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1.  Borderline Personality Disorder in Transition Age Youth with Bipolar Disorder 
Acta psychiatrica Scandinavica  2015;132(4):270-280.
To determine the longitudinal impact of Borderline Personality Disorder (BPD) on the course and outcome of Bipolar Disorder (BP) in a pediatric BP sample.
Participants (N=271) and parents from the Course and Outcome of Bipolar Youth (COBY) study were administered structured clinical interviews and self-reports on average every 8.7 months over a mean of 93 months starting at age 13.0 +/- 3.1 years. The Structured Interview for DSM-IV Personality Disorders (SIDP-IV) was administered at the first follow-up after age 18 to assess for symptoms of BPD. BPD operationalized at the disorder, factor, and symptom level, was examined as a predictor of poor clinical course of BP using all years of follow-up data.
The number of BPD symptoms was significantly associated with poor clinical course of BP, above and beyond BP characteristics. Affective dysregulation was most strongly associated with poor course at the factor level; the individual symptoms most strongly associated with poor course were dissociation/stress-related paranoid ideation, impulsivity, and affective instability.
BPD severity adds significantly to the burden of BP illness and is significantly associated with a more chronic and severe course and outcome beyond what can be attributable to BP characteristics.
PMCID: PMC4573347  PMID: 25865120
bipolar disorder; borderline personality disorder; comorbidity; longitudinal
2.  Inflammatory Markers among Adolescents and Young Adults with Bipolar Spectrum Disorders 
The Journal of clinical psychiatry  2015;76(11):1556-1563.
Despite burgeoning literature in middle-aged adults, little is known regarding pro-inflammatory markers (PIMs) among adolescents and young adults with bipolar disorder. Similarly, few prior studies have considered potential confounds when examining the association between PIMs and bipolar disorder characteristics. We therefore examined these topics in the Course and Outcome of Bipolar Youth (COBY) study.
Subjects were 123 adolescents and young adults (20.4±3.8 years; range 13.4–28.3 years) in COBY, enrolled between October 2000 and July 2006. DSM-IV diagnoses were determined using the Schedule for Affective Disorders and Schizophrenia for school-aged children (KSADS). Clinical characteristics over the preceding 6 months, including mood, comorbidity and treatment, were evaluated using the Longitudinal Interval Follow-up Evaluation (LIFE). Serum levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α, and high-sensitivity C-reactive protein (hsCRP) were assayed. Primary analyses examined the association of PIMs with bipolar disorder characteristics over the preceding 6 months.
Several lifetime clinical characteristics were significantly associated with PIMs in multivariable analyses, including longer illness duration (p=0.005 for IL-6; p=0.0004 for hsCRP), suicide attempts (p=0.01 for TNF-α), family history of suicide attempts or completion (p=0.01 for hsCRP), self-injurious behavior (p=0.005 for TNF-α), SUD (p<0.0001 for hsCRP) and family history of SUD (p=0.02 for TNF-α; p=0.01 for IL-6). The following bipolar disorder characteristics over the preceding 6 months remained significantly associated with PIMs in multivariable analyses that controlled for differences in comorbidity and treatment. For TNF-α: percentage of weeks with psychosis (χ2=5.7, p=0.02). For IL-6: percentage of weeks with subthreshold mood symptoms (χ2=8.3, p=0.004), and any suicide attempt (χ2=6.1, p=0.01). For hsCRP: maximum severity of depressive symptoms (χ2=8.3, p=0.004).
PIMs may be relevant to bipolar disorder characteristics as well as other clinical characteristics among adolescents and young adults with bipolar disorder. Traction toward validating PIMs as clinically relevant biomarkers in bipolar disorder will require repeated measures of PIMs and incorporation of relevant covariates.
PMCID: PMC4896394  PMID: 26646032
bipolar disorder; adolescent; young adult; inflammation; C-reactive protein; interleukin-6; tumor necrosis factor-alpha
3.  Exposure to Melan-A/MART-126-35 tumor epitope specific CD8+T cells reveals immune escape by affecting the ubiquitin-proteasome system (UPS) 
Scientific Reports  2016;6:25208.
Efficient processing of target antigens by the ubiquitin-proteasome-system (UPS) is essential for treatment of cancers by T cell therapies. However, immune escape due to altered expression of IFN-γ-inducible components of the antigen presentation machinery and consequent inefficient processing of HLA-dependent tumor epitopes can be one important reason for failure of such therapies. Here, we show that short-term co-culture of Melan-A/MART-1 tumor antigen-expressing melanoma cells with Melan-A/MART-126-35-specific cytotoxic T lymphocytes (CTL) led to resistance against CTL-induced lysis because of impaired Melan-A/MART-126-35 epitope processing. Interestingly, deregulation of p97/VCP expression, which is an IFN-γ-independent component of the UPS and part of the ER-dependent protein degradation pathway (ERAD), was found to be essentially involved in the observed immune escape. In support, our data demonstrate that re-expression of p97/VCP in Melan-A/MART-126-35 CTL-resistant melanoma cells completely restored immune recognition by Melan-A/MART-126-35 CTL. In conclusion, our experiments show that impaired expression of IFN-γ-independent components of the UPS can exert rapid immune evasion of tumor cells and suggest that tumor antigens processed by distinct UPS degradation pathways should be simultaneously targeted in T cell therapies to restrict the likelihood of immune evasion due to impaired antigen processing.
