The Mental Health Toll of the COVID-19 Pandemic on Adolescents Receiving Inpatient Psychiatric Treatment.

Objective: During the COVID-19 pandemic, the prevalence of depression and anxiety among children and adolescents significantly increased, along with the number of visits to emergency departments due to suicidality and/or suicide attempts. Relatedly, health care workers experienced significant burnout and symptoms of anxiety, depression, and posttraumatic stress disorder during this time. However, the corresponding impact on psychiatric inpatient treatment has not yet been researched. We hypothesized that during the pandemic, adolescents hospitalized in an acute care psychiatric inpatient unit had increased incidents of suicide attempts and nonsuicidal self-injurious behaviors and of aggressive behaviors toward others, resulting in greater use of constant observation and restraints. Method: This study was a retrospective chart review based on electronic medical record data examining use of restraints and constant observation one year before the pandemic (March 2019 to February 2020) and 1 year following the onset of the pandemic (March 2020 to February 2021) in an acute-care adolescent (12 to 17 years old) psychiatric inpatient unit. Results: There were 571 admissions during the year before the pandemic and 500 admissions during the pandemic. The number of patients who were restrained (χ2 = 7.86, p = 0.005), number of patients who were placed on constant observation (χ2 = 13.41, p < 0.001), and number of constant observation orders per patient (χ2 = 91.90, p < 0.001) were all significantly greater during the pandemic. Conclusion: Psychiatrically hospitalized adolescents during the pandemic received more intensive interventions such as restraints and constant observation. Severe patient psychopathology and staff shortages, as well as limitations of and decreases to the dialectical behavior therapy program, may have been the contributing factor.

Expanding Complex Morpholines Using Systematic Chemical Diversity.

The morpholine heterocycle is a structural unit found in many bioactive compounds and FDA-approved drugs, but the generation of more complex C-functionalized morpholine derivatives remains considerably underexplored. Using systematic chemical diversity (SCD), a concept that guides the expansion of saturated drug-like scaffolds through regiochemical and stereochemical variation, we describe the synthesis of a collection of methyl-substituted morpholine acetic acid esters starting from enantiomerically pure amino acids and amino alcohols. In total, 24 diverse substituted morpholines were produced that vary systematically in regiochemistry and stereochemistry (relative and absolute). These diverse C-substituted morpholines can be directly applied in fragment screening or incorporated as building blocks in medicinal chemistry and library synthesis.

Structure-Activity Relationships and Discovery of (S)-6-Isopropyl-2-methoxy-3-(3-methoxypropoxy)-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic Acid (AB-452), a Novel Orally Available HBV RNA Destabilizer.

Approved therapies for hepatitis B virus (HBV) treatment include nucleos(t)ides and interferon alpha (IFN-α) which effectively suppress viral replication, but they rarely lead to cure. Expression of viral proteins, especially surface antigen of the hepatitis B virus (HBsAg) from covalently closed circular DNA (cccDNA) and the integrated genome, is believed to contribute to the persistence of HBV. This work focuses on therapies that target the expression of HBV proteins, in particular HBsAg, which differs from current treatments. Here we describe the identification of AB-452, a dihydroquinolizinone (DHQ) analogue. AB-452 is a potent HBV RNA destabilizer by inhibiting PAPD5/7 proteins in vitro with good in vivo efficacy in a chronic HBV mouse model. AB-452 showed acceptable tolerability in 28-day rat and dog toxicity studies, and a high degree of oral exposure in multiple species. Based on its in vitro and in vivo profiles, AB-452 was identified as a clinical development candidate.

Race-Based Disparities in the Frequency and Duration of Restraint Use in a Psychiatric Inpatient Setting.

