Deriving the Transdiagnostic Scales From the Personality Assessment Inventory and SPECTRA: Indices of Psychopathology: A Demonstration.

Transdiagnostic models of psychopathology address many of the shortcomings common to categorical diagnostic systems. These empirically derived models conceptualize psychopathology as a few broad interrelated and hierarchically arranged dimensions, with an overarching general psychopathology dimension, the p-factor, at the apex. While transdiagnostic models are gaining prominence in mental health research, the lack of available tools has limited their clinical translation. The present study explored the potential of creating transdiagnostic scales from the joint factor structure of the Personality Assessment Inventory, Alternative Model of Personality Disorder trait scales (AMPD), and the clinical scales of the SPECTRA: Indices of Psychopathology (SPECTRA). Exploratory factor analysis in a clinical sample (n = 212) identified five factors corresponding to the Negative Affect/Internalizing, Detachment, Antagonism/Externalizing, Disinhibition/Externalizing, and Thought Disorder transdiagnostic dimensions. Goldberg's "Bass-Ackward" method supported a hierarchical structure. Five composite transdiagnostic scales were created by summing each factor's highest loading PAI and SPECTRA scales. A global psychopathology scale was created by summing the five composite scales. All the composite scales demonstrated adequate internal consistency. Correlations between the composite scales and the NEO Five-Factor Inventory-3 provide initial validity evidence for four composite and global scales. The composite thought disorder scale had no conceptually corresponding NEO domain. Clinical implications and study limitations are discussed.

No need to "sugar coat": Removing glycocalyx on apoptotic blebs promotes phagocytosis.

The viscous glycocalyx of mammalian cells, composed of glucosaminoglycans, glycolipids, and glycoproteins, "sugar coat" the outer plasma membrane. In this issue of Developmental Cell, Le et al. (2024) show that the glycocalyx is removed from apoptotic blebs via disassembly of the cortical cytoskeleton, exposing the "eat-me" signals necessary for efferocytosis.

Pkd1l1-deficiency drives biliary atresia through ciliary dysfunction in biliary epithelial cells.

BACKGROUND & AIMS: Syndromic biliary atresia is a cholangiopathy characterized by fibro-obliterative changes in the extrahepatic bile duct (EHBD) and congenital malformations including laterality defects. The etiology remains elusive and faithful animal models are lacking. Genetic syndromes provide important clues regarding the pathogenic mechanisms underlying the disease. We investigated the role of the gene Pkd1l1 in the pathophysiology of syndromic biliary atresia. METHODS: Constitutive and conditional Pkd1l1 knockout mice were generated to explore genetic pathology as a cause of syndromic biliary atresia. We investigated congenital malformations, EHBD and liver pathology, EHBD gene expression, and biliary epithelial cell turnover. Biliary drainage was functionally assessed with cholangiography. Histology and serum chemistries were assessed after DDC (3,5-diethoxycarbony l-1,4-dihydrocollidine) diet treatment and inhibition of the ciliary signaling effector GLI1. RESULTS: Pkd1l1-deficient mice exhibited congenital anomalies including malrotation and heterotaxy. Pkd1l1-deficient EHBDs were hypertrophic and fibrotic. Pkd1l1-deficient EHBDs were patent but displayed delayed biliary drainage. Pkd1l1-deficient livers exhibited ductular reaction and periportal fibrosis. After DDC treatment, Pkd1l1-deficient mice exhibited EHBD obstruction and advanced liver fibrosis. Pkd1l1-deficient mice had increased expression of fibrosis and extracellular matrix remodeling genes (Tgfα, Cdkn1a, Hb-egf, Fgfr3, Pdgfc, Mmp12, and Mmp15) and decreased expression of genes mediating ciliary signaling (Gli1, Gli2, Ptch1, and Ptch2). Primary cilia were reduced on biliary epithelial cells and altered expression of ciliogenesis genes occurred in Pkd1l1-deficient mice. Small molecule inhibition of the ciliary signaling effector GLI1 with Gant61 recapitulated Pkd1l1-deficiency. CONCLUSIONS: Pkd1l1 loss causes both laterality defects and fibro-proliferative EHBD transformation through disrupted ciliary signaling, phenocopying syndromic biliary atresia. Pkd1l1-deficient mice function as an authentic genetic model for study of the pathogenesis of biliary atresia. IMPACT AND IMPLICATIONS: The syndromic form of biliary atresia is characterized by fibro-obliteration of extrahepatic bile ducts and is often accompanied by laterality defects. The etiology is unknown, but Pkd1l1 was identified as a potential genetic candidate for syndromic biliary atresia. We found that loss of the ciliary gene Pkd1l1 contributes to hepatobiliary pathology in biliary atresia, exhibited by bile duct hypertrophy, reduced biliary drainage, and liver fibrosis in Pkd1l1-deficient mice. Pkd1l1-deficient mice serve as a genetic model of biliary atresia and reveal ciliopathy as an etiology of biliary atresia. This model will help scientists uncover new therapeutic approaches for patients with biliary atresia, while pediatric hepatologists should validate the diagnostic utility of PKD1L1 variants.

