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1.  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
2.  Germline Signaling Mediates the Synergistically Prolonged Longevity Produced by Double Mutations in daf-2 and rsks-1 in C. elegans 
Cell reports  2013;5(6):1600-1610.
Inhibition of DAF-2 (IGF-1 receptor) or RSKS-1 (S6K), key molecules in the insulin/IGF-1 signaling (IIS) and target of rapamycin (TOR) pathways respectively, extends lifespan in C. elegans. However it has not been clear how they interact with each other and in which tissues to modulate longevity. Here we demonstrate that mutations in daf-2 and rsks-1 when combined produce a nearly five-fold increase in longevity that is much greater than the sum of single mutations. This synergistic lifespan extension requires positive feedback regulation of DAF-16 (FOXO) via the AMP-activated protein kinase (AMPK) complex. We further identify germ line as the key tissue for the synergistic longevity. Moreover, germline-specific inhibition of rsks-1 activates DAF-16 in the intestine. Together, our findings highlight the importance of the germ line in significantly prolonged longevity by daf-2 rsks-1, which provides important implications for interactions between the two major conserved longevity pathways in more complex organisms.
PMCID: PMC3904953  PMID: 24332851
C. elegans; daf-2; rsks-1; daf-16; AMPK; germ line; synergistic lifespan extension
3.  Toward Clinically Applicable Biomarkers in Bipolar Disorder: Focus on BDNF, Inflammatory Markers, and Endothelial Function 
Current psychiatry reports  2013;15(12):425.
The importance of biomarkers to many branches of medicine is illustrated by their utility in diagnosis and monitoring treatment response and outcome. There is much enthusiasm in the field of mood disorders on the emergence of clinically relevant biomarkers with several potential targets. While there are generally accepted criteria to establish a biomarker, such approaches are premature for our field as we acquire evidence on the most relevant candidates. A number of components of the inflammatory pathway are supported by published data together with an increasing focus on brain derived neurotrophic factors (BDNF). These factors may have measurable impacts on endothelial function which may be particularly amenable to study in clinical samples. The adolescent population is a key focus since identifying biomarkers before the onset of comorbid medical conditions and which may help direct early intervention seem especially promising. A systematic approach to biomarker development in mood disorders is clearly warranted.
PMCID: PMC3926699  PMID: 24243532
Bipolar disorder; biomarkers; inflammation; inflammatory; neurotrophic; brain-derived neurotrophic factor; cardiovascular; endothelium; endothelial function
The Journal of pediatrics  2013;163(5):10.1016/j.jpeds.2013.06.019.
To examine the prospective relationship between age of onset of bipolar disorder and the demographic and clinical characteristics, treatment, new onset of psychiatric comorbidity, and psychosocial functioning among adults with bipolar disorder.
Study design
As part of the National Epidemiologic Survey on Alcohol and Related Conditions, 1600 adults who met lifetime DSM-IV criteria for bipolar disorder-I (n=1172) and bipolar disorder-II (n=428) were included. Individuals were evaluated using the Alcohol Use Disorder and Associated Disabilities Interview Schedule-DMS-IV Version and data was analyzed from Waves 1 and 2, approximately 3 years apart. Individuals with bipolar disorder were divided into three age at onset groups: childhood (<13 years old, n=115), adolescence (13-18 years old, n=396), and adulthood (>19 year old, n=1017).
After adjusting for confounding factors, adults with childhood-onset bipolar disorder were more likely to see a counselor, have been hospitalized and have received emergency room treatment for depression compared with those with adulthood-onset bipolar disorder. By contrast, there were no differences in the severity of mania or hypomania, new onset of comorbidity, and psychosocial functioning by age of bipolar disorder onset.
Childhood-onset bipolar disorder is prospectively associated with seeking treatment for depression, an important proxy for depressive severity. Longitudinal studies are needed in order to determine whether prompt identification, accurate diagnosis, and early intervention can serve to mitigate the burden of childhood onset on the long-term depressive burden of bipolar disorder.
PMCID: PMC3812265  PMID: 23896190
5.  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
6.  Trends in Relative Mortality Between Hispanic and Non-Hispanic Whites Initiating Dialysis: A Retrospective Study of the US Renal Data System 
Hispanic patients undergoing long-term dialysis experience better survival compared with non-Hispanic whites. It is unknown whether this association differs by age, has changed over time, or is due to differential access to kidney transplantation.