OBJECTIVE: Patients' race and age have each been identified as risk factors for experiencing restraint events during psychiatric hospitalization. Restraint duration is also an important variable in determining disparities in treatment. To the authors' knowledge, no studies to date have examined the effect of the interaction of race and age on restraint use and duration in inpatient psychiatric settings. This retrospective chart review of electronic medical records of patients admitted between 2012 and 2019 sought to examine whether race and age interacted in predicting differences in the use and duration of restraints in a psychiatric inpatient setting. METHODS: Logistic and hierarchical regression analyses were conducted on data from a sample of 29,739 adolescent (ages 12-17 years) and adult (ages ≥18 years) inpatients to determine whether the interaction of race and age group (adolescent or adult) significantly predicted a restraint event or differences in restraint duration. RESULTS: Black (adjusted OR [AOR]=1.85) and multiracial (AOR=1.36) patients were more likely to experience a restraint event than were their White peers. Black race was also significantly (p=0.001) associated with longer restraint duration. No significant interaction was detected between race and age in predicting restraint events or duration. CONCLUSIONS: Although the interaction between race and age did not predict restraint events or duration, the findings indicate racial disparities in the frequency and duration of restraint events among Black and multiracial individuals and may inform efforts to reduce these events.

Racial and ethnic inequities in psychiatric inpatient building and unit assignment.

Racism is a social determinant of mental health which has a disproportionally negative impact on the experiences of psychiatric inpatients of color. Distinct differences in the physical space and clinical settings of two inpatient buildings at a hospital system in the tristate (New York, New Jersey, Connecticut) area of the United States led to the present investigation of racial inequities in the assignment of patients to specific buildings and units. Archival electronic medical record data were analyzed from over 18,000 unique patients over a period of six years. Hierarchical logistic regression analyses were conducted with assigned building (old vs. new building) as the binary outcome variable. Non-Hispanic White patients were set as the reference group. Black, Hispanic/Latinx, and Asian patients were significantly less likely to be assigned to better resourced units in the new building. When limiting the analysis to only general adult units, Black and Hispanic/Latinx patients were significantly less likely to be assigned to units in the new building. These results suggest ethnoracial inequities in patient assignment to buildings which differed in clinical and physical conditions. The findings serve as a call to action for hospital systems to examine the ways in which structural racism impact clinical care.

Rational Screening for Cooperativity in Small-Molecule Inducers of Protein-Protein Associations.

The hallmark of a molecular glue is its ability to induce cooperative protein-protein interactions, leading to the formation of a ternary complex, despite weaker binding toward one or both individual proteins. Notably, the extent of cooperativity distinguishes molecular glues from bifunctional compounds, which constitute a second class of inducers of protein-protein interactions. However, apart from serendipitous discovery, there have been limited rational screening strategies for the high cooperativity exhibited by molecular glues. Here, we propose a binding-based screen of DNA-barcoded compounds on a target protein in the presence or absence of a presenter protein, using the "presenter ratio", the ratio of ternary enrichment to binary enrichment, as a predictive measure of cooperativity. Through this approach, we identified a range of cooperative, noncooperative, and uncooperative compounds in a single DNA-encoded library screen with bromodomain containing protein (BRD)9 and the VHL-elongin C-elongin B (VCB) complex. Our most cooperative hit compound, 13-7, exhibits micromolar binding affinity to BRD9 but nanomolar affinity for the ternary complex with BRD9 and VCB, with cooperativity comparable to classical molecular glues. This approach may enable the rational discovery of molecular glues for preselected proteins and thus facilitate the transition to a new paradigm of small-molecule therapeutics.

Design, synthesis, and structure-activity relationship of a bicyclic HBV capsid assembly modulator chemotype leading to the identification of clinical candidate AB-506.

Disruption of the HBV capsid assembly process through small-molecule interaction with HBV core protein is a validated target for the suppression of hepatitis B viral replication and the development of new antivirals. Through combination of key structural features associated with two distinct series of capsid assembly modulators, a novel aminochroman-based chemotype was identified. Optimization of anti-HBV potency through generation of SAR in addition to further core modifications provided a series of related functionalized aminoindanes. Key compounds demonstrated excellent cellular potency in addition to favorable ADME and pharmacokinetic profiles and were shown to be highly efficacious in a mouse model of HBV replication. Aminoindane derivative AB-506 was subsequently advanced into clinical development.

