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2.  Identification of p18INK4c as a Tumor Suppressor Gene in Glioblastoma Multiforme 
Cancer research  2008;68(8):2564-2569.
Genomic alterations leading to aberrant activation of cyclin/cyclin-dependent kinase (cdk) complexes drive the pathogenesis of many common human tumor types. In the case of glioblastoma multiforme (GBM), these alterations are most commonly due to homozygous deletion of p16INK4a and less commonly due to genomic amplifications of individual genes encoding cyclins or cdks. Here, we describe deletion of the p18INK4c cdk inhibitor as a novel genetic alteration driving the pathogenesis of GBM. Deletions of p18INK4c often occurred in tumors also harboring homozygous deletions of p16INK4a. Expression of p18INK4c was completely absent in 43% of GBM primary tumors studied by immunohistochemistry. Lentiviral reconstitution of p18INK4c expression at physiologic levels in p18INK4c-deficient but not p18INK4c-proficient GBM cells led to senescence-like G1 cell cycle arrest. These studies identify p18INK4c as a GBM tumor suppressor gene, revealing an additional mechanism leading to aberrant activation of cyclin/cdk complexes in this terrible malignancy.
PMCID: PMC4394609  PMID: 18381405
3.  Glioblastoma cells containing mutations in the cohesin component, STAG2, are sensitive to PARP inhibition 
Molecular cancer therapeutics  2013;13(3):724-732.
Recent data has identified STAG2, a core subunit of the multifunctional cohesin complex, as a highly recurrently mutated gene in several types of cancer. We sought to identify a therapeutic strategy to selectively target cancer cells harboring inactivating mutations of STAG2 using two independent pairs of isogenic glioblastoma cell lines containing either an endogenous mutant STAG2 allele or a wild-type STAG2 allele restored by homologous recombination. We find that STAG2 mutation is associated with significantly increased sensitivity to inhibitors of the DNA repair enzyme poly ADP-ribose polymerase (PARP). STAG2-mutated, PARP-inhibited cells accumulated in G2 phase and had a higher percentage of micronuclei, fragmented nuclei and chromatin bridges compared to wild-type STAG2 cells. We also observed more 53BP1 foci in STAG2-mutated glioblastoma cells suggesting that these cells have defects in DNA repair. Furthermore, cells with STAG2 mutations were more sensitive than cells with wild-type STAG2 when PARP inhibitors were used in combination with DNA damaging agents. These data suggest that PARP is a potential target for tumours harbouring inactivating mutations in STAG2, and strongly recommend that STAG2 status be determined and correlated with therapeutic response to PARP inhibitors, both prospectively and retrospectively, in clinical trials.
PMCID: PMC4130349  PMID: 24356817
poly (ADP-ribose) polymerase; STAG2; cohesin; olaparib; glioblastoma
4.  Diagnostic Value of Bronchoalveolar Lavage in Leukemic and Bone Marrow Transplant Patients: The Impact of Antimicrobial Therapy 
There is significant morbidity and mortality from pneumonia in leukemic and bone marrow transplant patients. We sought to explore the diagnostic yield of bronchoalveolar lavage (BAL) in these patients with new pulmonary infiltrates. A retrospective chart review of approximately 200 Non- human immunodeficiency virus (HIV) leukemic and Hematopoietic stem cell transplantation (HSCT) patients who underwent bronchoscopy at a single academic cancer center was performed. Antimicrobial use for less than 24 hours at the time of BAL was associated with a higher yield in this population (56.8% versus 32.8%, p<0.001). This supports performing bronchoscopy with BAL within 24 hours of antimicrobial therapy in leukemic and HSCT patients.
PMCID: PMC4283926  PMID: 25574361
5.  The impact of digital dissemination for research and scholarship 
ecancermedicalscience  2014;8:ed44.
PMCID: PMC4170977  PMID: 25368669
6.  Aneurysm of the Posterior Meningeal Artery Embedded Within a Dorsal Exophytic Medullary Hemangioblastoma: Surgical Management and Review of Literature 
Hemangioblastomas are World Health Organization (WHO) Grade I neoplasms of the hindbrain and spinal cord, whose management can be complicated by preoperative hemorrhage. We report on a case of a young female in extremis with posterior fossa hemorrhage following rupture of a fusiform posterior meningeal artery aneurysm embedded within a medullary hemangioblastoma. We discuss management options, including operative staging and embolization, and review similar cases of hemangioblastoma associated with aneurysm.
