Optimality of broken extremals

In this paper we analyse the optimality of broken Pontryagin extremal for an n-dimensional affine control system with a control parameter, taking values in a k- dimensional closed ball. We prove the optimality of broken normal extremals when n = 3 and the controllable vector fields form a contact distribution, and when the Lie algebra of the controllable fields is locally orthogonal to the singular locus and the drift does not belong to it. Moreover, if k = 2, we show the optimality of any broken extremal even abnormal when the controllable fields do not form a contact distribution in the point of singularity.Comment: arXiv admin note: text overlap with arXiv:1610.0675

Psychometric evaluation of the Swedish Traumatic Grief Inventory Self-Report Plus (TGI-SR+) in bereaved parents

The International Classification of Diseases Eleventh Edition (ICD-11), and the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR), now include prolonged grief disorder (PGD). Since criteria for PGD in both classification systems differ from prior proposed grief disorders and each other, the validation of a single instrument to screen for prolonged grief (PG) symptoms of both new diagnoses is critical for bereavement research and care. Therefore, we evaluated the psychometric properties of the Swedish version of the Traumatic Grief Inventory Self-Report Plus (TGI-SR+). Two-hundred and forty-eight bereaved parents completed questions about sociodemographic and loss-related variables, the TGI-SR+, and symptom measures of post-traumatic stress (PTS), depression and an older measure of PG symptoms, the Prolonged Grief Disorder-13 (PG-13). Confirmatory factor analyses showed that a one-factor model best fit DSM-5-TR and ICD-11 PG symptoms and the analyses of the internal consistency and inter-item correlations showed that these symptoms could be reliably assessed. In support of convergent validity, DSM-5-TR and ICD-11 PG symptoms correlated with symptoms of PTS, depression and PG assessed with the PG-13. In support of known-groups validity, DSM-5-TR and ICD-11 PG symptoms were higher among lower educated (vs. higher educated) participants and related negatively to time since loss. ROC analyses showed optimal cut-off score of ≥71 and ≥72 to determine probable caseness for DSM-5-TR and ICD-11 PGD, respectively. Results support the reliability and validity of the Swedish TGI-SR+ as a screening instrument for PG in research and bereavement care.</p

Transcriptome instability in colorectal cancer identified by exon microarray analyses: Associations with splicing factor expression levels and patient survival

Background Colorectal cancer (CRC) is a heterogeneous disease that, on the molecular level, can be characterized by inherent genomic instabilities; chromosome instability and microsatellite instability. In the present study we analyze genome-wide disruption of pre-mRNA splicing, and propose transcriptome instability as a characteristic that is analogous to genomic instability on the transcriptome level. Methods Exon microarray profiles from two independent series including a total of 160 CRCs were investigated for their relative amounts of exon usage differences. Each exon in each sample was assigned an alternative splicing score calculated by the FIRMA algorithm. Amounts of deviating exon usage per sample were derived from exons with extreme splicing scores. Results There was great heterogeneity within both series in terms of sample-wise amounts of deviating exon usage. This was strongly associated with the expression levels of approximately half of 280 splicing factors (54% and 48% of splicing factors were significantly correlated to deviating exon usage amounts in the two series). Samples with high or low amounts of deviating exon usage, associated with overall transcriptome instability, were almost completely separated into their respective groups by hierarchical clustering analysis of splicing factor expression levels in both sample series. Samples showing a preferential tendency towards deviating exon skipping or inclusion were associated with skewed transcriptome instability. There were significant associations between transcriptome instability and reduced patient survival in both sample series. In the test series, patients with skewed transcriptome instability showed the strongest prognostic association (P = 0.001), while a combination of the two characteristics showed the strongest association with poor survival in the validation series (P = 0.03). Conclusions We have described transcriptome instability as a characteristic of CRC. This transcriptome instability has associations with splicing factor expression levels and poor patient survival

Diagnostic Utility of the Impact of Event Scale-Revised in Two Samples of Survivors of War