Characterizing and detecting delirium with clinical and computational measures of speech and language disturbance.

BACKGROUND: Delirium is a critically underdiagnosed syndrome of altered mental status affecting more than 50% of older adults admitted to hospital. Few studies have incorporated speech and language disturbance in delirium detection. We sought to describe speech and language disturbances in delirium, and provide a proof of concept for detecting delirium using computational speech and language features. METHODS: Participants underwent delirium assessment and completed language tasks. Speech and language disturbances were rated using standardized clinical scales. Recordings and transcripts were processed using an automated pipeline to extract acoustic and textual features. We used binomial, elastic net, machine learning models to predict delirium status. RESULTS: We included 33 older adults admitted to hospital, of whom 10 met criteria for delirium. The group with delirium scored higher on total language disturbances and incoherence, and lower on category fluency. Both groups scored lower on category fluency than the normative population. Cognitive dysfunction as a continuous measure was correlated with higher total language disturbance, incoherence, loss of goal and lower category fluency. Including computational language features in the model predicting delirium status increased accuracy to 78%. LIMITATIONS: This was a proof-of-concept study with limited sample size, without a set-aside cross-validation sample. Subsequent studies are needed before establishing a generalizable model for detecting delirium. CONCLUSION: Language impairments were elevated among patients with delirium and may also be used to identify subthreshold cognitive disturbances. Computational speech and language features are promising as accurate, noninvasive and efficient biomarkers of delirium.

Rational screening for cooperativity in small-molecule inducers of protein-protein associations.

The hallmark of a molecular glue is its ability to induce cooperative protein-protein interactions, leading to the formation of a ternary complex, despite weaker binding towards one or both individual proteins. Notably, the extent of cooperativity distinguishes molecular glues from bifunctional compounds, a second class of inducers of protein-protein interactions. However, apart from serendipitous discovery, there have been limited rational screening strategies for the high cooperativity exhibited by molecular glues. Here, we propose a binding-based screen of DNA-barcoded compounds on a target protein in the presence and absence of a presenter protein, using the "presenter ratio", the ratio of ternary enrichment to binary enrichment, as a predictive measure of cooperativity. Through this approach, we identified a range of cooperative, noncooperative, and uncooperative compounds in a single DNA-encoded library screen with bromodomain (BRD)9 and the VHL-elongin C-elongin B (VCB) complex. Our most cooperative hit compound, 13-7 , exhibits micromolar binding affinity to BRD9 but nanomolar affinity for the ternary complex with BRD9 and VCB, with cooperativity comparable to classical molecular glues. This approach may enable the discovery of molecular glues for pre-selected proteins and thus facilitate the transition to a new paradigm of molecular therapeutics.

Latent Factors of Language Disturbance and Relationships to Quantitative Speech Features.

BACKGROUND AND HYPOTHESIS: Quantitative acoustic and textual measures derived from speech ("speech features") may provide valuable biomarkers for psychiatric disorders, particularly schizophrenia spectrum disorders (SSD). We sought to identify cross-diagnostic latent factors for speech disturbance with relevance for SSD and computational modeling. STUDY DESIGN: Clinical ratings for speech disturbance were generated across 14 items for a cross-diagnostic sample (N = 334), including SSD (n = 90). Speech features were quantified using an automated pipeline for brief recorded samples of free speech. Factor models for the clinical ratings were generated using exploratory factor analysis, then tested with confirmatory factor analysis in the cross-diagnostic and SSD groups. The relationships between factor scores and computational speech features were examined for 202 of the participants. STUDY RESULTS: We found a 3-factor model with a good fit in the cross-diagnostic group and an acceptable fit for the SSD subsample. The model identifies an impaired expressivity factor and 2 interrelated disorganized factors for inefficient and incoherent speech. Incoherent speech was specific to psychosis groups, while inefficient speech and impaired expressivity showed intermediate effects in people with nonpsychotic disorders. Each of the 3 factors had significant and distinct relationships with speech features, which differed for the cross-diagnostic vs SSD groups. CONCLUSIONS: We report a cross-diagnostic 3-factor model for speech disturbance which is supported by good statistical measures, intuitive, applicable to SSD, and relatable to linguistic theories. It provides a valuable framework for understanding speech disturbance and appropriate targets for modeling with quantitative speech features.

