Comparing self-reported quality of life in youth with bipolar versus other disorders.

OBJECTIVES: This study benchmarks quality of life (QoL) of youth with bipolar disorder (BD) against healthy youth, youth with chronic medical conditions, and youth with other psychiatric disorders. The relative impacts of depressive, (hypo)manic, mixed, and externalizing symptoms on QoL are tested for youth with BD. METHOD: In total, 657 youth completed the Schedule for Affective Disorders and Schizophrenia for Children (KSADS), the KSADS depression and mania scales, the Parent General Behavior Inventory (PGBI), and the Child Behavior Checklist (CBCL). Youth-reported QoL was determined by the Revised Children Quality of Life Questionnaire (KINDL) and was compared to healthy youth, youth with chronic medical conditions, and youth with other psychiatric disorders. RESULTS: Youth with BD reported poorer QoL overall and on most subscales compared to healthy youth, youth with chronic medical conditions, youth with behavior disorders, and youth with other non-behavior/non-mood disorders. QoL in youth with BD did not differ significantly from QoL in youth with unipolar depression. Parent-report and interview-rated depressive symptoms were associated with decreases in Total QoL and all QoL subscales except Family. Externalizing symptoms were associated with decreases in Family QoL and increases in Friend QoL, and (hypo)manic symptoms were associated with increases in Emotional Well-Being QoL. CONCLUSIONS: Depressive symptoms may drive the decline in QoL causing youth with BD to rate their QoL worse than healthy youth, youth with chronic medical conditions, and youth with behavior disorders, but not worse than youth with unipolar depression.

A Machine-Learning Approach to Assess Factors Associated With Hospitalization of Children and Youths in Psychiatric Crisis.

OBJECTIVE: The authors used a machine-learning approach to model clinician decision making regarding psychiatric hospitalization of children and youths in crisis and to identify factors associated with the decision to hospitalize. METHODS: Data consisted of 4,786 mobile crisis response team assessments of children and youths, ages 4.0-19.5 years (mean±SD=14.0±2.7 years, 56% female), in Nevada. The sample assessments were split into training and testing data sets. A random-forest machine-learning algorithm was used to identify variables related to the decision to hospitalize a child or youth after the crisis assessment. Results from the training sample were externally validated in the testing sample. RESULTS: The random-forest model had good performance (area under the curve training sample=0.91, testing sample=0.92). Variables found to be important in the decision to hospitalize a child or youth were acute suicidality, followed by poor judgment or decision making, danger to others, impulsivity, runaway behavior, other risky behaviors, nonsuicidal self-injury, psychotic or depressive symptoms, sleep problems, oppositional behavior, poor functioning at home or with peers, depressive or schizophrenia spectrum disorders, and age. CONCLUSIONS: In crisis settings, clinicians were found to mostly focus on acute factors that increased risk for danger to self or others (e.g., suicidality, poor judgment), current psychiatric symptoms (e.g., psychotic symptoms), and functioning (e.g., poor home functioning, problems with peer relationships) when deciding whether to hospitalize or stabilize a child or youth. To reduce psychiatric hospitalization, community-based services should target interventions to address these important factors associated with the need for a higher level of care among youths in psychiatric crisis.

Improving accuracy of ADHD subtype diagnoses with the ADHD symptom rating scale.

Neuropsychologists evaluate children and adults with ADHD to establish a diagnosis, quantify cognitive deficits associated with ADHD and other common comorbid conditions, and provide recommendations for education and vocational planning. Standardized instruments that align with DSM ADHD symptom criteria are recommended for increasing ADHD diagnostic accuracy. This study examined whether a brief DSM-based symptom rating scale would assist in differentiating subtypes of ADHD. Participants were 253 children diagnosed with ADHD-Inattentive (n = 163) or ADHD-Combined (n = 90). Parents completed the Behavior Assessment System for Children, Second Edition (BASC-2) and DSM-IV ADHD Symptom Rating Scale (SRS) as part of a comprehensive evaluation to establish ADHD diagnoses. The SRS displayed expected convergent and discriminant validity with BASC-2 subscales. The diagnostic accuracy of the SRS subscales to differentiate ADHD was also examined and compared with the BASC-2. Results indicated that SRS Impulsivity, SRS Hyperactivity, and BASC-2 Hyperactivity had significantly better classification accuracy than BASC-2 Attention Problems and SRS Inattention, although they did not differ from each other. The SRS produced symptom profiles consistent with ADHD-Inattentive and Combined subtypes with good classification accuracy when differentiating subtypes. Overall, the SRS is an economical measure that can assist in ADHD presentation differentiation when used as a component of ADHD evaluations.

