Recognizing Borderline Personality Disorder in Men: Gender Differences in BPD Symptom Presentation.

Women are predominantly diagnosed with BPD, with studies estimating a 3:1 female-to-male diagnostic ratio in clinical settings. Previous studies present conflicting findings regarding gender-level criterion differences, with some indicating differences in contradictory criteria. These studies primarily utilize outpatient samples, highlighting gaps in the literature. Thus, the current study investigates gender-level criterion differences, functioning, and impairment within a novel, partial hospital sample. Participants included (a) a sample of 1,153 individuals from the total population of partial hospital patients regardless of BPD diagnosis and (b) 365 BPD-positive patients who were assessed via semistructured clinical interview and provided consent for data collection during the intake process. Results indicated that (a) women endorsed higher relationship instability than men and (b) there were no significant differences in level of functioning across the gender subsamples. Examining gender differences in BPD symptomatology has clinical implications in improving recognition and addressing potential biases associated with men and mental health.

Lineage specific transcription factor waves reprogram neuroblastoma from self-renewal to differentiation.

Temporal regulation of super-enhancer (SE) driven transcription factors (TFs) underlies normal developmental programs. Neuroblastoma (NB) arises from an inability of sympathoadrenal progenitors to exit a self-renewal program and terminally differentiate. To identify SEs driving TF regulators, we use all-trans retinoic acid (ATRA) to induce NB growth arrest and differentiation. Time-course H3K27ac ChIP-seq and RNA-seq reveal ATRA coordinated SE waves. SEs that decrease with ATRA link to stem cell development (MYCN, GATA3, SOX11). CRISPR-Cas9 and siRNA verify SOX11 dependency, in vitro and in vivo. Silencing the SOX11 SE using dCAS9-KRAB decreases SOX11 mRNA and inhibits cell growth. Other TFs activate in sequential waves at 2, 4 and 8 days of ATRA treatment that regulate neural development (GATA2 and SOX4). Silencing the gained SOX4 SE using dCAS9-KRAB decreases SOX4 expression and attenuates ATRA-induced differentiation genes. Our study identifies oncogenic lineage drivers of NB self-renewal and TFs critical for implementing a differentiation program.

Validity of the DSM-5 Mixed Features Specifier Interview.

OBJECTIVES: To examine the reliability and validity of a semi-structured interview assessing the features of the DSM-5 mixed features specifier. Our goal was to develop an instrument that could be used for both diagnostic and severity measurement purposes. METHODS: Four hundred fifty-nine psychiatric patients in a depressive episode were interviewed by a trained diagnostic rater who administered semi-structured interviews including the DSM-5 Mixed Features Specifier Interview (DMSI). We examined the inter-rater reliability and psychometric properties of the DMSI. The patients were rated on clinician rating scales of depression, anxiety, and irritability, and measures of psychosocial functioning, suicidality, and family history of bipolar disorder. RESULTS: The DMSI had excellent joint-interview interrater reliability. More than twice as many patients met the DSM-5 mixed features specifier criteria during the week before the assessment than for the majority of the episode (9.4% vs. 3.9%). DMSI total scores were more highly correlated with a clinician-rated measure of manic symptoms than with measures of depression and anxiety. More patients with bipolar depression met the mixed features specifier than patients with MDD. Amongst patients with MDD, those with mixed features more frequently had a family history of bipolar disorder, were more frequently diagnosed with anxiety disorders, attention deficit disorder, and borderline personality disorder, more frequently had attempted suicide, and were more severely depressed, anxious, and irritable. CONCLUSION: The DMSI is a reliable and valid measure of the presence of the DSM-5 mixed features specifier in depressed patients as well as the severity of the features of the specifier.

Hyperactive STAT5 hijacks T cell receptor signaling and drives immature T cell acute lymphoblastic leukemia.

