Activation of executioner caspases is a predictor of progression-free survival in glioblastoma patients: a systems medicine approach.

Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. GBM cells are highly resistant to apoptosis induced by antitumor drugs and radiotherapy resulting in cancer progression. We assessed whether a systems medicine approach, analysing the ability of tumor cells to execute apoptosis could be utilized to predict the response of GBM patients to treatment. Concentrations of the key proapoptotic proteins procaspase-3, procaspase-9, Smac and Apaf-1 and the antiapopotic protein XIAP were determined in a panel of GBM cell lines and GBM patient tumor resections. These values were used as input for APOPTO-CELL, a systems biological based mathematical model built to predict cellular susceptibility to undergo caspase activation. The modeling was capable of accurately distinguishing between GBM cells that die or survive in response to treatment with temozolomide in 10 of the 11 lines analysed. Importantly the results obtained using GBM patient samples show that APOPTO-CELL was capable of stratifying patients according to their progression-free survival times and predicted the ability of tumor cells to support caspase activation in 16 of the 21 GBM patients analysed. Calculating the susceptibility to apoptosis execution may be a potent tool in predicting GBM patient therapy responsiveness and may allow for the use of APOPTO-CELL in a clinical setting

Rates of severe complications in patients undergoing colorectal surgery for deep endometriosis-a retrospective multicenter observational study.

INTRODUCTION Surgical experience and hospital procedure volumes have been associated with the risk of severe complications in expert centers for endometriosis in France. However, little is known about other certified units in Central European countries. MATERIAL AND METHODS This retrospective observational study included 937 women who underwent surgery for colorectal endometriosis between January 2018 and January 2020 in 19 participating expert centers for endometriosis. All women underwent complete excision of colorectal endometriosis by rectal shaving, discoid or segmental resection. Postoperative severe complications were defined as grades III-IV of the Clavien-Dindo classification system including anastomotic leakage, fistula, pelvic abscess and hematoma. Surgical outcomes of centers performing less than 40 (group 1), 40-59 (group 2) and ≥60 procedures (group 3) over a period of 2 years were compared. RESULTS The overall complication rate of grade III and IV complications was 5.1% (48/937), with rates of anastomotic leakage, fistula formation, abscess and hemorrhage in segmental resection, discoid resection and rectal shaving, respectively, as follows: anastomotic leakage 3.6% (14/387), 1.4% (3/222), 0.6% (2/328); fistula formation 1.6% (6/387), 0.5% (1/222), 0.9%; (3/328); abscess 0.5% (2/387), 0% (0/222) and 0.6% (2/328); hemorrhage 2.1% (8/387), 0.9% (2/222) and 1.5% (5/328). Higher overall complication rates were observed for segmental resection (30/387, 7.8%) than for discoid (6/222, 2.7%, P = 0.015) or shaving procedures (12/328, 3.7%, P = 0.089). No significant correlation was observed between the number of procedures performed and overall complication rates (rSpearman  = -0.115; P = 0.639) with a high variability of complications in low-volume centers (group 1). However, an intergroup comparison revealed a significantly lower overall severe complication rate in group 3 than in group 2 (2.9% vs 6.9%; P = 0.017) without significant differences between other groups. CONCLUSIONS A high variability in complication rates does exist in centers with a low volume of activity. Major complications may decrease with an increase in the volume of activity but this effect cannot be generally applied to all institutions and settings

The Molecular Genetic Architecture of Self-Employment

Economic variables such as income, education, and occupation are known to affect mortality and morbidity, such as cardiovascular disease, and have also been shown to be partly heritable. However, very little is known about which genes influence economic variables, although these genes may have both a direct and an indirect effect on health. We report results from the first large-scale collaboration that studies the molecular genetic architecture of an economic variable-entrepreneurship-that was operationalized using self-employment, a widely-available proxy. Our results suggest that common SNPs when considered jointly explain about half of the narrow-sense heritability of self-employment estimated in twin data (σg2/σP2= 25%, h2= 55%). However, a meta-analysis of genome-wide association studies across sixteen studies comprising 50,627 participants did not identify genome-wide significant SNPs. 58 SNPs with p<10-5were tested in a replication sample (n = 3,271), but none replicated. Furthermore, a gene-based test shows that none of the genes that were previously suggested in the literature to influence entrepreneurship reveal significant associations. Finally, SNP-based genetic scores that use results from the meta-analysis capture less than 0.2% of the variance in self-employment in an independent sample (p≥0.039). Our results are consistent with a highly polygenic molecular genetic architecture of self-employment, with many genetic variants of small effect. Although self-employment is a multi-faceted, heavily environmentally influenced, and biologically distal trait, our results are similar to those for other genetically complex and biologically more proximate outcomes, such as height, intelligence, personality, and several diseases