Rapid unleashing of macrophage efferocytic capacity via transcriptional pause release.

During development, inflammation or tissue injury, macrophages may successively engulf and process multiple apoptotic corpses via efferocytosis to achieve tissue homeostasis1. How macrophages may rapidly adapt their transcription to achieve continuous corpse uptake is incompletely understood. Transcriptional pause/release is an evolutionarily conserved mechanism, in which RNA polymerase (Pol) II initiates transcription for 20-60 nucleotides, is paused for minutes to hours and is then released to make full-length mRNA2. Here we show that macrophages, within minutes of corpse encounter, use transcriptional pause/release to unleash a rapid transcriptional response. For human and mouse macrophages, the Pol II pause/release was required for continuous efferocytosis in vitro and in vivo. Interestingly, blocking Pol II pause/release did not impede Fc receptor-mediated phagocytosis, yeast uptake or bacterial phagocytosis. Integration of data from three genomic approaches-precision nuclear run-on sequencing, RNA sequencing, and assay for transposase-accessible chromatin using sequencing (ATAC-seq)-on efferocytic macrophages at different time points revealed that Pol II pause/release controls expression of select transcription factors and downstream target genes. Mechanistic studies on transcription factor EGR3, prominently regulated by pause/release, uncovered EGR3-related reprogramming of other macrophage genes involved in cytoskeleton and corpse processing. Using lysosomal probes and a new genetic fluorescent reporter, we identify a role for pause/release in phagosome acidification during efferocytosis. Furthermore, microglia from egr3-deficient zebrafish embryos displayed reduced phagocytosis of apoptotic neurons and fewer maturing phagosomes, supporting defective corpse processing. Collectively, these data indicate that macrophages use Pol II pause/release as a mechanism to rapidly alter their transcriptional programs for efficient processing of the ingested apoptotic corpses and for successive efferocytosis.

Using the Personality Assessment Inventory to Assess the Alternative Model for Personality Disorders: Criterion Validity in a Clinical Sample.

The Personality Assessment Inventory (PAI) is a broadband measure of psychopathology that is widely used in applied settings. Researchers developed regression-based estimates that use the PAI to measure constructs of the Alternative Model for Personality Disorders (AMPD) - a hybrid dimensional and categorical approach to conceptualizing personality disorders. Although prior work has linked these estimates to formal measures of the AMPD, there is little work investigating the clinical correlates of this scoring approach of the PAI. The current study examines associations between these PAI-based AMPD estimates and life data in a large, archival dataset of psychiatric outpatients and inpatients. We found general support for the criterion validity of AMPD estimate scores, such that a theoretically consistent pattern of associations emerged with indicators such as prior academic achievement, antisocial behavior, psychiatric history, and substance abuse. These results provide preliminary support to this scoring approach for use in clinical samples.

Psychopathic Traits in a Swedish Court-Ordered Forensic Sample: Preferential Associations of Boldness, Meanness, and Disinhibition.

The construct validity of the triarchic psychopathy model has yet to be evaluated in the Swedish forensic psychiatric context. We examined associations between the three phenotypic constructs of the triarchic model of psychopathy (i.e., boldness, meanness, disinhibition), self-assessed empathy and anxiety, and clinical variables in 91 individuals undergoing pretrial forensic psychiatric evaluation in Sweden. Participants completed the Triarchic Psychopathy Measure (TriPM) and self-report measures of empathy and anxiety. Clinical variables, including psychiatric diagnoses and criminal behavior, were collected from the forensic psychiatric evaluations (FPE). All three subscales of the TriPM displayed significant and predominantly anticipated correlations with empathy and trait anxiety measures. TriPM Disinhibition was the only subscale with significant associations with the clinical variables collected from the FPEs. The results provide evidence for the reliability and construct validity of the Swedish translation of the TriPM in a pretrial forensic setting.