PMCID: PMC4855237  PMID: 27143649
4.  Cognitive-Behavioural Analysis System of Psychotherapy (CBASP), a drug, or their combination: differential therapeutics for persistent depressive disorder: a study protocol of an individual participant data network meta-analysis 
BMJ Open  2016;6(5):e011769.
Despite important advances in psychological and pharmacological treatments of persistent depressive disorders in the past decades, their responses remain typically slow and poor, and differential responses among different modalities of treatments or their combinations are not well understood. Cognitive-Behavioural Analysis System of Psychotherapy (CBASP) is the only psychotherapy that has been specifically designed for chronic depression and has been examined in an increasing number of trials against medications, alone or in combination. When several treatment alternatives are available for a certain condition, network meta-analysis (NMA) provides a powerful tool to examine their relative efficacy by combining all direct and indirect comparisons. Individual participant data (IPD) meta-analysis enables exploration of impacts of individual characteristics that lead to a differentiated approach matching treatments to specific subgroups of patients.
Methods and analysis
We will search for all randomised controlled trials that compared CBASP, pharmacotherapy or their combination, in the treatment of patients with persistent depressive disorder, in Cochrane CENTRAL, PUBMED, SCOPUS and PsycINFO, supplemented by personal contacts. Individual participant data will be sought from the principal investigators of all the identified trials. Our primary outcomes are depression severity as measured on a continuous observer-rated scale for depression, and dropouts for any reason as a proxy measure of overall treatment acceptability. We will conduct a one-step IPD-NMA to compare CBASP, medications and their combinations, and also carry out a meta-regression to identify their prognostic factors and effect moderators. The model will be fitted in OpenBUGS, using vague priors for all location parameters. For the heterogeneity we will use a half-normal prior on the SD.
Ethics and dissemination
This study requires no ethical approval. We will publish the findings in a peer-reviewed journal. The study results will contribute to more finely differentiated therapeutics for patients suffering from this chronically disabling disorder.
Trial registration number
PMCID: PMC4861112  PMID: 27147393
Systematic review; Differential therapeutics
5.  Longitudinal Associations Between Interpersonal Relationship Functioning and Mood Episode Severity in Youth with Bipolar Disorder 
This study examined the longitudinal association between mood episode severity and relationships in BP youth. Participants were 413 Course and Outcome of Bipolar Youth study youth, aged 12.6 ± 3.3 years. Monthly ratings of relationships (parents, siblings, and friends) and mood episode severity were assessed by the Adolescent Longitudinal Interval Follow-Up Evaluation (ALIFE) Psychosocial Functioning Schedule (PFS) and Psychiatric Rating Scales (PSR) on average every 8.2 months over 5.1 years. Correlations examined whether participants with increased episode severity also reported poorer relationships, and also examined whether fluctuations in episode severity predicted fluctuations in relationships, and vice versa. Results indicated that participants with greater mood episode severity also had worse relationships. Longitudinally, participants had largely stable relationships. To the extent that there were associations, changes in parental relationships may precede changes in episode severity, although the magnitude of this finding was small. Findings have implications for relationship interventions in BP youth.
PMCID: PMC4342291  PMID: 25668652
bipolar disorder; interpersonal relationship functioning; longitudinal
6.  Posttraumatic stress disorder in African Americans: A two year follow-up study 
Psychiatry research  2014;220(0):376-383.
The present study was a prospective, naturalistic, longitudinal investigation of the two year course of posttraumatic stress disorder (PTSD) in a sample of African Americans with anxiety disorders. The study objectives were to examine the two year course of PTSD and to evaluate differences between African Americans with PTSD and anxiety disorders and African Americans with anxiety disorders but no PTSD with regard to comorbidity, psychosocial impairment, physical and emotional functioning, and treatment participation. The participants were 67 African Americans with PTSD and 98 African Americans without PTSD (mean age 41.5 years, 67.3% female). Individuals with PTSD were more likely to have higher comorbidity, lower functioning, and they were less likely to seek treatment than those with other anxiety disorders but no PTSD. The rate of recovery from PTSD over two years was .10 and recovery from comorbid Major Depressive Disorder was .55. PTSD appears to be persistent over time in this populattion. The rates of recovery were lower than what has been reported in previous longitudinal studies with predominantly non-Latino Whites. It is imperative to examine barriers to treatment and factors related to treatment engagement for this population.