PMCID: PMC4205258  PMID: 25340034
Aneurysm; Hemangioblastoma; Embolization; Posterior fossa hemorrhage
7.  The Genomic Landscape of the Ewing Sarcoma Family of Tumors Reveals Recurrent STAG2 Mutation 
PLoS Genetics  2014;10(7):e1004475.
The Ewing sarcoma family of tumors (EFT) is a group of highly malignant small round blue cell tumors occurring in children and young adults. We report here the largest genomic survey to date of 101 EFT (65 tumors and 36 cell lines). Using a combination of whole genome sequencing and targeted sequencing approaches, we discover that EFT has a very low mutational burden (0.15 mutations/Mb) but frequent deleterious mutations in the cohesin complex subunit STAG2 (21.5% tumors, 44.4% cell lines), homozygous deletion of CDKN2A (13.8% and 50%) and mutations of TP53 (6.2% and 71.9%). We additionally note an increased prevalence of the BRCA2 K3326X polymorphism in EFT patient samples (7.3%) compared to population data (OR 7.1, p = 0.006). Using whole transcriptome sequencing, we find that 11% of tumors pathologically diagnosed as EFT lack a typical EWSR1 fusion oncogene and that these tumors do not have a characteristic Ewing sarcoma gene expression signature. We identify samples harboring novel fusion genes including FUS-NCATc2 and CIC-FOXO4 that may represent distinct small round blue cell tumor variants. In an independent EFT tissue microarray cohort, we show that STAG2 loss as detected by immunohistochemistry may be associated with more advanced disease (p = 0.15) and a modest decrease in overall survival (p = 0.10). These results significantly advance our understanding of the genomic and molecular underpinnings of Ewing sarcoma and provide a foundation towards further efforts to improve diagnosis, prognosis, and precision therapeutics testing.
Author Summary
The Ewing sarcoma family of tumors is a group of aggressive cancers that primarily affects the pediatric and young adult population. Increasingly, genomics are being used to better define the disease biology and to identify targets for therapy in many cancer types. Here, we report one of the first and largest genomic studies to date in the Ewing sarcoma family of tumors. Using a combination of modern sequencing techniques in >100 samples, we discover that Ewing sarcomas have a genome that is less complex compared to most cancer types previously surveyed. We find that this cancer is frequently affected by mutations in STAG2, a gene that has recently gained attention due to its importance in the biology of several cancer types. We show that Ewing sarcoma patients whose tumors are affected by STAG2 loss may have a worse prognosis. Additionally, we identify a subset of tumors that were diagnosed as Ewing sarcoma that appear to be distinct from the majority based on genetic and molecular characteristics. Our findings help to define the genetic landscape of Ewing sarcoma and provide a starting point for improving individualization of diagnosis, prognosis and treatment in this cancer.
PMCID: PMC4091782  PMID: 25010205
8.  Cohesin gene mutations in tumorigenesis: from discovery to clinical significance 
BMB Reports  2014;47(6):299-310.
Cohesin is a multi-protein complex composed of four core subunits (SMC1A, SMC3, RAD21, and either STAG1 or STAG2) that is responsible for the cohesion of sister chromatids following DNA replication until its cleavage during mitosis thereby enabling faithful segregation of sister chromatids into two daughter cells. Recent cancer genomics analyses have discovered a high frequency of somatic mutations in the genes encoding the core cohesin subunits as well as cohesin regulatory factors (e.g. NIPBL, PDS5B, ESPL1) in a select subset of human tumors including glioblastoma, Ewing sarcoma, urothelial carcinoma, acute myeloid leukemia, and acute megakaryoblastic leukemia. Herein we review these studies including discussion of the functional significance of cohesin inactivation in tumorigenesis and potential therapeutic mechanisms to selectively target cancers harboring cohesin mutations. [BMB Reports 2014; 47(6): 299-310]
PMCID: PMC4163871  PMID: 24856830
Acute myeloid leukemia; Aneuploidy; Bladder cancer; Chromosomal instability; Cohesin; Ewing sarcoma; Glioblastoma; Mitosis; Sister chromatid cohesion; STAG2; Urothelial carcinoma
9.  Seasonal variation of manic and depressive symptoms in bipolar disorder 
Bipolar disorders  2013;15(4):377-384.