Phagocytosis in the retina promotes local insulin production in the eye.

The retina is highly metabolically active, relying on glucose uptake and aerobic glycolysis. Situated in close contact to photoreceptors, a key function of cells in the retinal pigment epithelium (RPE) is phagocytosis of damaged photoreceptor outer segments (POS). Here we identify RPE as a local source of insulin in the eye that is stimulated by POS phagocytosis. We show that Ins2 messenger RNA and insulin protein are produced by RPE cells and that this production correlates with RPE phagocytosis of POS. Genetic deletion of phagocytic receptors ('loss of function') reduces Ins2, whereas increasing the levels of the phagocytic receptor MerTK ('gain of function') increases Ins2 production in male mice. Contrary to pancreas-derived systemic insulin, RPE-derived local insulin is stimulated during starvation, which also increases RPE phagocytosis. Global or RPE-specific Ins2 gene deletion decreases retinal glucose uptake in starved male mice, dysregulates retinal physiology, causes defects in phototransduction and exacerbates photoreceptor loss in a mouse model of retinitis pigmentosa. Collectively, these data identify RPE cells as a phagocytosis-induced local source of insulin in the retina, with the potential to influence retinal physiology and disease.

Antisocial personality disorder and psychopathy: The AMPD in review.

The current review examines the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) alternative model for personality disorders' (AMPD) operationalization of antisocial personality disorder (ASPD), particularly as it relates to the construct of psychopathy. We review the available literature on the AMPD conceptualization of ASPD, its potential improvement over previous versions of the DSM, and its relationship to established measures of psychopathy. In addition, we review the literature on the AMPD's psychopathy specifier, including its utility in differentiating between ASPD and psychopathy. We provide a critical commentary for what these findings mean moving forward and discuss areas for future research direction. We argue that the DSM-5 conceptualization of ASPD is a vast improvement over previous iterations of the diagnosis; however, we discuss potential limitations and disagreements that could arise in its overlap with the construct of psychopathy. Finally, we argue that work moving forward should focus more broadly on dimensional traits and their prediction of outcomes, rather than continuing to seek diagnostic accuracy in conceptualizing ASPD and/or psychopathy and that the AMPD provides a good framework for this work. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Exploring the Alternative Model for Personality Disorders Using SCORS-G Ratings on Thematic Apperception Test Narratives.

The Alternative Model for Personality Disorders (AMPD) in Section III of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5; American Psychiatric Association, 2013) conceptualizes personality pathology as a combination of impairment (Criterion A) and traits (Criterion B). One measure used to develop Criterion A was the Social Cognition and Object Relations Scale - Global Rating Method (SCORS-G), which is a multidimensional, object-relational clinician-rated measure of personality functioning. Although there are conceptual links between the AMPD and SCORS-G dimensions, there exists no research examining the relationship. To address this, we examined associations between the SCORS-G dimensions and measures of the AMPD constructs in a large, archival dataset of outpatients and inpatients. More pathological scores on SCORS-G dimensions reflecting self- and interpersonal functioning were associated with greater pathological traits and impairment. Overall, results support further investigation into SCORS-G as a useful measure in AMPD research and assessment.

Pediatric Gastric Mucosal Calcinosis.

Gastric mucosal calcinosis (GMC) is the deposition of calcium salts in gastric tissue. We report a case of GMC in a pediatric patient with a prior history of cholelithiasis and nephrolithiasis who presented with abdominal pain and vomiting. Laboratory evaluation did not show any abnormalities. Upper endoscopy revealed numerous gastric nodules; biopsies revealed calcium deposition in the superficial lamina propria. Recognizing GMC may aid with evaluation of a patient with vague gastrointestinal symptoms.

Putting the brakes on phagocytosis: "don't-eat-me" signaling in physiology and disease.