Study Design
National retrospective cohort study.
Setting & Participants
Using the US Renal Data System, we identified 615,618 white patients 18 years or older who initiated dialysis therapy between January 1, 1995, and December 31, 2007.
Hispanic ethnicity (vs non-Hispanic whites), year of end-stage renal disease incidence, age (as potential effect modifier).
All-cause and cause-specific mortality.
We found that Hispanics initiating dialysis therapy experienced lower mortality, but age modified this association (P < 0.001). Compared with non-Hispanic whites, mortality in Hispanics was 33% lower at ages 18–39 years (adjusted cause-specific HR [HRcs], 0.67; 95% CI, 0.64–0.71) and 40–59 years (HRcs, 0.67; 95% CI, 0.66–0.68), 19% lower at ages 60–79 years (HRcs, 0.81; 95% CI, 0.80–0.82), and 6% lower at 80 years or older (HRcs, 0.94; 95% CI, 0.91–0.97). Accounting for the differential rates of kidney transplantation, the associations were attenuated markedly in the younger age strata; the survival benefit for Hispanics was reduced from 33% to 10% at ages 18–39 years (adjusted subdistribution-specific HR [HRsd], 0.90; 95% CI, 0.85–0.94) and from 33% to 19% among those aged 40–59 years (HRsd, 0.81; 95% CI, 0.80–0.83).
Inability to analyze Hispanic subgroups that may experience heterogeneous mortality outcomes.
Overall, Hispanics experienced lower mortality, but differential access to kidney transplantation was responsible for much of the apparent survival benefit noted in younger Hispanics. Am J Kidney Dis. 62(2):312–321.
PMCID: PMC4169882  PMID: 23647836
Clinical epidemiology; Hispanic ethnicity; survival; dialysis
7.  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
8.  Early acute lung injury: Criteria for identifying lung Injury prior to the need for positive pressure ventilation 
Critical care medicine  2013;41(8):1929-1937.
Mortality associated with acute lung injury (ALI) remains high. Early identification of ALI prior to onset of respiratory failure may provide a therapeutic window to target in future clinical trials. The recently validated Lung Injury Prediction Score (LIPS) identifies patients at risk for ALI but may be limited for routine clinical use. We sought to empirically derive clinical criteria for a pragmatic definition of Early Acute Lung Injury (EALI) to identify patients with lung injury prior to the need for positive pressure ventilation.
Prospective observational cohort study.
Stanford University Hospital.
We prospectively evaluated 256 patients admitted to Stanford University Hospital with bilateral opacities on chest radiograph without isolated left atrial hypertension.
Measurements and Main Results
Of the 256 patients enrolled, 62 (25%) progressed to ALI requiring positive pressure ventilation. Clinical variables (through first 72 hours or up to 6 hours prior to ALI) associated with progression to ALI were analyzed by backward regression. Oxygen requirement, maximal respiratory rate, and baseline immune suppression were independent predictors of progression to ALI. A simple 3 component EALI score (1 point for oxygen requirement > 2 to 6 liters/min or 2 points for > 6 liters/min; and 1 point each for a respiratory rate ≥ 30 and immune suppression) accurately identified patients who progressed to ALI requiring positive pressure ventilation (AUC 0.86) and performed similarly to the LIPS. An EALI score ≥ 2 identified patients who progressed to ALI with 89% sensitivity and 75% specificity. Median time of progression from EALI criteria to ALI requiring positive pressure ventilation was 20 hours.
This pragmatic definition of EALI accurately identified patients who progressed to ALI prior to requiring positive pressure ventilation. Pending further validation, these criteria could be useful for future clinical trials targeting early treatment of ALI.
PMCID: PMC3748809  PMID: 23782966
acute lung injury; acute respiratory distress syndrome; early diagnosis; cohort study; critical care; emergency medicine
9.  Simple, standardized incorporation of genetic risk into non-genetic risk prediction tools for complex traits: coronary heart disease as an example 
Frontiers in Genetics  2014;5:254.
