We report the identification of a recurrent, 520-kb 16p12.1 microdeletion associated with childhood developmental delay. The microdeletion was detected in 20 of 11,873 cases compared with 2 of 8,540 ...controls (P = 0.0009, OR = 7.2) and replicated in a second series of 22 of 9,254 cases compared with 6 of 6,299 controls (P = 0.028, OR = 2.5). Most deletions were inherited, with carrier parents likely to manifest neuropsychiatric phenotypes compared to non-carrier parents (P = 0.037, OR = 6). Probands were more likely to carry an additional large copy-number variant when compared to matched controls (10 of 42 cases, P = 5.7 x 10(-5), OR = 6.6). The clinical features of individuals with two mutations were distinct from and/or more severe than those of individuals carrying only the co-occurring mutation. Our data support a two-hit model in which the 16p12.1 microdeletion both predisposes to neuropsychiatric phenotypes as a single event and exacerbates neurodevelopmental phenotypes in association with other large deletions or duplications. Analysis of other microdeletions with variable expressivity indicates that this two-hit model might be more generally applicable to neuropsychiatric disease.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Abstract Background DSM-IV criteria for mania/hypomania overlap considerably. We sought to examine the utility of a model differentiating bipolar I and II disorders by weighting the presence or ...absence of psychosis during manic/hypomanic episodes as opposed to simply weighting symptom severity. Methods A set of 632 patients with a so-assigned clinical bipolar I or II disorder diagnosis contributed to the principal analyses, and a subset of 210 was included in a comparative analyses of DSM-assigned diagnoses. We also examined the impact of duration of highs on symptom patterns and the extent to which depressive episodes were psychotic or non-psychotic melancholic in type. Results There were no group differences for bipolar I and II patients (clinical or DSM groups) by age, gender, age of onset or age of formal bipolar diagnosis. Clinically assigned bipolar I patients returned higher severity scores than bipolar II patients on manic/hypomanic symptoms, but such differentiation was limited. Clinically-assigned bipolar I patients were more likely than bipolar II patients to be diagnosed with psychotic depression, and had lower rates of non-melancholic depression. Duration of highs had some impact on the phenomenology of highs, but not on the phenomenology of depression. Limitations We cannot establish the degree to which clinicians validly differentiated those with bipolar disorder, and accurately judged the lifetime presence of psychotic features and of depressive subtype differentiation. Conclusions Findings support the utility of an alternative model to DSM-IV in weighting the respective presence or absence of psychotic symptoms during highs in differentiating bipolar I and II disorders.
SUMMARYThe International Pancreas and Islet Transplant Association (IPITA), in conjunction with the Transplantation Society (TTS), convened a workshop to consider the future of pancreas and islet ...transplantation in the context of potential competing technologies that are under development, including the artificial pancreas, transplantation tolerance, xenotransplantation, encapsulation, stem cell derived beta cells, beta cell proliferation, and endogenous regeneration. Separate workgroups for each topic and then the collective group reviewed the state of the art, hurdles to application, and proposed research agenda for each therapy that would allow widespread application. Herein we present the executive summary of this workshop that focuses on obstacles to application and the research agenda to overcome them; the full length article with detailed background for each topic is published as an online supplement to Transplantation.
Trust between law enforcement officers and the communities they serve is essential to the safety of our citizens. Relationships between police and communities have, however, become increasingly ...strained, with reports of deadly events and wrongful convictions filling the television, newspapers, and the Internet. While the model of conducting internal investigations to determine blame and penalize the individuals involved has been used for years, a new paradigm to bring systemic change is increasingly being embraced by the criminal justice field. Historically used in other disciplines, sentinel event reviews have been employed to understand organizational failures. Multiple key community stakeholders gather to conduct a root cause analysis, which is an empirical approach that involves data collection to understand the systems-level causes of organizational events. The purpose of this paper is to examine the literature on sentinel event reviews in the criminal justice system, borrowing heavily from other disciplines where they are already well-established. We then examine the literature on organizational adoption, since the ultimate goal of sentinel event reviews is to lead to stronger systems that can learn from systemic mistakes and allow the dissemination of best practices to benefit both law enforcement and the individuals they serve.
Objective
To pursue the previously long‐standing but formally untested clinical view that melancholia is preferentially responsive to antidepressant medication in comparison with psychotherapy ...specifically Cognitive Behavior Therapy (CBT). Second, to determine whether a broader action antidepressant medication sequencing regimen is superior to a Selective Serotonin Reuptake Inhibitor (SSRI) alone.
Method
We sought to recruit a large sample of participants with melancholic depression for a 12‐week trial but inclusion criteria compromised recruitment and testing the second hypothesis. The first hypothesis was evaluated by comparing 18 participants receiving antidepressant medication to 11 receiving CBT. Primary study measures were the Hamilton Rating Scale for Depression (HAM‐D) and the Hamilton Endogenous Subscale (HES), rated blindly, while several secondary measures also evaluated outcome.
Results
Participants receiving medication had a superior 12‐week outcome to those receiving CBT, with significant differences present on primary measures as early as 4 weeks. At trial conclusion, the percentage improvement in HAM‐D scores was 61.1% vs. 34.4%, respectively Number Needed to Treat (NNT) = 3.7 and with those in receipt of medication returning non‐significantly higher HAM‐D responder (66.6% vs. 36.4%, NNT = 2.8) and remission (66.7% vs. 45.4%, NNT = 4.7) rates.