The study aimed at examining the diagnostic utility of the Impact of Event Scale-Revised (IES-R) as a screening tool for post-traumatic stress disorder (PTSD) in survivors of war. The IES-R was completed by two independent samples that had survived the war in the Balkans: a sample of randomly selected people who had stayed in the area of former conflict (n = 3,313) and a sample of refugees to Western European countries (n = 854). PTSD was diagnosed using the MINI International Neuropsychiatric Interview. Prevalence of PTSD was 20.1% in the Balkan sample and 33.1% in the refugee sample. Results revealed that when considering a minimum value of specificity of 0.80, the optimally sensitive cut-off score for screening for PTSD in the Balkan sample was 34. In both the Balkan sample and the refugee sample, this cut-off score provided good values on sensitivity (0.86 and 0.89, respectively) and overall efficiency (0.81 and 0.79, respectively). Further, the kappa coefficients for sensitivity for the cut-off of 34 were 0.80 in both samples. Findings of this study support the clinical utility of the IES-R as a screening tool for PTSD in large-scale research studies and intervention studies if structured diagnostic interviews are regarded as too labor-intensive and too costly

Relative contribution of clinicopathological variables, genomic markers, transcriptomic subtyping and microenvironment features for outcome prediction in stage II/III colorectal cancer

Background: It remains unknown to what extent consensus molecular subtype (CMS) groups and immune-stromal infiltration patterns improve our ability to predict outcomes over tumor-node-metastasis (TNM) staging and microsatellite instability (MSI) status in early-stage colorectal cancer (CRC). Patients and methods: We carried out a comprehensive retrospective biomarker analysis of prognostic markers in adjuvant chemotherapy-untreated (N = 1656) and treated (N = 980), stage II (N = 1799) and III (N = 837) CRCs. We defined CMS scores and estimated CD8+ cytotoxic lymphocytes (CytoLym) and cancer-associated fibroblasts (CAF) infiltration scores from bulk tumor tissue transcriptomes (CMSclassifier and MCPcounter R packages); constructed a stratified multivariable Cox model for disease-free survival (DFS); and calculated the relative proportion of explained variation by each marker (clinicopathological [ClinPath], genomics [Gen: MSI, BRAF and KRAS mutations], CMS scores [CMS] and microenvironment cells [MicroCells: CytoLym+CAF]). Results: In multivariable models, only ClinPath and MicroCells remained significant prognostic factors, with both CytoLym and CAF infiltration scores improving survival prediction beyond other markers. The explained variation for DFS models of ClinPath, MicroCells, Gen markers and CMS4 scores was 77%, 14%, 5.3% and 3.7%, respectively, in stage II; and 55.9%, 35.1%, 4.1% and 0.9%, respectively, in stage III. Patients whose tumors were CytoLym high/CAF low had better DFS than other strata [HR=0.71 (0.6-0.9); P = 0.004]. Microsatellite stable tumors had the strongest signal for improved outcomes with CytoLym high scores (interaction P = 0.04) and the poor prognosis linked to high CAF scores was limited to stage III disease (interaction P = 0.04). Conclusions: Our results confirm that tumor microenvironment infiltration patterns represent potent determinants of the risk for distant dissemination in early-stage CRC. Multivariable models suggest that the prognostic value of MSI and CMS groups is largely explained by CytoLym and CAF infiltration patterns

Construct dimensionality and properties of the categories in the ICF Core Set for low back pain

Objective: The aim of this study was to explore by Rasch analysis whether the Comprehensive International Classification of Functioning, Disability and Health (ICF) Core Set might represent a future clinical tool for measuring functioning of patients with low back pain. Material and methods: The Comprehensive ICF Core Set for low back pain was scored by health professionals for 118 patients with low back pain. Qualifier levels, invariance, construct validity and ordering of the categories in the components of Body function, Body structure, Activities and participation and Environmental factors were explored by Rasch analysis. Results: The number of qualifier levels had to be reduced. Categories within Body functions and within Environmental factors reflected a single underlying construct. The categories within the component of Activities and Participation did not meet the requirements of a single underlying construct in the present population. Few categories covered the problems reported by patients with a relatively high level of function.Conclusion: Rasch analysis indicated that the Comprehensive ICF Core Set for low back pain may be used with some modification of categories as a common tool for assessing problems within the components Body functions, and Activity and Participation. However, detecting ICF categories that reflect the higher functional levels in patients with low back pain, and revision of the qualifier levels may be necessary

