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Objective: The authors assessed whether subthreshold hypomanic symptoms in patients with major depression predicted new-onset mania or hypomania.Method: The authors identified 550 individuals followed for at least 1 year in the National Institute of Mental Health Collaborative Depression Study with a diagnosis of major depression at intake. All participants were screened at baseline for five manic symptoms: elevated mood, decreased need for sleep, unusually high energy, increased goal-directed activity, and grandiosity. Participants were followed prospectively for a mean of 17.5 years and up to 31 years. The Longitudinal Interval Follow-up Examination was used to monitor course of illness and to identify any hypomania or mania. The association of subthreshold hypomanic symptoms at baseline with subsequent hypomania or mania was determined in survival analyses using Cox proportional hazards regression.Results: With a cumulative probability of one in four on survival analysis, 19.6% (N=108) of the sample experienced hypomania or mania, resulting in revision of diagnoses for 12.2% to bipolar II disorder and 7.5% to bipolar I disorder. Number of subthreshold hypomanic symptoms, presence of psychosis, and age at illness onset predicted progression to bipolar disorder. Decreased need for sleep, unusually high energy, and increased goal-directed activity were specifically implicated.Conclusions: Symptoms of hypomania, even when of low intensity, were frequently associated with subsequent progression to bipolar disorder, although the majority of patients who converted did not have any symptoms of hypomania at baseline. These results suggest that continued monitoring for the possibility of progression to bipolar disorder is necessary over the long-term course of major depressive disorder. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to examine the use of benzodiazepines (BZs) and selective serotonin reuptake inhibitors/selective norepinephrine reuptake inhibitors (SSRIs/SNRIs) over nine years of follow-up in middle-aged and older adults with diagnoses of panic disorder with or without agoraphobia, social phobia, or generalized anxiety disorder.Setting and Participants: Participants in this study were enrolled in the Harvard/Brown Anxiety Research Project (HARP). HARP is a naturalistic, longitudinal, multisite study of adults with anxiety disorders who are recruited from psychiatric settings. The analytic sample consisted of 51 participants with anxiety disorders who were 55 to 70 years old at baseline and a younger cohort of 211 participants added for comparative analysis.Design: The authors examined patterns of medication use (BZs and SSRIs/SNRIs) in participants with anxiety disorders as they aged, by assessing the proportion of participants taking these medications using generalized estimating equation modeling.Measurements: The present data were derived from the structured diagnostic interview administered at enrollment using a combination of the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Third Edition-R Non-Affective Disorder, Patient Version, Research Diagnostic Criteria Schedule for Affective Disorders-Lifetime, and subsequent follow-up interviews over a nine-year period using the Longitudinal Interval Follow-up Evaluation-Pharmacia & Upjohn to assess the weekly course of disorders to indicate syndrome severity and document medication use by specific type and dose on a weekly basis.Results: Findings showed that rates of BZ use were high among both the older (53% at baseline) and the younger (57.4%) age groups and did not significantly decrease over time, after controlling for time in episode of their anxiety disorders. There was a statistically significant increase in SSRI/SNRI use over time in both groups. At the beginning of the study, 18% of the older group and 21% of the younger group were using SSRIs/SNRIs; however, at the end of the study, the rates increased to 35% and 43%, respectively.Conclusions: Although there was an increase in SSRI/SNRI use in older participants with anxiety disorders over the course of study, at nine years of follow-up, only 35% of participants were utilizing SSRI/SNRI medication, while more than one-half of the same participants were continuing to use BZs. To the authors' knowledge, there are no randomized clinical trials that have addressed comparative efficacy and safety of BZs and SSRIs/SNRIs in this population. However, there is documented evidence of adverse effects of chronic BZ use and the risk of developing dependency in older populations. [ABSTRACT FROM AUTHOR]

The present study examined whether post-traumatic stress disorder (PTSD) and comorbid substance use disorder (SUD) is associated with greater social and health morbidity than PTSD without SUD in a sample of female primary care patients. Participants were administered diagnostic interviews and assessed for work productivity, quality of interpersonal relationships, and degree of health functioning. No significant differences were found between the women with current PTSD and a comorbid lifetime substance use disorder (N = 56) and those with current PTSD and no lifetime substance use disorders (N = 60) in degree of work productivity, interpersonal functioning, and overall well-being and health, as well as number of lifetime medical illnesses. These findings suggest that the presence of comorbid SUD may not explain the level of social and health difficulties associated with the dual diagnosis of PTSD and SUD. Copyright © 2003 by Elsevier Science (USA). [ABSTRACT FROM AUTHOR]

Context: Extracts of St John's wort are widely used to treat depression. Although more than 2 dozen clinical trials have been conducted with St John's wort, most have significant flaws in design and do not enable meaningful interpretation.Objective: To compare the efficacy and safety of a standardized extract of St John's wort with placebo in outpatients with major depression.Design and Setting: Randomized, double-blind, placebo-controlled clinical trial conducted between November 1998 and January 2000 in 11 academic medical centers in the United States.Participants: Two hundred adult outpatients (mean age, 42.4 years; 67.0% female; 85.9% white) diagnosed as having major depression and having a baseline Hamilton Rating Scale for Depression (HAM-D) score of at least 20.Intervention: Participants completed a 1-week, single-blind run-in of placebo, then were randomly assigned to receive either St John's wort extract (n = 98; 900 mg/d for 4 weeks, increased to 1200 mg/d in the absence of an adequate response thereafter) or placebo (n = 102) for 8 weeks.Main Outcome Measures: The primary outcome measure was rate of change on the HAM-D over the treatment period. Secondary measures included the Beck Depression Inventory (BDI), Hamilton Rating Scale for Anxiety (HAM-A), the Global Assessment of Function (GAF) scale, and the Clinical Global Impression-Severity and -Improvement scales (CGI-S and CGI-I).Results: The random coefficient analyses for the HAM-D, HAM-A, CGI-S, and CGI-I all showed significant effects for time but not for treatment or time-by-treatment interaction (for HAM-D scores, P<.001, P =.16, and P =.58, respectively). Analysis of covariance showed nonsignificant effects for BDI and GAF scores. The proportion of participants achieving an a priori definition of response did not differ between groups. The number reaching remission of illness was significantly higher with St John's wort than with placebo (P =.02), but the rates were very low in the full intention-to-treat analysis (14/98 [14.3%] vs 5/102 [4.9%], respectively). St John's wort was safe and well tolerated. Headache was the only adverse event that occurred with greater frequency with St John's wort than placebo (39/95 [41%] vs 25/100 [25%], respectively).Conclusion: In this study, St John's wort was not effective for treatment of major depression. [ABSTRACT FROM AUTHOR]

OBJECTIVE: We report rates and causes of death for a cohort of 246 eating-disordered women and provide descriptive information on their eating disorder and comorbid diagnoses. METHOD: Data on mortality were collected as part of a longitudinal study of anorexia nervosa and bulimia nervosa, now in its 11th year. Other data sources included death certificates, autopsy reports, relative interviews, and a National Death Index search. RESULTS: Seven deaths have occurred during the study, all among anorexic subjects with a history of binging and purging and with comorbid Axis I disorders. The crude mortality rate was 5.1%. The standardized mortality ratios for death (9.6) and suicide (58.1) were significantly elevated (p <. 001). CONCLUSIONS: Anorexia nervosa is associated with a substantial risk of death and suicide. Features correlated with fatal outcome are longer duration of illness, binging and purging, comorbid substance abuse, and comorbid affective disorders. Copyright 2000 by John Wiley & Sons, Inc. [ABSTRACT FROM AUTHOR]

Background: Patients with chronic forms of major depression are difficult to treat, and the relative efficacy of medications and psychotherapy is uncertain.Methods: We randomly assigned 681 adults with a chronic nonpsychotic major depressive disorder to 12 weeks of outpatient treatment with nefazodone (maximal dose, 600 mg per day), the cognitive behavioral-analysis system of psychotherapy (16 to 20 sessions), or both. At base line, all patients had scores of at least 20 on the 24-item Hamilton Rating Scale for Depression (indicating clinically significant depression). Remission was defined as a score of 8 or less at weeks 10 and 12. For patients who did not have remission, a satisfactory response was defined as a reduction in the score by at least 50 percent from base line and a score of 15 or less. Raters were unaware of the patients' treatment assignments.Results: Of the 681 patients, 662 attended at least one treatment session and were included in the analysis of response. The overall rate of response (both remission and satisfactory response) was 48 percent in both the nefazodone group and in the psychotherapy group, as compared with 73 percent in the combined-treatment group. (P<0.001 for both comparisons). Among the 519 subjects who completed the study, the rates of response were 55 percent in the nefazodone group and 52 percent in the psychotherapy group, as compared with 85 percent in the combined-treatment group (P<0.001 for both comparisons). The rates of withdrawal were similar in the three groups. Adverse events in the nefazodone group were consistent with the known side effects of the drug (e.g., headache, somnolence, dry mouth, nausea, and dizziness).Conclusions: Although about half of patients with chronic forms of major depression have a response to short-term treatment with either nefazodone or a cognitive behavioral-analysis system of psychotherapy, the combination of the two is significantly more efficacious than either treatment alone. [ABSTRACT FROM AUTHOR]