Timely removal of dying or pathogenic cells by phagocytes is essential to maintaining host homeostasis. Phagocytes execute the clearance process with high fidelity while sparing healthy neighboring cells, and this process is at least partially regulated by the balance of "eat-me" and "don't-eat-me" signals expressed on the surface of host cells. Upon contact, eat-me signals activate "pro-phagocytic" receptors expressed on the phagocyte membrane and signal to promote phagocytosis. Conversely, don't-eat-me signals engage "anti-phagocytic" receptors to suppress phagocytosis. We review the current knowledge of don't-eat-me signaling in normal physiology and disease contexts where aberrant don't-eat-me signaling contributes to pathology.

Age-Related Differences in White Matter: Understanding Tensor-Based Results Using Fixel-Based Analysis.

Aging is associated with widespread alterations in cerebral white matter (WM). Most prior studies of age differences in WM have used diffusion tensor imaging (DTI), but typical DTI metrics (e.g., fractional anisotropy; FA) can reflect multiple neurobiological features, making interpretation challenging. Here, we used fixel-based analysis (FBA) to investigate age-related WM differences observed using DTI in a sample of 45 older and 25 younger healthy adults. Age-related FA differences were widespread but were strongly associated with differences in multi-fiber complexity (CX), suggesting that they reflected differences in crossing fibers in addition to structural differences in individual fiber segments. FBA also revealed a frontolimbic locus of age-related effects and provided insights into distinct microstructural changes underlying them. Specifically, age differences in fiber density were prominent in fornix, bilateral anterior internal capsule, forceps minor, body of the corpus callosum, and corticospinal tract, while age differences in fiber cross section were largest in cingulum bundle and forceps minor. These results provide novel insights into specific structural differences underlying major WM differences associated with aging.

Assessing comfort level with pediatric skin specimens among dermatopathologists and pediatric pathologists: A national cross-sectional survey.

BACKGROUND: Cutaneous histopathologic diagnoses in children often differ from those in adults. Depending on practice setting, these specimens may be evaluated by dermatopathologists or pediatric pathologists. We sought to determine whether comfort level with pediatric dermatopathology is associated with prior training, pediatric dermatopathology exposure during fellowship, career duration, or specimen subtype. METHODS: We surveyed dermatopathologists and pediatric pathologists practicing in the United States. Training and practice variables were evaluated by multivariable regression for association with comfort level. RESULTS: Of the 156 respondents, 72% were dermatopathologists (response rate 11.6%) and 28% were pediatric pathologists (response rate 9.3%). Dermatopathologists reported higher comfort overall (P < .001); this was also true for inflammatory dermatoses and melanocytic neoplasms (P < .001). Thirty-four percent and 75% of dermatopathologists and pediatric pathologists, respectively, reported lower comfort with pediatric skin specimens than their usual cases. Pediatric pathologists were 28% more likely to refer these cases to colleagues. Among dermatopathologists, dermatology-trained were more comfortable than pathology-trained colleagues interpreting inflammatory dermatoses (P < .001). CONCLUSIONS: Pathologists' comfort with pediatric dermatopathology varied significantly based upon prior training, career duration, and specimen subtype. These results suggest opportunities for improving education in this domain.

Can the Comprehensive Assessment of Psychopathic Personality Be Used to Measure the Triarchic Model Constructs of Boldness, Meanness, and Disinhibition? A Scale Derivation Study.

Can the components of the triarchic model of psychopathy (i.e., boldness, meanness, disinhibition) be operationalized using the item pool comprising the Comprehensive Assessment of Psychopathic Personality (CAPP) model? To address this question, the authors first derived CAPP-based triarchic scales using standard item-selection procedures and then examined the external correlates of these provisional scales in three archival data sets: (a) U.S. jail inmates administered the institutional rating scale version of the CAPP and (b and c) prototypicality ratings of the CAPP traits provided by Swedish forensic mental health professionals and U.S. probation officers. Although most research on triarchic constructs has relied exclusively on self-report inventories, the results suggest that the CAPP model can be reorganized to reflect boldness, meanness, and disinhibition and that its institutional rating scale items can effectively quantify these constructs using interview and file review data. Implications for future research on the measurement and assessment of psychopathic traits are discussed.

Opportunities to Improve Antibiotic Appropriateness in U.S. ICUs: A Multicenter Evaluation.