Analyses of seasonal variation of manic and depressive symptoms in bipolar disorder in retrospective studies examining admission data have yielded conflicting results. We examined seasonal variation of mood symptoms in a prospective cohort with long-term follow-up: The Collaborative Depression Study (CDS).
The CDS included participants from five academic centers with a prospective diagnosis of bipolar I or II disorder. The sample was limited to those who were followed for at least 10 years of annual or semi-annual assessments. Time series analyses and autoregressive integrated moving average (ARIMA) models were used assess seasonal patterns of manic and depressive symptoms.
A total of 314 individuals were analyzed [bipolar I disorder: (n = 202) and bipolar II disorder: (n = 112)] with both disorders exhibiting the lowest depressive symptoms in summer and highest around the winter solstice, though the winter peak in symptoms was statistically significant only with bipolar I disorder. Variation of manic symptoms was more pronounced in bipolar II disorder, with a significant peak in hypomanic symptomatology in the months surrounding the fall equinox.
Significant seasonal variation exists in bipolar disorder with manic/hypomanic symptoms peaking around the fall equinox and depressive symptoms peaking in months surrounding the winter solstice in bipolar I disorder.
PMCID: PMC3731411  PMID: 23621686
bipolar I disorder; bipolar II disorder; depression; hypomania; mania; seasonal variation
10.  Frequent truncating mutations of STAG2 in bladder cancer 
Nature genetics  2013;45(12):10.1038/ng.2800.
Here we report the discovery of truncating mutations of the gene encoding the cohesin subunit STAG2, which regulates sister chromatid cohesion and segregation, in 36% of papillary non-invasive urothelial carcinomas and 16% of invasive urothelial carcinomas of the bladder. Our studies suggest that STAG2 plays a role in controlling chromosome number but not proliferation of bladder cancer cells. These findings identify STAG2 as among the most commonly mutated genes in bladder cancer discovered to date.
PMCID: PMC3875130  PMID: 24121789
11.  A survey of authors publishing in four megajournals 
PeerJ  2014;2:e365.
Aim. To determine the characteristics of megajournal authors, the nature of the manuscripts they are submitting to these journals, factors influencing their decision to publish in a megajournal, sources of funding for article processing charges (APCs) or other fees and their likelihood of submitting to a megajournal in the future.
Methods. Web-based survey of 2,128 authors who recently published in BMJ Open, PeerJ, PLOS ONE or SAGE Open.
Results. The response rate ranged from 26% for BMJ Open to 47% for SAGE Open. The authors were international, largely academics who had recently published in both subscription and Open Access (OA) journals. Across journals about 25% of the articles were preliminary findings and just under half were resubmissions of manuscripts rejected by other journals. Editors from other BMJ journals and perhaps to a lesser extent SAGE and PLOS journals appear to be encouraging authors to submit manuscripts that were rejected by the editor’s journals to a megajournal published by the same publisher. Quality of the journal and speed of the review process were important factors across all four journals. Impact factor was important for PLOS ONE authors but less so for BMJ Open authors, which also has an impact factor. The review criteria and the fact the journal was OA were other significant factors particularly important for PeerJ authors. The reputation of the publisher was an important factor for SAGE Open and BMJ Open. About half of PLOS ONE and around a third of BMJ Open and PeerJ authors used grant funding for publishing charges while only about 10% of SAGE Open used grant funding for publication charges. Around 60% of SAGE Open and 32% of PeerJ authors self-funded their publication fees however the fees are modest for these journals. The majority of authors from all 4 journals were pleased with their experience and indicated they were likely to submit to the same or similar journal in the future.
Conclusions. Megajournals are drawing an international group of authors who tend to be experienced academics. They are choosing to publish in megajournals for a variety of reasons but most seem to value the quality of the journal and the speed of the review/publication process. Having a broad scope was not a key factor for most authors though being OA was important for PeerJ and SAGE Open authors. Most authors appeared pleased with the experience and indicated they are likely to submit future manuscripts to the same or similar megajournal which seems to suggest these journals will continue to grow in popularity.
PMCID: PMC4006221  PMID: 24795855
Open access; Megajournals; Survey; Authors
12.  Recovery from Multiple Episodes of Bipolar I Depression 
The Journal of clinical psychiatry  2013;74(3):10.4088/JCP.12m08049.