Purpose: Genetic risk assessment is becoming an important component of clinical decision-making. Genetic Risk Scores (GRSs) allow the composite assessment of genetic risk in complex traits. A technically and clinically pertinent question is how to most easily and effectively combine a GRS with an assessment of clinical risk derived from established non-genetic risk factors as well as to clearly present this information to patient and health care providers.
Materials and Methods: We illustrate a means to combine a GRS with an independent assessment of clinical risk using a log-link function. We apply the method to the prediction of coronary heart disease (CHD) in the Atherosclerosis Risk in Communities (ARIC) cohort. We evaluate different constructions based on metrics of effect change, discrimination, and calibration.
Results: The addition of a GRS to a clinical risk score (CRS) improves both discrimination and calibration for CHD in ARIC. Results are similar regardless of whether external vs. internal coefficients are used for the CRS, risk factor single nucleotide polymorphisms (SNPs) are included in the GRS, or subjects with diabetes at baseline are excluded. We outline how to report the construction and the performance of a GRS using our method and illustrate a means to present genetic risk information to subjects and/or their health care provider.
Conclusion: The proposed method facilitates the standardized incorporation of a GRS in risk assessment.
PMCID: PMC4117937  PMID: 25136350
genetic risk scores; personalized medicine; coronary heart disease; electronic health records
10.  Temporal sequencing of nicotine dependence and bipolar disorder in the national epidemiologic survey on alcohol and related conditions (NESARC) 
Journal of psychiatric research  2013;47(7):858-864.
Bipolar disorder (BD) and nicotine dependence (ND) often co-occur. However, the mechanisms underlying this association remain unclear. We aimed to examine, for the first time in a national and representative sample, the magnitude and direction of the temporal relationship between BD and ND; and to compare, among individuals with lifetime ND and BD, the sociodemographic and clinical characteristics of individuals whose onset of ND preceded the onset of BD (ND-prior) with those whose onset of ND followed the onset of BD (BD-prior). The sample included individuals with lifetime BD type I or ND (n=7958) from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC, n=43093). Survival analyses and logistic regression models were computed to study the temporal association between ND and BD, and to compare ND-prior (n=135) and BD-prior (n=386) individuals. We found that ND predicted the onset of BD and BD also predicted the onset of ND. Furthermore, the risk of developing one disorder following the other one was greatest early in the course of illness. Most individuals with lifetime ND and BD were BD-prior (72.6%). BD-prior individuals had an earlier onset of BD and a higher number of manic episodes. By contrast, ND-prior individuals had an earlier onset of both daily smoking and ND, and an increased prevalence of alcohol use disorder. In conclusion, ND and BD predict the development of each other. The phenomenology and course of ND and BD varied significantly depending on which disorder had earlier onset.
PMCID: PMC3674324  PMID: 23582710
bipolar disorder; nicotine dependence; age of onset; smoking; epidemiology
11.  Dimensional psychopathology in preschool offspring of parents with bipolar disorder 
The purpose of this study is to compare the dimensional psychopathology, as ascertained by parental report, in preschool offspring of parents with bipolar disorder (BP) and offspring of community control parents.
122 preschool offspring (mean age 3.3 years) of 84 parents with BP, with 102 offspring of 65 control parents (36 healthy, 29 with non-BP psychopathology), were evaluated using the Child Behavior Checklist (CBCL), the CBCL-Dysregulation Profile (CBCL-DP), the Early Childhood Inventory (ECI-4), and the Emotionality Activity Sociability (EAS) survey. Teachers’ Report Forms (TRF) were available for 51 preschoolers.
After adjusting for confounders, offspring of parents with BP showed higher scores in the CBCL total, externalizing, somatic, sleep, aggressive, and CBCL-DP subscales; the ECI-4 sleep problem scale; and the EAS total and emotionality scale. The proportion of offspring with CBCL T-scores ≥2 SD above the norm was significantly higher on most CBCL subscales and the CBCL-DP in offspring of parents with BP compared to offspring of controls even after excluding offspring with attention deficit hyperactivity disorder and/or oppositional defiant disorder. Compared to offspring of parents with BP-I, offspring of parents with BP-II showed significantly higher scores in total and most CBCL subscales, the ECI-4 anxiety and sleep scales and the EAS emotionality scale. For both groups of parents, there were significant correlations between CBCL and TRF scores (r = .32–.38, p-values ≤.02).
