Genetic inhibitors of APOBEC3B-induced mutagenesis.

The cytidine deaminases APOBEC3A (A3A) and APOBEC3B (A3B) are prominent mutators of human cancer genomes. However, tumor-specific genetic modulators of APOBEC-induced mutagenesis are poorly defined. Here, we used a screen to identify 61 gene deletions that increase A3B-induced mutations in yeast. We also determined whether each deletion was epistatic with Ung1 loss, which indicated whether the encoded factors participate in the homologous recombination (HR)-dependent bypass of A3B/Ung1-dependent abasic sites or suppress A3B-catalyzed deamination by protecting against aberrant formation of single-stranded DNA (ssDNA). We found that the mutation spectra of A3B-induced mutations revealed genotype-specific patterns of strand-specific ssDNA formation and nucleotide incorporation across APOBEC-induced lesions. Combining these three metrics, we were able to establish a multifactorial signature of APOBEC-induced mutations specific to (1) failure to remove H3K56 acetylation, (2) defective CTF18-RFC complex function, and (3) defective HR-mediated bypass of APOBEC-induced lesions. We extended these results by analyzing mutation data for human tumors and found BRCA1/2-deficient breast cancers display three- to fourfold more APOBEC-induced mutations. Mirroring our results in yeast, Rev1-mediated C-to-G substitutions are mainly responsible for increased APOBEC-signature mutations in BRCA1/2-deficient tumors, and these mutations associate with lagging strand synthesis during replication. These results identify important factors that influence DNA replication dynamics and likely the abundance of APOBEC-induced mutation during tumor progression. They also highlight a novel role for BRCA1/2 during HR-dependent lesion bypass of APOBEC-induced lesions during cancer cell replication.

Fast response times signal social connection in conversation.

Clicking is one of the most robust metaphors for social connection. But how do we know when two people "click"? We asked pairs of friends and strangers to talk with each other and rate their felt connection. For both friends and strangers, speed in response was a robust predictor of feeling connected. Conversations with faster response times felt more connected than conversations with slower response times, and within conversations, connected moments had faster response times than less-connected moments. This effect was determined primarily by partner responsivity: People felt more connected to the degree that their partner responded quickly to them rather than by how quickly they responded to their partner. The temporal scale of these effects (<250 ms) precludes conscious control, thus providing an honest signal of connection. Using a round-robin design in each of six closed networks, we show that faster responders evoked greater feelings of connection across partners. Finally, we demonstrate that this signal is used by third-party listeners as a heuristic of how well people are connected: Conversations with faster response times were perceived as more connected than the same conversations with slower response times. Together, these findings suggest that response times comprise a robust and sufficient signal of whether two minds "click."

Enhancing Quality of Care Through Evidence-Based Practice: Training and Supervision Experiences.

OBJECTIVE: Evidence-based practice (EBP) is the preferred approach to treatment in mental health settings because it involves the integration of the best available research, clinical expertise, and patient values to optimize patient outcomes. Training on empirically supported treatments (ESTs) in mental health settings is an important component of EBP, and supervision of therapists' implementation of ESTs is critical for therapists to develop and maintain a strong EBP skill set. This study aimed to evaluate training and supervision histories of therapists in outpatient and inpatient psychiatric care settings as an essential first step in improving patient outcomes. METHODS: Electronic surveys were completed by 69 therapists, most of whom had a master's degree, within a psychiatry and behavioral sciences department at an academic institution. Participating therapists were recruited from several outpatient and inpatient mental health settings serving children, adolescents, and adults. RESULTS: Although most therapists reported completing some form of EST-related coursework, a majority did not receive any supervision related to implementation of ESTs (51% for cognitive-behavioral therapy cases, 76% for dialectical behavior therapy cases, and 52% for other EST cases) during graduate and postgraduate training. CONCLUSIONS: Although research from the past decade has supported the need for improvements in training on ESTs, and especially in supervision, problems related to limited exposure to training and supervision among therapists still exist. These findings have implications for how mental health centers can evaluate staff members' EST training and supervision experiences, training needs, and associated training targets to improve the quality of routine care.

Pediatric single large-scale mtDNA deletion syndromes: The power of patient reported outcomes.