Context: The chronic form of major depression is associated with a high rate of prevalence and disability, but no controlled research has examined the impact of long-term treatment on the course and burden of illness.Objective: To determine if maintenance therapy with sertraline hydrochloride can effectively prevent recurrence of depression in the high-risk group of patients experiencing chronic major depression or major depression with antecedent dysthymic disorder ("double depression").Design: A 76-week randomized, double-blind, parallel-group study, conducted from September 1993 to November 1996.Setting: Outpatient psychiatric clinics at 10 academic medical centers and 2 clinical research centers.Intervention: Maintenance treatment with either sertraline hydrochloride (n = 77) in flexible doses up to 200 mg or placebo (n = 84).Patients: A total of 161 outpatients with chronic major or double depression who responded to sertraline in a 12-week, double-blind, acute-phase treatment trial and continued to have a satisfactory therapeutic response during a subsequent 4-month continuation phase.Main Outcome Measure: Time to recurrence of major depression.Results: Sertraline afforded significantly greater prophylaxis against recurrence than did placebo (5 [6%] of 77 in the sertraline group vs 19 [23%] of 84 in the placebo group; P = .002 for the log-rank test of time-to-recurrence distributions). Clinically significant depressive symptoms reemerged in 20 (26%) of 77 patients treated with sertraline vs 42 (50%) of 84 patients who received placebo (P = .001). With use of a Cox proportional hazards model, patients receiving placebo were 4.07 times more likely (95% CI, 1.51-10.95; P = .005) to experience a depression recurrence, after adjustment for study site, type of depression, and randomization strata.Conclusions: Maintenance therapy with sertraline is well tolerated and has significant efficacy in preventing recurrence or reemergence of depression in chronically depressed patients. [ABSTRACT FROM AUTHOR]

Objective: A consensus conference on the reasons for the undertreatment of depression was organized by the National Depressive and Manic Depressive Association (NDMDA) on January 17-18, 1996. The target audience included health policymakers, clinicians, patients and their families, and the public at large. Six key questions were addressed: (1) Is depression undertreated in the community and in the clinic? (2) What is the economic cost to society of depression? (3) What have been the efforts in the past to redress undertreatment and how successful have they been? (4) What are the reasons for the gap between our knowledge of the diagnosis and treatment of depression and actual treatment received in this country? (5) What can we do to narrow this gap? (6) What can we do immediately to narrow this gap?Participants: Consensus panel members were drawn from psychiatry, psychology, family practice, internal medicine, managed care and public health, consumers, and the general public. The panelists listened to a set of presentations with background papers from experts on diagnosis, epidemiology, treatment, and cost of treatment.Evidence: Experts summarized relevant data from the world scientific literature on the 6 questions posed for the conference.Consensus Process: Panel members discussed openly all material presented to them in executive session. Selected panelists prepared first drafts of the consensus statements for each question. All of these drafts were read by all panelists and were edited and reedited until consensus was achieved.Conclusions: There is overwhelming evidence that individuals with depression are being seriously undertreated. Safe, effective, and economical treatments are available. The cost to individuals and society of this undertreatment is substantial. Long suffering, suicide, occupational impairment, and impairment in interpersonal and family relationships exist. Efforts to redress this gap have included provider educational programs and public educational programs. Reasons for the continuing gap include patient, provider, and health care system factors. Patient-based reasons include failure to recognize the symptoms, underestimating the severity, limited access, reluctance to see a mental health care specialist due to stigma, noncompliance with treatment, and lack of health insurance. Provider factors include poor professional school education about depression, limited training in interpersonal skills, stigma, inadequate time to evaluate and treat depression, failure to consider psychotherapeutic approaches, and prescription of inadequate doses of antidepressant medication for inadequate durations. Mental health care systems create barriers to receiving optimal treatment. Strategies to narrow the gap include enhancing the role of patients and families as participants in care and advocates; developing performance standards for behavioral health care systems, including incentives for positive identification, assessment, and treatment of depression; enhancing educational programs for providers and the public; enhancing collaboration among provider subtypes (eg, primary care providers and mental health professionals); and conducting research on development and testing of new treatments for depression. [ABSTRACT FROM AUTHOR]

Background: Psychosocial outcomes from the Prevention of Recurrent Episodes of Depression with Venlafaxine ER for Two Years (PREVENT) study were evaluated.Methods: Adult outpatients with recurrent major depressive disorder (MDD) and response or remission following 6-month continuation treatment with venlafaxine extended release (ER) were randomized to receive venlafaxine ER or placebo for 1 year. Patients without recurrence on venlafaxine ER during year 1 were randomized to venlafaxine ER or placebo for year 2. Psychosocial functioning was assessed using the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q), Life Enjoyment Scale-Short Version (LES-S), Social Adjustment Scale-Self-Report (SAS-SR) total and individual factors, Short Form Health Survey (SF-36) (vitality, social functioning, and role function-emotional items), and Longitudinal Interval Follow-up Evaluation (LIFE).Results: At year 1 end, better overall psychosocial functioning was seen among patients randomly assigned to venlafaxine ER (n=129) vs placebo (n=129), with significant differences at end point on SF-36 role function-emotional, Q-LES-Q, and SAS-SR total, and work, house work, social/leisure, and extended-family factor scores (p≤0.05). At year 2 end, significant differences favored venlafaxine ER (n=43) vs placebo (n=40) on SF-36 vitality and role function-emotional, Q-LES-Q, LES-S, LIFE, and SAS-SR total, social/leisure, and extended-family factor scores (p≤0.05).Limitations: Patients with chronic MDD or treatment resistance were excluded and long-term specialist care was a financial incentive for treatment compliance. Discontinuation-related adverse events may have compromised the integrity of the treatment blind.Conclusions: For patients with recurrent MDD, 2 years' maintenance therapy with venlafaxine ER may improve psychosocial functioning vs placebo. [ABSTRACT FROM AUTHOR]

Background: Lung transplant recipients are traditionally monitored with pulmonary function testing (PFT) and lung biopsy to detect post-transplant complications and guide treatment. Plasma donor-derived cell free DNA (dd-cfDNA) is a novel molecular approach of assessing allograft injury, including subclinical allograft dysfunction. The aim of this study was to determine if episodes of extreme molecular injury (EMI) in lung transplant recipients increases the risk of chronic lung allograft dysfunction (CLAD) or death., Methods: This multicenter prospective cohort study included 238 lung transplant recipients. Serial plasma samples were collected for dd-cfDNA measurement by shotgun sequencing. EMI was defined as a dd-cfDNA above the third quartile of levels observed for acute rejection (dd-cfDNA level of ≥5% occurring after 45 days post-transplant). EMI was categorized as Secondary if associated with co-existing acute rejection, infection or PFT decline; or Primary if not associated with these conditions., Results: EMI developed in 16% of patients at a median 343.5 (IQR: 177.3-535.5) days post-transplant. Over 50% of EMI episodes were classified as Primary. EMI was associated with an increased risk of severe CLAD or death (HR: 2.78, 95% CI: 1.26-6.22, p = 0.012). The risk remained consistent for the Primary EMI subgroup (HR: 2.34, 95% CI 1.18-4.85, p = 0.015). Time to first EMI episode was a significant predictor of the likelihood of developing CLAD or death (AUC=0.856, 95% CI=0.805-0.908, p < 0.001)., Conclusions: Episodes of EMI in lung transplant recipients are often isolated and may not be detectable with traditional clinical monitoring approaches. EMI is associated with an increased risk of severe CLAD or death, independent of concomitant transplant complications., (Copyright © 2024 International Society for the Heart and Lung Transplantation. All rights reserved.)