PMCID: PMC4351655  PMID: 25086766
African Americans; minority mental health; posttraumatic stress disorder; longitudinal study; clinical course
7.  Two-Year Course of Generalized Anxiety Disorder, Social Anxiety Disorder and Panic Disorder with Agoraphobia in a Sample of Latino Adults 
It is imperative to study the clinical course of anxiety disorders among Latinos, given the implications for culturally-sensitive treatment in this population. The current study is the first prospective, observational, longitudinal study of anxiety disorders among Latinos.
Data are reported on 139 adult Latinos (mean age 34.65, SD =10.98, 70.5% female) diagnosed with social anxiety disorder (SAD, n = 86), generalized anxiety disorder (GAD, n = 90) or panic disorder with agoraphobia (PDA, n = 62). The participants were interviewed with standardized clinical interviews at intake and annually over two years of follow-up. Probabilities of recovery were calculated using standard survival analysis methods.
The two-year recovery rates in this study were 0.07 for SAD, 0.14 for GAD, 0.03 for PDA, and 0.50 for major depressive disorder (MDD). Overall functioning, social adjustment and life satisfaction in this sample were poor.
The recovery rates for anxiety disorders in this Latino sample were markedly low. Although caution must be used in comparing these data with prior longitudinal studies, these recovery rates seem to be much lower than in non-Latino White samples. However, the clinical course of MDD in this sample was similar to its course among non-Latino Whites, invoking the pressing question of whether there is something about the experience of anxiety disorders (but not MDD) among Latinos that makes them more impairing and persistent. The answer to that question should inform future treatment development for this population.
PMCID: PMC4197105  PMID: 24731232
anxiety disorders; longitudinal course; Latinos; recovery; social phobia; social anxiety disorder; generalized anxiety disorder; panic disorder; agoraphobia
8.  Heterobimetallic Zeolite, InV-ZSM-5, Enables Efficient Conversion of Biomass Derived Ethanol to Renewable Hydrocarbons 
Scientific Reports  2015;5:16039.
Direct catalytic conversion of ethanol to hydrocarbon blend-stock can increase biofuels use in current vehicles beyond the ethanol blend-wall of 10–15%. Literature reports describe quantitative conversion of ethanol over zeolite catalysts but high C2 hydrocarbon formation renders this approach unsuitable for commercialization. Furthermore, the prior mechanistic studies suggested that ethanol conversion involves endothermic dehydration step. Here, we report the complete conversion of ethanol to hydrocarbons over InV-ZSM-5 without added hydrogen and which produces lower C2 (<13%) as compared to that over H-ZSM-5. Experiments with C2H5OD and in situ DRIFT suggest that most of the products come from the hydrocarbon pool type mechanism and dehydration step is not necessary. Thus, our method of direct conversion of ethanol offers a pathway to produce suitable hydrocarbon blend-stock that may be blended at a refinery to produce fuels such as gasoline, diesel, JP-8, and jet fuel, or produce commodity chemicals such as BTX.
PMCID: PMC4630624  PMID: 26526963
9.  Seasonal Variation of Depressive Symptoms in Unipolar Major Depressive Disorder 
Comprehensive psychiatry  2014;55(8):1891-1899.
Retrospective and cross-sectional studies of seasonal variation of depressive symptoms in unipolar major depression have yielded conflicting results. We examined seasonal variation of mood symptoms in a long-term prospective cohort – the Collaborative Depression Study (CDS).
The sample included 298 CDS participants from five academic centers with a prospectively derived diagnosis of unipolar major depression who were followed for at least ten years of annual or semi-annual assessments. Generalized linear mixed models were utilized to investigate the presence of seasonal patterns. In a subset of 271 participants followed for at least 20 years, the stability of a winter depressive pattern was assessed across the first two decades of follow-up.
A small increase in proportion of time depressed was found in the months surrounding the winter solstice, although the greatest symptom burden was seen in December through April with a peak in March. The relative burden of winter depressive symptoms in the first decade demonstrated no relationship to that of the second decade. The onset of new episodes was highest October through January, peaking in January.
There exists a small but statistically significant peak in depressive symptoms from the month of the winter solstice to the month of the spring equinox. However, the predominance of winter depressive symptoms did not appear stable over the long-term course of illness.
PMCID: PMC4254297  PMID: 25176622
Seasonal Affective Disorder; Seasonal Mood Disorder; Major Depressive Disorder; Seasonal Pattern; Seasonality; Stability; Prospective Studies; Longitudinal Studies
10.  Near-Complete Genome Sequence of the Cellulolytic Bacterium Bacteroides (Pseudobacteroides) cellulosolvens ATCC 35603 
Genome Announcements  2015;3(5):e01022-15.
