Impact of Comorbid Personality Disorders on Depression Treatment in Routine Outpatient Care

Item does not contain fulltextObjective: The impact of personality disorder on treatment effectiveness for depression has been debated, and study results have been inconsistent. However, studies that report a negative impact of personality disorders on depression treatment outcomes are often characterized by uncontrolled treatment designs. Within such contexts, individuals with depression and personality disorders are at risk to receive suboptimal treatment. The aim of this retrospective observational study was to investigate whether and to what extent comorbid personality disorders were associated with the type and amount of depression treatment received in routine outpatient care. Methods: Retrospectively extracted data from electronic records of 1,455 outpatients treated for depression at several sites of a nationwide mental health provider in the Netherlands were included. The type and number of treatment sessions and visits were analyzed by using regression models. Results: Individuals with depression and comorbid personality disorders received more psychotherapy sessions than individuals without personality disorders, irrespective of depression severity. The number of pharmacotherapy sessions and supportive and crisis visits did not differ between individuals with and without comorbid personality disorders. Conclusions: Individuals with depression and personality disorders received more intensive treatment than individuals without comorbid personality disorders. These results conflict with treatment guidelines and recommendations from high-quality studies and may be indicative of overtreatment among this large group of patients.7 p

Target actionability review to evaluate CDK4/6 as a therapeutic target in paediatric solid and brain tumours

BACKGROUND: Childhood cancer is still a leading cause of death around the world. To improve outcomes, there is an urgent need for tailored treatment. The systematic evaluation of existing preclinical data can provide an overview of what is known and identify gaps in the current knowledge. Here, we applied the target actionability review (TAR) methodology to assess the strength and weaknesses of available scientific literature on CDK4/6 as a therapeutic target in paediatric solid and brain tumours by structured critical appraisal. METHODS: Using relevant search terms in PubMed, a list of original publications investigating CDK4/6 in paediatric solid tumour types was identified based on relevancy criteria. Each publication was annotated for the tumour type and categorised into separate proof-of-concept (PoC) data modules. Based on rubrics, quality and experimental outcomes were scored independently by two reviewers. A third reviewer evaluated and adjudicated score discrepancies. Scores for each PoC module were averaged for each tumour type and visualised in a heatmap matrix in the publicly available R2 data portal. RESULTS AND CONCLUSIONS: This CDK4/6 TAR, generated by analysis of 151 data entries from 71 publications, showed frequent genomic aberrations of CDK4/6 in rhabdomyosarcoma, osteosarcoma, high-grade glioma, medulloblastoma, and neuroblastoma. However, a clear correlation between CDK4/6 aberrations and compound efficacy is not coming forth from the literature. Our analysis indicates that several paediatric indications would need (further) preclinical evaluation to allow for better recommendations, especially regarding the dependence of tumours on CDK4/6, predictive biomarkers, resistance mechanisms, and combination strategies. Nevertheless, our TAR heatmap provides support for the relevance of CDK4/6 inhibition in Ewing sarcoma, medulloblastoma, malignant peripheral nerve sheath tumour and to a lesser extent neuroblastoma, rhabdomyosarcoma, rhabdoid tumour and high-grade glioma. The interactive heatmap is accessible through R2 [r2platform.com/TAR/CDK4_6]

Defects in 8-oxo-guanine repair pathway cause high frequency of C > A substitutions in neuroblastoma

Neuroblastomas are childhood tumors with frequent fatal relapses after induction treatment, which is related to tumor evolution with additional genomic events. Our whole-genome sequencing data analysis revealed a high frequency of somatic cytosine > adenine (C > A) substitutions in primary neuroblastoma tumors, which was associated with poor survival. We showed that increased levels of C > A substitutions correlate with copy number loss (CNL) of OGG1 or MUTYH. Both genes encode DNA glycosylases that recognize 8-oxo-guanine (8-oxoG) lesions as a first step of 8-oxoG repair. Tumor organoid models with CNL of OGG1 or MUTYH show increased 8-oxoG levels compared to wild-type cells. We used CRISPR-Cas9 genome editing to create knockout clones of MUTYH and OGG1 in neuroblastoma cells. Whole-genome sequencing of single-cell OGG1 and MUTYH knockout clones identified an increased accumulation of C > A substitutions. Mutational signature analysis of these OGG1 and MUTYH knockout clones revealed enrichment for C > A signatures 18 and 36, respectively. Clustering analysis showed that the knockout clones group together with tumors containing OGG1 or MUTYH CNL. In conclusion, we demonstrate that defects in 8-oxoG repair cause accumulation of C > A substitutions in neuroblastoma, which contributes to mutagenesis and tumor evolution

Riociguat treatment in patients with chronic thromboembolic pulmonary hypertension: Final safety data from the EXPERT registry

Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase

Integrating clinical and genetic observations in facioscapulohumeral muscular dystrophy

Functional Genomics of Muscle, Nerve and Brain Disorder

Predicting clinical course in major depressive disorder: The association between DM-TRD score and symptom severity over time in 1115 outpatients

Item does not contain fulltextBackground: The Dutch Measure for Quantification of Treatment Resistance in Depression (DM-TRD) is a promising prediction tool for major depressive disorder (MDD) based on variables associated with treatment outcome. The objective of our study was to examine the association between the DM-TRD and clinical course in a large cohort of MDD outpatients receiving treatment as usual. Furthermore, we examined whether the addition of an item measuring the presence of childhood adversity improved this association. Methods: We included 1115 subjects with MDD (according to the DSM-IV) who were naturalistically treated at seven outpatient departments of a secondary mental healthcare center in the Netherlands. Data on subjects who had a diagnostic work-up between June 2014 and June 2016 were analyzed. Multilevel analyses were performed to examine the association between the DM-TRD score at baseline and clinical course, defined by symptom severity according to scores on the Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR) over time. We also investigated whether an extra item measuring childhood adversity improved the model. Results: The model including the DM-TRD and its interaction with time was superior to previous models. The addition of childhood adversity and its interaction with time did not improve the model. Conclusions: In depressed outpatients receiving treatment as usual, the solid longer-term association between higher DM-TRD scores and worse clinical course supports its usefulness in clinical practice. Childhood adversity did not improve the model value indicating that - counterintuitively - this parameter offers no additional predictive power to the variables included.8 p

The Cowl - v.82 - n.4 - Sep 28, 2017

The Cowl - student newspaper of Providence College. Volume 82, Number 4 - September 28, 2017. 24 pages

Fusion of hIgG1-Fc to In-111-anti-amyloid single domain antibody fragment VHH-pa2H prolongs blood residential time in APP/PS1 mice but does not increase brain uptake

Functional Genomics of Muscle, Nerve and Brain Disorder

Double SMCHD1 variants in FSHD2: the synergistic effect of two SMCHD1 variants on D4Z4 hypomethylation and disease penetrance in FSHD2

Functional Genomics of Muscle, Nerve and Brain Disorder