There is a limited understanding of system-level clinical outcomes and interventions associated with single large-scale mitochondrial DNA deletion syndromes (SLSMDS). Additionally, no research exists that describes patient reported outcomes (PROs) of children with SLSMDS. A global and observational registry was established to understand the multi-systemic course of SLSMDS and track clinical outcomes. The development and design of the registry is described. Demographic characteristics, history and diagnoses, and system level prevalence of problems and interventions are reported for 42 children. System level problems and interventions include information on the following body systems: audiology, cardiac, endocrine, gastrointestinal (including pancreatic and hepatobiliary system), hematological, metabolic, neurological (including autonomic, mobility, & learning), ophthalmic, psychiatric, renal, and respiratory. Results emphasize the need of patient registries and suggest that the diagnostic odyssey and burden of disease for children with SLSMDS is significant. System-level findings may help families and clinical providers with diagnosis, prognostication, and treatment. A multidisciplinary team of clinical experts with a central coordinating specialist for children with SLSMDS is recommended.

Assessing child quality of life impairments following pediatric burn injuries: Rasch analysis of the children's dermatology life quality index.

AIMS: There is a need for a brief, validated measure of quality of life (QOL) for children to monitor their adjustment to burn injuries. We aimed to apply a Rasch analysis to an existing measure of QOL from the dermatology literature to a clinical sample of pediatric burn patients. METHODS: The Children's Dermatology Life Quality Index (CDLQI) was administered to pediatric burn patients (N = 253) during a standard clinic visit. Rasch analysis was used to examine psychometric properties of this measure with a burn sample. RESULTS: The CDLQI showed an adequate fit to the Rasch model. Test difficulty is .61 logits greater than person ability. Results of item reliability and separation analyses were sufficiently strong and indicated a unidimensional latent trait. Person reliability (.74) and separation analyses (1.64) were moderate. Finally, the CDLQI was able to moderately separate the group of respondents into low and high levels of QOL impairments related to burn injuries. CONCLUSION: The Rasch model demonstrated that the CDLQI is a reliable and valid scale that adequately measures QOL impairments in children following burn injuries.

How Early Maternal Language Input Varies by Race and Education and Predicts Later Child Language.

The maternal language input literature suggests that mothers with more education use a greater quantity and complexity of language with their young children compared to mothers with less education although race and socioeconomic status have been confounded in most studies because of small sample sizes. The current Family Life study included a representative sample of 1,292 children, oversampling for poverty and African American, followed from birth. This study found no race differences within maternal education levels on five measures of maternal language input from 6 to 36 months. Maternal language input variables of number of different words, mean length of utterance and number of wh-questions were partial mediators of the relationship between maternal education and later child language at school age.

Acute psychiatric care for pediatric patients.

Higher level or acute psychiatric care for youth is intended to be active but short-term treatment focussing on crisis stabilisation, assessment, safety monitoring, and longer-term treatment planning. The focus of this article is on describing common challenges and the effort to address these challenges through new approaches to acute psychiatric care for children and adolescents. The review finds that (1) inpatient paediatric psychiatry beds are in high demand and often difficult to access, (2) there are a number of common challenges these units face including managing length of stays, readmissions, and adverse events, and (3) there are encouraging therapeutic approaches adapted for this setting. There is still much work to be done to advance the evidence-base for acute psychiatric care for youth particularly in defining and assessing an effective admission. Paediatric psychiatry patients are a vulnerable population and call for our best tools to be put to use to improve the quality and safety of care.

Risk Factors for Seclusion in Children and Adolescents Inpatient Psychiatry: The Role of Demographic Characteristics, Clinical Severity, Life Experiences and Diagnoses.

OBJECTIVE: To understand the risk factors for seclusion in a sample of children and adolescents admitted to an inpatient psychiatry unit looking at demographic, clinical severity, life experience, and diagnostic characteristics. METHODS: An unmatched case-control retrospective analysis of psychiatric records in a pediatric inpatient unit from December 2011 to December 2015 (N = 1986) RESULTS: Individual characteristics, including demographics, clinical severity, and clinical presentation as per the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) jointly predicted seclusion in adolescents, with younger age, male sex, black race, having a prior admission, and having a disruptive behavior or bipolar and related disorder diagnoses being predictive of seclusion. While demographic and clinical severity factors were predictive of seclusion in multivariate models, clinical diagnoses only added modestly to the variance explained. CONCLUSIONS: High-risk demographic and clinical characteristics for seclusion events in children and adolescents can provide valuable information to guide interventions to prevent seclusion events during their hospitalization.