Independent of categorical axis-I psychopathology and other demographic or clinical factors in both biological parents, preschool offspring of parents with BP have significantly greater aggression, mood dysregulation, sleep disturbances, and somatic complaints compared to offspring of control parents. Interventions to target these symptoms are warranted.
PMCID: PMC4017915  PMID: 24372351
BP; offspring; dimensional psychopathology
12.  Mood lability among offspring of parents with bipolar disorder and community controls 
Bipolar disorders  2013;15(3):253-263.
Early identification of bipolar disorder (BP) symptomatology is crucial for improving the prognosis of this illness. Increased mood lability has been reported in BP. However, mood lability is ubiquitous across psychiatric disorders and may be a marker of severe psychopathology and not specific to BP. To clarify this issue, this study examined the prevalence of mood lability and its components in offspring of BP parents and offspring of community control parents recruited through the Pittsburgh Bipolar Offspring Study.
Forty-one school-age BP offspring of 38 BP parents, 257 healthy or non-BP offspring of 174 BP parents, and 192 offspring of 117 control parents completed a scale that was developed to evaluate mood lability in youth, i.e., the Children’s Affective Lability Scale (CALS).
A factor analysis of the parental CALS, and in part the child CALS, revealed Irritability, Mania, and Anxiety/Depression factors, with most of the variance explained by the Irritability factor. After adjusting for confounding factors (e.g., parental and offspring non-BP psychopathology), BP offspring of BP parents showed the highest parental and child total and factor scores, followed by the non-BP offspring of BP parents, and then the offspring of the controls.
Mood lability overall and mania-like, anxious/depressed, and particularly irritability symptoms may be a prodromal phenotype of BP among offspring of parents with BP. Prospective studies are warranted to clarify whether these symptoms will predict the development of BP and/or other psychopathology. If confirmed, these symptoms may become a target of treatment and biological studies before BP develops.
PMCID: PMC3644367  PMID: 23551755
anxiety; bipolar disorder; bipolar offspring; Children’s Affective Lability Scale; depression; irritability; mania; mood lability
13.  Obesity and the three-year longitudinal course of bipolar disorder 
Bipolar disorders  2013;15(3):284-293.
Despite substantial cross-sectional evidence that obesity is associated with increased medical and psychiatric burden in bipolar disorder (BD), few longitudinal studies have examined this topic.
Subjects with BD (n = 1,600) who completed both Wave 1 and Wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions were included. Analyses examined the association between obesity at Wave 1, and the subsequent course of BD, and of psychiatric and medical comorbidities, between Wave 1 and Wave 2.
BD subjects with obesity (n = 506; 29.43%), compared to BD subjects without obesity (n = 1,094; 70.57%) were significantly more likely to have a major depressive episode and to receive counseling for depression during follow-up, more likely to report a lifetime suicide attempt, and less likely to develop new onset alcohol use disorders. These differences were no longer significant, however, after controlling for baseline demographic variables. No significant differences in new episodes or treatment of mania/hypomania were observed. After controlling for demographic variables, obese subjects remained significantly more likely to report any new-onset medical condition [odds ratio (OR) = 2.32, 95% confidence interval (CI): 1.63–3.30], and new-onset hypertension (OR = 1.81, 95% CI: 1.16–2.82) and arthritis (OR = 1.64, 95% CI: 1.07–2.52). Obese subjects were significantly more likely to report physician-diagnosed diabetes (OR = 6.98, 95% CI: 4.27–11.40) and hyperlipidemia (OR = 2.32, 95% CI: 1.63–3.30) (assessed in Wave 2 only). The incidence of heart attacks was doubled among obese subjects, although this difference was not statistically significant.
The association between obesity and increased prospective depressive burden appears to be explained by baseline demographic variables. In contrast, obesity independently predicts the accumulation of medical conditions among adults with BD. Treatment of obesity could potentially mitigate the psychiatric and medical burden of BD.
PMCID: PMC3620842  PMID: 23286532
bipolar disorder; epidemiologic; longitudinal; obesity
14.  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
15.  Determinants of Peritoneal Dialysis Technique Failure in Incident US Patients 
♦ Objectives: Switching from peritoneal dialysis (PD) to hemodialysis (HD) is undesirable, because of complications from temporary vascular access, disruption of daily routine, and higher costs. Little is known about the role that social factors play in technique failure.