Conclusion
As the sample size was small and participants evidenced only moderate levels of depression severity, the study risked being underpowered and idiosyncratic. Despite the small sample, the superiority of antidepressant medication to CBT in those with a melancholic depression was distinctive in this pilot study.
Abstract Objectives Our aim was to identify the diagnostic profile of patients classified as ‘false positives’ on two bipolar screening measures; the Mood Swings Questionnaire (MSQ) and the Mood ...Disorders Questionnaire (MDQ). Methods A total of 1534 patients attending the Black Dog Institute Depression Clinic completed the MSQ-46, and a smaller subset of 852 completed the MDQ. All patients underwent clinical assessment by one or more Institute psychiatrists. Results Using clinical assignment (i.e. bipolar vs. unipolar) as the criterion measure for assessing the screening measures, the overall agreement rates were 84% for the MSQ-46 and 74% for the MDQ. Patients identified as ‘false positives’ were most likely to be clinically diagnosed as having a unipolar non-melancholic depression (37% for MSQ-46; 46% for MDQ), or a primary anxiety condition with secondary non-melancholic depression (19% for MSQ-46; 15% for MDQ). In addition, within the unipolar non-melancholic group, 46% of the MSQ-46 assigned false positives and 63% of the MDQ assigned false positives had co-morbid anxiety conditions. Conclusions These findings suggest that patients with anxiety conditions account for a significant proportion of false positive diagnoses on bipolar screening tests — a finding that should be conceded in the development and refinement of such screening measures and in clinical assessment of the possibility of a bipolar disorder.
Objectives
The aim of the study was to determine the impact of a first‐time diagnosis of bipolar disorder in patients previously generally managed as having a unipolar disorder, and to quantify the ...impact of disorder‐specific management strategies for such newly diagnosed patients over the following three months.
Methods
A total of 157 patients receiving a diagnosis of bipolar disorder for the first time by a psychiatrist at a specialist depression clinic completed a research interview and questionnaires, with 106 (68%) also completing 12‐week quantitative and qualitative evaluations. Assessing psychiatrists undertook baseline and follow‐up assessments recording management changes, reactions to the diagnosis and global changes in functioning over time.
Results
The majority of patients had a positive response to receiving a diagnosis of bipolar disorder, and most implemented a number of clinician‐suggested bipolar management strategies. Patients showed improvement on five of the six self‐report measures over the three‐month study period. Multivariate analyses quantified lamotrigine as making the most distinctive contribution to ‘improver’ status, particularly for the bipolar II disorder subset.
Conclusions
Results are encouraging in identifying a generally positive acceptance of a diagnosis of bipolar disorder, improved outcome following the introduction of diagnostic‐specific management components, and a distinctive contribution of lamotrigine to improved three‐month outcome.
Parkinson's disease is a complex heterogeneous disorder with urgent need for disease-modifying therapies. Progress in successful therapeutic approaches for PD will require an unprecedented level of ...collaboration. At a workshop hosted by Parkinson's UK and co-organized by Critical Path Institute's (C-Path) Coalition Against Major Diseases (CAMD) Consortiums, investigators from industry, academia, government and regulatory agencies agreed on the need for sharing of data to enable future success. Government agencies included EMA, FDA, NINDS/NIH and IMI (Innovative Medicines Initiative). Emerging discoveries in new biomarkers and genetic endophenotypes are contributing to our understanding of the underlying pathophysiology of PD. In parallel there is growing recognition that early intervention will be key for successful treatments aimed at disease modification. At present, there is a lack of a comprehensive understanding of disease progression and the many factors that contribute to disease progression heterogeneity. Novel therapeutic targets and trial designs that incorporate existing and new biomarkers to evaluate drug effects independently and in combination are required. The integration of robust clinical data sets is viewed as a powerful approach to hasten medical discovery and therapies, as is being realized across diverse disease conditions employing big data analytics for healthcare. The application of lessons learned from parallel efforts is critical to identify barriers and enable a viable path forward. A roadmap is presented for a regulatory, academic, industry and advocacy driven integrated initiative that aims to facilitate and streamline new drug trials and registrations in Parkinson's disease.
Abstract Background Since its introduction in DSM-III, the validity of dysthymia has been debated. Our objective is to further examine the concept of dysthymia in an outpatient sample, and explore ...whether its constituents can be meaningfully apportioned. Methods 318 patients attending the Black Dog Institute Depression Clinic were assessed by the Mini-International Neuropsychiatric Interview, and completed several self-report measures, in addition to a clinical assessment by an Institute psychiatrist. The characteristics of patients with major depressive disorder (MDD), dysthymic disorder and double depression were examined. Latent Class Analysis (LCA) and Latent Profile Analysis (LPA) were then conducted with the aim of detecting distinct classes based on depressive symptomatology and personality domains, respectively. Finally, clinicians' formulations of the study patients were examined. Results Depression groups mainly differed on parameters of severity. Although LCA and LPA analyses indicated the presence of distinct classes, these only moderately correlated with the MINI-diagnosed groups. Finally, there was evidence for considerable heterogeneity within clinicians' formulations of dysthymia. Limitations Inadequate sample numbers for various measures limited the power of the LPA and our sample was weighted to patients with a more severe depressive condition which may affect the detection of a distinct ‘dysthymic’ personality profile. Conclusions Despite employing a variety of techniques, we were unable to obtain a clear homogeneous picture of dysthymia. Rather, there was evidence for a distinct heterogeneity in clinician-derived diagnoses. These findings allude to the questionable discriminant validity of dysthymia and may encourage future research and discussion on this important topic.
PDF