We report the single-contig genome sequence of the anaerobic, mesophilic, cellulolytic bacterium, Bacteroides cellulosolvens. The bacterium produces a particularly elaborate cellulosome system, wherein the types of cohesin-dockerin interactions are opposite of other known cellulosome systems: cell-surface attachment is thus mediated via type-I interactions, whereas enzymes are integrated via type-II interactions.
PMCID: PMC4582573  PMID: 26404597
The Journal of emergency medicine  2014;47(2):150-154.
Traumatic coronary artery dissection (CAD) after blunt chest trauma (BCT) is extremely rare, particularly in children. Among coronary dissections, left main coronary artery (LMCA) dissection is the least common, with only two pediatric cases reported previously. Manifestations of coronary dissections can range from ST segment changes to sudden death. However, these manifestations are not specific and can be present with other cardiac injuries. To our knowledge we present the first pediatric case of traumatic LMCA dissection after sport-related BCT that was treated successfully with coronary stenting.
Case Report
A 14-year-old child sustained BCT during a baseball game. Early in the clinical course, he had episodes of ventricular arrhythmias, diffuse ST changes, rising troponin I, and hemodynamic instability. Emergent cardiac catheterization revealed an LMCA dissection with extension into the proximal left anterior descending artery (LADA). A bare metal stent was placed from the LMCA to the LADA, which improved blood flow through the area of dissection. He has had almost full recovery of myocardial function and has been managed as an outpatient with oral heart failure and antiplatelet medications. Why Should an Emergency Physician Be Aware of This?: Our case highlights that CAD, although rare, can occur after pediatric BCT. Pediatric emergency responders must have a heightened awareness that evidence of ongoing myocardial ischemia, such as evolving and focal myocardial infarction on electrocardiogram, persistent elevation or rising troponin I, and worsening cardiogenic shock, can represent a coronary event and warrant further evaluation. Cardiac catheterization can be both a diagnostic and therapeutic modality in such cases. Early recognition and management is vital for myocardial recovery.
PMCID: PMC4537366  PMID: 24928544
blunt chest trauma; left main coronary artery; dissection; pediatric
12.  Changes in Standing and Walking Performance Under Dual-Task Conditions Across the Lifespan 
Sports Medicine (Auckland, N.z.)  2015;45:1739-1758.
Simultaneous performance of a postural and a concurrent task is rather unproblematic as long as the postural task is executed in an automatic way. However, in situations where postural control requires more central processing, cognitive resources may be exceeded by the addition of an attentionally demanding task. This may lead to interference between the two tasks, manifested in a decreased performance in one or both tasks (dual-task costs). Owing to changes in attentional demands of postural tasks as well as processing capacities across the lifespan, it might be assumed that dual-task costs are particularly pronounced in children and older adults probably leading to a U-shaped pattern for dual-task costs as a function of age. However, these changes in the ability of dual-tasking posture from childhood to old age have not yet been systematically reviewed. Therefore, Web of Science and PubMed databases were searched for studies comparing dual-task performance with one task being standing or walking in healthy groups of young adults and either children or older adults. Seventy-nine studies met inclusion criteria. For older adults, the expected increase in dual-task costs could be confirmed. In contrast, in children there was only feeble evidence for a trend towards enlarged dual-task costs. More good-quality studies comparing dual-task ability in children, young, and, ideally, also older adults within the same paradigm are needed to draw unambiguous conclusions about lifespan development of dual-task performance in postural tasks. There is evidence that, in older adults, dual-task performance can be improved by training. For the other age groups, these effects have yet to be investigated.
PMCID: PMC4656695  PMID: 26253187
13.  Disparities in Psychosocial Functioning in a Diverse Sample of Adults with Anxiety Disorders 
Journal of anxiety disorders  2014;28(3):335-343.
Anxiety disorders are associated with psychosocial functional impairments, but no study has compared how these impairments might vary by ethno-racial status. We examined whether minority status was uniquely associated with functional impairments in 431 adults with anxiety disorders. Functioning was measured in the rater-assessed domains of: global assessment of functioning (GAF); global psychosocial functioning; work, relationship, and recreational functioning; and, self-reported: life satisfaction, mental health functioning, physical functioning, and disability status. After controlling for demographic and clinical variables, results revealed evidence of disparities, whereby African Americans (AAs), particularly those with low income, had worse GAF, worse global psychosocial functioning, and were more likely to be disabled compared to non-Latino Whites. Latinos, particularly those with low income, had worse global psychosocial functioning than non-Latino Whites. Results suggest AAs and Latinos are at increased risk for functional impairments not better accounted for by other demographic or clinical variables.
PMCID: PMC4028956  PMID: 24685821
Anxiety Disorders; Psychosocial Functioning; Minorities; Risk Factors
14.  Management and outcomes of traumatic hemothorax in children 
Adult guidelines for the management of traumatic hemothorax are well established; however, there have been no similar studies conducted in the pediatric population. The purpose of our study was to assess the management and outcomes of children with traumatic hemothorax.