To describe the duration of bipolar I major and minor depressive episodes and factors associated with time to recovery.
219 participants with bipolar I disorder based on Research Diagnostic Criteria analogs to DSM-IV-TR criteria were recruited from 1978–1981 and followed for up to 25 years. Psychopathology was assessed with the Longitudinal Interval Follow-up Evaluation. The probability of recovery over time from multiple successive depressive episodes was examined with survival analytic techniques, including mixed-effects grouped-time survival models.
The median duration of major depressive episodes was 14 weeks, and over 70% recovered within 12 months of onset of the episode. The median duration of minor depressive episodes was 8 weeks, and approximately 90% recovered within 6 months of onset of the episode. Aggregated data demonstrated similar durations of the first three major depressive episodes. However, for each participant with multiple episodes of major depression or minor depression, the duration of each episode was not consistent (intraclass correlation coefficient=0.07 and 0.25 for major and minor depression, respectively). The total number of years in episode over follow-up with major plus minor depression prior to onset of a major depressive episode was significantly associated with a decreased probability of recovery from that episode; with each additional year, the likelihood of recovery was reduced by 7% (hazard ratio: 0.93, 95% CI: 0.89–0.98, p=0.002).
Bipolar I major depression generally lasts longer than minor depression, and the duration of multiple episodes within an individual varies. However, the probability of recovery over time from an episode of major depression appears to decline with each successive episode.
PMCID: PMC3837577  PMID: 23561241
13.  Using cloud-based mobile technology for assessment of competencies among medical students 
PeerJ  2013;1:e164.
Valid, direct observation of medical student competency in clinical settings remains challenging and limits the opportunity to promote performance-based student advancement. The rationale for direct observation is to ascertain that students have acquired the core clinical competencies needed to care for patients. Too often student observation results in highly variable evaluations which are skewed by factors other than the student’s actual performance. Among the barriers to effective direct observation and assessment include the lack of effective tools and strategies for assuring that transparent standards are used for judging clinical competency in authentic clinical settings. We developed a web-based content management system under the name, Just in Time Medicine (JIT), to address many of these issues. The goals of JIT were fourfold: First, to create a self-service interface allowing faculty with average computing skills to author customizable content and criterion-based assessment tools displayable on internet enabled devices, including mobile devices; second, to create an assessment and feedback tool capable of capturing learner progress related to hundreds of clinical skills; third, to enable easy access and utilization of these tools by faculty for learner assessment in authentic clinical settings as a means of just in time faculty development; fourth, to create a permanent record of the trainees’ observed skills useful for both learner and program evaluation. From July 2010 through October 2012, we implemented a JIT enabled clinical evaluation exercise (CEX) among 367 third year internal medicine students. Observers (attending physicians and residents) performed CEX assessments using JIT to guide and document their observations, record their time observing and providing feedback to the students, and their overall satisfaction. Inter-rater reliability and validity were assessed with 17 observers who viewed six videotaped student-patient encounters and by measuring the correlation between student CEX scores and their scores on subsequent standardized-patient OSCE exams. A total of 3567 CEXs were completed by 516 observers. The average number of evaluations per student was 9.7 (±1.8 SD) and the average number of CEXs completed per observer was 6.9 (±15.8 SD). Observers spent less than 10 min on 43–50% of the CEXs and 68.6% on feedback sessions. A majority of observers (92%) reported satisfaction with the CEX. Inter-rater reliability was measured at 0.69 among all observers viewing the videotapes and these ratings adequately discriminated competent from non-competent performance. The measured CEX grades correlated with subsequent student performance on an end-of-year OSCE. We conclude that the use of JIT is feasible in capturing discrete clinical performance data with a high degree of user satisfaction. Our embedded checklists had adequate inter-rater reliability and concurrent and predictive validity.
PMCID: PMC3792179  PMID: 24109549
Educational technology; Educational measurement; Medical students; Smart phones; Competency based assessment; Direct observation; Medical faculty; Clinical competence; iPhone; miniCEX
14.  Course of illness following prospectively observed mania or hypomania in individuals presenting with unipolar depression 
Bipolar disorders  2012;14(6):664-671.