OBJECTIVES: To use a standardized tool for a multicenter assessment of antibiotic appropriateness in ICUs and identify local antibiotic stewardship improvement opportunities. DESIGN: Pilot point prevalence conducted on October 5, 2016; point prevalence survey conducted on March 1, 2017. SETTING: ICUs in 12 U.S. acute care hospitals with median bed size 563. PATIENTS: Receiving antibiotics on participating units on March 1, 2017. INTERVENTIONS: The Centers for Disease Control and Prevention tool for the Assessment of Appropriateness of Inpatient Antibiotics was made actionable by an expert antibiotic stewardship panel and implemented across hospitals. Data were collected by antibiotic stewardship program personnel at each hospital, deidentified and submitted in aggregate for benchmarking. hospital personnel identified most salient reasons for inappropriate use by category and agent. MEASUREMENTS AND MAIN RESULTS: Forty-seven ICUs participated. Most hospitals (83%) identified as teaching with median licensed ICU beds of 70. On March 1, 2017, 362 (54%) of 667 ICU patients were on antibiotics (range, 8-81 patients); of these, 112 (31%) were identified as inappropriate and administered greater than 72 hours among all 12 hospitals (range, 9-82%). Prophylactic antibiotic regimens and PICU patients demonstrated a statistically significant risk ratio of 1.76 and 1.90 for inappropriate treatment, respectively. Reasons for inappropriate use included unnecessarily broad spectrum (29%), no infection or nonbacterial syndrome (22%), and duration longer than necessary (21%). Of patients on inappropriate antibiotic therapy in surgical ICUs, a statistically significant risk ratio of 2.59 was calculated for noninfectious or nonbacterial reasons for inappropriate therapy. CONCLUSIONS: In this multicenter point prevalence study, 31% of ICU antibiotic regimens were inappropriate; prophylactic regimens were often inappropriate across different ICU types, particularly in surgical ICUs. Engaging intensivists in antibiotic stewardship program efforts is crucial to sustain the efficacy of antibiotics and quality of infectious diseases care in critical care settings. This study underscores the value of standardized assessment tools and benchmarking to be shared with local leaders for targeted antibiotic stewardship program interventions.

Extramedullary hematopoiesis masquerading as a cranial (clivus) tumor.

Extramedullary hematopoiesis (EMH) is a well-known phenomenon occurring during fetal development. In the postfetal condition, EMH is commonly associated with hematologic conditions including chronic myeloproliferative or lymphoproliferative disorders, leukemias, and chronic and inherited anemias. We report an unusual location for EMH that masqueraded as a cranial tumor.

Decitabine and Vorinostat with Chemotherapy in Relapsed Pediatric Acute Lymphoblastic Leukemia: A TACL Pilot Study.

PURPOSE: Treatment failure from drug resistance is the primary reason for relapse in acute lymphoblastic leukemia (ALL). Improving outcomes by targeting mechanisms of drug resistance is a potential solution. PATIENTS AND METHODS: We report results investigating the epigenetic modulators decitabine and vorinostat with vincristine, dexamethasone, mitoxantrone, and PEG-asparaginase for pediatric patients with relapsed or refractory B-cell ALL (B-ALL). Twenty-three patients, median age 12 years (range, 1-21) were treated in this trial. RESULTS: The most common grade 3-4 toxicities included hypokalemia (65%), anemia (78%), febrile neutropenia (57%), hypophosphatemia (43%), leukopenia (61%), hyperbilirubinemia (39%), thrombocytopenia (87%), neutropenia (91%), and hypocalcemia (39%). Three subjects experienced dose-limiting toxicities, which included cholestasis, steatosis, and hyperbilirubinemia (n = 1); seizure, somnolence, and delirium (n = 1); and pneumonitis, hypoxia, and hyperbilirubinemia (n = 1). Infectious complications were common with 17 of 23 (74%) subjects experiencing grade ≥3 infections including invasive fungal infections in 35% (8/23). Nine subjects (39%) achieved a complete response (CR + CR without platelet recovery + CR without neutrophil recovery) and five had stable disease (22%). Nine (39%) subjects were not evaluable for response, primarily due to treatment-related toxicities. Correlative pharmacodynamics demonstrated potent in vivo modulation of epigenetic marks, and modulation of biologic pathways associated with functional antileukemic effects. CONCLUSIONS: Despite encouraging response rates and pharmacodynamics, the combination of decitabine and vorinostat on this intensive chemotherapy backbone was determined not feasible in B-ALL due to the high incidence of significant infectious toxicities. This study is registered at http://www.clinicaltrials.gov as NCT01483690.