Combating a Global Threat to a Clonal Crop: Banana Black Sigatoka Pathogen Pseudocercospora fijiensis (Synonym Mycosphaerella fijiensis) Genomes Reveal Clues for Disease Control.

Black Sigatoka or black leaf streak disease, caused by the Dothideomycete fungus Pseudocercospora fijiensis (previously: Mycosphaerella fijiensis), is the most significant foliar disease of banana worldwide. Due to the lack of effective host resistance, management of this disease requires frequent fungicide applications, which greatly increase the economic and environmental costs to produce banana. Weekly applications in most banana plantations lead to rapid evolution of fungicide-resistant strains within populations causing disease-control failures throughout the world. Given its extremely high economic importance, two strains of P. fijiensis were sequenced and assembled with the aid of a new genetic linkage map. The 74-Mb genome of P. fijiensis is massively expanded by LTR retrotransposons, making it the largest genome within the Dothideomycetes. Melting-curve assays suggest that the genomes of two closely related members of the Sigatoka disease complex, P. eumusae and P. musae, also are expanded. Electrophoretic karyotyping and analyses of molecular markers in P. fijiensis field populations showed chromosome-length polymorphisms and high genetic diversity. Genetic differentiation was also detected using neutral markers, suggesting strong selection with limited gene flow at the studied geographic scale. Frequencies of fungicide resistance in fungicide-treated plantations were much higher than those in untreated wild-type P. fijiensis populations. A homologue of the Cladosporium fulvum Avr4 effector, PfAvr4, was identified in the P. fijiensis genome. Infiltration of the purified PfAVR4 protein into leaves of the resistant banana variety Calcutta 4 resulted in a hypersensitive-like response. This result suggests that Calcutta 4 could carry an unknown resistance gene recognizing PfAVR4. Besides adding to our understanding of the overall Dothideomycete genome structures, the P. fijiensis genome will aid in developing fungicide treatment schedules to combat this pathogen and in improving the efficiency of banana breeding programs.

Evaluation of the Environmental Supports Scale with a Community Sample of Adolescents.

Environmental sources of psychosocial support have been found to modulate or protect against the development of psychopathology and risk behavior among adolescents. Capturing sources of environmental support across multiple developmental contexts requires the availability of well-validated, concise assessments-of which there are few in the existing literature. In order to address this need, the current study explored the factor structure, concurrent and convergent validity of the Environmental Supports Scale (ESS; Genetic, Social, and General Psychology Monographs, 117; 395-417, 1991) with a community sample of adolescents. An unconstrained exploratory factor analysis revealed a separate factor for home, school, and neighborhood settings. Internal consistency and test-retest reliability were evaluated for each factor. Concurrent and predictive validity analyses revealed that the ESS was associated in the expected directions across a range of constructs relevant to adolescent development including internalizing symptoms, well-being, external influences, and engagement in risk behavior. Convergent validity for the neighborhood context was established with an assessment of neighborhood environmental adversity. A brief assessment of perceived environmental support across key developmental contexts provides an important tool for research on resilience processes during adolescence and may help illuminate key protective factors and inform intervention and prevention efforts.

Risk Factors for Seclusion and Restraint in a Pediatric Psychiatry Day Hospital.

The use of seclusion and restraints (SR) in acute hospital settings remains a controversial practice. Despite the focus on SR in the psychiatric services literature, data on SR use in pediatric day hospital settings is lacking. A case-control retrospective analysis for children admitted into a pediatric psychiatry day hospital in a 2-year span examined predictors of SR use. Demographic and clinical descriptors were examined in relation to SR events using univariate and multivariate regression models. Significant univariate risk factors for SR use were psychiatric morbidity, history of physical abuse, post-traumatic stress disorder, having any anxiety disorder, and younger age. Knowledge of risk factors for SR use in pediatric psychiatric day hospitals can avert use of SR and lead to improved safety in a trauma-informed care model.

Management and Treatment of Attention-Deficit/Hyperactivity Disorder on College Campuses.

Attention-deficit/hyperactivity disorder (ADHD) on college campuses is a serious and often underdiagnosed condition. The current investigation analyzed current best practice guidelines for the management of ADHD in a mid-sized university in the Midwestern United States. Best practices were identified through a review of current evidence-based literature on ADHD management. A data collection tool was developed and used to organize data and determine adherence with best practice guidelines. Investigators revealed that policy and procedures followed best practice guidelines. Development and implementation of ADHD protocols on college campuses allows nurse practitioners to confidently provide safe, quality care to patients diagnosed with ADHD.