In a well-defined sample, we sought to determine what clinical variables, some of potential nosological relevance, influence subsequent course following prospectively observed initial episodes of hypomania or mania (H/M).
We identified 108 individuals in the National Institute of Mental Health Collaborative Depression Study diagnosed with unipolar major depression at intake who subsequently developed H/M. We assessed time to repeat H/M based on whether one had been started on an antidepressant or electroconvulsive therapy within eight weeks of developing H/M, had longer episodes, or had a family history of bipolar disorder.
Modeling age of onset, treatment-associated H/M, family history of bipolar disorder, duration of index H/M episode, and psychosis in Cox regression analysis, family history of bipolar disorder (n = 21) was strongly associated with repeat episodes of H/M [hazard ratio (HR) = 2.01, 95% confidence interval (CI): 1.06–3.83, p = 0.03]. Those with treatment-associated episodes (n = 12) were less likely to experience subsequent episodes of H/M, though this was not significant in the multivariate model (HR = 0.25, 95% CI: 0.06–1.05, p = 0.06). These individuals also had a later age of onset for affective illness and were more likely to be depressed. Duration of illness with a temporal resolution of one week, psychosis, and age of onset were not associated with time to repeat H/M episode.
Family history of bipolar disorder influences course of illness even after an initial H/M episode. In this select sample, treatment-associated H/M did not appear to convey the same risk for a course of illness characterized by recurrent H/M episodes.
PMCID: PMC3432672  PMID: 22816725
bipolar disorder; depressive disorder; antidepressants; prospective studies
15.  Sample Type Bias in the Analysis of Cancer Genomes 
Cancer research  2009;69(14):5630-5633.
There is widespread agreement that cancer gene discovery requires high-quality tumor samples. However, whether primary tumors or cultured samples are superior for cancer genomics has been a longstanding subject of debate. This debate has recently become more important because federally funded cancer genomics has been centralized under The Cancer Genome Atlas, which has chosen to focus exclusively on primary tumors. Here, we provide a data-driven “perspective” on the effect of sample type selection on cancer genomics research. We show that, in the case of glioblastoma multiforme, primary tumors and xenografts are best for the identification of amplifications, whereas xenografts and cell lines are superior for the identification of homozygous deletions. We also note that many of the most important oncogenes and tumor suppressor genes have been discovered through the use of cell lines and xenografts, and highlight the lack of published evidence supporting the dogma that ex vivo culture generates artifactual genetic lesions. Based on this analysis, we suggest that cancer genomics projects such as The Cancer Genome Atlas should include a variety of sample types such as xenografts and cell lines in their integrated genomic analysis of cancer.
PMCID: PMC3690469  PMID: 19567670
16.  A randomized, placebo-controlled trial of risperidone augmentation for patients with difficult-to-treat unipolar, non-psychotic major depression 
Journal of psychiatric research  2008;43(3):205-214.
Patients (30–50%) with non-psychotic major depression will not respond despite an adequate trial of antidepressant medication. This study evaluated risperidone as an augmenting agent for patients who failed or only partially responded to an adequate trial of an antidepressant medication.
Ninety-seven patients with unipolar non-psychotic major depression who were not responsive to antidepressant monotherapy were randomized to risperidone (0.5–3 mg/day) or placebo augmentation in a four-week, double-blind, placebo controlled treatment trial. The primary outcome measure was remission defined by a score of ≤10 on the Montgomery–Asberg Depression Rating Scale (MADRS). Secondary outcomes measures were the Hamilton Rating Scale for Depression, the Clinician Global Impression of Severity scale and the overall satisfaction item of the Quality of Life and Enjoyment Questionnaire.
Subjects in both treatment groups improved significantly over time. The odds of remitting were significantly better for patients in the risperidone vs. placebo arm (OR = 3.33, p = .011). At the end of 4 weeks of treatment 52% of the risperidone augmentation group remitted (MADRS ≤ 10) compared to 24% of the placebo augmentation group (CMH(1) = 6.48, p = .011), but the two groups were converging. Patients in the risperidone group also reported significantly more improvement in quality-of-life than patients in the placebo group. There were no between-group differences in the number of adverse events reported, however, weight gain was significantly higher in the group receiving risperidone.
Augmentation of an antidepressant with risperidone for patients with difficult-to-treat depression leads to more rapid response and a higher remission rate and better quality-of-life.