Elucidating early pubertal timing effects on disordered eating symptoms in young adult women.

INTRODUCTION: Early pubertal timing increases risk for disordered eating (DE) in females, but the extent to which associations persist after puberty and are relevant to all types of DE symptoms is unclear. Factors that link pubertal timing and DE also remain unknown, although leading theories posit that adiposity and body-focused psychosocial factors play a key role. Thus, this study examined pubertal timing effects on several types of DE symptoms in young adult women and evaluated whether body mass index (BMI), pressures for thinness, thin-ideal internalization, and/or history of weight-based teasing account for such associations. METHODS: This study included a racially and ethnically diverse sample of 342 female college students (Mage = 20.44, SD = 3.46). Women retrospectively reported their age at onset of menses, which served as the pubertal timing indicator, and completed self-report questionnaires on DE symptoms, perceived pressures for thinness, thin-ideal internalization, and history of weight-based teasing. BMI was calculated from height/weight measurements. RESULTS: Earlier pubertal timing was associated with body dissatisfaction and binge eating, but not other DE symptoms (dieting, excessive exercise, muscle building) in young adult women. BMI accounted for pubertal timing effects on body dissatisfaction, whereas none of the examined factors explained pubertal timing effects on binge eating. CONCLUSIONS: Earlier pubertal timing may exert long-term effects on only some DE symptoms in women, and the etiologic factors underlying pubertal timing effects on DE outcomes may differ across symptom types.

Decreasing rate of inpatient pediatric bipolar disorder diagnosis in the US between 2004 and 2010.

OBJECTIVES: Diagnosis of bipolar disorder (BD) increased substantially among youth between the mid-1990s and mid-2000s in the United States. This dramatic increase in diagnosis resulted in concern regarding the potential for misdiagnosis of BD among youth. However, the rate of BD diagnosis in the United States had not been evaluated nationally since the mid-2000s. It was unclear whether changes in diagnostic rates continued to occur. Therefore, the present study aimed to assess the pattern of longitudinal trends in the rate of national inpatient BD diagnosis subsequent to 2004. METHODS: Data included a nationally representative dataset of inpatient hospitalizations between 1996 and 2010. De-identified data were obtained from the National Hospital Discharge Survey (NHDS) conducted annually by the National Center for Health Statistics. RESULTS: The proportion of BD diagnoses relative to all psychiatric diagnoses increased between 1996 and 2004 among children and adolescents. The proportion of BD diagnoses then decreased between 2004 and 2010 among children but continued to increase for adolescents. However, population-adjusted rates of BD diagnosis per 10,000 individuals in the general population initially increased until the mid-2000s and then decreased until 2010 for both children and adolescents. CONCLUSIONS: Rates of BD diagnosis substantially decreased for youth between the mid-2000s and 2010. This decline coincided with recommendations for more conservative diagnostic practices due to concerns about overdiagnosis and increasing awareness of the side effects of front-line medications used to treat BD in youth. Findings provide insight into changing trends in inpatient service utilization for BD in the United States.

Unleashing TNF cytotoxicity to enhance cancer immunotherapy.

Tumor necrosis factor (TNF) is a proinflammatory cytokine that is produced and secreted by cytotoxic lymphocytes upon tumor target recognition. Depending on the context, TNF can mediate either pro-survival or pro-death signals. The potential cytotoxicity of T cell-produced TNF, particularly in the context of T cell-directed immunotherapies, has been largely overlooked. However, a spate of recent studies investigating tumor immune evasion through the application of CRISPR-based gene-editing screens have highlighted TNF-mediated killing as an important component of the mammalian T cell antitumor repertoire. In the context of the current understanding of the role of TNF in antitumor immunity, we discuss these studies and touch on their therapeutic implications. Collectively, we provide an enticing prospect to augment immunotherapy responses through TNF cytotoxicity.

