The dynamic changes and sex differences of 147 immune-related proteins during acute COVID-19 in 580 individuals.

INTRODUCTION: Severe COVID-19 leads to important changes in circulating immune-related proteins. To date it has been difficult to understand their temporal relationship and identify cytokines that are drivers of severe COVID-19 outcomes and underlie differences in outcomes between sexes. Here, we measured 147 immune-related proteins during acute COVID-19 to investigate these questions. METHODS: We measured circulating protein abundances using the SOMAscan nucleic acid aptamer panel in two large independent hospital-based COVID-19 cohorts in Canada and the United States. We fit generalized additive models with cubic splines from the start of symptom onset to identify protein levels over the first 14 days of infection which were different between severe cases and controls, adjusting for age and sex. Severe cases were defined as individuals with COVID-19 requiring invasive or non-invasive mechanical respiratory support. RESULTS: 580 individuals were included in the analysis. Mean subject age was 64.3 (sd 18.1), and 47% were male. Of the 147 proteins, 69 showed a significant difference between cases and controls (p < 3.4 × 10-4). Three clusters were formed by 108 highly correlated proteins that replicated in both cohorts, making it difficult to determine which proteins have a true causal effect on severe COVID-19. Six proteins showed sex differences in levels over time, of which 3 were also associated with severe COVID-19: CCL26, IL1RL2, and IL3RA, providing insights to better understand the marked differences in outcomes by sex. CONCLUSIONS: Severe COVID-19 is associated with large changes in 69 immune-related proteins. Further, five proteins were associated with sex differences in outcomes. These results provide direct insights into immune-related proteins that are strongly influenced by severe COVID-19 infection.

Understanding Assessment Systems for Clinical Competency Committee Decisions: Evidence from a Multisite Study of Psychiatry Residency Training Programs.

OBJECTIVE: This multisite study examines how clinical competency committees in Psychiatry synthesize resident assessments to inform milestones decisions to provide guidelines that support their use. METHODS: The study convened training directors and associate training directors from three psychiatry residency programs to examine decision-making processes of clinical competency committees. Annual resident assessments for one second year and one third year resident were used in a mock clinical competency committee format to assign milestones for two consecutive reporting periods. The committees reflected on the process and rated how the assessment tools impacted the assessment of milestones and evaluated the overall process. The authors compared reliability of assessment between the mock committees and examined both reliability of end of rotation assessments and their composite scores when combined with clinical skills evaluations. RESULTS: End of rotation evaluations were the most informative tool for assigning milestones and clarifying discrepancies in performance. In particular, the patient care and medical knowledge competencies were the easiest to rate, while the systems-based practice and practice-based learning and improvement were the most difficult. Reliability between committees was low although higher number of available evaluations improved reliability in decision-making. CONCLUSIONS: The results indicate that the medical knowledge and patient care competencies are the easiest to rate and informed most by end of rotation evaluations and clinical skills examinations. Other evaluation tools may better capture performance on specific sub-competencies beyond workplace-based assessment, or it may be helpful to reconsider the utility of how individual sub-competencies are evaluated.

Implementation of the AAMC's Holistic Review Model for Psychiatry Resident Recruitment.

Introduction: In psychiatry, several converging factors are impacting the recruitment of residents: the increased competitiveness of the specialty, the national trend to take active steps to improve diversity and inclusion, and the decision from USMLE to change Step 1 to a pass/fail result. Methods: We developed a workshop for psychiatry residency program directors to meet these challenges and transition into using a holistic review model during recruitment. The workshop included (1) a didactic session providing background on the AAMC holistic review model; (2) a small-group exercise to determine and prioritize experiences, attributes, competencies, and metrics (EACMs) aligned with the program's mission and aims; (3) a review of the rankings from the previous exercise, selection of two "very important" criteria for each of the four domains of the EACM model, and operationalization of these criteria based on the recruitment process; and (4) a discussion focused on application of program criteria with example applicants. Results: The holistic review workshop was conducted at the American Association of Psychiatry Residency Directors conference in 2021 with 48 self-selected attendees. Following the workshop, 74% of attendees reported a likelihood of implementing holistic applications during their next application cycle, 78% were able to leave with at least one actionable item, 100% thought that the session was interactive, and 78% felt that the session met their expectations. Discussion: Implementing a holistic review for psychiatry residency recruitment can assist programs in responding to the rapidly changing landscape and achieve aims for improving diversity and inclusion.