Background: A prior single-center, retrospective cohort study identified baseline lung allograft dysfunction (BLAD) as a risk factor for death in bilateral lung transplant recipients. In this multicenter prospective cohort study, we test the association of BLAD with death in bilateral lung transplant recipients, identify clinical risk factors for BLAD, and assess its association with allograft injury on the molecular level., Methods: This multicenter, prospective cohort study included 173 bilateral lung transplant recipients that underwent serial pulmonary function testing and plasma collection for donor-derived cell-free DNA at prespecified time points. BLAD was defined as failure to achieve ≥80% predicted for both forced expiratory volume in 1 s and forced vital capacity after lung transplant, on 2 consecutive measurements at least 3 mo apart., Results: BLAD was associated with increased risk of death (hazard ratio, 1.97; 95% confidence interval [CI], 1.05-3.69; P  = 0.03) but not chronic lung allograft dysfunction alone (hazard ratio, 1.60; 95% CI, 0.87-2.95; P = 0.13). Recipient obesity (odds ratio, 1.69; 95% CI, 1.15-2.80; P  = 0.04) and donor age (odds ratio, 1.03; 95% CI, 1.02-1.05; P  = 0.004) increased the risk of developing BLAD. Patients with BLAD did not demonstrate higher log 10 (donor-derived cell-free DNA) levels compared with no BLAD (slope [SE]: -0.0095 [0.0007] versus -0.0109 [0.0007]; P  = 0.15)., Conclusions: BLAD is associated with an increased risk of death following lung transplantation, representing an important posttransplant outcome with valuable prognostic significance; however, early allograft specific injury on the molecular level does not increase the risk of BLAD, supporting further mechanistic insight into disease pathophysiology., (Copyright © 2024 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Rationale: The association of acute cellular rejection (ACR) with chronic lung allograft dysfunction (CLAD) in lung transplant recipients has primarily been described before consensus recommendations incorporating restrictive phenotypes. Furthermore, the association of the degree of molecular allograft injury during ACR with CLAD or death remains undefined. Objectives: To investigate the association of ACR with the risk of CLAD or death and to further investigate if this risk depends on the degree of molecular allograft injury. Methods: This multicenter, prospective cohort study included 188 lung transplant recipients. Subjects underwent serial plasma collections for donor-derived cell-free DNA (dd-cfDNA) at prespecified time points and bronchoscopy. Multivariable Cox proportional-hazards analysis was conducted to analyze the association of ACR with subsequent CLAD or death as well as the association of dd-cfDNA during ACR with risk of CLAD or death. Additional outcomes analyses were performed with episodes of ACR categorized as "high risk" (dd-cfDNA ⩾ 1%) and "low risk" (dd-cfDNA < 1%). Measurements and Main Results: In multivariable analysis, ACR was associated with the composite outcome of CLAD or death (hazard ratio [HR], 2.07 [95% confidence interval (CI), 1.05-4.10]; P  = 0.036). Elevated dd-cfDNA ⩾ 1% at ACR diagnosis was independently associated with increased risk of CLAD or death (HR, 3.32; 95% CI, 1.31-8.40; P  = 0.012). Patients with high-risk ACR were at increased risk of CLAD or death (HR, 3.13; 95% CI, 1.41-6.93; P  = 0.005), whereas patients with low-risk status ACR were not. Conclusions: Patients with ACR are at higher risk of CLAD or death, but this may depend on the degree of underlying allograft injury at the molecular level. Clinical trial registered with www.clinicaltrials.gov (NCT02423070).

Background: The association between organizing pneumonia (OP) after lung transplantation with the development of acute rejection (AR) remains undefined. In addition, molecular allograft injury, as measured by donor-derived cell-free DNA (dd-cfDNA), during episodes of OP and its relationship to episodes of AR, chronic lung allograft dysfunction (CLAD), or death is unknown., Methods: This multicenter, prospective cohort study collected serial plasma samples from 188 lung transplant recipients for dd-cfDNA at the time of bronchoscopy with biopsy. Multivariable Cox regression was used to analyze the association between OP with the development of AR (antibody-mediated rejection (AMR) and acute cellular rejection (ACR)), CLAD, and death. Multivariable models were performed to test the association of dd-cfDNA at OP with the risk of AR, CLAD, or death., Results: In multivariable analysis, OP was associated with increased risk of AMR (hazard ratio (HR) = 2.26, 95% confidence interval (CI) 1.04-4.92, p = 0.040) but not ACR (HR = 1.29, 95% CI: 0.66-2.5, p = 0.45) or the composite outcome of CLAD or death (HR = 0.88, 95% CI, 0.47-1.65, p = 0.69). Median levels of dd-cfDNA were higher in OP compared to stable controls (1.33% vs 0.43%, p = 0.0006). Multivariable analysis demonstrated that levels of dd-cfDNA at diagnosis of OP were associated with increased risk of both AMR (HR = 1.29, 95% CI 1.03-1.62, p = 0.030) and death (HR = 1.16, 95% CI, 1.02-1.31, p = 0.026)., Conclusions: OP is independently associated with an increased risk of AMR but not CLAD or death. The degree of molecular allograft injury at the diagnosis of OP may further predict the risk of AMR and death., (Copyright © 2023. Published by Elsevier Inc.)

Rationale: Plasma cell-free DNA levels correlate with disease severity in many conditions. Pretransplant cell-free DNA may risk stratify lung transplant candidates for post-transplant complications. Objectives: To evaluate if pretransplant cell-free DNA levels and tissue sources identify patients at high risk of primary graft dysfunction and other pre- and post-transplant outcomes. Methods: This multicenter, prospective cohort study recruited 186 lung transplant candidates. Pretransplant plasma samples were collected to measure cell-free DNA. Bisulfite sequencing was performed to identify the tissue sources of cell-free DNA. Multivariable regression models determined the association between cell-free DNA levels and the primary outcome of primary graft dysfunction and other transplant outcomes, including Lung Allocation Score, chronic lung allograft dysfunction, and death. Measurements and Main Results: Transplant candidates had twofold greater cell-free DNA levels than healthy control patients (median [interquartile range], 23.7 ng/ml [15.1-35.6] vs. 12.9 ng/ml [9.9-18.4]; P  < 0.0001), primarily originating from inflammatory innate immune cells. Cell-free DNA levels and tissue sources differed by native lung disease category and correlated with the Lung Allocation Score ( P  < 0.001). High pretransplant cell-free DNA increased the risk of primary graft dysfunction (odds ratio, 1.60; 95% confidence interval [CI], 1.09-2.46; P  = 0.0220), and death (hazard ratio, 1.43; 95% CI, 1.07-1.92; P   =  0.0171) but not chronic lung allograft dysfunction (hazard ratio, 1.37; 95% CI, 0.97-1.94; P   =  0.0767). Conclusions: Lung transplant candidates demonstrate a heightened degree of tissue injury with elevated cell-free DNA, primarily originating from innate immune cells. Pretransplant plasma cell-free DNA levels predict post-transplant complications.