PMCID: PMC3685867  PMID: 18586273
Antidepressants; Antipsychotic; Clinical drug studies; Mood disorders – unipolar
17.  Longitudinal Course of Bipolar I Disorder 
Archives of general psychiatry  2010;67(4):339-347.
The phenomenology of bipolar I disorder affects treatment and prognosis.
To describe the duration of bipolar I mood episodes and factors associated with recovery from these episodes.
Subjects with Research Diagnostic Criteria bipolar I disorder were prospectively followed up for as long as 25 years. The probability of recovery over time from multiple successive mood episodes was examined with survival analytic techniques, including a mixed-effects grouped-time survival model.
Five US academic medical centers.
Two hundred nineteen subjects with bipolar I disorder.
Main Outcome Measures
Level of psychopathology was assessed with the Longitudinal Interval Follow-up Evaluation every 6 months for the first 5 years of follow-up and annually thereafter.
The median duration of bipolar I mood episodes was 13 weeks. More than 75% of the subjects recovered from their mood episodes within 1 year of onset. The probability of recovery was significantly less for an episode with severe onset (psychosis or severe psychosocial impairment in week 1 of the episode) (hazard ratio [HR]=0.746; 95% confidence interval [CI], 0.578–0.963; P=.02) and for subjects with greater cumulative morbidity (total number of years spent ill with any mood episode) (HR=0.917; 95% CI, 0.886–0.948; P<.001). Compared with the probability of recovery from a major depressive episode, there was a significantly greater probability of recovery from an episode of mania (HR=1.713; 95% CI, 1.373–2.137; P<.001), hypomania (HR=4.502; 95% CI, 3.466–5.849; P<.001), or minor depression (HR = 2.027; 95% CI, 1.622–2.534; P<.001) and, conversely, a significantly reduced probability of recovery from a cycling episode (switching from one pole to the other without an intervening period of recovery) (HR=0.438; 95% CI, 0.351–0.548; P<.001).
The median duration of bipolar I mood episodes was 13 weeks, and the probability of recovery was significantly decreased for cycling episodes, mood episodes with severe onset, and subjects with greater cumulative morbidity.
PMCID: PMC3677763  PMID: 20368510
18.  Prevalence and clinical significance of subsyndromal manic symptoms, including irritability and psychomotor agitation, during bipolar major depressive episodes 
Journal of affective disorders  2012;138(3):440-448.
There is increasing evidence that subsyndromal manic symptoms occur frequently during bipolar major depressive episodes (MDEs) and may be a subtle form of ‘depressive mixed state.’ This paper examines the prevalence and clinical characteristics of MDEs with subsyndromal manic symptoms. The specific effects of overt irritability and psychomotor agitation are examined.
Bipolar (type I or II) patients with an MDE at intake (N=142) were compared based on the presence or absence of concurrent subsyndromal manic symptoms. The groups were further subdivided by the presence of symptoms of overt irritability and/or psychomotor agitation.
Subsyndromal manic symptoms during bipolar MDEs were highly prevalent (76.1%), and were associated with significantly increased severity of depression/dysphoria in the intake episode, longer episode duration, and more suicidal ideation and behavior (past, current, and during long-term follow-up). Overt irritability and psychomotor agitation were the most prevalent subsyndromal manic symptoms (co-occurring in 57% and 39% of MDEs, respectively), and accounted for most of the negative effects associated with subsyndromal manic symptoms.
The findings need to be confirmed in larger samples, which also examine the relationship to adequate antidepressant and/or mood stabilizing treatment.
The presence of one or more subsyndromal manic symptoms appears to be the modal presentation of bipolar MDEs and a marker for a subtle form of bipolar mixed depressive state. In particular, patients with symptoms of overt irritability and/or psychomotor agitation should be monitored closely to avoid serious clinical outcomes such as longer affective episodes, exacerbation of manic symptoms syndromal mania, and heightened suicidality.
PMCID: PMC3677770  PMID: 22314261
Bipolar; Major depressive episodes; Subsyndromal manic symptoms; Irritability; Psychomotor agitation
19.  Effects of anxiety on the long-term course of depressive disorders† 
The British Journal of Psychiatry  2012;200(3):210-215.
It is well established that the presence of prominent anxiety within depressive episodes portends poorer outcomes. Important questions remain as to which anxiety features are important to outcome and how sustained their prognostic effects are over time.