♦ Design, Setting, Participants, Measurements: We followed for 3 years a nationally representative cohort of US patients who initiated PD in 1996 - 1997. Technique failure was defined as any switch from PD to HD for 30 days or more. We used Cox regression to examine associations between technique failure and demographic, medical, social, and pre-dialysis factors. We estimated hazard ratios (HRs) with 95% confidence intervals (CIs).
♦ Results: We identified an inception cohort of 1587 patients undergoing PD. In multivariate analysis, female sex (HR: 0.78; 95% CI: 0.64 to 0.95) was associated with lower rates of technique failure, and black race [compared with white race (HR: 1.48; 95% CI: 1.20 to 1.82)] and receiving Medicaid (HR: 1.48; 95% CI: 1.17 to 1.86) were associated with higher rates. Compared with patients who worked full-time, those who were retired (HR: 1.49; 95% CI: 1.07 to 2.08) or disabled (HR: 1.38; 95% CI: 1.01 to 1.88) had higher rates of failure. Patients with a systolic blood pressure of 140 - 160 mmHg had a higher rate of failure than did those with a pressure of 120 - 140 mmHg (HR: 1.24; 95% CI: 1.00 to 1.52). Earlier referral to a nephrologist (>3 months before dialysis initiation) and the primary decision-maker for the dialysis modality (physician vs patient vs shared) were not associated with technique failure.
♦ Conclusions: This study confirms that several socio-demographic factors are associated with technique failure, emphasizing the potential importance of social and financial support in maintaining PD.
PMCID: PMC3598105  PMID: 23032086
Technique failure; modality failure; socio-demographic
16.  Use of Mental Health Services in Transition Age Youth with Bipolar Disorder 
Journal of psychiatric practice  2013;19(6):10.1097/01.pra.0000438185.81983.8b.
There is concern that treatment of serious mental illness in the United States declines precipitously following legal emancipation at age 18 years and transition from specialty youth clinical settings. We examined age transition effects on treatment utilization in a sample of youth with bipolar disorder.
Youth with bipolar disorder (N = 413) 7–18 years of age were assessed approximately twice per year (mean interval 8.2 months) for at least 4 years. Annual use of any individual, group, and family therapy, psychopharmacology visits, and hospitalization at each year of age, and monthly use from ages 17 through 19 years, were examined. The effect of age transition to 18 years on monthly visit probability was tested in the subsample with observed transitions (n = 204). Putative sociodemographic moderators and the influence of clinical course were assessed.
Visit probabilities for the most common modalities—psychopharmacology, individual psychotherapy, and home-based care— generally fell from childhood to young adulthood. For example, the annual probability of at least one psychopharmacology visit was 97% at age 8, 75% at age 17, 60% at age 19, and 46% by age 22. Treatment probabilities fell in transition-age youth from age 17 through 19, but a specific transition effect at age 18 was not found. Declines did not vary based on sociodemographic characteristics and were not explained by changing severity of the bipolar illness or functioning.
Mental health treatment declined with age in this sample of youth with bipolar disorder, but reductions were not concentrated during or after the transition to age 18 years. Declines were unrelated to symptom severity or impairment.
PMCID: PMC3885866  PMID: 24241500
bipolar disorder; longitudinal studies; treatment use; transition-age youth; children; adolescents
17.  Impact of San Francisco’s Toy Ordinance on Restaurants and Children’s Food Purchases, 2011–2012 
In 2011, San Francisco passed the first citywide ordinance to improve the nutritional standards of children’s meals sold at restaurants by preventing the giving away of free toys or other incentives with meals unless nutritional criteria were met. This study examined the impact of the Healthy Food Incentives Ordinance at ordinance-affected restaurants on restaurant response (eg, toy-distribution practices, change in children’s menus), and the energy and nutrient content of all orders and children’s-meal–only orders purchased for children aged 0 through 12 years.
Restaurant responses were examined from January 2010 through March 2012. Parent–caregiver/child dyads (n = 762) who were restaurant customers were surveyed at 2 points before and 1 seasonally matched point after ordinance enactment at Chain A and B restaurants (n = 30) in 2011 and 2012.
