our study provides evidence for a role of prenatal GABAergic and cholinergic neuron development in later susceptibility to schizophrenia.

Collaborative care implementation: lessons learned.

The authors drafted a "Shared Values of Collaborative Care" document with fundamental principles to make better group decisions in implementing collaborative care.

Posttraumatic Cognitions and Posttraumatic Stress Symptoms Among Young People Who Have Experienced Commercial Sexual Exploitation and Trafficking.

OBJECTIVES: The impact of posttraumatic cognitions on the development and maintenance of posttraumatic stress symptoms (PTSS) is understudied among children and adolescents who have experienced commercial sexual exploitation/trafficking (CSE/T). The objectives of this study were to (1) explore posttraumatic cognitions among help-seeking young people aged 11-19 who have experienced CSE/T; (2) determine whether experiencing direct violence, witnessing violence, polyvictimization (ie, multiple exposures to different categories of potentially traumatic events), or demographic characteristics differentially affect whether these young people meet clinical criteria for posttraumatic cognitions using established cutoffs; and (3) explore associations between posttraumatic cognitions and PTSS among young people who have experienced CSE/T. METHODS: This study is a secondary analysis of a baseline cross-sectional survey of 110 young people with substantiated CSE/T experiences who started trauma-focused cognitive behavioral therapy (mean [SD] age = 15.8 [1.5]) from August 1, 2013, through March 31, 2020, in a southeastern US state. We used descriptive statistics, adjusted modified Poisson regression, and adjusted linear regression to test study objectives. RESULTS: Fifty-seven of 110 (51.8%) young people aged 11-19 met clinical criteria for posttraumatic cognitions. Increased age and a greater number of trauma categories experienced were significantly associated with meeting clinical criteria for posttraumatic cognitions. On average, higher posttraumatic cognition scores were associated with higher PTSS scores, controlling for demographic characteristics (ß = 0.95; 95% CI, 0.64-1.26). CONCLUSIONS: These findings underscore the importance of assessing comprehensive trauma history and PTSS of young people who have experienced CSE/T, with added usefulness of measuring cognitive appraisals to inform a therapeutic treatment plan. Measuring cognitive appraisals that may influence PTSS and therapeutic success can ensure an effective public health response for this population.