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive immature T cell cancer. Mutations in IL7R have been analyzed genetically, but downstream effector functions such as STAT5A and STAT5B hyperactivation are poorly understood. Here, we studied the most frequent and clinically challenging STAT5BN642H driver in T cell development and immature T cell cancer onset and compared it with STAT5A hyperactive variants in transgenic mice. Enhanced STAT5 activity caused disrupted T cell development and promoted an early T cell progenitor-ALL phenotype, with upregulation of genes involved in T cell receptor (TCR) signaling, even in absence of surface TCR. Importantly, TCR pathway genes were overexpressed in human T-ALL and mature T cell cancers and activation of TCR pathway kinases was STAT5 dependent. We confirmed STAT5 binding to these genes using ChIP-Seq analysis in human T-ALL cells, which were sensitive to pharmacologic inhibition by dual STAT3/5 degraders or ZAP70 tyrosine kinase blockers in vitro and in vivo. We provide genetic and biochemical proof that STAT5A and STAT5B hyperactivation can initiate T-ALL through TCR pathway hijacking and suggest similar mechanisms for other T cell cancers. Thus, STAT5 or TCR component blockade are targeted therapy options, particularly in patients with chemoresistant clones carrying STAT5BN642H.

STAT3 couples activated tyrosine kinase signaling to the oncogenic core transcriptional regulatory circuitry of anaplastic large cell lymphoma.

Anaplastic large cell lymphoma (ALCL) is an aggressive, CD30+ T cell lymphoma of children and adults. ALK fusion transcripts or mutations in the JAK-STAT pathway are observed in most ALCL tumors, but the mechanisms underlying tumorigenesis are not fully understood. Here, we show that dysregulated STAT3 in ALCL cooccupies enhancers with master transcription factors BATF3, IRF4, and IKZF1 to form a core regulatory circuit that establishes and maintains the malignant cell state in ALCL. Critical downstream targets of this network in ALCL cells include the protooncogene MYC, which requires active STAT3 to facilitate high levels of MYC transcription. The core autoregulatory transcriptional circuitry activity is reinforced by MYC binding to the enhancer regions associated with STAT3 and each of the core regulatory transcription factors. Thus, activation of STAT3 provides the crucial link between aberrant tyrosine kinase signaling and the core transcriptional machinery that drives tumorigenesis and creates therapeutic vulnerabilities in ALCL.

Negative Mood Dysregulation Loads Strongly Onto Common Factors With Many Forms of Psychopathology: Considerations for Assessing Nonspecific Symptoms.

There have been proposals to expand definitions for categorical disorders and dimensionally conceptualized syndromes (e.g., psychopathy) to include negative mood lability and dysregulation (NMD). Factor analytic results are often presented in support of these proposals, and we provide factor analytic demonstrations across clinically oriented samples showing that NMD indicators load strongly onto factors with a range of psychopathology. This is unsurprising from a transdiagnostic perspective but shows that factor analysis could potentially be used to justify expanding definitions for specific constructs even though NMD indicators show strong, nonspecific loadings on psychopathology factors ranging widely in nature. Expanding construct definitions and assessment approaches to emphasize NMD also may negatively impact discriminant validity. We agree that targeting NMD is essential for comprehensive assessment, but our demonstrative analyses highlight a need for using factor analysis and other statistical methods in a careful, theoretically driven manner when evaluating psychopathology structure and developing measures.

Examining Measurement Invariance in the Personality Inventory for DSM-5 Brief Form Across Sexual and Gender Minority Status.

The Personality Inventory for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Brief Form (PID-5-BF) was developed with an assumption of invariance across sexual and gender minority (SGM) individuals. This assumption has yet to be tested empirically. Using multigroup confirmatory factor analysis, we examined measurement invariance in the PID-5-BF across the SGM status in clinical (N = 1,174; n = 254 SGM) and nonclinical (N = 1,456; n = 151 SGM) samples. Measurement invariance was supported for the PID-5-BF structure, item thresholds, and factor loadings, but not at the item intercept level. SGM individuals endorsed higher negative affectivity, antagonism, disinhibition, and psychoticism domains in both samples. In the clinical sample, adjusting for partial invariance decreased detachment and antagonism levels for SGM persons. In the nonclinical sample, adjusting for partial invariance reduced antagonism disparities in the SGM group, even rendering original group differences null. Our results support the use of the PID-5-BF in SGM populations but indicate that some measurement bias may drive observed disparities in maladaptive trait domains and, in turn, personality disorder diagnosis.