Background: Bipolar disorder (BD) conveys the highest risk of suicide of all mental disorders. We sought to externally validate a risk calculator (RC) of suicide attempts developed in youth with BD from the Course and Outcome of Bipolar Youth (COBY) study in an adult sample., Methods: A prospective cohort of adults with BD from the National Institute of Mental Health Collaborative Depression Study (CDS; N = 427; mean (+/- SD) age at intake (36 +/- 13 years)) was secondarily analyzed to validate the COBY RC for one-year risk of suicide attempts/deaths. Nine of the ten predictor variables from the COBY RC were available in the CDS and used: age, age of mood disorder onset, first and second (partial) degree family history of suicide, history of psychotic symptoms, substance use disorder, prior suicide attempt, socioeconomic status, and non-suicidal self-injury (prospectively, incompletely at baseline)., Results: Over a mean (SD) follow-up of 19 (10) years, 29 % of the CDS sample attempted suicide. The RC predicted suicide attempts/deaths over one-year follow-up with an area under the receiver operating characteristic curve (AUC) of 0.78 (95 % CI 0.75-0.80). The RC performed slightly better in those with a younger age of mood disorder onset., Limitations: Clinical samples may limit generalizability; the RC does not assess more acute suicide risk., Conclusions: One-year risk of suicide attempts/deaths can be predicted with acceptable accuracy in youth and adults with BD, comparable to commonly used RCs to predict cardiovascular risk. This RC may help identify higher-risk individuals with BD for personalized treatment and research. https://cobysuicideattemptsrc.shinyapps.io/Shiny., Competing Interests: Declaration of competing interest Dr. Fiedorowicz has received research support from the National Institute of Mental Health (NIMH) and National Center for Advancing Translational Sciences (NCATS). He receives support from Elsevier for duties as an Editor-in-Chief, and from the United States Food and Drug Administration (USFDA) for service on the Psychopharmacologic Drugs Advisory Committee. Dr. T. Goldstein has received research support from NIMH, the American Foundation for Suicide Prevention (AFSP), and The Brain and Behavior Foundation, and royalties from Guilford Press. Dr. Strober has received research support from NIMH, and support from the Resnick Endowed Chair in Eating Disorders. Dr. Hafeman has received research support from NIHM and the Klingenstein Third Generation Foundation. Dr. Keller has received research support from NIMH and the John J. McDonnell and Margaret T. O’Brien Foundation. Dr. Iyengar has received research support from NIMH. Dr. Diler has received research support from NIMH. Ms. Hower has received honoraria from the Department of Defense (DOD) and from the Department of Psychiatry, University of California at San Diego (UCSD) School of Medicine. Dr. Hunt has received honorarium from Wiley Publishers and has received support from the NIMH. Dr. B. Goldstein has received research support from the Brain and Behavior Research Foundation (NARSAD), Brain Canada, the Canadian Institutes of Health Research, the Heart & Stroke Foundation, NIMH, and the Ontario Ministry of Research and Innovation. Dr. Birmaher has received research support from the National Institute of Mental Health (NIMH), and royalties for publications from Random House, Inc., UpToDate, and Lippincott Williams and Wilkins. Mr. Merranko, Ms. Siddiqi report no financial relationships with commercial interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Importance: Many U.S. State crisis standards of care (CSC) guidelines incorporated Sequential Organ Failure Assessment (SOFA), a sepsis-related severity score, in pandemic triage algorithms. However, SOFA performed poorly in COVID-19. Although disease-specific scores may perform better, their prognostic utility over time and in overcrowded care settings remains unclear., Objectives: We evaluated prognostication by the modified 4C (m4C) score, a COVID-19-specific prognosticator that demonstrated good predictive capacity early in the pandemic, as a potential tool to standardize triage across time and hospital-surge environments., Design: Retrospective observational cohort study., Setting: Two hundred eighty-one U.S. hospitals in an administrative healthcare dataset., Participants: A total of 298,379 hospitalized adults with COVID-19 were identified from March 1, 2020, to January 31, 2022. m4C scores were calculated from admission diagnosis codes, vital signs, and laboratory values., Main Outcomes and Measures: Hospital-surge index, a severity-weighted measure of COVID-19 caseload, was calculated for each hospital-month. Discrimination of in-hospital mortality by m4C and surge index-adjusted models was measured by area under the receiver operating characteristic curves (AUC). Calibration was assessed by training models on early pandemic waves and measuring fit (deviation from bisector) in subsequent waves., Results: From March 2020 to January 2022, 298,379 adults with COVID-19 were admitted across 281 U.S. hospitals. m4C adequately discriminated mortality in wave 1 (AUC 0.779 [95% CI, 0.769-0.789]); discrimination was lower in subsequent waves (wave 2: 0.772 [95% CI, 0.765-0.779]; wave 3: 0.746 [95% CI, 0.743-0.750]; delta: 0.707 [95% CI, 0.702-0.712]; omicron: 0.729 [95% CI, 0.721-0.738]). m4C demonstrated reduced calibration in contemporaneous waves that persisted despite periodic recalibration. Performance characteristics were similar with and without adjustment for surge., Conclusions and Relevance: Mortality prediction by the m4C score remained robust to surge strain, making it attractive for when triage is most needed. However, score performance has deteriorated in recent waves. CSC guidelines relying on defined prognosticators, especially for dynamic disease processes like COVID-19, warrant frequent reappraisal to ensure appropriate resource allocation., Competing Interests: The authors have disclosed that they do not have any potential conflict of interest.

The successful enzymatic degradation of polyester substrates has fueled worldwide investigation into the treatment of plastic waste using bio-based processes. Within this realm, marine-associated microorganisms have emerged as a promising source of polyester-degrading enzymes. In this work, we describe the hydrolysis of the synthetic polymer PET by SM14est, a polyesterase which was previously identified from Streptomyces sp. SM14, an isolate of the marine sponge Haliclona simulans . The PET hydrolase activity of purified SM14est was assessed using a suspension-based assay and subsequent analysis of reaction products by UV-spectrophotometry and RP-HPLC. SM14est displayed a preference for high salt conditions, with activity significantly increasing at sodium chloride concentrations from 100 mM up to 1,000 mM. The initial rate of PET hydrolysis by SM14est was determined to be 0.004 s -1 at 45°C, which was increased by 5-fold to 0.02 s -1 upon addition of 500 mM sodium chloride. Sequence alignment and structural comparison with known PET hydrolases, including the marine halophile PET6, and the highly efficient, thermophilic PHL7, revealed conserved features of interest. Based on this work, SM14est emerges as a useful enzyme that is more similar to key players in the area of PET hydrolysis, like PHL7 and IsPETase, than it is to its marine counterparts. Salt-tolerant polyesterases such as SM14est are potentially valuable in the biological degradation of plastic particles that readily contaminate marine ecosystems and industrial wastewaters., Competing Interests: KJ is employed by Novozymes A/S. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Carr, Keller, Paul, Schubert, Clausen, Jensen, Clarke, Westh and Dobson.)

In nature, enzymatic degradation of recalcitrant polysaccharides such as chitin and cellulose takes place by a synergistic interaction between glycoside hydrolases (GHs) and lytic polysaccharide monooxygenases (LPMOs). The two different families of carbohydrate-active enzymes use two different mechanisms when breaking glycosidic bonds between sugar moieties. GHs employ a hydrolytic activity and LPMOs are oxidative. Consequently, the topologies of the active sites differ dramatically. GHs have tunnels or clefts lined with a sheet of aromatic amino acid residues accommodating single polymer chains being threaded into the active site. LPMOs are adapted to bind to the flat crystalline surfaces of chitin and cellulose. It is believed that the LPMO oxidative mechanism provides new chain ends that the GHs can attach to and degrade, often in a processive manner. Indeed, there are many reports of synergies as well as rate enhancements when LPMOs are applied in concert with GHs. Still, these enhancements vary in magnitude with respect to the nature of the GH and the LPMO. Moreover, impediment of GH catalysis is also observed. In the present review, we discuss central works where the interplay between LPMOs and GHs has been studied and comment on future challenges to be addressed to fully use the potential of this interplay to improve enzymatic polysaccharide degradation., (© 2023 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Plasma donor-derived cell-free DNA (dd-cfDNA) is a sensitive biomarker for the diagnosis of acute rejection in lung transplant recipients; however, differences in dd-cfDNA levels between single and double lung transplant remains unknown. We performed an observational analysis that included 221 patients from two prospective cohort studies who had serial measurements of plasma dd-cfDNA at the time of bronchoscopy and pulmonary function testing, and compared dd-cfDNA between single and double lung transplant recipients across a range of disease states. Levels of dd-cfDNA were lower for single vs. double lung transplant in stable controls (median [IQR]: 0.15% [0.07, 0.44] vs. 0.46% [0.23, 0.74], p < .01) and acute rejection (1.06% [0.75, 2.32] vs. 1.78% [1.18, 5.73], p = .05). Doubling dd-cfDNA for single lung transplant to account for differences in lung mass eliminated this difference. The area under the receiver operating curve (AUC) for the detection of acute rejection was 0.89 and 0.86 for single and double lung transplant, respectively. The optimal dd-cfDNA threshold for the detection of acute rejection was 0.54% in single lung and 1.1% in double lung transplant. In conclusion, accounting for differences in dd-cfDNA in single versus double lung transplant is key for the interpretation of dd-cfDNA testing in research and clinical settings., (© 2022 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