Effects of naltrexone on adolescent alcohol cue reactivity and sensitivity: an initial randomized trial.

Adolescent alcohol use is associated with myriad adverse consequences and contributes to the leading causes of mortality among youth. Despite the magnitude of this public health problem, evidenced-based treatment initiatives for alcohol use disorders in youth remain inadequate. Identifying promising pharmacological approaches may improve treatment options. Naltrexone is an opiate receptor antagonist that is efficacious for reducing drinking in adults by attenuating craving and the rewarding effects of alcohol. Implications of these findings for adolescents are unclear; however, given that randomized trials of naltrexone with youth are non-existent. We conducted a randomized, double-blinded, placebo-controlled cross-over study, comparing naltrexone (50 mg/daily) and placebo in 22 adolescent problem drinkers aged 15-19 years (M = 18.36, standard deviation = 0.95; 12 women). The primary outcome measures were alcohol use, subjective responses to alcohol consumption, and alcohol-cue-elicited craving assessed in the natural environment using ecological momentary assessment methods, and craving and physiological reactivity assessed using standard alcohol cue reactivity procedures. Results showed that naltrexone reduced the likelihood of drinking and heavy drinking (P's ≤ 0.03), blunted craving in the laboratory and in the natural environment (P's ≤ 0.04), and altered subjective responses to alcohol consumption (P's ≤ 0.01). Naltrexone was generally well tolerated by participants. This study provides the first experimentally controlled evidence that naltrexone reduces drinking and craving, and alters subjective responses to alcohol in a sample of adolescent problem drinkers, and suggests larger clinical trials with long-term follow-ups are warranted.

Analogue study of peer influence on risk-taking behavior in older adolescents.

This experimental study aimed to examine whether adolescents act in a riskier manner in the presence of peers and whether peer presence alone influences risk behavior or if a direct influence process is necessary. Utilizing a behavioral task assessing risk-taking, 183 older adolescents (18­20 year olds) came to the laboratory alone once and then were randomized to one of three conditions as follows: alone, peers present, and peers encouraging. An interaction was found such that at baseline, there were no significant differences between the three conditions, but at the experimental session, there was a significant increase in risk task scores particularly for the encouraging condition. These findings challenge proposed models of the interaction between peer influence and risk taking by providing evidence that adolescents take more risks when being encouraged by peers, but that the presence of peers on its own does not lead to more risks than when completing the task alone.

Subtypes of Depressed Youth Admitted for Inpatient Psychiatric Care: A Latent Profile Analysis.

Depressed youth frequently present with comorbid symptoms. Comorbidity is related to a poorer prognosis, including treatment resistance, academic problems, risk of suicide, and overall impairment. Studies examining the latent structure of depression support the notion of multiple presentations of depressed youth; however, it is unclear how these presentations are represented among acutely impaired youth. Participants (n = 457) in this naturalistic study were admitted to a psychiatric inpatient unit (Mean age = 14.33 years, SD = 1.94;76% female;46.6% Black/African-American). Selected subscales from the parent-report Behavior Assessment System for Children, Second Edition, were utilized as indicators in a latent profile analysis. Subgroups were validated based on their relationships with meaningful clinical correlates (e.g., family factors, discharge diagnosis) and further described by their associations with demographic variables. A five-class model provided the best balance of fit and parsimony. Subtypes of depressed youth included Predominantly Depressed (39.1%), Oppositional (28.2%), Severely Disruptive (12.3%), Anxious-Oppositional (11.6%), and Anxious-Withdrawn (8.8%). Comorbid symptoms were present in four of the five classes (60.9% of sample). High levels of externalizing symptoms were a prominent clinical feature associated with three classes (52.1% of the sample). Construct validity of the respective classes was demonstrated by differential association with clinical correlates, family characteristics, and demographics. Findings suggest that depressed youth presenting for acute inpatient psychiatric care displayed varied clinical presentations. The identified latent groups aligned with existing research reflecting comorbidity with anxiety, inattention, and externalizing disorders. Findings underscore the need for an increased clinical appreciation of comorbidity and encourage more targeted and effective prevention and treatment strategies.

Percutaneous tibial nerve stimulation versus sacral nerve stimulation for the treatment of faecal incontinence.