Fluctuations in anger, depressive symptoms, and self-injurious thoughts and behaviors throughout partial hospitalization treatment.

Self-injurious thoughts and behavior (SITB), including passive and active suicidal ideation (SI) and self-harm (SH) urges and behavior, are critical phenomena to predict and target during treatment. Partial hospital programs (PHP) provide unique opportunities to understand how negative affect (e.g., depression and anger) and SITB fluctuate daily. The current study aimed to explore associations between aspects of negative affect (depression and anger) and types of SITB throughout PHP treatment. PHP patients (N = 1625) who attend at least five days of treatment were included in the current sample. Anger-related symptoms, depressive symptoms, SH urges, SH occurrence, passive SI, and active SI were measured daily. A series of generalized linear mixed models were conducted to examine whether depressive and anger-related symptoms predicted SITB across patients (between-person) and throughout PHP treatment (within-person). At the between-person level, higher average depressive symptoms predicted greater severity of all forms of SITB, whereas higher average anger-related symptoms predicted greater severity SH urges and occurrence. At the within-person level, increases in depressive symptoms were associated with increases in all aspects of SITB, whereas increases in anger-related symptoms predicted increases in passive and active SI. The current study suggests that monitoring changes in negative affect throughout treatment can provide possible targets to reduce SITB.

Identifying the DSM-5 mixed features specifier in depressed patients: A comparison of measures.

BACKGROUND: A commonly used measure to assess mixed features in depressed patients is the Young Mania Rating Scale (YMRS), which only partially aligns with the DSM-5 criteria. Different algorithms on the YMRS have been used to approximate the DSM-5 mixed features criteria. In the present report from the Rhode Island Methods to Improve Diagnostic Assessment and Services (MIDAS) project, we examined the agreement and validity of different approaches towards assessing the mixed features specifier. METHODS: Three hundred nine depressed psychiatric patients were interviewed with the Structured Clinical Interview for DSM-IV, the DSM-5 Mixed Features Specifier Interview (DMSI) and the YMRS. Seven definitions of mixed features were examined, two based on the DMSI and five from the YMRS. RESULTS: The prevalence of mixed features varied 8-fold amongst the 7 definitions. The level of agreement between the YMRS definitions and the DMSI was poor. For each definition, mixed features were significantly more common in patients with bipolar disorder than major depressive disorder. A family history of bipolar disorder was significantly associated with the DMSI assessment of mixed features but none of the YMRS approaches. LIMITATIONS: The ratings on the measures were not independent of each other. The sample size was too small to compare the patients with bipolar I and bipolar II disorder. CONCLUSIONS: While there was evidence of validity for both the DSM-5 and YMRS approaches towards identifying mixed features, the 2 approaches are not interchangeable. The algorithm on the YMRS used to classify patients has a significant impact on prevalence.

Better than we think: Is the treatment of depressed patients more effective than we think?

BACKGROUND: Most studies of depression treatment rely on measures of symptom severity to evaluate outcome. We hypothesized that many patients would consider themselves to have benefitted significantly from treatment despite not being considered a responder according to a measure of depression symptom severity (ie, 50% reduction in symptom score). METHODS: In our study, 854 patients with major depressive disorder completed the Remission from Depression Questionnaire, a self-report measure that assesses several constructs patients consider to be relevant for assessing treatment outcome. At discharge, patients completed the Patient Global Rating of Improvement (PGI) to gauge effectiveness of treatment. RESULTS: Less than 40% of patients were responders on the depressive symptom subscale, whereas two-thirds of the sample were PGI responders. Among patients who were PGI responders but nonresponders on the depression symptoms scale, more than one-half were responders on at least 1 of 4 nonsymptom domains (functioning, quality of life, coping ability, positive mental health). CONCLUSIONS: A patient-centered approach to evaluating outcome goes beyond an assessment of symptoms. When viewed from a broader perspective, the results of our study suggest that patients with depression benefit more from treatment than is suggested by only examining outcome from a symptom-based perspective.