HOIP limits anti-tumor immunity by protecting against combined TNF and IFN-gamma-induced apoptosis.

The success of cancer immunotherapy is limited to a subset of patients, highlighting the need to identify the processes by which tumors evade immunity. Using CRISPR/Cas9 screening, we reveal that melanoma cells lacking HOIP, the catalytic subunit of LUBAC, are highly susceptible to both NK and CD8+ T-cell-mediated killing. We demonstrate that HOIP-deficient tumor cells exhibit increased sensitivity to the combined effect of the inflammatory cytokines, TNF and IFN-γ, released by NK and CD8+ T cells upon target recognition. Both genetic deletion and pharmacological inhibition of HOIP augment tumor cell sensitivity to combined TNF and IFN-γ. Together, we unveil a protective regulatory axis, involving HOIP, which limits a transcription-dependent form of cell death that engages both intrinsic and extrinsic apoptotic machinery upon exposure to TNF and IFN-γ. Our findings highlight HOIP inhibition as a potential strategy to harness and enhance the killing capacity of TNF and IFN-γ during immunotherapy.

MAIT cells regulate NK cell-mediated tumor immunity.

The function of MR1-restricted mucosal-associated invariant T (MAIT) cells in tumor immunity is unclear. Here we show that MAIT cell-deficient mice have enhanced NK cell-dependent control of metastatic B16F10 tumor growth relative to control mice. Analyses of this interplay in human tumor samples reveal that high expression of a MAIT cell gene signature negatively impacts the prognostic significance of NK cells. Paradoxically, pre-pulsing tumors with MAIT cell antigens, or activating MAIT cells in vivo, enhances anti-tumor immunity in B16F10 and E0771 mouse tumor models, including in the context of established metastasis. These effects are associated with enhanced NK cell responses and increased expression of both IFN-γ-dependent and inflammatory genes in NK cells. Importantly, activated human MAIT cells also promote the function of NK cells isolated from patient tumor samples. Our results thus describe an activation-dependent, MAIT cell-mediated regulation of NK cells, and suggest a potential therapeutic avenue for cancer treatment.

Irritability Is Associated with Illness Severity and Anhedonia Is Associated with Functional Impairment Among Depressed Children and Adolescents.

Objectives: Irritability and anhedonia are cardinal symptoms of depression for children and adolescents. However, anhedonia may be more strongly associated with illness severity compared with irritability. The present study evaluated the impact of irritability and anhedonia on symptom severity and functional impairment among depressed children and adolescents. Methods: Participants were 383 children and adolescents presenting for outpatient treatment at a community mental health center or academic medical center. Children and adolescents were diagnosed with unipolar depression or bipolar disorder. Regression models predicted depression severity and functional impairment from irritability and anhedonia after covarying age, gender, depressive and hypomanic symptoms, and diagnosis. Results: Greater irritability and anhedonia were associated with more severe depression symptoms. Greater irritability, but not anhedonia, was associated with lower global functioning and family quality of life (QoL), and more externalizing problems. Greater anhedonia was associated with lower overall, emotional, self-esteem, and social QoL. Neither irritability nor anhedonia was associated with school or physical QoL, nonsuicidal self-injury, suicidal ideation, number of comorbid diagnoses, or internalizing problems. Conclusions: Irritability was associated with more markers of depression severity, whereas anhedonia was associated with indicators of functional impairment. This study used a cross-sectional observational design and therefore cannot provide information about cause and effect relationships between variables. Irritability and anhedonia were derived from their respective subscales of the General Behavior Inventory and included only caregiver-reported symptoms but not child- or adolescent-reported symptoms. Identifying the impact of specific symptoms of depression may assist clinicians in delivering more individualized interventions to target symptoms that result in greater impairment.

Examination of the Influence of Cognitive Behavior Therapy Components, Consumer Satisfaction and Engagement in Mothers Referred for Drug Abuse and Child Neglect on Treatment Outcomes.