To examine the relative prognostic importance of specific anxiety features and to determine whether their effects persist over decades and apply to both unipolar and bipolar conditions.
Participants with unipolar (n = 476) or bipolar (n = 335) depressive disorders were intensively followed for a mean of 16.7 years (s.d. = 8.5).
The number and severity of anxiety symptoms, but not the presence of pre-existing anxiety disorders, showed a robust and continuous relationship to the subsequent time spent in depressive episodes in both unipolar and bipolar depressive disorder. The strength of this relationship changed little over five successive 5-year periods.
The severity of current anxiety symptoms within depressive episodes correlates strongly with the persistence of subsequent depressive symptoms and this relationship is stable over decades.
PMCID: PMC3290796  PMID: 21984801
20.  Anxiety and Outcome in Bipolar Disorder 
The American journal of psychiatry  2009;166(11):1238-1243.
PMCID: PMC3551283  PMID: 19797434
anxiety; bipolar disorder; symptom persistence
21.  Age Transitions in the Course of Bipolar I Disorder 
Psychological medicine  2009;39(8):1247-1252.
This analysis aimed to show whether symptoms of either pole change in their persistence as individuals move through two decades, whether such changes differ by age-grouping, and whether age of onset plays an independent role in symptom persistence.
Participants in the NIMH Collaborative Depression Study who completed at least twenty years of follow-up and who met study criteria for bipolar I or schizoaffective manic disorder, before intake or during follow-up, were divided by age at intake into youngest (18–29 years, n = 56), middle (30–44 years, n = 68) and oldest (greater than 44 years, n = 24) groups.
The persistence of depressive symptoms increased significantly in the two younger groups. Earlier ages of onset were associated with higher depressive morbidity throughout the twenty years of follow-up but did not predict changes in symptom persistence. The proportions of weeks spent in episodes of either pole correlated across follow-up periods in all age groupings, though correlations were stronger for depressive symptoms and for shorter intervals.
Regardless of age at onset, the passage of decades in bipolar illness appears to bring an increase in the predominance of depressive symptoms in individuals in their third, fourth and fifth decades and an earlier age of onset portends a persistently greater depressive symptom burden. The degree to which either depression or manic/hypomanic symptoms persist has significant stability over lengthy periods and appears to reflect traits that manifest early an individual’s illness.
PMCID: PMC3551474  PMID: 19335937
major depression; age periods; age of onset; symptom persistence
22.  Are students ready for meaningful use? 
Medical Education Online  2013;18:10.3402/meo.v18i0.22495.
The meaningful use (MU) of electronic medical records (EMRs) is being implemented in three stages. Key objectives of stage one include electronic analysis of data entered into structured fields, using decision-support tools (e.g., checking drug–drug interactions [DDI]) and electronic information exchange.
The authors assessed the performance of medical students on 10 stage-one MU tasks and measured the correlation between students’ MU performance and subsequent end-of-clerkship professionalism assessments and their grades on an end-of-year objective structured clinical examination.
Two-hundred and twenty-two third-year medical students on the internal medicine (IM) clerkship.
Design/main measures
From July 2010 to February 2012, all students viewed 15 online tutorials covering MU competencies. The authors measured student MU documentation and performance in the chart of a virtual patient using a fully functional training EMR. Specific MU measurements included, adding: a new problem, a new medication, an advanced directive, smoking status, the results of screening tests; and performing a DDI (in which a major interaction was probable), and communicating a plan for this interaction.
Key results
A total of 130 MU errors were identified. Sixty-eight (30.6%) students had at least one error, and 30 (13.5%) had more than one (range 2–6). Of the 130 errors, 90 (69.2%) were errors in structured data entry. Errors occurred in medication dosing and instructions (18%), DDI identification (12%), documenting smoking status (15%), and colonoscopy results (23%). Students with MU errors demonstrated poorer performance on end-of-clerkship professionalism assessments (r =−0.112, p=0.048) and lower observed structured clinical examination (OSCE) history-taking skills (r =−0.165, p=0.008) and communication scores (r= − 0.173, p=0.006).
MU errors among medical students are common and correlate with subsequent poor performance in multiple educational domains. These results indicate that without assessment and feedback, a substantial minority of students may not be ready to progress to more advanced MU tasks.