A Bridge Between DSM-5 Section II Personality Disorder Criteria and ICD-11 Personality Disorder Trait Domains.

The organization of personality pathology into trait domains (vs. specific disorders) in ICD-11 represents an important shift in personality disorder (PD) nosology. However, to facilitate clinical implementation, a bridge is needed between this system and the DSM-5 Section II system familiar to many researchers and clinicians. In this study, individual DSM-5 PD criteria were assigned to ICD-11 trait domains based on the published Clinical Descriptions and Diagnostic Requirements. This scoring scheme was examined empirically alongside DSM-5 PD dimensions (using SIDP ratings from the MIDAS project; N = 2,147 outpatients) in terms of descriptive properties and relations with psychosocial morbidity and functioning. Most PD criteria could be matched to at least one ICD-11 trait domain, indicating considerable cross-system continuity. However, points of incongruity are noteworthy for research and clinical applications. Results provide key information for bridging categorical and dimensional frameworks, indicating that the shift toward trait-based PD models need not be as disruptive as feared.

A Pilot Randomized Controlled Trial of the Feasibility and Acceptability of Acceptance and Commitment Therapy for Comorbid Social Anxiety Disorder in a Routine Practice Setting.

A prior open trial of acceptance and commitment therapy (ACT) for comorbid social anxiety disorder (SAD) and depression showed clinically significant improvement over the course of 16 sessions. The aim of the current study was to test the feasibility and acceptability of ACT for this population in a pilot randomized trial within a routine practice setting. Patients (n = 26) were randomly assigned to 16 weeks of medication treatment as usual (mTAU) versus mTAU plus ACT (mTAU + ACT). Results showed that a significantly greater percentage of patients in mTAU not only dropped out of the study but also dropped out of treatment at the practice altogether, compared to patients in mTAU + ACT. Overall, results from this study suggest that having a comparison condition of mTAU alone in a randomized trial in a routine practice setting is not feasible and that patients with comorbid forms of SAD may require psychotherapy to remain engaged in treatment in standard clinical practice. Preliminary results for patients within the mTAU + ACT condition on treatment satisfaction and outcomes were comparable to results from the prior open trial, suggesting that ACT itself is worthy of further investigation. Further modifications to the study design may be needed to develop a feasible and acceptable comparison condition against which to test ACT for comorbid SAD in a routine practice setting.

50% Improvement: Should Treatment Response Go Beyond Symptom Improvement When Evaluating the Treatment of Depression?

Background: The emphasis on symptom resolution in depression treatment research is at variance with the recommendations of official treatment guidelines and the results of surveys of depressed patients' views of the most important treatment goals. In the present study, we examined the interrelationship between response rates on various outcome domains and whether response on each domain was associated with patients' global rating of improvement (PGI) reported upon treatment completion. We also examined whether the PGI was associated with the number of domains on which the patients had achieved responder status and which domains were independent predictors of PGI response.Methods: Between January 2016 to April 2022, 844 patients with DSM-IV major depressive disorder completed the Remission from Depression Questionnaire (RDQ), a self-report measure that assesses 6 constructs considered by patients to be relevant to assessing treatment outcome. The patients completed the RDQ at admission and discharge from the treatment program. For each domain, response was defined as a 50% or greater reduction in scores. At discharge, the patients rated the PGI.Results: The patients significantly improved from admission to discharge on each of the 6 domains assessed on the RDQ (Cohen d range, 1.09-1.55). The responders on each domain reported significantly greater improvement on the global rating of improvement at discharge (all P values < .001). Responder status in one domain mostly co-occurred with responder status in another domain. In a logistic regression analysis, responses on all domains except nondepressive symptoms were independently associated with PGI response.Conclusions: The results of the present study are consistent with the results of multiple patient surveys which have suggested that focusing on symptom reduction is too narrow of an approach when measuring outcome in the treatment of depression. Expanding the assessment of outcome beyond symptoms and viewing nonsymptomatic outcome domains as critical composites of primary endpoints would be more consistent with a patient-centered approach toward the treatment of depression.