Clinical and computational speech measures are associated with social cognition in schizophrenia spectrum disorders.

In this study, we compared three domains of social cognition (emotion processing, mentalizing, and attribution bias) to clinical and computational language measures in 63 participants with schizophrenia spectrum disorders. Based on the active inference model for discourse, we hypothesized that emotion processing and mentalizing, but not attribution bias, would be related to language disturbances. Clinical ratings for speech disturbance assessed disorganized and underproductive dimensions. Computational features included speech graph metrics, use of modal verbs, use of first-person pronouns, cosine similarity of adjacent utterances, and measures of sentiment; these were represented by four principal components. We found that higher clinical ratings for disorganized speech were predicted by greater impairments in both emotion processing and mentalizing, and that these relationships remained significant when accounting for demographic variables, overall psychosis symptoms, and verbal ability. Similarly, a computational speech component reflecting insular speech was consistently predicted by impairment in emotion processing. There were notable trends for computational speech components reflecting underproductive speech and decreased content-rich speech predicting mentalizing ability. Exploratory longitudinal analyses in a small subset of participants (n = 17) found that improvements in both emotion processing and mentalizing predicted improvements in disorganized speech. Attribution bias did not demonstrate strong relationships with language measures. Altogether, our findings are consistent with the active inference model of discourse and suggest greater emphasis on treatments that target social cognitive and language systems.

Feasibility of Mobile Health and Social Media-Based Interventions for Young Adults With Early Psychosis and Clinical Risk for Psychosis: Survey Study.

BACKGROUND: Digital technology, the internet, and social media are increasingly investigated as promising means for monitoring symptoms and delivering mental health treatment. These apps and interventions have demonstrated preliminary acceptability and feasibility, but previous reports suggest that access to technology may still be limited among individuals with psychotic disorders relative to the general population. OBJECTIVE: We evaluated and compared access to and use of technology and social media in young adults with psychotic disorders (PD), young adults with clinical risk for psychosis (CR), and psychosis-free youths (PF). METHODS: Participants were recruited through a coordinated specialty care clinic dedicated toward early psychosis as well as ongoing studies. We surveyed 21 PD, 23 CR, and 15 PF participants regarding access to technology and use of social media, specifically Facebook and Twitter. Statistical analyses were conducted in R. Categorical variables were compared among groups using Fisher exact test, continuous variables were compared using 1-way ANOVA, and multiple linear regressions were used to evaluate for covariates. RESULTS: Access to technology and social media were similar among PD, CR, and PF participants. Individuals with PD, but not CR, were less likely to post at a weekly or higher frequency compared to PF individuals. We found that decreased active social media posting was unique to psychotic disorders and did not occur with other psychiatric diagnoses or demographic variables. Additionally, variation in age, sex, and White versus non-White race did not affect posting frequency. CONCLUSIONS: For young people with psychosis spectrum disorders, there appears to be no "technology gap" limiting the implementation of digital and mobile health interventions. Active posting to social media was reduced for individuals with psychosis, which may be related to negative symptoms or impairment in social functioning.

Who does what to whom? graph representations of action-predication in speech relate to psychopathological dimensions of psychosis.