Psychological interventions for child maltreatment have predominately been limited to family-supported, multi-component behavioral therapies. Although these comprehensive programs have resulted in positive outcomes, they are relatively costly and there is limited information available as to how the components of these programs influence treatment outcomes. In this study, the CBT components of an evidence-based treatment for child neglect and drug abuse (Family Behavior Therapy) were examined in regards to consumer preferences, consumer engagement and treatment outcomes. Thirty-five mothers identified for child neglect and drug abuse were administered various CBT components successively and cumulatively based on their preferences. Repeated measure ANOVAs indicated that participants chose to receive components that were specific to managing antecedents to drug abuse and child neglect most frequently, followed by parenting skills training, communication skills training, and job/financial skills training. No differences were found in treatment providers' ratings of the participants' engagement across intervention components throughout treatment. Participants rated the intervention components as similarly helpful. Partial correlations revealed that participants' ratings of helpfulness and provider ratings of participants' engagement were not associated with improved drug use outcomes at 6- and 10-months post baseline. Participants' ratings of helpfulness were associated with child maltreatment outcomes at 10-month post baseline, and provider ratings of participants' engagement were associated with child maltreatment outcomes at both 6- and 10-month post baseline. Participants identified for neglect not related to drug exposure in utero improved at a higher percentage than did participants identified for in utero drug exposure, and receiving behavioral intervention components more frequently led to greater percentages of participants improving in both drug use and child maltreatment outcomes.

Social Cognition in Children With ADHD.

Objective: Despite evidence of social skill deficits in children with ADHD, there is no consensus regarding a social cognitive profile and whether these skills predict behavior. Therefore, a comprehensive battery was used to investigate the relationship between social cognition and behavioral functioning. Method: Children ages 7 to 13 with ADHD (n = 25) and controls (n = 25) completed tests assessing social cognitive domains (affect recognition and theory of mind [ToM]). Parents completed measures of social cognition (pragmatic language ability and empathy), behavioral symptoms, and adaptive functioning. Results: Children with ADHD performed significantly worse on measures of cognitive ToM and affect recognition and received lower ratings of pragmatic language and cognitive empathy than typically developing peers. These domains, particularly pragmatic language, predicted parent ratings of problematic and adaptive behaviors. Conclusion: Results establish a relationship between specific social cognitive abilities and daily functioning, which has implications for treatment.

Decreasing rate of inpatient pediatric bipolar disorder diagnosis between 2005 and 2015.

INTRODUCTION: The rate of bipolar disorder (BD) diagnosis in youth increased between the mid-1990s and mid-2000s in the U.S. and remained low in other countries. The discrepancy resulted in concerns regarding misdiagnosis of BD. However, the longitudinal trajectory of BD diagnosis subsequent to the mid-2000s was unclear. Therefore, the current study assessed longitudinal changes in the rate of inpatient BD diagnosis in the state of Nevada between 2005 and 2015. METHODS: Data included Medicaid administrative billing claims (n = 48,108 unique admissions) for youth 5-17 hospitalized at one of five psychiatric inpatient hospitals in Nevada. Regressions assessed changes in the rate of diagnosis over time for BD and compared to depressive disorders (DD). RESULTS: The rate of BD diagnosis declined between 2005 and 2015. The rate of DD diagnosis remained stable for boys and increased substantially for girls during the same time period. LIMITATIONS: Some individuals may have been repeatedly hospitalized throughout the study period and contribute more than one unique admission. Findings from this study were limited to a sample of Medicaid-insured youth in a single state. CONCLUSIONS: The rate of mood disorder diagnosis in inpatient units is changing. The use of BD as a diagnosis is decreasing in Nevada which may reflect US trends nationally, though still high by international comparison. In contrast, DD increased for girls but not boys. Awareness of the current diagnostic trends for BD may assist inpatient administrators and clinicians in preparing for anticipated service utilization and planning allocation of resources.

Comparing the accuracy and speed of four data-checking methods.