Genetic predisposition to neuroblastoma results from a regulatory polymorphism that promotes the adrenergic cell state.

Childhood neuroblastomas exhibit plasticity between an undifferentiated neural crest-like mesenchymal cell state and a more differentiated sympathetic adrenergic cell state. These cell states are governed by autoregulatory transcriptional loops called core regulatory circuitries (CRCs), which drive the early development of sympathetic neuronal progenitors from migratory neural crest cells during embryogenesis. The adrenergic cell identity of neuroblastoma requires LMO1 as a transcriptional cofactor. Both LMO1 expression levels and the risk of developing neuroblastoma in children are associated with a single nucleotide polymorphism, G/T, that affects a GATA motif in the first intron of LMO1. Here, we showed that WT zebrafish with the GATA genotype developed adrenergic neuroblastoma, while knock-in of the protective TATA allele at this locus reduced the penetrance of MYCN-driven tumors, which were restricted to the mesenchymal cell state. Whole genome sequencing of childhood neuroblastomas demonstrated that TATA/TATA tumors also exhibited a mesenchymal cell state and were low risk at diagnosis. Thus, conversion of the regulatory GATA to a TATA allele in the first intron of LMO1 reduced the neuroblastoma-initiation rate by preventing formation of the adrenergic cell state. This mechanism was conserved over 400 million years of evolution, separating zebrafish and humans.

Reliability and validity of the difficult to treat depression questionnaire (DTDQ).

It has recently been recommended that treatment resistant depression be reconceptualized and renamed as difficult to treat depression (DTD). A consensus statement by an expert panel identified multiple variables associated with DTD and emphasized the importance of conducting a comprehensive evaluation of patients to identify predictors of inadequate treatment response. For practical reasons, it would be desirable to develop a self-report scale that can be incorporated into clinical practice that identifies patient, clinical, and treatment risk factors for DTD. Nine hundred twenty depressed patients completed the Difficult to Treat Depression Questionnaire (DTDQ). A subset of patients completed the scale a second time and completed the Remission from Depression Questionnaire at admission and discharge from a partial hospital program. The DTDQ demonstrated excellent internal consistency and test-retest reliability. Both the total DTDQ and the number of prior failed medication trials, the metric primarily relied upon to classify treatment resistant depression, predicted outcome. However, the DTDQ continued to be significantly associated with outcome after controlling for the number of failed trials, whereas the number of failed trials did not predict outcome after controlling for DTDQ scores. The DTDQ is a reliable and valid measure of the recently discussed concept of DTD.

SOX11 regulates SWI/SNF complex components as member of the adrenergic neuroblastoma core regulatory circuitry.

The pediatric extra-cranial tumor neuroblastoma displays a low mutational burden while recurrent copy number alterations are present in most high-risk cases. Here, we identify SOX11 as a dependency transcription factor in adrenergic neuroblastoma based on recurrent chromosome 2p focal gains and amplifications, specific expression in the normal sympatho-adrenal lineage and adrenergic neuroblastoma, regulation by multiple adrenergic specific (super-)enhancers and strong dependency on high SOX11 expression in adrenergic neuroblastomas. SOX11 regulated direct targets include genes implicated in epigenetic control, cytoskeleton and neurodevelopment. Most notably, SOX11 controls chromatin regulatory complexes, including 10 SWI/SNF core components among which SMARCC1, SMARCA4/BRG1 and ARID1A. Additionally, the histone deacetylase HDAC2, PRC1 complex component CBX2, chromatin-modifying enzyme KDM1A/LSD1 and pioneer factor c-MYB are regulated by SOX11. Finally, SOX11 is identified as a core transcription factor of the core regulatory circuitry (CRC) in adrenergic high-risk neuroblastoma with a potential role as epigenetic master regulator upstream of the CRC.

Genetic Predisposition to Neuroblastoma Results from a Regulatory Polymorphism that Promotes the Adrenergic Cell State.