Graphical representations of speech generate powerful computational measures related to psychosis. Previous studies have mostly relied on structural relations between words as the basis of graph formation, i.e., connecting each word to the next in a sequence of words. Here, we introduced a method of graph formation grounded in semantic relationships by identifying elements that act upon each other (action relation) and the contents of those actions (predication relation). Speech from picture descriptions and open-ended narrative tasks were collected from a cross-diagnostic group of healthy volunteers and people with psychotic or non-psychotic disorders. Recordings were transcribed and underwent automated language processing, including semantic role labeling to identify action and predication relations. Structural and semantic graph features were computed using static and dynamic (moving-window) techniques. Compared to structural graphs, semantic graphs were more strongly correlated with dimensional psychosis symptoms. Dynamic features also outperformed static features, and samples from picture descriptions yielded larger effect sizes than narrative responses for psychosis diagnoses and symptom dimensions. Overall, semantic graphs captured unique and clinically meaningful information about psychosis and related symptom dimensions. These features, particularly when derived from semi-structured tasks using dynamic measurement, are meaningful additions to the repertoire of computational linguistic methods in psychiatry.

A Concise Synthetic Method for Constructing 3-Substituted Piperazine-2-Acetic Acid Esters from 1,2-Diamines.

We report a short synthetic route for synthesizing 2,3-substituted piperazine acetic acid esters. Optically pure amino acids were efficiently converted into 1,2-diamines that could be utilized to deliver the title 2,3-substituted piperazines in five steps with a high enantiomeric purity. The novel route facilitated, for the first time, the synthesis of 3-phenyl substituted-2-piperazine acetic acid esters that were difficult to achieve using other methods; however, in this case, the products underwent racemization.

Metabolic disturbances, hemoglobin A1c, and social cognition impairment in Schizophrenia spectrum disorders.

Social cognitive impairments are core features of schizophrenia spectrum disorders (SSD) and are associated with greater functional impairment and decreased quality of life. Metabolic disturbances have been related to greater impairment in general neurocognition, but their relationship to social cognition has not been previously reported. In this study, metabolic measures and social cognition were assessed in 245 participants with SSD and 165 healthy comparison subjects (HC), excluding those with hemoglobin A1c (HbA1c) > 6.5%. Tasks assessed emotion processing, theory of mind, and social perception. Functional connectivity within and between social cognitive networks was measured during a naturalistic social task. Among SSD, a significant inverse relationship was found between social cognition and cumulative metabolic burden (ß = -0.38, p < 0.001) and HbA1c (ß = -0.37, p < 0.001). The relationship between social cognition and HbA1c was robust across domains and measures of social cognition and after accounting for age, sex, race, non-social neurocognition, hospitalization, and treatment with different antipsychotic medications. Negative connectivity between affect sharing and motor resonance networks was a partial mediator of this relationship across SSD and HC groups (ß = -0.05, p = 0.008). There was a group x HbA1c effect indicating that SSD participants were more adversely affected by increasing HbA1c. Thus, we provide the first report of a robust relationship in SSD between social cognition and abnormal glucose metabolism. If replicated and found to be causal, insulin sensitivity and blood glucose may present as promising targets for improving social cognition, functional outcomes, and quality of life in SSD.

The identification of highly efficacious functionalised tetrahydrocyclopenta[c]pyrroles as inhibitors of HBV viral replication through modulation of HBV capsid assembly.

Disruption of the HBV viral life cycle with small molecules that prevent the encapsidation of pregenomic RNA and viral polymerase through binding to HBV core protein is a clinically validated approach to inhibiting HBV viral replication. Herein we report the further optimisation of clinical candidate AB-506 through core modification with a focus on increasing oral exposure and oral half-life. Maintenance of high levels of anti-HBV cellular potency in conjunction with improvements in pharmacokinetic properties led to multi-log10 reductions in serum HBV DNA following low, once-daily oral dosing for key analogues in a preclinical animal model of HBV replication.

Preclinical characterization of AB-506, an inhibitor of HBV replication targeting the viral core protein.