Both restaurant chains responded to the ordinance by selling toys separately from children’s meals, but neither changed their menus to meet ordinance-specified nutrition criteria. Among children for whom children’s meals were purchased, significant decreases in kilocalories, sodium, and fat per order were likely due to changes in children’s side dishes and beverages at Chain A.
Although the changes at Chain A did not appear to be directly in response to the ordinance, the transition to a more healthful beverage and default side dish was consistent with the intent of the ordinance. Study results underscore the importance of policy wording, support the concept that more healthful defaults may be a powerful approach for improving dietary intake, and suggest that public policies may contribute to positive restaurant changes.
PMCID: PMC4110247  PMID: 25032837
Circulation  2012;126(19):2293-2301.
One sixth of U.S. dialysis patients older than 65 years have been diagnosed with atrial fibrillation/flutter (AF) and the prevalence is increasing. Little is known, however, about the incidence of AF in this population.
Methods and Results
From the U.S. Renal Data System, we identified 258,605 older patients (≥67 years) with fee-for-service Medicare initiating dialysis between 1995 and 2007, who had not been diagnosed with AF within the previous 2 years. Patients were followed for newly diagnosed AF, which was ascertained from 1 inpatient or 2 outpatient claims containing an AF code. Multivariable proportional hazards regression was used to examine temporal trends and associations of race and ethnicity with incident AF. We also studied temporal trends in the mortality and risk of ischemic stroke after new AF. Over 514,395 person years of follow-up, 76,252 patients experienced incident AF for a crude AF incidence rate of 148/1,000 person years. Incidence of AF increased by 11% (95%CI: 5%-16%) from 1995-2007. Compared with non-Hispanic whites, African Americans (−30%), Asians (−19%), Native Americans (−42%), and Hispanics (−29%) all had lower rates of incident AF. Mortality after incident AF decreased by 22% from 1995-2008. Even more pronounced reductions were seen for incident ischemic stroke during these years.
The incidence of AF is high in older patients initiating dialysis in the U.S. and has been increasing over the 13 years of study. Mortality declined during that time, but remained >50% during the first year after newly diagnosed AF. Since data on warfarin use were not available, we were unable to understand whether trends towards better outcomes could be explained by higher rates of oral anticoagulation in more recent years.
PMCID: PMC3640842  PMID: 23032326
end-stage renal disease; atrial fibrillation; disparities; outcomes; cardiovascular; mortality
19.  Donor Predictors of Allograft Utilization and Recipient Outcomes after Heart Transplantation 
Circulation. Heart failure  2013;6(2):300-309.
Despite a national organ donor shortage and a growing population of patients with end-stage heart disease, the acceptance rate of donor hearts for transplantation is low. We sought to identify donor predictors of allograft non-utilization, and to determine whether these predictors are in fact associated with adverse recipient post-transplant outcomes.
Methods and Results
We studied a cohort of 1,872 potential organ donors managed by the California Transplant Donor Network from 2001–2008. Forty five percent of available allografts were accepted for heart transplantation. Donor predictors of allograft non-utilization included age>50 years, female sex, death due to cerebrovascular accident, hypertension, diabetes, a positive troponin assay, left ventricular dysfunction and regional wall motion abnormalities, and left ventricular hypertrophy. For hearts that were transplanted, only donor cause of death was associated with prolonged recipient hospitalization post-transplant, and only donor diabetes was predictive of increased recipient mortality.
While there are many donor predictors of allograft discard in the current era, these characteristics appear to have little effect on recipient outcomes when the hearts are transplanted. Our results suggest that more liberal use of cardiac allografts with relative contraindications may be warranted.
PMCID: PMC3805361  PMID: 23392789
Organ donor; Heart transplantation; Transplant recipients; Transplant outcomes
20.  Irritability and Elation in a Large Bipolar Youth Sample: Relative Symptom Severity and Clinical Outcomes Over 4 Years 
The Journal of clinical psychiatry  2013;74(1):e110-e117.
To assess whether relative severity of irritability symptoms versus elation symptoms in mania is stable and predicts subsequent illness course in youth with DSM-IV bipolar I or II disorder or operationally defined bipolar disorder not otherwise specified.