PMCID: PMC3835789  PMID: 24256741
documentation/methods; electronic health records; professional competence; students; medical; curriculum
23.  Does Major Depressive Disorder Change with Age? 
Psychological medicine  2009;39(10):1689-1695.
The authors used results from a twenty-year, high-intensity follow-up to measure the influence of aging, and of age at onset, on the long-term persistence of symptoms in major depressive disorder (MDD).
Subjects who completed a 20-year series of semi-annual and then annual assessments with a stable diagnosis of MDD, or schizoaffective disorder other than mainly schizophrenic, (n = 220), were divided according to their ages at intake into youngest (18–29 years), middle (30–44 years), and oldest (≥45 years) groups. Depressive morbidity was quantified as the proportion of weeks spent in major depressive or schizoaffective episodes. General linear models (GLM) then tested for effects of time and time-by-group interactions on these measures. Regression analyses compared the influence of age of onset and of current age.
Analyses revealed no significant time or group-by-time effects on the proportions of weeks in major depressive episodes in any of three age groups. Earlier ages of onset were associated with greater symptom persistence, particularly in the youngest group. The proportions of weeks ill showed intra-individual stability over time that was most evident in the oldest group.
These results indicate that the persistence of depressive symptoms in MDD does not change as individuals move from their third to their fifth decade, from their fourth to their sixth decade, or from their sixth to their eighth decade. An early age of onset, rather than youth per se, is associated with greater morbidity over two decades.
PMCID: PMC3533492  PMID: 19296865
major depression; age periods; age of onset; symptom persistence
24.  Open access versus subscription journals: a comparison of scientific impact 
BMC Medicine  2012;10:73.
In the past few years there has been an ongoing debate as to whether the proliferation of open access (OA) publishing would damage the peer review system and put the quality of scientific journal publishing at risk. Our aim was to inform this debate by comparing the scientific impact of OA journals with subscription journals, controlling for journal age, the country of the publisher, discipline and (for OA publishers) their business model.
The 2-year impact factors (the average number of citations to the articles in a journal) were used as a proxy for scientific impact. The Directory of Open Access Journals (DOAJ) was used to identify OA journals as well as their business model. Journal age and discipline were obtained from the Ulrich's periodicals directory. Comparisons were performed on the journal level as well as on the article level where the results were weighted by the number of articles published in a journal. A total of 610 OA journals were compared with 7,609 subscription journals using Web of Science citation data while an overlapping set of 1,327 OA journals were compared with 11,124 subscription journals using Scopus data.
Overall, average citation rates, both unweighted and weighted for the number of articles per journal, were about 30% higher for subscription journals. However, after controlling for discipline (medicine and health versus other), age of the journal (three time periods) and the location of the publisher (four largest publishing countries versus other countries) the differences largely disappeared in most subcategories except for journals that had been launched prior to 1996. OA journals that fund publishing with article processing charges (APCs) are on average cited more than other OA journals. In medicine and health, OA journals founded in the last 10 years are receiving about as many citations as subscription journals launched during the same period.
Our results indicate that OA journals indexed in Web of Science and/or Scopus are approaching the same scientific impact and quality as subscription journals, particularly in biomedicine and for journals funded by article processing charges.
PMCID: PMC3398850  PMID: 22805105
impact; open access; peer review; scientific publishing
25.  Mutational Inactivation of STAG2 Causes Aneuploidy in Human Cancer 
Science (New York, N.y.)  2011;333(6045):1039-1043.
Most cancer cells are characterized by aneuploidy, an abnormal number of chromosomes. We have identified a clue to the mechanistic origins of aneuploidy through integrative genomic analyses of human tumors. A diverse range of tumor types were found to harbor deletions or inactivating mutations of STAG2, a gene encoding a subunit of the cohesin complex, which regulates the separation of sister chromatids during cell division. Because STAG2 is on the X chromosome, its inactivation requires only a single mutational event. Studying a near-diploid human cell line with a stable karyotype, we found that targeted inactivation of STAG2 led to chromatid cohesion defects and aneuploidy, whereas in two aneuploid human glioblastoma cell lines, targeted correction of the endogenous mutant alleles of STAG2 led to enhanced chromosomal stability. Thus, genetic disruption of cohesin is a cause of aneuploidy in human cancer.
PMCID: PMC3374335  PMID: 21852505

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