Materials and Methods:
Following Institutional Review Board approval, we conducted a retrospective cross-sectional study of all trauma patients diagnosed with a hemothorax at a Level-1 pediatric trauma center from 2007 to 2012.
Forty-six children with hemothorax were identified, 23 from blunt mechanism and 23 from penetrating mechanism. The majority of children injured by penetrating mechanisms were treated with tube thoracostomy while the majority of blunt injury patients were observed (91.3% vs. 30.4% tube thoracostomy, penetrating vs. blunt, P = 0.00002). Among patients suffering from blunt mechanism, children who were managed with chest tubes had a greater volume of hemothorax than those who were observed. All children who were observed underwent serial chest radiographs demonstrating no progression and required no delayed procedures. Children with a hemothorax identified only by computed tomography, after negative plain radiograph, did not require intervention. No child developed a delayed empyema or fibrothorax.
The data suggest that a small-volume hemothorax resulting from blunt mechanism may be safely observed without mandatory tube thoracostomy and with overall low complication rates.
PMCID: PMC4411582  PMID: 25949037
Hemothorax; thoracic trauma; tube thoracostomy
15.  Effects of Comorbid Anxiety Disorders on the Longitudinal Course of Pediatric Bipolar Disorders 
To examine the longitudinal effects of comorbid anxiety disorders in youth with bipolar spectrum disorder (BP).
As part of the Course and Outcome of Bipolar Youth study, 413 youth, ages 7 to 17 years who met criteria for DSM-IV BP-I (n=244), BP-II (n=28), and operationally defined bipolar disorder not otherwise specified (BP-NOS) (n=141) were included. Subjects were followed on average 5 years using the Longitudinal Interval Follow-up Evaluation. Effects of anxiety on the time to mood recovery and recurrence and percentage of time with syndromal and subsyndromal mood symptomatology during the follow-up period were analyzed.
At intake and during the follow-up, 62% of youth with BP met criteria for at least one anxiety disorder. About 50% of the BP youth with anxiety had ≥ 2 anxiety disorders. Compared to BP youth without anxiety, those with anxiety had significantly more depressive recurrences and significantly longer median time to recovery. The effects of anxiety on recovery disappeared when the severity of depression at intake was taken into account. After adjusting for confounding factors, BP youth with anxiety, particularly those with ≥ 2 anxiety disorders, spent significantly less follow-up time asymptomatic and more time with syndromal mixed/cycling and subsyndromal depressive symptomatology compared to those without anxiety.
Anxiety disorders are common and adversely affect the course of BP in youth, as characterized by more mood recurrences, longer time to recovery, less time euthymic, more time in mixed/cycling and depressive episodes. Prompt recognition and the development of treatments for BP youth with anxiety are warranted.
PMCID: PMC3868011  PMID: 24342387
anxiety disorders; bipolar disorders; longitudinal study
16.  Activity-dependent plasticity of mouse hippocampal assemblies in vitro 
Memory formation is associated with the generation of transiently stable neuronal assemblies. In hippocampal networks, such groups of functionally coupled neurons express highly ordered spatiotemporal activity patterns which are coordinated by local network oscillations. One of these patterns, sharp wave-ripple complexes (SPW-R), repetitively activates previously established groups of memory-encoding neurons, thereby supporting memory consolidation. This function implies that repetition of specific SPW-R induces plastic changes which render the underlying neuronal assemblies more stable. We modeled this repetitive activation in an in vitro model of SPW-R in mouse hippocampal slices. Weak electrical stimulation upstream of the CA3-CA1 networks reliably induced SPW-R of stereotypic waveform, thus representing re-activation of similar neuronal activity patterns. Frequent repetition of these patterns (100 times) reduced the variance of both, evoked and spontaneous SPW-R waveforms, indicating stabilization of pre-existing assemblies. These effects were most pronounced in the CA1 subfield and depended on the timing of stimulation relative to spontaneous SPW-R. Additionally, plasticity of SPW-R was blocked by application of a NMDA receptor antagonist, suggesting a role for associative synaptic plasticity in this process. Thus, repetitive activation of specific patterns of SPW-R causes stabilization of memory-related networks.
PMCID: PMC4435105  PMID: 26041998
plasticity; sharp wave-ripple; SPW-R; oscillation; hippocampus; assembly; neuronal assemblies; neuronal plasticity
17.  Two-Year Course of Generalized Anxiety Disorder, Social Anxiety Disorder, and Panic Disorder in a Longitudinal Sample of African American Adults 
Anxiety disorders are the most common group of psychiatric disorders in adults. In addition to high prevalence, anxiety disorders are associated with significant functional impairment, and published research has consistently found them to have a chronic course. To date, very little research has explored the clinical characteristics and prospective course of anxiety disorders in racial and ethnic minority samples. The aims of this paper are to present clinical and demographic characteristics at intake and prospective two-year course findings in a sample of African American adults.