Circulating proteins to predict COVID-19 severity.

Predicting COVID-19 severity is difficult, and the biological pathways involved are not fully understood. To approach this problem, we measured 4701 circulating human protein abundances in two independent cohorts totaling 986 individuals. We then trained prediction models including protein abundances and clinical risk factors to predict COVID-19 severity in 417 subjects and tested these models in a separate cohort of 569 individuals. For severe COVID-19, a baseline model including age and sex provided an area under the receiver operator curve (AUC) of 65% in the test cohort. Selecting 92 proteins from the 4701 unique protein abundances improved the AUC to 88% in the training cohort, which remained relatively stable in the testing cohort at 86%, suggesting good generalizability. Proteins selected from different COVID-19 severity were enriched for cytokine and cytokine receptors, but more than half of the enriched pathways were not immune-related. Taken together, these findings suggest that circulating proteins measured at early stages of disease progression are reasonably accurate predictors of COVID-19 severity. Further research is needed to understand how to incorporate protein measurement into clinical care.

A shift in lung macrophage composition is associated with COVID-19 severity and recovery.

Although it has been more than 2 years since the start of the coronavirus disease 2019 (COVID-19) pandemic, COVID-19 continues to be a worldwide health crisis. Despite the development of preventive vaccines, therapies to treat COVID-19 and other inflammatory diseases remain a major unmet need in medicine. Our study sought to identify drivers of disease severity and mortality to develop tailored immunotherapy strategies to halt disease progression. We assembled the Mount Sinai COVID-19 Biobank, which was composed of almost 600 hospitalized patients followed longitudinally through the peak of the pandemic in 2020. Moderate disease and survival were associated with a stronger antigen presentation and effector T cell signature. In contrast, severe disease and death were associated with an altered antigen presentation signature, increased numbers of inflammatory immature myeloid cells, and extrafollicular activated B cells that have been previously associated with autoantibody formation. In severely ill patients with COVID-19, lung tissue-resident alveolar macrophages not only were drastically depleted but also had an altered antigen presentation signature, which coincided with an influx of inflammatory monocytes and monocyte-derived macrophages. In addition, we found that the size of the alveolar macrophage pool correlated with patient outcome and that alveolar macrophage numbers and functionality were restored to homeostasis in patients who recovered from COVID-19. These data suggest that local and systemic myeloid cell dysregulation are drivers of COVID-19 severity and modulation of alveolar macrophage numbers and activity in the lung may be a viable therapeutic strategy for the treatment of critical inflammatory lung diseases.

Shift of lung macrophage composition is associated with COVID-19 disease severity and recovery.

Though it has been 2 years since the start of the Coronavirus Disease 19 (COVID-19) pandemic, COVID-19 continues to be a worldwide health crisis. Despite the development of preventive vaccines, very little progress has been made to identify curative therapies to treat COVID-19 and other inflammatory diseases which remain a major unmet need in medicine. Our study sought to identify drivers of disease severity and death to develop tailored immunotherapy strategies to halt disease progression. Here we assembled the Mount Sinai COVID-19 Biobank which was comprised of ~600 hospitalized patients followed longitudinally during the peak of the pandemic. Moderate disease and survival were associated with a stronger antigen (Ag) presentation and effector T cell signature, while severe disease and death were associated with an altered Ag presentation signature, increased numbers of circulating inflammatory, immature myeloid cells, and extrafollicular activated B cells associated with autoantibody formation. Strikingly, we found that in severe COVID-19 patients, lung tissue resident alveolar macrophages (AM) were not only severely depleted, but also had an altered Ag presentation signature, and were replaced by inflammatory monocytes and monocyte-derived macrophages (MoMΦ). Notably, the size of the AM pool correlated with recovery or death, while AM loss and functionality were restored in patients that recovered. These data therefore suggest that local and systemic myeloid cell dysregulation is a driver of COVID-19 severity and that modulation of AM numbers and functionality in the lung may be a viable therapeutic strategy for the treatment of critical lung inflammatory illnesses.

Downregulation of exhausted cytotoxic T cells in gene expression networks of multisystem inflammatory syndrome in children.