Pulmonary chronic graft-versus-host disease (PcGVHD) is a devastating complication of allogeneic hematopoietic stem cell transplant (HCT). The 2014 National Institutes of Health cGVHD consensus criteria (NIH criteria) only captures bronchiolitis obliterans syndrome (BOS). In this study, we adapted the 2019 International Society for Heart and Lung Transplantation (ISHLT) criteria of chronic lung allograft dysfunction (CLAD) to define novel phenotypes of PcGVHD and compared the performance of this criteria with the NIH criteria to identify patients with high-risk PcGVHD. We reviewed consecutive patients in a cGVHD natural history protocol (#NCT00092235) and adapted the 2019 CLAD criteria (the adapted criteria) to define PcGVHD as post-HCT forced expiratory volume at 1 second < 80% predicted value, with 4 phenotypes: obstructive, restrictive, mixed obstructive/restrictive, and undefined. An independent adjudication committee evaluated subjects for diagnosis and phenotyping. We identified 166 (47.4%) patients who met the adapted criteria, including obstruction (n = 12, 3.4%), restriction (n = 67, 19.1%), mixed obstruction/restriction (n = 47, 13.4%), and undefined (n = 40, 11.4%). In these patients, less than half (n = 78) met the NIH criteria for BOS (NIH+); the rest (n = 88) did not (NIH-). The NIH- subjects showed increased risk of death compared with those without PcGVHD (hazard ratio = 1.88, 95% confidence interval = 1.20-2.95; P = .006) that was similar to NIH+ subjects (P = .678). Our study demonstrated the potential of the adapted criteria in identifying patients with high-risk PcGVHD that have been missed by the NIH criteria. The adapted criteria could become a valuable tool to better phenotype and study lung disease in cGVHD., (Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Objectives: Prior research has hypothesized the Sequential Organ Failure Assessment (SOFA) score to be a poor predictor of mortality in mechanically ventilated patients with COVID-19. Yet, several U.S. states have proposed SOFA-based algorithms for ventilator triage during crisis standards of care. Using a large cohort of mechanically ventilated patients with COVID-19, we externally validated the predictive capacity of the preintubation SOFA score for mortality prediction with and without other commonly used algorithm elements., Design: Multicenter, retrospective cohort study using electronic health record data., Setting: Eighty-six U.S. health systems., Patients: Patients with COVID-19 hospitalized between January 1, 2020, and February 14, 2021, and subsequently initiated on mechanical ventilation., Interventions: None., Measurements and Main Results: Among 15,122 mechanically ventilated patients with COVID-19, SOFA score alone demonstrated poor discriminant accuracy for inhospital mortality in mechanically ventilated patients using the validation cohort (area under the receiver operating characteristic curve [AUC], 0.66; 95% CI, 0.65-0.67). Discriminant accuracy was even poorer using SOFA score categories (AUC, 0.54; 95% CI, 0.54-0.55). Age alone demonstrated greater discriminant accuracy for inhospital mortality than SOFA score (AUC, 0.71; 95% CI, 0.69-0.72). Discriminant accuracy for mortality improved upon addition of age to the continuous SOFA score (AUC, 0.74; 95% CI, 0.73-0.76) and categorized SOFA score (AUC, 0.72; 95% CI, 0.71-0.73) models, respectively. The addition of comorbidities did not substantially increase model discrimination. Of 36 U.S. states with crisis standards of care guidelines containing ventilator triage algorithms, 31 (86%) feature the SOFA score. Of these, 25 (81%) rely heavily on the SOFA score (12 exclusively propose SOFA; 13 place highest weight on SOFA or propose SOFA with one other variable)., Conclusions: In a U.S. cohort of over 15,000 ventilated patients with COVID-19, the SOFA score displayed poor predictive accuracy for short-term mortality. Our findings warrant reappraisal of the SOFA score's implementation and weightage in existing ventilator triage pathways in current U.S. crisis standards of care guidelines., (Copyright © 2022 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Background: To identify prospectively ascertained individual and family factors that are associated with improvement in Bipolar Disorder (BD) among youths who initially presented with poor course., Methods: 82 youths with BD with persistent poor mood symptomatology ("predominantly ill course") were compared to 70 youths with BD who at intake had poor course, but showed improvement during the follow-up ("ill with improving course"), (ages 12.3 ± 3.3, vs. 11.7 ± 3.3 years old, at intake). Improvement was measured by the percentage of time euthymic during a mean follow-up of 12.8 years. Youths and parents were interviewed to assess psychopathology, functioning, treatment, and familial functioning and psychopathology., Results: Compared to the ill group, since intake, the improving group showed significantly lower subthreshold depression and hypo/mania, Attention Deficit Hyperactivity Disorder, and Disruptive Behavior Disorders. Parental Socioeconomic Status (SES) remained unchanged over time in the ill group, but progressively increased in the improving group. Importantly, the change in SES predated the improvement in the mood trajectory. The most influential variables that predicted improvement were higher SES, and absence of parental BD and Substance Use Disorder (SUD). Parental SUD also negatively affected the parental SES, which was directly associated with worse mood course., Limitations: Predominantly self-reported White samples may limit generalizability; other factors potentially associated with outcome (e.g., treatment adherence), were not ascertained., Conclusions: In addition to treating mood/comorbid psychopathology in symptomatic BD youths, to improve their prognosis, it is crucial to address their parent's BD and SUD and promote parental education/employment., (Copyright © 2022. Published by Elsevier B.V.)