Data are presented from 152 African Americans diagnosed with generalized anxiety disorder (GAD, n = 94), social anxiety disorder (SAD, n = 85), and panic disorder with agoraphobia (PDA, n = 77) who are participating in the Harvard/Brown Anxiety Research Project-Phase II (HARP-II). HARP-II is an observational, prospective, longitudinal study of the course of anxiety disorders. Participants were interviewed at intake and annually for 2 years of follow-up. Probabilities of recovery over two years of follow-up were calculated using standard survival analysis methods.
Results and Conclusions
Survival analyses revealed a chronic course for all anxiety disorders, with rates of recovery of 0.23, 0.07, and 0.00 over two years for GAD, SAD, and PDA, respectively. These rates of recovery were lower than those reported in predominantly Non-Latino White longitudinal samples, especially for SAD and PDA, suggesting that anxiety disorders may have a more chronic course for African Americans, with increased psychosocial impairment and high rates of co-morbid Axis-I disorders. Clinical implications of these findings are discussed.
PMCID: PMC3951438  PMID: 24041233
anxiety disorders; longitudinal course; African American; recovery; social phobia; social anxiety disorder; generalized anxiety disorder; panic disorder; agoraphobia
18.  Predictors of First-Onset Substance Use Disorders During the Prospective Course of Bipolar Spectrum Disorders in Adolescents 
Substance use disorders (SUD) are common and problematic in bipolar disorder (BP). We prospectively examined predictors of first-onset SUD among adolescents with BP.
Adolescents (12–17 years old; N=167) in the Course and Outcome of Bipolar Youth (COBY) study fulfilling criteria for BP-I, BP-II, or operationalized BP not otherwise specified, without SUD at intake, were included. Baseline demographic, clinical, and family history variables, and clinical variables assessed during follow-up, were examined in relation to first-onset SUD. Participants were prospectively interviewed every 38.5±22.2 weeks for an average of 4.25±2.11 years.
First-onset SUD developed among 32% of subjects, after a mean of 2.7±2.0 years from intake. Lifetime alcohol experimentation at intake most robustly predicted first-onset SUD. Lifetime oppositional defiant disorder and panic disorder, family history of SUD, low family cohesiveness, and absence of antidepressant treatment at intake were also associated with increased risk of SUD, whereas BP subtype was not. Risk of SUD increased with increasing number of these six predictors: 54.7% of subjects with ≥3 predictors developed SUD vs. 14.1% of those with <3 predictors (Hazard Ratio 5.41 95% CI 2.7–11.0 p<0.0001). Greater hypo/manic symptom severity in the preceding 12 weeks predicted greater likelihood of SUD onset. Lithium exposure in the preceding 12 weeks predicted lower likelihood of SUD.
This study identifies several predictors of first-onset SUD in the COBY sample which, if replicated, may suggest targets of preventive interventions for SUD among youth with BP. Treatment-related findings are inconclusive and must be interpreted tentatively given the limitations of observational naturalistic treatment data. There is a substantial window of opportunity between BP and SUD onset during which preventive strategies may be employed.
PMCID: PMC3787940  PMID: 24074469
bipolar; predictors; prevention; prospective; substance use disorder
19.  Management of Traumatic Wounds and a Novel Approach to Delivering Wound Care in Children 
Advances in Wound Care  2014;3(4):335-343.
Significance: The costs and morbidity of pediatric traumatic wounds are not well known. The literature lacks a comprehensive review of the volume, management, and outcomes of children sustaining soft tissue injury. We briefly review the existing literature for traumatic wounds such as open fractures and burns. Such injuries require dedicated wound care and we propose a novel approach for more efficient and more effective delivery of dedicated pediatric wound care.
Recent Advances: New pediatric literature is emerging regarding the long-term effects of wound care pain in traumatic injuries—especially burns. A variety of wound dressings and alternative management techniques exist and are geared toward reducing wound care pain. Our institution utilizes a unique model to provide adequate sedation and pain control through a dedicated pediatric wound care unit. We believe that this model reduces the cost of wound care by decreasing emergency department and operating room visits as well as hospital length of stay.
Critical Issues: First, medical costs related to pediatric traumatic wound care are not insignificant. The need for adequate pain control and sedation in children with complex wounds is traditionally managed with operating room intervention. Afterward, added costs can be from a hospital stay for ongoing acute wound management. Second, morbidities of complex traumatic wounds are shown to be related to the acute wound care received.
Future Directions: Further guidelines are needed to determine the most effective and efficient care of complex traumatic soft tissue injuries in the pediatric population.
PMCID: PMC3985539  PMID: 24761364
20.  Longitudinal Trajectories and Associated Baseline Predictors in Youths With Bipolar Spectrum Disorders 
The American journal of psychiatry  2014;171(9):990-999.
The authors sought to identify and evaluate longitudinal mood trajectories and associated baseline predictors in youths with bipolar disorder.