Introduction: Faecal incontinence (FI) is a common condition with a significant impact on quality of life (QoL). Neuromodulation treatments delivered by members of the multidisciplinary team including sacral nerve stimulation (SNS) and percutaneous tibial nerve stimulation (PTNS) are options for FI refractory to conservative management. The aim of this study was to assess whether a successful treatment with one neuromodulation modality corresponds with success in the other. Methods: A retrospective review of a prospectively managed neuromodulation database identified 15 patients who had undergone both PTNS and SNS. The definition of success of each treatment was a >50% improvement in any of The St. Mark's Incontinence Score, Manchester Health Questionnaire, or weekly faecal urgency or FI episodes. Results: Complete data from 12 patients was available for assessment and PTNS was delivered as the first treatment in nine patients. Overall, seven patients (58%) had successful PTNS treatment, with 10 (83%) having a successful SNS trials. Of the seven patients who had successful PTNS treatment, six patients (85.4%) went on to have success with SNS. Of the five patients who failed PTNS, four (80%) went on to have SNS success. Five (71%) of those who had positive PTNS outcomes had permanent SNS implantation as their final treatment decision. Conclusion: This study suggests that there is no clear relationship between successful PTNS treatment and an SNS trial period which may be explained by differing mechanisms of action or the potential placebo effect of PTNS. Further work is required to investigate any association in larger studies to inform clinical practice.

Linking Angelman and dup15q data for expanded research (LADDER) database: a model for advancing research, clinical guidance, and therapeutic development for rare conditions.

Angelman syndrome (AS) and duplication 15q (dup15q) syndrome are rare neurogenetic conditions arising from a common locus on the long arm of chromosome 15. Individuals with both conditions share some clinical features (e.g. intellectual disability, epilepsy) and often require lifelong care. Disease-modifying therapies for both conditions are emerging, resulting in a significant need for a better understanding of the natural history of both AS and dup15q. Patient advocacy groups for both conditions recognized a need for a data repository that would link data on individuals from multiple sources to expand research, increase understanding of natural history, and accelerate the development of treatments, resulting in the Linking Angelman and Dup15q Data for Expanded Research (LADDER) Database. This paper describes the development and functionality of the LADDER Database - including challenges, lessons learned, and preliminary feasibility - and how it can be used as a model for other rare conditions.

The LADDER database: a model for advancing research, clinical guidance, and therapeutic development for rare conditions This paper describes the development and functionality of the Linking Angelman and Dup15q Data for Expanded Research (LADDER) Database, which is a data repository for two rare neurogenetic conditions: Angelman syndrome (AS) and duplication 15q (dup15q) syndrome. AS and dup15q syndrome arise from genetic abnormalities on chromosome 15 and share some clinical features (e.g. intellectual disability, epilepsy). LADDER was developed by patient advocacy organizations representing each condition in partnership with RTI International. LADDER links data on individuals from multiple sources to expand research, increase understanding of natural history, and accelerate the development of treatments for both AS and dup15q syndrome. The LADDER Database can be used as a model for expanding research and enhancing clinical trial readiness in other rare conditions.

Ribosome subunit attrition and activation of the p53-MDM4 axis dominate the response of MLL-rearranged cancer cells to WDR5 WIN site inhibition.

The chromatin-associated protein WD Repeat Domain 5 (WDR5) is a promising target for cancer drug discovery, with most efforts blocking an arginine-binding cavity on the protein called the 'WIN' site that tethers WDR5 to chromatin. WIN site inhibitors (WINi) are active against multiple cancer cell types in vitro, the most notable of which are those derived from MLL-rearranged (MLLr) leukemias. Peptidomimetic WINi were originally proposed to inhibit MLLr cells via dysregulation of genes connected to hematopoietic stem cell expansion. Our discovery and interrogation of small-molecule WINi, however, revealed that they act in MLLr cell lines to suppress ribosome protein gene (RPG) transcription, induce nucleolar stress, and activate p53. Because there is no precedent for an anticancer strategy that specifically targets RPG expression, we took an integrated multi-omics approach to further interrogate the mechanism of action of WINi in human MLLr cancer cells. We show that WINi induce depletion of the stock of ribosomes, accompanied by a broad yet modest translational choke and changes in alternative mRNA splicing that inactivate the p53 antagonist MDM4. We also show that WINi are synergistic with agents including venetoclax and BET-bromodomain inhibitors. Together, these studies reinforce the concept that WINi are a novel type of ribosome-directed anticancer therapy and provide a resource to support their clinical implementation in MLLr leukemias and other malignancies.