Background: Childhood abuse negatively impacts the course of Bipolar Disorder (BD). Yet, no study has examined risk factors associated with prospectively evaluated physical/sexual abuse, specifically, those preceding first abuse among BD youth. We investigate past/intake/follow-up factors preceding first physical/sexual abuse among BD youth., Methods: Childhood-onset BD participants (n = 279 youth, mean age at intake = 12, mean length of follow-up = 12 years) enrolled in the Course and Outcome of Bipolar Youth (COBY) study. Demographic, clinical and family history variables were assessed every 7 months on average using Longitudinal Interval Follow-up Evaluation and Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS-PL). Abuse was evaluated at intake using the K-SADS-PL, over follow-up with a Traumatic Events Screen. Family psychopathology was assessed using Family History Screen/Structured Clinical Interview for Diagnostic Statistical Manual-IV., Results: Fifteen-percent of youth reported new-onset abuse during follow-up (62% physical, 26% sexual; 12% both). Intake predictors included more severe depressive symptoms (HR = 1.29), low socioeconomic-status (SES) in families with substance abuse (HR = 0.84) (physical abuse), and female sex (HR = 2.41) (sexual abuse). Follow-up predictors preceding physical abuse included: older age (HR = 1.42), disruptive disorders (HR = 1.39), and the interaction between low SES and family substance abuse (HR = 0.86). For sexual abuse, female sex (HR = 4.33) and a non-biologically related father presence in the household (HR = 2.76). Good relationships with friends (prospectively evaluated) protected against physical/sexual abuse (HR = 0.72/0.70, respectively)., Limitations: Prospective data was gathered longitudinally but assessed retrospectively at every follow-up; perpetrator information and abuse severity were not available., Conclusions: Identifying factors temporally preceding new onset physical/sexual abuse may hold promise for identifying high-risk youth with BD., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Neurocognitive deficits, such as cognitive flexibility impairments, are common in bipolar disorder (BD) and predict poor academic, occupational, and functional outcomes. However, the association between neurocognition and illness trajectory is not well understood, especially across developmental transitions. This study examined cognitive flexibility and subsequent mood symptom and suicidal ideation (SI) course in young adults with childhood-onset BD-I (with distinct mood episodes) vs. BD-not otherwise specified (BD-NOS) vs. typically-developing controls (TDCs). Sample included 93 young adults (ages 18-30) with prospectively verified childhood-onset DSM-IV BD-I (n = 34) or BD-NOS (n = 15) and TDCs (n = 44). Participants completed cross-sectional neuropsychological tasks and clinical measures. Then participants with BD completed longitudinal assessments of mood symptoms and SI at 6-month intervals (M = 39.18 ± 16.57 months of follow-up data). Analyses included ANOVAs, independent-samples t tests, chi-square analyses, and multiple linear regressions. Participants with BD-I had significant deficits in cognitive flexibility and executive functioning vs. BD-NOS and TDCs, and impaired spatial working memory vs. TDCs only. Two significant BD subtype-by-cognitive flexibility interactions revealed that cognitive flexibility deficits were associated with subsequent percentage of time depressed and with SI in BD-I but not BD-NOS, regardless of other neurocognitive factors (full-scale IQ, executive functioning, spatial working memory) and clinical factors (current and prior mood and SI symptoms, age of BD onset, global functioning, psychiatric medications, comorbidity). Thus, cognitive flexibility may be an important etiological brain/behavior mechanism, prognostic indicator, and intervention target for childhood-onset BD-I, as this deficit appears to endure into young adulthood and is associated with worse prognosis for subsequent depression and SI., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The ability to predict an individual's risk of mood episode recurrence can facilitate personalized medicine in bipolar disorder (BD). We sought to externally validate, in an adult sample, a risk calculator of mood episode recurrence developed in youth/young adults with BD from the Course and Outcome of Bipolar Youth (COBY) study., Methods: Adult participants from the National Institute of Mental Health Collaborative Depression Study (CDS; N=258; mean(SD) age=35.5(12.0) years; mean follow-up=24.9 years) were utilized as a sample to validate the youth COBY risk calculator for onset of depressive, manic, or any mood episodes., Results: In this older validation sample, the risk calculator predicted recurrence of any episode over 1, 2, 3, or 5-year follow-up intervals, with Area Under the Curves (AUCs) approximating 0.77. The AUC for prediction of depressive episodes was about 0.81 for each of the time windows, which was higher than for manic or hypomanic episodes (AUC=0.72). While the risk calculator was well-calibrated across the range of risk scores, it systematically underestimated risk in the CDS sample by about 20%. The length of current remission was a highly significant predictor of recurrence risk in the CDS sample., Limitations: Predominantly self-reported White samples may limit generalizability; the risk calculator does not assess more proximal risk (e.g., 1 month)., Conclusions: Risk of mood episode recurrence can be predicted with good accuracy in youth and adults with BD in remission. The risk calculators may help identify higher risk BD subgroups for treatment and research., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Facial emotion recognition deficits are common in bipolar disorder (BD) and associated with impairment. However, the relationship between facial emotion recognition and mood course is not well understood. This study examined facial emotion recognition and subsequent mood symptoms in young adults with childhood-onset BD versus typically developing controls (TDCs). The sample included 116 young adults (ages 18-30, 58% male, 78% White) with prospectively verified childhood-onset BD (n = 52) and TDCs (n = 64). At baseline, participants completed a facial emotion recognition task (Diagnostic Analysis of Non-Verbal Accuracy-2) and clinical measures. Then, participants with BD completed mood symptom assessments every 6 months (M = 8.7 ± 5.2 months) over two years. Analyses included independent-samples t tests and mixed-effects regression models. Participants with BD made significantly more recognition errors for child expressions than TDCs. There were no significant between-group differences for recognition errors for adult expressions, or errors for specific child or adult emotional expressions. Participants had moderate baseline mood symptoms. Significant time-by-facial emotion recognition interactions revealed more recognition errors for child emotional expressions predicted lower baseline mania and stable/consistent trajectory; fewer recognition errors for child expressions predicted higher baseline mania and decreasing trajectory. In addition, more recognition errors for adult sad expressions predicted stable/consistent depression trajectory and decreasing mania; fewer recognition errors for adult sad expressions predicted decreasing depression trajectory and stable/consistent mania. Effects remained when controlling for baseline demographics and clinical variables. Facial emotion recognition may be an important brain/behavior mechanism, prognostic indicator, and intervention target for childhood-onset BD, which endures into young adulthood and is associated with mood trajectory., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Acute rejection, which includes antibody-mediated rejection and acute cellular rejection, is a risk factor for lung allograft loss. Lung transplant patients often undergo surveillance transbronchial biopsies to detect and treat acute rejection before irreversible chronic rejection develops. Limitations of this approach include its invasiveness and high interobserver variability. We tested the performance of percent donor-derived cell-free DNA (%ddcfDNA), a non-invasive blood test, to detect acute rejection., Methods: This multicenter cohort study monitored 148 lung transplant subjects over a median of 19.6 months. We collected serial plasma samples contemporaneously with TBBx to measure %ddcfDNA. Clinical data was collected to adjudicate for acute rejection. The primary analysis consisted of computing the area-under-the-receiver-operating-characteristic-curve of %ddcfDNA to detect acute rejection. Secondary analysis determined %ddcfDNA rule-out thresholds for acute rejection., Results: ddcfDNA levels were high after transplant surgery and decayed logarithmically. With acute rejection, ddcfDNA levels rose six-fold higher than controls. ddcfDNA levels also correlated with severity of lung function decline and histological grading of rejection. %ddcfDNA area-under-the-receiver-operating-characteristic-curve for acute rejection, AMR, and ACR were 0.89, 0.93, and 0.83, respectively. ddcfDNA levels of <0.5% and <1.0% showed a negative predictive value of 96% and 90% for acute rejection, respectively. Histopathology detected one-third of episodes with ddcfDNA levels ≥1.0%, even though >90% of these events were coincident to clinical complications missed by histopathology., Conclusions: This study demonstrates that %ddcfDNA reliably detects acute rejection and other clinical complications potentially missed by histopathology, lending support to its use as a non-invasive marker of allograft injury., (Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Objectives: While adults with bipolar disorder (BD) often report symptoms starting in childhood, continuity of mania and/or hypomania (mania/hypomania) from childhood to adulthood has been questioned. Using longitudinal data from the Course and Outcome of Bipolar Youth (COBY) study, we assessed threshold mania/hypomania in young adults who manifested BD as youth., Methods: COBY is a naturalistic, longitudinal study of 446 youth with BD (84% recruited from outpatient clinics), 7-17 years old at intake, and over 11 years of follow-up. Focusing on youth with BD-I/II (n = 297), we examined adult mania/hypomania risk (>18 years old; mean 7.9 years of follow-up) according to child (<13 years old) versus adolescent (13-17 years old) onset. We next used penalized regression to test demographic and clinical predictors of young adult mania/hypomania., Results: Most participants (64%) had child-onset mania/hypomania, 57% of whom also experienced mania/hypomania in adolescence. Among those who experienced an episode in adolescence, over 40% also had mania/hypomania during adulthood; the risk did not differ according to child versus adolescent onset. In contrast, 7% with mania/hypomania in childhood, but not adolescence, experienced mania/hypomania in adulthood. Family history (of mania and suicide attempts) predicted mania/hypomania in young adulthood (p-values <0.05); age of onset was not a significant predictor. Among participants with no mania/hypomania during adulthood, 53% (105/198) still experienced subthreshold manic episodes., Discussion: We find substantial continuity across developmental stage indicating that, in this carefully characterized sample, children who experience mania/hypomania-particularly those who also experience mania/hypomania in adolescence-are likely to experience mania/hypomania in young adulthood., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Youth with bipolar disorder (BD) are at high risk for suicidal thoughts and behaviors and frequently experience interpersonal impairment, which is a risk factor for suicide. Yet, no study to date has examined the longitudinal associations between relationship quality in family/peer domains and suicidal thoughts and behaviors among youth with BD. Thus, we investigated how between-person differences - reflecting the average relationship quality across time - and within-person changes, reflecting recent fluctuations in relationship quality, act as distal and/or proximal risk factors for suicidal ideation (SI) and suicide attempts., Methods: We used longitudinal data from the Course and Outcome of Bipolar Youth Study (N = 413). Relationship quality variables were decomposed into stable (i.e., average) and varying (i.e., recent) components and entered, along with major clinical covariates, into separate Bayesian multilevel models predicting SI and suicide attempt. We also examined how the relationship quality effects interacted with age and sex., Results: Poorer average relationship quality with parents (β = -.33, 95% Bayesian highest density interval (HDI) [-0.54, -0.11]) or friends (β = -.33, 95% HDI [-0.55, -0.11]) was longitudinally associated with increased risk of SI but not suicide attempt. Worsening recent relationship quality with parents (β = -.10, 95% HDI [-0.19, -0.03]) and, to a lesser extent, friends (β = -.06, 95% HDI [-0.15, 0.03]) was longitudinally associated with increased risk of SI, but only worsening recent relationship quality with parents was also associated with increased risk of suicide attempt (β = -.15, 95% HDI [-0.31, 0.01]). The effects of certain relationship quality variables were moderated by gender but not age., Conclusions: Among youth with BD, having poorer average relationship quality with peers and/or parents represents a distal risk factor for SI but not suicide attempts. Additionally, worsening recent relationship quality with parents may be a time-sensitive indicator of increased risk for SI or suicide attempt., (© 2020 Association for Child and Adolescent Mental Health.)