A total of 367 outpatient youths (mean age, 12.6 years) with bipolar disorder with at least 4 years of follow-up were included. After intake, participants were interviewed on average 10 times (SD=3.2) over a mean of 93 months (SD=8.3). Youths and parents were interviewed for psychopathology, functioning, treatment, and familial psychopathology and functioning.
Latent class growth analysis showed four different longitudinal mood trajectories: “predominantly euthymic” (24.0%), “moderately euthymic” (34.6%), “ill with improving course” (19.1%), and “predominantly ill” (22.3%). Within each class, youths were euthymic on average 84.4%, 47.3%, 42.8%, and 11.5% of the follow-up time, respectively. Multivariate analyses showed that better course was associated with higher age at onset of mood symptoms, less lifetime family history of bipolar disorder and substance abuse, and less history at baseline of severe depression, manic symptoms, suicidality, subsyndromal mood episodes, and sexual abuse. Most of these factors were more noticeable in the “predominantly euthymic” class. The effects of age at onset were attenuated in youths with lower socioeconomic status, and the effects of depression severity were absent in those with the highest socioeconomic status.
A substantial proportion of youths with bipolar disorder, especially those with adolescent onset and the above-noted factors, appear to be euthymic over extended periods. Nonetheless, continued syndromal and subsyndromal mood symptoms in all four classes underscore the need to optimize treatment.
PMCID: PMC4164021  PMID: 24874203
Depression and anxiety  2013;31(5):443-450.
We examined the adequacy of pharmacotherapy and psychotherapy received by primary care patients with anxiety disorders over up to 5 years of follow-up.
Five hundred thirty-four primary care patients at 15 US sites, who screened positive for anxiety symptoms, were assessed for anxiety disorders. Those meeting anxiety disorder criteria were offered participation and interviewed again at six and 12 months postintake, and yearly thereafter for up to 5 years. We utilized existing definitions of appropriate pharmacotherapy and created definitions of potentially adequate psychotherapy/cognitive-behavioral therapy (CBT).
At intake, of 534 primary care participants with anxiety disorders, 19% reported receiving appropriate pharmacotherapy and 14% potentially adequate CBT. Overall, 28% of participants reported receiving potentially adequate anxiety treatment, whether pharmacotherapy, psychotherapy, or both. Over up to five years of follow-up, appropriate pharmacotherapy was received by 60% and potentially adequate CBT by 36% of the sample. Examined together, 69% of participants received any potentially adequate treatment during the follow-up period. Over the course of follow-up, primary care patients with MDD, panic disorder with agoraphobia, and with medicaid/medicare were more likely to receive appropriate anxiety treatment. Ethnic minority members were less likely to receive potentially adequate care.
Potentially adequate anxiety treatment was rarely received by primary care patients with anxiety disorders at intake. Encouragingly, rates improved over the course of the study. However, potentially adequate CBT remained much less utilized than pharmacotherapy and racial-ethnic minority members were less likely to received care, suggesting much room for improved dissemination of quality treatment.
PMCID: PMC4157338  PMID: 24190762
anxiety disorders; primary healthcare; cognitive behavioral therapy; pharmacotherapy; dissemination/implementation; panic disorder/agoraphobia; generalized anxiety disorder; PTSD/posttraumatic stress disorder; social phobia/social anxiety disorder
22.  Risk of Suicidal Behavior With Antidepressants in Bipolar and Unipolar Disorders 
To examine the risk ofsuicidal behavior (suicide attempts and deaths) associated with antidepressants in participants with bipolar I, bipolar n, and unipolar major depressive disorders.
A 27-year longitudinal (1981-2008) observational study ofmood disorders (Research Diagnostic Criteria diagnoses based on Schedule Dr Afi:ctive Disorders and Schizophrenia and review ofmedical records) was used to evaluate antidepressants and risk Dr suicidal behavior. Mixed-efi:cts logistic regression models examined propensity Dr antidepressant exposure. Mixed-efi:cts swvival models that were matched on the propensity score examined exposure status as a risk factor for time until suicidal behavior.
Five US academic medical centers.
Analyses of206 participants with bipolar I disorder revealed 2,010 exposure intervals (980 exposed to antidepressants; 1,030 unexposed); 139 participants with bipolar II disorder had 1 ,407 exposure intervals (694 exposed; 713 unexposed); and 361 participants with unipolar depressive disorder had 2, 745 exposure intervals (1,328 exposed; 1,417 unexposed). Propensity score analyses confinned that more severely ill participants were more likely to initiate antidepressant treatment. In mixed-elects swvival analyses, those with bipolar I disorder had a significant reduction in risk of suicidal behavior by 54% (HR = 0.46; 95% CI, 0.31-0.69; t = -3.74; P < .001) during periods of antidepressant exposure compared to propensity-matched unexposed intervals. Similarly, the risk was reduced by 35% (HR = 0.65; 95% CI, 0.43-0.99; t = −2.01; P = .045) in bipolar II disorder. By contrast, there was no evidence of an increased or decreased risk with antidepressant exposure in unipolar disorder.