Investigators used the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children to assess the most severe lifetime manic episode in bipolar youth aged 7–17 years who were recruited from 2000 to 2006 as part of the Course and Outcomes of Bipolar Youth prospective cohort study (N = 361), conducted at university-affiliated mental health clinics. Subjects with at least 4 years of follow-up (N = 309) were categorized as irritable-only (n = 30), elated-only (n = 42), or both irritable and elated (n = 237) at baseline. Stability of this categorization over follow-up was the primary outcome. The course of mood symptoms and episodes, risk of suicide attempt, and functioning over follow-up were also compared between baseline groups.
Most subjects experienced both irritability and elation during follow-up, and agreement between baseline and follow-up group assignment did not exceed that expected by chance (κ = 0.03; 95% CI, −0.06 to 0.12). Elated-only subjects were most likely to report the absence of both irritability and elation symptoms at every follow-up assessment (35.7%, versus 26.7% of irritable-only subjects and 16.9% of those with both irritability and elation; P = .01). Baseline groups experienced mania or hypomania for a similar proportion of the follow-up period, but irritable-only subjects experienced depression for a greater proportion of the follow-up period than did subjects who were both irritable and elated (53.9% versus 39.7%, respectively; P = .01). The groups did not otherwise differ by course of mood episode duration, polarity, bipolar diagnostic type, suicide attempt risk, or functional impairment.
Most bipolar youth eventually experienced both irritability and elation irrespective of history. Irritable-only youth were at similar risk for mania but at greater risk for depression compared with elated-only youth and youth who had both irritability and elation symptoms.
PMCID: PMC3600607  PMID: 23419232
Journal of Psychiatric Research  2012;46(7):865-872.
To examine the prevalence and correlates of comorbid anxiety disorders among individuals with bipolar disorders (BP) and their association with prospectively ascertained comorbidities, treatment, and psychosocial functioning.
As part of the National Epidemiologic Survey on Alcohol and Related Conditions, 1600 adults who met lifetime DSM-IV criteria for BP-I (n=1172) and BP-II (n=428) were included. Individuals were evaluated using the Alcohol Use Disorder and Associated Disabilities Interview Schedule-DMS-IV Version and data was analyzed from Waves 1 and 2, approximately 3 years apart.
Sixty percent of individuals with BP had at least one lifetime comorbid anxiety disorder. Individuals with BP and anxiety disorders shared lifetime risk factors for major depressive disorder and had prospectively more depressive and manic/hypomanic episodes, suicidal ideation, suicide attempts, and more treatment seeking than those without anxiety. During the follow-up, higher incidence of panic disorder, drug use disorders, and lower psychosocial functioning were found in individuals with BP with versus without anxiety disorders.
Anxiety disorders are prospectively associated with elevated BP severity and BP-related mental health service use. Early identification and treatment of anxiety disorders are warranted to improve the course and outcome of individuals with BP.
PMCID: PMC3372764  PMID: 22534180
anxiety; bipolar disorder; outcome; comorbidity
22.  Electrocardiographic Characteristics of Potential Organ Donors and Associations with Cardiac Allograft Utilization 
Circulation. Heart Failure  2012;5(4):475-483.
Current regulations require that all cardiac allograft offers for transplantation must include an interpreted 12-lead electrocardiogram (ECG). However, little is known about the expected ECG findings in potential organ donors, or the clinical significance of any identified abnormalities in terms of cardiac allograft function and suitability for transplantation.
Methods and Results
A single experienced reviewer interpreted the first ECG obtained after brainstem herniation in 980 potential organ donors managed by the California Transplant Donor Network from 2002-2007. ECG abnormalities were summarized, and associations between specific ECG findings and cardiac allograft utilization for transplantation were studied. ECG abnormalities were present in 51% of all cases reviewed. The most common abnormalities included voltage criteria for left ventricular hypertrophy (LVH), prolongation of the corrected QT interval (QTc), and repolarization changes (ST/T wave abnormalities). Fifty seven percent of potential cardiac allografts in this cohort were accepted for transplantation. LVH on ECG was a strong predictor of allograft non-utilization. No significant associations were seen between QTc prolongation, repolarization changes and allograft utilization for transplantation, after adjusting for donor clinical variables and echocardiographic findings.