Enzyme reactions, both in Nature and technical applications, commonly occur at the interface of immiscible phases. Nevertheless, stringent descriptions of interfacial enzyme catalysis remain sparse, and this is partly due to a shortage of coherent experimental data to guide and assess such work. In this work, we produced and kinetically characterized 83 cellulases, which revealed a conspicuous linear free energy relationship (LFER) between the substrate binding strength and the activation barrier. The scaling occurred despite the investigated enzymes being structurally and mechanistically diverse. We suggest that the scaling reflects basic physical restrictions of the hydrolytic process and that evolutionary selection has condensed cellulase phenotypes near the line. One consequence of the LFER is that the activity of a cellulase can be estimated from its substrate binding strength, irrespectively of structural and mechanistic details, and this appears promising for in silico selection and design within this industrially important group of enzymes.

Lytic polysaccharide monooxygenases (LPMOs), monocopper enzymes that oxidatively cleave recalcitrant polysaccharides, have important biotechnological applications. Thermothelomyces thermophilus is a rich source of biomass-active enzymes, including many members from auxiliary activities family 9 LPMOs. Here, we report biochemical and structural characterization of recombinant TtLPMO9H which oxidizes cellulose at the C1 and C4 positions and shows enhanced activity in light-driven catalysis assays. TtLPMO9H also shows activity against xyloglucan. The addition of TtLPMO9H to endoglucanases from four different glucoside hydrolase families (GH5, GH12, GH45 and GH7) revealed that the product formation was remarkably increased when TtLPMO9H was combined with GH7 endoglucanase. Finally, we determind the first low resolution small-angle X-ray scattering model of the two-domain TtLPMO9H in solution that shows relative positions of its two functional domains and a conformation of the linker peptide, which can be relevant for the catalytic oxidation of cellulose and xyloglucan., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Pediatric bipolar disorders are often characterized by disruptions in cognitive functioning, and exposure to child maltreatment (e.g., physical and sexual abuse) is associated with a significantly poorer course of illness. Although clinical and developmental research has shown maltreatment to be robustly associated with poorer cognitive functioning, it is unclear whether maltreatment and cognitive function jointly influence the clinical course of bipolar symptoms., Methods: This secondary analysis examined moderating effects of lifetime childhood physical and sexual abuse, and cognitive disruptions (sustained attention, affective information processing), on longitudinal ratings of depression symptom severity in youths from the Course and Outcome of Bipolar Youth (COBY) study, examined from intake (M = 12.24 years) through age 22 (N = 198; 43.9% female; Mean age of bipolar onset = 8.85 years)., Results: A significant moderating effect was detected for sustained attention and maltreatment history. In the context of lower sustained attention, maltreatment exposure was associated with higher depression symptom severity during childhood, but not late adolescence. There was no association between maltreatment and symptom severity in the context of higher sustained attention, and no association between attention and depression symptom severity for non-maltreated youths., Limitations: Depression symptom ratings at each assessment were subject to retrospective recall bias despite the longitudinal design. Cognitive assessments were administered at different ages across youths., Conclusions: Depressive symptoms in pediatric bipolar may be jointly moderated by impairments in attention and exposure to maltreatment. Assessment of these risks, particularly in childhood, may be beneficial for considering risk of recurrence or chronicity of depressive symptoms., (Copyright © 2020. Published by Elsevier B.V.)

Lytic polysaccharide monooxygenases (LPMOs) are known to act synergistically with glycoside hydrolases in industrial cellulolytic cocktails. However, a few studies have reported severe impeding effects of C1-oxidizing LPMOs on the activity of reducing-end cellobiohydrolases. The mechanism for this effect remains unknown, but it may have important implications as reducing-end cellobiohydrolases make up a significant part of such cocktails. To elucidate whether the impeding effect is general for different reducing-end cellobiohydrolases and study the underlying mechanism, we conducted a comparative biochemical investigation of the cooperation between a C1-oxidizing LPMO from Thielavia terrestris and three reducing-end cellobiohydrolases; Trichoderma reesei (TrCel7A), T. terrestris (TtCel7A), and Myceliophthora heterothallica (MhCel7A). The enzymes were heterologously expressed in the same organism and thoroughly characterized biochemically. The data showed distinct differences in synergistic effects between the LPMO and the cellobiohydrolases; TrCel7A was severely impeded, TtCel7A was moderately impeded, while MhCel7A was slightly boosted by the LPMO. We investigated effects of C1-oxidations on cellulose chains on the activity of the cellobiohydrolases and found reduced activity against oxidized cellulose in steady-state and pre-steady-state experiments. The oxidations led to reduced maximal velocity of the cellobiohydrolases and reduced rates of substrate complexation. The extent of these effects differed for the cellobiohydrolases and scaled with the extent of the impeding effect observed in the synergy experiments. Based on these results, we suggest that C1-oxidized chain ends are poor attack sites for reducing-end cellobiohydrolases. The severity of the impeding effects varied considerably among the cellobiohydrolases, which may be relevant to consider for optimization of industrial cocktails., Competing Interests: Conflicts of interest The authors declare the following conflicts of interest: Nanna Røjel, Trine H. Sørensen, Kim Borch, and Brett McBrayer work for Novozymes A/S, a major manufacturer of industrial enzymes., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Despite substantial literature on sex differences in adults with bipolar disorder (BD), little is known about this topic in youth; this study examines sex differences in mood symptomatology and psychiatric comorbidity in prospectively followed youth with BD., Methods: A subsample of the Course and Outcome of Bipolar Youth study (N = 370; female n = 199, male n = 171) enrolled October 2000-July 2006 (age at intake = 7-17.11 years) who met DSM-IV criteria for bipolar I disorder (BD-I; n = 221), bipolar II disorder (BD-II; n = 26), or operationalized BD not otherwise specified (BD-NOS; n = 123) with ≥ 4 years follow-up was included. Analyses examined sex differences at intake and, prospectively, in mood symptomatology and psychiatric comorbidity for a mean ± SD follow-up of 10.5 ± 1.72 years., Results: Females were older than males at intake (mean ± SD age = 13.33 ± 3.32 vs 12.04 ± 3.16 years; P = .0002) and at age at mood onset (9.33 ± 4.22 vs 7.53 ± 3.74 years; P < .0001). After adjustment for confounders, males spent more time with syndromal ADHD (Padjusted = .001) and females spent more time with syndromal anxiety (Padjusted = .02). There were trends toward males spending more time with substance use disorder and females having more non-suicidal self-injurious behavior (Padjusted = .07 and .09, respectively). There were no sex differences on outcome variables, including rate of or time to recovery and recurrence., Conclusions: Contrasting with adult literature, this study identified minimal sex differences in the course of youth with BD. Longer-term studies are needed to clarify if youth-onset BD remains a "sex neutral" subtype of BD or diverges according to sex in adulthood., (© Copyright 2020 Physicians Postgraduate Press, Inc.)