Based on obsetVational data adjusted Dr propensity to receive antidepressants, antidepressants may protect patients with bipolar disorders but not unipolar depressive disorder from suicidal behavior.
PMCID: PMC4142755  PMID: 25093469
23.  The Bi-Directional Relationship Between Parent–Child Conflict and Treatment Outcome in Treatment-Resistant Adolescent Depression 
To examine the bidirectional relationship between parent–child discord and treatment outcome for adolescent treatment-resistant depression.
Depressed youth who had not responded to an adequate course of a selective serotonin reuptake inhibitor (SSRI) were randomized to either a switch to another SSRI or venlafaxine, with or without the addition of cognitive behavior therapy (CBT) in the Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) study. The Conflict Behavior Questionnaire was used to assess adolescent (CBQ-A) and parent-reported (CBQ-P) parent–child discord. The impact of remission on parent–child conflict, and the differential impact of medication and CBT on the CBQ-A and CBQ-P, were assessed using generalized linear models.
Although there were no differential treatment effects on parent or adolescent-report of conflict, remission was associated with improvement in the CBQ-P. In general, intake family conflict did not predict remission, except in the sub-group of participants whose parents reported clinically significant parent–child conflict at intake, for whom high levels of parent-reported conflict predicted a lower likelihood of remission. Conflict also did not moderate treatment response.
Remission of depression may be sufficient to reduce parent-reported parent–child conflict. However, higher parent-reported conflict, in the clinically significant range, predicts a lower likelihood of remission from depression. Clinical trial registration information—Treatment of SSRI-Resistant Depression in Adolescents (TORDIA);;NCT00018902.
PMCID: PMC3737571  PMID: 23582868
parent–child conflict; selective serotonin reuptake inhibitor (SSRI); cognitive behavior therapy (CBT); venlafaxine; depression
24.  Age of Onset and the Prospectively Observed Course of Illness in Bipolar Disorder 
Journal of affective disorders  2012;146(1):34-38.
To test the validity of age-of-onset grouping in bipolar disorder through the use of prospectively observed time in mood episodes.
Age-of-onset ranges from prior admixture analyses were used to divide 427 individuals with bipolar I or bipolar II disorder into early-, middle- and late- onset groups. These were compared by the proportions of weeks depressed and manic or hypomanic during a mean (SD) prospective follow-up of 17.4 (8.4) years.
As predicted, the group with the earliest onsets reported at intake more previous episodes, more suicide attempts and panic attacks. An early age of onset, but not current age, was predictive of significantly more time in depressive episodes during follow-up but was not predictive of time in manic or hypomanic episodes.
This was a naturalistic study with no control of treatment so variability in treatment may have obscured relationships between predictors and outcomes. Age of onset was retrospectively determined and subject to inaccuracies in recall.
An early age of onset conveys, to a modest degree, a poorer prognosis as expressed in more depressive morbidity.
PMCID: PMC3605729  PMID: 23062746
bipolar disorder; age-of-onset; follow-up; prognosis
25.  Manic Symptoms in Youth With Bipolar Disorder: Factor Analysis by Age of Symptom Onset and Current Age 
Journal of affective disorders  2012;145(3):409-412.
Factor analysis has been used to identify potential clinical subtypes of mania in pediatric bipolar disorder. Results vary in the number of factors retained. The present study used a formal diagnostic instrument to examine how symptoms of mania in young people are expressed, depending on age of symptom onset and current age.
Trained clinicians completed the Schedule of Affective Disorders and Schizophrenia for School-Age Children (K-SADS) Mania Rating Scale (MRS) with parents of 163 children with child-onset of symptoms (before age 12), 94 adolescents with child-onset of symptoms, and 90 adolescents with adolescent-onset of symptoms (after age 12). Factor analysis of symptom ratings during the most severe lifetime manic episode was performed for each age group.
Symptom factor structures were established for each age group. Two factors were evident for children with child-onset of symptoms (“activated/pleasure seeking” and “labile/disorganized”), one factor was present for adolescents with child-onset of symptoms (“activated/pleasure seeking/disorganized”) and two factors were evident for adolescents with adolescent-onset of symptoms (“activated/pleasure seeking” and “disorganized/psychotic”). The factor structures for children with child-onset and adolescents with adolescent-onset of symptoms were highly similar, with the latter factor structure including psychotic symptoms.
Limitations include reliance on retrospective parent report and potential issues with generalizability.
Findings suggest mania symptomatology is largely similar when examined by both age of onset and current age, with some notable differences. Specifically, psychotic symptoms begin emerging as a distinct factor in adolescents with adolescent-onset of symptoms.
PMCID: PMC3535567  PMID: 23021377
pediatric bipolar disorder; course; onset

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