Childhood neuroblastomas exhibit plasticity between an undifferentiated neural crest-like "mesenchymal" cell state and a more differentiated sympathetic "adrenergic" cell state. These cell states are governed by autoregulatory transcriptional loops called core regulatory circuitries (CRCs), which drive the early development of sympathetic neuronal progenitors from migratory neural crest cells during embryogenesis. The adrenergic cell identity of neuroblastoma requires LMO1 as a transcriptional co-factor. Both LMO1 expression levels and the risk of developing neuroblastoma in children are associated with a single nucleotide polymorphism G/T that affects a G ATA motif in the first intron of LMO1. Here we show that wild-type zebrafish with the G ATA genotype develop adrenergic neuroblastoma, while knock-in of the protective T ATA allele at this locus reduces the penetrance of MYCN-driven tumors, which are restricted to the mesenchymal cell state. Whole genome sequencing of childhood neuroblastomas demonstrates that T ATA/ T ATA tumors also exhibit a mesenchymal cell state and are low risk at diagnosis. Thus, conversion of the regulatory G ATA to a T ATA allele in the first intron of LMO1 reduces the neuroblastoma initiation rate by preventing formation of the adrenergic cell state, a mechanism that is conserved over 400 million years of evolution separating zebrafish and humans.

Pathways to effective surgical coverage in a lower-middle-income country: A multiple methods study of the family physician-led generalist surgical team in rural Nepal.

The Lancet Commission on Global Surgery (LCoGS) recommends using specialist surgical workforce density as one of 6 core indicators for monitoring universal access to safe, affordable surgical and anaesthesia care. Using Nepal as a case study, we explored the capacity of a generalist workforce (led by a family physician or MD general practitioner and non-physician anaesthetist) to enable effective surgical delivery through task-shifting. Using a multiple-methods approach, we retrospectively mapped essential surgical care and the enabling environment for surgery in 39 hospitals in 25 remote districts in Nepal and compared it with LCoGS indicators. All 25 districts performed surgery, 21 performed Caesarean section (CS), and 5 met at least 50% of district CS needs. Generalist surgical teams performed CS, the essential major operation at the district level, and very few laparotomies, but no operative orthopaedics. The density of specialist Surgeon/Anaesthesiologist/Obstetrician (SAO) was 0·4/100,000; that of Generalist teams (gSAO) led by a family physician (MD General Practitioners-MDGP) supported by non-physician anaesthetists was eight times higher at 3·1/100,000. gSAO presence was positively associated with a two-fold increase in CS availability. All surgical rates were well below LCoGS targets. 46% of hospitals had adequate enabling environments for surgery, 28% had functioning anaesthesia machines, and 75% had blood transfusion services. Despite very low SAO density, and often inadequate enabling environment, surgery can be done in remote districts. gSAO teams led by family physicians are providing essential surgery, with CS the commonest major operation. gSAO density is eight times higher than specialists and they can undertake more complex operations than just CS alone. These family physician-led functional teams are providing a pathway to effective surgical coverage in remote Nepal.

Nonresponder does not mean not better: Improvement in nonsymptom domains in complex depressed patients who are not symptomatic responders to intensive treatment.

In treatment studies of depression, response is typically defined as a 50% or greater reduction in symptom severity. However, multiple surveys of depressed patients have found that patients prioritize improved functioning and quality of life objectives over symptom improvement as the most important goal of treatment. The goal of the present study is to widen the lens of assessing outcome by examining response in nonsymptom domains in patients who are, by convention, considered nonresponders to treatment. Eight hundred and forty-four patients with major depressive disorder completed the Remission from Depression Questionnaire (RDQ), a self-report measure that assesses multiple constructs considered by patients to be relevant to assessing treatment outcome. At discharge, the patients made a global rating of the effectiveness of treatment. The 517 patients who were nonresponders on the depression symptom subscale of the RDQ are the focus of this report. The patients showed significant levels of improvement from admission to discharge in all nonsymptom domains, with medium to large effect sizes. Approximately one-third of the patients were responders on at least 1 of the nonsymptom domains. The failure to meet the conventional definition of treatment response based on symptom severity does not preclude significant improvement in nonsymptom domains.