Background: Exposure to severe Traumatic Events (TEs) has been associated with poor course and outcomes among individuals with Bipolar Disorder (BD). However, there is limited research on TEs among youth with BD, and few studies are longitudinal. This study prospectively followed a large sample of BD youth, examining the associations of lifetime TEs with their mood and functioning., Methods: BD participants (n=375; mean age=17; range 8-25y) were assessed, on average, every 7 months for a median 8.7 years. Psychopathology and lifetime trauma history were prospectively evaluated using the Longitudinal Interval Follow-Up Evaluation, and a traumatic events screening., Results: Accounting for covariates, participants with one or more lifetime TEs (84%) showed earlier BD onset, poorer psychosocial functioning, worse mood symptoms, and more suicidal ideation, comorbidities, and family psychopathology than those without TEs. TEs during recovery periods increased recurrence risk (p<0.02). More TEs were associated with poorer mood course, particularly among victims of violence/abuse (p<0.02). Abused participants (34% physical; 17% sexual) showed earlier onset of substance use disorders, more suicidality and comorbidities compared to those without abuse. Comparisons of mood course before and after abuse occurred, and with participants without abuse, showed worsening mood symptoms after, specifically hypo/mania (p<0.03)., Limitations: Prospective data was gathered longitudinally but assessed retrospectively at every follow-up; given approximate dates causality cannot be inferred; TEs severity was not assessed., Conclusions: Severe TEs, particularly abuse, were associated with poorer course and outcomes among BD youth. Prompt screening of trauma and early intervention may be warranted to minimize TEs impact., Competing Interests: Declaration of Competing Interest Dr. Andreu Pascual has received a grant from the Alicia Koplowitz Foundation. Dr. Levenson receives salary support and grant funding from NICHD, grant funding American Academy of Sleep Medicine Foundation and the University of Pittsburgh, and royalties from American Psychological Association Book. Dr. Birmaher reports grants from NIMH, during the conduct of the study; royalties from Random House, Woltas Kluwer (UpToDate) and Lippincott, Williams & Wilkins, outside of the submitted work. Ms. Hower has received research support from NIMH, and honoraria from the Department of Defense (DOD). Dr. Yen has received research support from NIMH, NCCIH, and the American Foundation for Suicide Prevention. Dr. Strober has received research support from NIMH, and support from the Resnick Endowed Chair in Eating Disorders. Dr. T. Goldstein reports grants from NIMH, The American Foundation for Suicide Prevention, University of Pittsburgh Clinical and Translational Science Institute (CTSI) and The Brain and Behavior Foundation and royalties from Guilford Press, outside the submitted work. Dr. B Goldstein reports grants from Brain & Behavior Research Foundation, Brain Canada, Canadian Institutes of Health Research, Heart & Stroke Foundation, and the departments of psychiatry of Sunnybrook Health Sciences Centre and the University of Toronto Department of Psychiatry. Dr. Ryan reports grants from NIH and Axsome Therapeutics. Dr. Weinstock has received research support from NIMH, NCCIH, the NIH OBSSR, and NIJ. Dr. Keller has received research support from NIMH and the John J. McDonnell and Margaret T. O'Brien Foundation. Dr. Axelson reports grants from NIMH, during the conduct of the study; personal fees from Janssen Research and Development, LLC, and UpToDate, outside the submitted work. Mr. Merranko, Ms. Gill report no financial relationships with commercial interests., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Fungal beta-glucosidases (BGs) from glucoside hydrolase family 3 (GH3) are industrially important enzymes, which convert cellooligosaccharides into glucose; the end product of the cellulolytic process. They are highly active against the β-1,4 glycosidic bond in soluble substrates but typically reported to be inactive against insoluble cellulose., Results: We studied the activity of four fungal GH3 BGs on cellulose and found significant activity. At low temperatures (10 ℃), we derived the approximate kinetic parameters k cat  = 0.3 ± 0.1 s -1 and K M  = 80 ± 30 g/l for a BG from Aspergillus fumigatus ( Af BG) acting on Avicel. Interestingly, this maximal turnover is higher than reported values for typical cellobiohydrolases (CBH) at this temperature and comparable to those of endoglucanases (EG). The specificity constant of Af GB on Avicel was only moderately lowered compared to values for EGs and CBHs., Conclusions: Overall these observations suggest a significant promiscuous side activity of the investigated GH3 BGs on insoluble cellulose. This challenges the traditional definition of a BG and supports suggestions that functional classes of cellulolytic enzymes may represent a continuum of overlapping modes of action., Competing Interests: Competing interestsThe authors declare the following conflicts of interest: Kim Borch, Trine H. Sørensen, Kristian B. R. M. Krogh, and Mark Wogulis work for Novozymes A/S, a major manufacturer of industrial enzymes., (© The Author(s) 2020.)

Objectives: Compare longitudinal trajectories of youth with Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV Bipolar Disorder (BD), grouped at baseline by presence/absence of increased energy during their worst lifetime mood episode (required for DSM-5)., Methods: Participants from the parent Course and Outcome of Bipolar Youth study (N = 446) were assessed utilizing The Schedule for Affective Disorders and Schizophrenia for School-Age Children (KSADS), KSADS Mania Rating Scale (KMRS), and KSADS Depression Rating Scale (KDRS). Youth were grouped at baseline into those with increased energy (meeting DSM-5 Criteria A for mania) vs. without increased energy (meeting DSM-IV, but not DSM-5, Criteria A for mania), for those who had worst lifetime mood episode recorded (n = 430). Youth with available longitudinal data had the presence/absence of increased energy measured, as well as psychiatric symptomatology/clinical outcomes (evaluated via the Adolescent Longitudinal Interval Follow-Up Evaluation), at each follow-up for 12.5 years (n = 398)., Results: At baseline, the increased energy group (based on endorsed increased energy during worst lifetime mood episode; 86% of participants) vs. the without increased energy group, were more likely to meet criteria for BD-I and BD Not Otherwise Specified, had higher KMRS/KDRS total scores, and displayed poorer family/global psychosocial functioning. However, frequency of increased energy between groups was comparable after 5 years, and no significant group differences were found on clinical/psychosocial functioning outcomes after 12.5 years., Limitations: Secondary data limited study design; groupings were based on one time point., Conclusions: Results indicate no clinically relevant longitudinal group differences., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objectives: Few studies have examined domain-specific psychosocial functioning in Bipolar Disorder (BD) youths. This prospective study examines (1) Interpersonal Relationships with Family; (2) Interpersonal Relationships with Friends; (3) School/Work; (4) Recreation; (5) Life Satisfaction, in BD youths., Method: A Course and Outcome of Bipolar Youth subsample (n = 367; mean intake age = 12.6 years, SD = 3.3; 46.6% female) was previously grouped into 4 Classes based on their illness trajectories and percentage of time euthymic using Latent Class Growth Analysis: Class 1 Predominantly Euthymic; Class 2 Moderately Euthymic; Class 3 Ill with Improving Course; Class 4 Predominantly Ill. Psychosocial functioning within the domains were examined for greater than 10 years using the Adolescent Longitudinal Interval Follow-Up Evaluation., Results: Class 1 demonstrated better functioning across all domains; Class 4 demonstrated worse functioning across all domains. Class 2 showed worsening relationships and recreation, and improvement in work/schoolwork. Class 3 showed variable domain declines and improvements. Despite symptomatic remission, 13%-20% of Class 1 and 20-47% of Classes 1/3 still had impairments across different domains. Early age of BD onset impacted impairment across most domains, and low SES significantly predicted impairment in family relationships., Limitations: The study does not have a healthy control group to compare functioning findings., Conclusions: Participants with more symptomatic mood trajectories had greater impairment across domains. Moreover, even with symptomatic remission, participants still exhibited impairment. Each Class and domain had different trajectories for impairment. Results suggest the importance of examining specific (vs. global) domains for targeted treatment, even when symptomatically remitted., Competing Interests: Declaration of Competing Interest Dr.. Birmaher receives royalties for publications from Random House, Inc., UpToDate, and Lippencott Williams and Wilkins. Dr.. T. Goldstein receives royalties from Guilford Press. Dr.. Hunt receives honoraria from Wiley Publishers as a Senior Editor of the Brown University Child and Adolescent Psychopharmacology Update. Dr.. Ryan served on the Scientific Advisory Board of the Child Mind Institute. Dr.. Axelson receives royalties from UpToDate, and serves as a consultant to Janssen Research and Development, LLC. Dr.. Yen is a consultant at Janssen Research and Development, LLC. All other authors declare no conflicts of interest., (Copyright © 2020. Published by Elsevier B.V.)

This study examines how relationship quality in family and peer domains are associated with suicidal ideation (SI) in youth with bipolar disorder (BP). We assessed 404 Course and Outcome of Bipolar Youth study participants for psychiatric disorders and SI at intake and for family/peer relationships the month after intake. Multivariate logistic regression examined associations between relationships and SI, controlling for significant covariates. There were 144 youth (36%) who reported SI at intake; bivariate analyses indicated they had significantly worse family/peer relationships. Multivariate analyses showed that family/peer relationships were associated with current SI, controlling for significant covariates. Results support associations between poor relationships and SI in BP youth, regardless of current mood symptom severity. Clinicians should assess relationships when completing risk assessments with BP youth.

Objective: The development of an enzymatic assay for the specific quantification of the C1-oxidation product, i.e. gluconic acid of cellulose active lytic polysaccharide monooxygenases (LPMOs)., Results: In combination with a β-glucosidase, the spectrophotometrical assay can reliably quantify the specific C1- oxidation product of LPMOs acting on cellulose. It is applicable for a pure cellulose model substrate as well as lignocellulosic biomass. The enzymatic assay compares well with the quantification performed by HPAEC-PAD. In addition, we show that simple boiling is not sufficient to inactivate LPMOs and we suggest to apply a metal chelator in addition to boiling or to drastically increase pH for proper inactivation., Conclusions: We conclude that the versatility of this simple enzymatic assay makes it useful in a wide range of experiments in basic and applied LPMO research and without the need for expensive instrumentation, e.g. HPAEC-PAD.