We have performed the first comprehensive study of ECG findings in potential donors for cardiac transplantation. Many of the common ECG abnormalities seen in organ donors may result from the heightened state of sympathetic activation that occurs after brainstem herniation, and are not associated with allograft utilization for transplantation.
PMCID: PMC3400714  PMID: 22615333
electrocardiography; echocardiography; organ donor; long QT; transplantation
23.  A Randomized Trial of Personal Genomics for Preventive Cardiology: Design and Challenges 
PMCID: PMC3394683  PMID: 22715281
personalized medicine; coronary artery disease; genotyping; SNP; preventive cardiology
24.  Association Between the Chromosome 9p21 Locus and Angiographic Coronary Artery Disease Burden 
This study sought to ascertain the relationship of 9p21 locus with: 1) angiographic coronary artery disease (CAD) burden; and 2) myocardial infarction (MI) in individuals with underlying CAD.
Chromosome 9p21 variants have been robustly associated with coronary heart disease, but questions remain on the mechanism of risk, specifically whether the locus contributes to coronary atheroma burden or plaque instability.
We established a collaboration of 21 studies consisting of 33,673 subjects with information on both CAD (clinical or angiographic) and MI status along with 9p21 genotype. Tabular data are provided for each cohort on the presence and burden of angiographic CAD, MI cases with underlying CAD, and the diabetic status of all subjects.
We first confirmed an association between 9p21 and CAD with angiographically defined cases and control subjects (pooled odds ratio [OR]: 1.31, 95% confidence interval [CI]: 1.20 to 1.43). Among subjects with angiographic CAD (n = 20,987), random-effects model identified an association with multivessel CAD, compared with those with single-vessel disease (OR: 1.10, 95% CI: 1.04 to 1.17)/copy of risk allele). Genotypic models showed an OR of 1.15, 95% CI: 1.04 to 1.26 for heterozygous carrier and OR: 1.23, 95% CI: 1.08 to 1.39 for homozygous carrier. Finally, there was no significant association between 9p21 and prevalent MI when both cases (n = 17,791) and control subjects (n = 15,882) had underlying CAD (OR: 0.99, 95% CI: 0.95 to 1.03)/risk allele.
The 9p21 locus shows convincing association with greater burden of CAD but not with MI in the presence of underlying CAD. This adds further weight to the hypothesis that 9p21 locus primarily mediates an atherosclerotic phenotype.
PMCID: PMC3653306  PMID: 23352782
9p21; angiography; coronary artery disease; meta-analysis; myocardial infarction; single nucleotide polymorphism
25.  Is bipolar disorder specifically associated with aggression? 
Bipolar Disorders  2012;14(3):283-290.
Several studies have suggested that bipolar disorder (BP) in adults is associated with aggressive behaviors. However, most studies have only included inpatients and have not taken possible confounding factors into consideration. The goal of this study was to compare the prevalence of aggression in subjects with BP compared to subjects with other non-BP psychopathology and healthy controls.
Subjects with bipolar I disorder (BP-I) and bipolar II disorder (BP-II) (n = 255), non-BP psychopathology (n = 85), and healthy controls (n = 84) were recruited. Aggression was measured using the Aggression Questionnaire (AQ). Group comparisons were adjusted for demographic and clinical differences (e.g., comorbid disorders) and multiple comparisons. The effects of the subtype of BP, current versus past episode, polarity of current episode, psychosis, the presence of irritable mania/hypomania only, and pharmacological treatment were examined.
Subjects with BP showed significantly higher total and subscale AQ scores (raw and T-scores) when compared with subjects with non-BP psychopathology and healthy controls. Exclusion of subjects with current mood episodes and those with common comorbid disorders yielded similar results. There were no effects of BP subtype, polarity of the current episode, irritable manic/hypomanic episodes only, or current use of pharmacological treatments. Independent of the severity of BP and polarity of the episode, those in a current mood episode showed significantly higher AQ scores than those not in a current mood episode. Subjects with current psychosis showed significantly higher total AQ score, hostility, and anger than those without current psychosis.
Subjects with BP display greater rates of anger and aggressive behaviors, especially during acute and psychotic episodes. Early identification and management of these behaviors is warranted.
PMCID: PMC3342837  PMID: 22548901
aggression; Aggression Questionnaire; anger; bipolar disorder; irritability

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