Multisystem inflammatory syndrome in children (MIS-C) presents with fever, inflammation and pathology of multiple organs in individuals under 21 years of age in the weeks following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Although an autoimmune pathogenesis has been proposed, the genes, pathways and cell types causal to this new disease remain unknown. Here we perform RNA sequencing of blood from patients with MIS-C and controls to find disease-associated genes clustered in a co-expression module annotated to CD56dimCD57+ natural killer (NK) cells and exhausted CD8+ T cells. A similar transcriptome signature is replicated in an independent cohort of Kawasaki disease (KD), the related condition after which MIS-C was initially named. Probing a probabilistic causal network previously constructed from over 1,000 blood transcriptomes both validates the structure of this module and reveals nine key regulators, including TBX21, a central coordinator of exhausted CD8+ T cell differentiation. Together, this unbiased, transcriptome-wide survey implicates downregulation of NK cells and cytotoxic T cell exhaustion in the pathogenesis of MIS-C.

The recovery education in the academy program: transforming academic curricula with the principles of recovery and self-determination.

TOPIC: This article describes a curricular transformation initiative, the Recovery Education in the Academy Program (REAP), spearheaded by the University of Illinois at Chicago's National Research and Training Center on Psychiatric Disability. PURPOSE: REAP is designed to integrate principles of recovery, self-determination, and other evidence-based practices for people with psychiatric disabilities into medical, social, and behavioral sciences curricula. The principles on which the curricula transformation efforts are based, the instructional activities employed, early outcomes of the endeavor, and future plans for replication are delineated. SOURCES USED: As described in this paper, REAP builds on a theoretical framework derived from the evidence-based literature, multiple technical reports, and curricular initiatives, including the Institute of Medicine, the Annapolis Coalition for Behavioral Workforce Development, and the Final Report of President's New Freedom Commission on Mental Health. CONCLUSIONS: REAP has delivered state-of-the-science education to over 1,000 trainees, including medical students, psychiatry residents, psychology and social work interns, and rehabilitation counselors, pre/post-doctoral students and professionals within a variety of academic settings. REAP serves as a replicable structure to successfully integrate recovery education into existing, accredited academic programs and curricula using the parameters outlined by multiple experts and stakeholders. Barriers to curricular transformation and strategies to overcome these barriers are highlighted.

Treatment settings and metabolic monitoring for people experiencing first-episode psychosis.

Monitoring for metabolic sequelae of antipsychotic medications is inconsistent in clinical settings. In this study, frequency of such monitoring in 40 individuals experiencing a first episode of psychosis was analyzed according to the setting in which they received treatment (i.e., inpatient unit, outpatient clinic, or metabolic screening clinic). The traditional outpatient clinic was the least likely of the three settings to monitor blood glucose, blood pressure, weight, and waist circumference. In any setting, blood lipids were measured in only 2 of the 40 patients. Reasons for these findings and recommendations for reducing barriers to screening are presented.

Author Correction: Sampling the host response to SARS-CoV-2 in hospitals under siege.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Cytotoxic lymphocytes are dysregulated in multisystem inflammatory syndrome in children.

Multisystem inflammatory syndrome in children (MIS-C) presents with fever, inflammation and multiple organ involvement in individuals under 21 years following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. To identify genes, pathways and cell types driving MIS-C, we sequenced the blood transcriptomes of MIS-C cases, pediatric cases of coronavirus disease 2019, and healthy controls. We define a MIS-C transcriptional signature partially shared with the transcriptional response to SARS-CoV-2 infection and with the signature of Kawasaki disease, a clinically similar condition. By projecting the MIS-C signature onto a co-expression network, we identified disease gene modules and found genes downregulated in MIS-C clustered in a module enriched for the transcriptional signatures of exhausted CD8 + T-cells and CD56 dim CD57 + NK cells. Bayesian network analyses revealed nine key regulators of this module, including TBX21 , a central coordinator of exhausted CD8 + T-cell differentiation. Together, these findings suggest dysregulated cytotoxic lymphocyte response to SARS-Cov-2 infection in MIS-C.

Beneficial and adverse effects of antipsychotic medication on cognitive flexibility are related to COMT genotype in first episode psychosis.