Double entry locates and corrects more data-entry errors than does visual checking or reading the data out loud with a partner. However, many researchers do not use double entry, because it is substantially slower. Therefore, in this study we examined the speed and accuracy of solo read aloud, which has never before been examined and might be faster than double entry. To compare these four methods, we deliberately introduced errors while entering 20 data sheets and then asked 412 randomly assigned undergraduates to locate and correct these errors. Double entry was significantly and substantially more accurate than the other data-checking methods. However, the double-entry participants still made some errors. Close examination revealed that whenever double-entry participants made errors, they made the two sets of entries match, sometimes by introducing new errors into the dataset. This suggests that double entry can be improved by focusing attention on making entries match the original data sheets (rather than each other), perhaps by using a new person for mismatch correction. Solo read aloud was faster than double entry, but not as accurate. Double entry remains the gold standard in data-checking methods. However, solo read aloud was often substantially more accurate than partner read aloud and was more accurate than visual checking for one type of data. Therefore, when double entry is not possible, we recommend that researchers use solo read aloud or visual checking.

Natural Killer Cells Suppress T Cell-Associated Tumor Immune Evasion.

Despite the clinical success of cancer immunotherapies, the majority of patients fail to respond or develop resistance through disruption of pathways that promote neo-antigen presentation on MHC I molecules. Here, we conducted a series of unbiased, genome-wide CRISPR/Cas9 screens to identify genes that limit natural killer (NK) cell anti-tumor activity. We identified that genes associated with antigen presentation and/or interferon-γ (IFN-γ) signaling protect tumor cells from NK cell killing. Indeed, Jak1-deficient melanoma cells were sensitized to NK cell killing through attenuated NK cell-derived IFN-γ-driven transcriptional events that regulate MHC I expression. Importantly, tumor cells that became resistant to T cell killing through enrichment of MHC I-deficient clones were highly sensitive to NK cell killing. Taken together, we reveal the genes targeted by tumor cells to drive checkpoint blockade resistance but simultaneously increase their vulnerability to NK cells, unveiling NK cell-based immunotherapies as a strategy to antagonize tumor immune escape.

Patterns of treatment for psychiatric disorders among children and adolescents in Mississippi Medicaid.

The nature of services for psychiatric disorders in public health systems has been understudied, particularly with regard to frequency, duration, and costs. The current study examines patterns of service reception and costs among Medicaid-covered youth newly diagnosed with anxiety, depression, or behavioral disturbance in a large data set of provider billing claims submitted between 2015-2016. Eligibility criteria included: 1) identification of an initial diagnosis of a single anxiety, unipolar mood, or specific behavioral disorder; 2) continuous Medicaid eligibility over the duration of the time period studied; and 3) under 18 years of age on the date of initial psychiatric diagnosis. The final cohort included 7,627 cases with a mean age of 10.65 (±4.36), of which 58.04% were male, 57.09% were Black, 38.97% were White, and 3.95% were of other ethnicities. Data indicated that 65.94% of the cohort received at least some follow-up services within a median 18 days of diagnosis. Of those, 54.27% received a combination of medical and psychosocial services, 32.01% received medical services only, and 13.72% received psychosocial services only. Overall median costs for direct treatment were $576.69, with wide discrepancies between the lowest (anxiety = $308.41) and highest (behavioral disturbance = $653.59) diagnostic categories. Across all categories the frequency and duration of psychosocial services were much lower than would be expected in comparison to data from a well-known effectiveness trial. Overall, follow-up to psychiatric diagnosis could be characterized as highly variable, underutilized, and emphasizing biomedical treatment. Understanding more about these patterns may facilitate systematic improvements and greater cost efficiency in the future.

The registration continuum in clinical science: A guide toward transparent practices.

Clinical scientists can use a continuum of registration efforts that vary in their disclosure and timing relative to data collection and analysis. Broadly speaking, registration benefits investigators by offering stronger, more powerful tests of theory with particular methods in tandem with better control of long-run false positive error rates. Registration helps clinical researchers in thinking through tensions between bandwidth and fidelity that surround recruiting participants, defining clinical phenotypes, handling comorbidity, treating missing data, and analyzing rich and complex data. In particular, registration helps record and justify the reasons behind specific study design decisions, though it also provides the opportunity to register entire decision trees with specific endpoints. Creating ever more faithful registrations and standard operating procedures may offer alternative methods of judging a clinical investigator's scientific skill and eminence because study registration increases the transparency of clinical researchers' work. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Antagonism of IAPs Enhances CAR T-cell Efficacy.