AB-506, a small-molecule inhibitor targeting the HBV core protein, inhibits viral replication in vitro (HepAD38 cells: EC50 of 0.077 µM, CC50 > 25 µM) and in vivo (HBV mouse model: ∼3.0 log10 reductions in serum HBV DNA compared to the vehicle control). Binding of AB-506 to HBV core protein accelerates capsid assembly and inhibits HBV pgRNA encapsidation. Furthermore, AB-506 blocks cccDNA establishment in HBV-infected HepG2-hNTCP-C4 cells and primary human hepatocytes, leading to inhibition of viral RNA, HBsAg, and HBeAg production (EC50 from 0.64 µM to 1.92 µM). AB-506 demonstrated activity across HBV genotypes A-H and maintains antiviral activity against nucleos(t)ide analog-resistant variants in vitro. Evaluation of AB-506 against a panel of core variants showed that T33N/Q substitutions results in >200-fold increase in EC50 values, while L30F, L37Q, and I105T substitutions showed an 8 to 20-fold increase in EC50 values in comparison to the wild-type. In vitro combinations of AB-506 with NAs or an RNAi agent were additive to moderately synergistic. AB-506 exhibits good oral bioavailability, systemic exposure, and higher liver to plasma ratios in rodents, a pharmacokinetic profile supporting clinical development for chronic hepatitis B.

Natural language processing methods are sensitive to sub-clinical linguistic differences in schizophrenia spectrum disorders.

Computerized natural language processing (NLP) allows for objective and sensitive detection of speech disturbance, a hallmark of schizophrenia spectrum disorders (SSD). We explored several methods for characterizing speech changes in SSD (n = 20) compared to healthy control (HC) participants (n = 11) and approached linguistic phenotyping on three levels: individual words, parts-of-speech (POS), and sentence-level coherence. NLP features were compared with a clinical gold standard, the Scale for the Assessment of Thought, Language and Communication (TLC). We utilized Bidirectional Encoder Representations from Transformers (BERT), a state-of-the-art embedding algorithm incorporating bidirectional context. Through the POS approach, we found that SSD used more pronouns but fewer adverbs, adjectives, and determiners (e.g., "the," "a,"). Analysis of individual word usage was notable for more frequent use of first-person singular pronouns among individuals with SSD and first-person plural pronouns among HC. There was a striking increase in incomplete words among SSD. Sentence-level analysis using BERT reflected increased tangentiality among SSD with greater sentence embedding distances. The SSD sample had low speech disturbance on average and there was no difference in group means for TLC scores. However, NLP measures of language disturbance appear to be sensitive to these subclinical differences and showed greater ability to discriminate between HC and SSD than a model based on clinical ratings alone. These intriguing exploratory results from a small sample prompt further inquiry into NLP methods for characterizing language disturbance in SSD and suggest that NLP measures may yield clinically relevant and informative biomarkers.

Checkpoint inhibition through small molecule-induced internalization of programmed death-ligand 1.

Programmed death-ligand 1 is a glycoprotein expressed on antigen presenting cells, hepatocytes, and tumors which upon interaction with programmed death-1, results in inhibition of antigen-specific T cell responses. Here, we report a mechanism of inhibiting programmed death-ligand 1 through small molecule-induced dimerization and internalization. This represents a mechanism of checkpoint inhibition, which differentiates from anti-programmed death-ligand 1 antibodies which function through molecular disruption of the programmed death 1 interaction. Testing of programmed death ligand 1 small molecule inhibition in a humanized mouse model of colorectal cancer results in a significant reduction in tumor size and promotes T cell proliferation. In addition, antigen-specific T and B cell responses from patients with chronic hepatitis B infection are significantly elevated upon programmed death ligand 1 small molecule inhibitor treatment. Taken together, these data identify a mechanism of small molecule-induced programmed death ligand 1 internalization with potential therapeutic implications in oncology and chronic viral infections.