The effects of a dialogue-based intervention to promote psychosocial well-being after stroke: a randomized controlled trial

Objective: To evaluate the effect of a dialogue-based intervention targeting psychosocial well-being at 12 months post-stroke. Design: Multicenter, prospective, randomized, assessor-blinded, controlled trial with two parallel groups. Setting: Community. Subjects: Three-hundred and twenty-two adults (⩾18 years) with stroke within the last four weeks were randomly allocated into intervention group (n = 166) or control group (n = 156). Interventions: The intervention group received a dialogue-based intervention to promote psychosocial well-being, comprising eight individual 1–1½ hour sessions delivered during the first six months post-stroke. Main measures: The primary outcome measure was the General Health Questionnaire-28 (GHQ-28). Secondary outcome measures included the Stroke and Aphasia Quality of Life Scale-39g, the Sense of Coherence scale, and the Yale Brown single-item questionnaire. Results: The mean (SD) age of the participants was 66.8 (12.1) years in the intervention group and 65.7 (13.3) years in the control group. At 12 months post-stroke, the mean (SE) GHQ-28 score was 20.6 (0.84) in the intervention group and 19.9 (0.85) in the control group. There were no between-group differences in psychosocial well-being at 12 months post-stroke (mean difference: −0.74, 95% confidence interval (CI): −3.08, 1.60). The secondary outcomes showed no statistically significant between-group difference in health-related quality of life, sense of coherence, or depression at 12 months. Conclusion: The results of this trial did not demonstrate lower levels of emotional distress and anxiety or higher levels of health-related quality of life in the intervention group (dialogue-based intervention) as compared to the control group (usual care) at 12 months post-stroke

Colorectal Cancer Consensus Molecular Subtypes Translated to Preclinical Models Uncover Potentially Targetable Cancer Cell Dependencies

Purpose: Response to standard oncologic treatment is limited in colorectal cancer. The gene expression-based consensus molecular subtypes (CMS) provide a new paradigm for stratified treatment and drug repurposing; however, drug discovery is currently limited by the lack of translation of CMS to preclinical models. Experimental Design: We analyzed CMS in primary colorectal cancers, cell lines, and patient-derived xenografts (PDX). For classification of preclinical models, we developed an optimized classifier enriched for cancer cell-intrinsic gene expression signals, and performed high-throughput in vitro drug screening (n = 459 drugs) to analyze subtype-specific drug sensitivities. Results: The distinct molecular and clinicopathologic characteristics of each CMS group were validated in a single-hospital series of 409 primary colorectal cancers. The new, cancer cell-adapted classifier was found to perform well in primary tumors, and applied to a panel of 148 cell lines and 32 PDXs, these colorectal cancer models were shown to recapitulate the biology of the CMS groups. Drug screening of 33 cell lines demonstrated subtype-dependent response profiles, confirming strong response to EGFR and HER2 inhibitors in the CMS2 epithelial/canonical group, and revealing strong sensitivity to HSP90 inhibitors in cells with the CMS1 microsatellite instability/immune and CMS4 mesenchymal phenotypes. This association was validated in vitro in additional CMS-predicted cell lines. Combination treatment with 5-fluorouracil and luminespib showed potential to alleviate chemoresistance in a CMS4 PDX model, an effect not seen in a chemosensitive CMS2 PDX model. Conclusions: We provide translation of CMS classification to preclinical models and uncover a potential for targeted treatment repurposing in the chemoresistant CMS4 group. (C) 2017 AACR.Peer reviewe