Chimeric antigen receptor (CAR) T-cell therapy has proven successful in the treatment of hematological malignancies, notably acute lymphoblastic leukemia and B-cell lymphoma. However, the efficacy of CAR T cells against solid tumors is poor, likely due to tumor-associated immunosuppression. Here, we demonstrated that antagonizing the "inhibitor of apoptosis proteins" with the clinical smac-mimetic, birinapant, significantly enhanced the antitumor activity of CAR T cells in a tumor necrosis factor (TNF)-dependent manner. Enhanced tumor cell death occurred independently of the perforin-mediated granule exocytosis pathway, underscoring the cytotoxic potential of CAR T-cell-derived TNF. Combining CAR T-cell therapy with birinapant significantly reduced established tumor growth in vivo, where either therapy alone was relatively ineffective. Using patient biopsy-derived tumoroids, we demonstrated the synergistic potential of combining CAR T-cell therapy with smac-mimetics. Taken together, we identified CAR T-cell-derived TNF as a potent antitumor effector, which can be further harnessed by smac-mimetics.

Tumor immune evasion arises through loss of TNF sensitivity.

Immunotherapy has revolutionized outcomes for cancer patients, but the mechanisms of resistance remain poorly defined. We used a series of whole-genome clustered regularly interspaced short palindromic repeat (CRISPR)-based screens performed in vitro and in vivo to identify mechanisms of tumor immune evasion from cytotoxic lymphocytes [CD8+ T cells and natural killer (NK) cells]. Deletion of key genes within the tumor necrosis factor (TNF) signaling, interferon-γ (IFN-γ) signaling, and antigen presentation pathways provided protection of tumor cells from CD8+ T cell-mediated killing and blunted antitumor immune responses in vivo. Deletion of a number of genes in the TNF pathway also emerged as the key mechanism of immune evasion from primary NK cells. Our screens also identified that the metabolic protein 2-aminoethanethiol dioxygenase (Ado) modulates sensitivity to TNF-mediated killing by cytotoxic lymphocytes and is required for optimal control of tumors in vivo. Remarkably, we found that tumors delete the same genes when exposed to perforin-deficient CD8+ T cells, demonstrating that the dominant immune evasion strategy used by tumor cells is acquired resistance to T cell-derived cytokine-mediated antitumor effects. We demonstrate that TNF-mediated bystander killing is a potent T cell effector mechanism capable of killing antigen-negative tumor cells. In addition to highlighting the importance of TNF in CD8+ T cell- and NK cell-mediated killing of tumor cells, our study also provides a comprehensive picture of the roles of the TNF, IFN, and antigen presentation pathways in immune-mediated tumor surveillance.

DOCK8 Drives Src-Dependent NK Cell Effector Function.

Mutations in the dedicator of cytokinesis 8 (DOCK8) gene cause an autosomal recessive form of hyper-IgE syndrome, characterized by chronic immunodeficiency with persistent microbial infection and increased incidence of malignancy. These manifestations suggest a defect in cytotoxic lymphocyte function and immune surveillance. However, how DOCK8 regulates NK cell-driven immune responses remains unclear. In this article, we demonstrate that DOCK8 regulates NK cell cytotoxicity and cytokine production in response to target cell engagement or receptor ligation. Genetic ablation of DOCK8 in human NK cells attenuated cytokine transcription and secretion through inhibition of Src family kinase activation, particularly Lck, downstream of target cell engagement or NKp30 ligation. PMA/Ionomycin treatment of DOCK8-deficient NK cells rescued cytokine production, indicating a defect proximal to receptor ligation. Importantly, NK cells from DOCK8-deficient patients had attenuated production of IFN-γ and TNF-α upon NKp30 stimulation. Taken together, we reveal a novel molecular mechanism by which DOCK8 regulates NK cell-driven immunity.