This study evaluated the ability to flexibly shift cognitive set and to consistently maintain a new response preference using the Penn Conditional Exclusion Test (PCET). The relationship of performance errors with catechol-O-methyltransferase (COMT) rs4680 (Val158Met) genotype (Met carriers vs. Val homozygotes) on test performance before and after antipsychotic treatment in 32 first episode psychosis (FEP) patients was examined. After treatment, patients demonstrated a mixture of beneficial and adverse cognitive outcomes that varied in relation to COMT genotype. Met carriers showed decreased perseverative and regressive errors, reflecting improved cognitive flexibility and enhanced stability of behavioral preferences, respectively. In contrast, Val homozygotes exhibited an increase in regressive errors after treatment. These findings suggest that Val homozygotes may be vulnerable to adverse effects of antipsychotic medication on cognitive processes that maintain consistent adaptive response preferences, an ability linked to the striatum in rodent models.

Changing toddlers' and preschoolers' attachment classifications: the Circle of Security intervention.

The Circle of Security intervention uses a group treatment modality to provide parent education and psychotherapy that is based on attachment theory. The purpose of this study was to track changes in children's attachment classifications pre- and immediately postintervention. Participants were 65 toddler- or preschooler- caregiver dyads recruited from Head Start and Early Head Start programs. As predicted, there were significant within-subject changes from disorganized to organized attachment classifications, with a majority changing to the secure classification. In addition, only 1 of the 13 preintervention securely attached children shifted to an insecure classification. Results suggest that the Circle of Security protocol is a promising intervention for the reduction of disorganized and insecure attachment in high-risk toddlers and preschoolers.

Effects of antipsychotic treatment on emotion perception deficits in first-episode schizophrenia.

OBJECTIVE: The authors evaluated emotion perception in acutely ill patients experiencing a first episode of schizophrenia. They also investigated the effects of antipsychotic medication on emotion perception. METHOD: Tests of the ability to perceive and discriminate emotional expressions from the Penn Computerized Neuropsychological Battery were given to 13 patients experiencing their first episode of schizophrenia. Patients were also assessed with the Positive and Negative Syndrome Scale. The patients were tested while they were unmedicated and again following clinical stabilization. Healthy individuals were evaluated over a similar time interval. RESULTS: Patients with first-episode schizophrenia demonstrated impairments in emotion perception before treatment and no significant improvement after treatment. Emotion perception deficits were correlated with negative symptoms after clinical stabilization. CONCLUSIONS: Deficits in emotion perception are present at illness onset in schizophrenia and show minimal response to effective antipsychotic treatment.

Metabolic and inflammatory genes in schizophrenia.

Energy metabolism and immunity are characterized as abnormal in schizophrenia. Because these two systems are highly coordinated, we measured expression of prototypic obesogenic and immunogenic genes in freshly harvested PBMC from controls and participants with schizophrenia. We report significant increases in PPARγ, SREBP1, IL-6 and TNFα, and decreases in PPARα and C/EPBα and mRNA levels from patients with schizophrenia, with additional BMI interactions, characterizing dysregulation of genes relating to metabolic-inflammation in schizophrenia.

Disease and drug effects on internally-generated and externally-elicited responses in first episode schizophrenia and psychotic bipolar disorder.

Neurocognitive deficits are associated with most psychotic disorders, but may differ across diagnosis and by treatment status. This ambiguity is partly addressed in longitudinal pre/post treatment studies with first episode patients. Antipsychotic-naïve first-episode schizophrenia patients have shown intact performance on a predictive saccade task that assesses simple motor learning, spatial abilities, and response planning. After antipsychotic treatment, however, schizophrenia patients performing this task show a selective impairment in the accuracy of anticipatory responses, generated from learned internal representations of the task stimulus. This finding is in line with other observations of antipsychotic medication effects on frontostriatal systems, particularly dorsolateral prefrontal cortex. We sought to replicate this provocative finding with an independent sample of antipsychotic-naïve first-episode schizophrenia patients and extend it by including a group of patients with first episode bipolar disorder with psychosis (BDP). Matched healthy controls were also studied in parallel. Schizophrenia patients demonstrated intact performance pretreatment followed by impairment post-treatment for accuracy of anticipatory responses, and worse accuracy was associated with higher antipsychotic dose. BDP patients displayed saccade accuracy deficits before and after treatment and had no correlation of performance and antipsychotic dose. The findings suggest different neural alterations early in the course of each psychotic disorder, and different vulnerabilities to antipsychotic treatment effects between schizophrenia and BDP.