The Molecular Genetic Architecture of Self-Employment

Peer reviewe

Therapieziele in der Evaluation medizinisch-psychiatrischer Rehabilitation : Effekte eines Therapieziel-Inventars sowie Zusammenhänge der Zielerreichung mit Struktur-, Prozess- und Ergebnisqualität

Sowohl die aktive BeschÃ$ftigung wie auch die Nicht-Auseinandersetzung mit Therapiezielen haben Auswirkungen auf Seiten der Patient(inn)en und auf Seiten der Psychotherapeut(inn)en. Es besteht ein groÃes Repertoire an Zielkategorisierungen das stark von den verschiedenen Therapieschulen abhÃ$ngt. In der medizinisch psychiatrischen Rehabilitation ist die Definition von Therapiezielen aufgrund des Kurzzeit-Settings und aus der Perspektive der KostentrÃ$ger relevant. Die EinfÃhrung des BIT-CP als "Zielfindungsinstrument" in der Reha-Klinik fÃr Seelische Gesundheit hat ein inhaltlich erweitertes Spektrum an Therapiezielen gebracht. Zugenommen haben insbesondere selbstbezogene Ziele und Ziele im zwischenmenschlichen Bereich. Die formale QualitÃ$t der Zielformulierung ist zwar deutlich gestiegen, nicht aber der Grad der Zielerreichung oder die Nachhaltigkeit - ÃberprÃft im Zuge katamnestischer Befragungen. WÃ$hrend es kaum ZusammenhÃ$nge zwischen der Zielerreichung und der Ausgangsbelastung gibt, geht mit einem schlechteren gesundheitlichen Status bei Entlassung eine schlechtere Zielerreichung einher. Therapieziele und der Grad ihrer Erreichung halten als einziges individuelles Ergebniskriterium einen wichtigen Platz im Indikatorensystem der ErgebnisqualitÃ$t von Rehabilitationskliniken inne.Both active discussion and non-discussion of therapeutic goals affect patients and psychotherapists as well. There is a wide range of goal categorization that strongly depends on the different schools of therapy. Due to short-term settings and from the point of view of cost bearers it is important to define therapy goals in medical-psychiatric rehabilitation. The introduction of the BIT-CP as a "goal setting tool" at the Rehabilitation Clinic for Mental Health has resulted in an extended spectrum of therapy goals with regard to contents. In particular, self-related goals and interpersonal objectives have increased. Whereas formal quality of goal setting has clearly improved, this does not apply to the degree of goal achievement or sustainability - as reviewed in a follow-up survey. While there is little correlation between goal achievement and initial strain, there is clear indication that a poor health status causes less success in achievement of goals at the time of discharge. Therapeutic goals and the fact to what extent these goals are achieved form the only individual criterion and take an essential place in the indicators' system to measure the quality of results at rehabilitation clinics.Birgit SenftAbweichender Titel laut Übersetzung der Verfasserin/des VerfassersZsfassung in engl. SpracheKlagenfurt, Alpen-Adria-Univ., Diss., 2013OeBB(VLID)241450

Level of Structural Integration and Its Association with Intersession Experiences and Outcomes: A Pilot Study

The level of structural integration (LSI), a psychodynamic/psychoanalytic concept originally developed by the Operationalized Psychodynamic Diagnosis (OPD), provides a promising empirical approach that is recognized beyond the boundaries of psychoanalysis and is highly relevant for therapy and research. The aim of our study was to investigate the intersession experiences of patients in psychotherapy with different levels of structural integration. The sample consisted of 69 inpatients who were undergoing psychotherapeutic treatment. The patients were asked to complete the German version of the Intersession Experience Questionnaire (IEQ), the short version of the OPD Structure Questionnaire (OPD-SQS) and the Brief-Symptom Inventory (BSI). LSI is associated with the situations, contents and negative emotions in the intersession experiences of patients, as well as their symptom distress over the course of therapy. Furthermore, the level of structural integration is a significant predictor of outcomes. Patients with different LSI had different intersession experiences

Development of a patient-reported outcome questionnaire for aplastic anemia and paroxysmal nocturnal hemoglobinuria (PRO-AA/PNH)

The introduction of new therapy modalities has significantly improved the outcome of aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH) patients. However, relatively little is known about the exact disease burden of AA/PNH since standardized assessments of symptoms including health-related quality of life (HRQoL) are frequently missing or inadequately designed for this rare patient group. We aimed to develop AA/PNH-specific questionnaires for self-reporting of symptoms, which could be included in electronic platforms for data collection and patient care.; By scoping review, we extracted any reported symptoms in AA/PNH and their prevalence from the literature (Phase I). Consensus rounds with patients and medical experts were conducted to identify core symptoms reported in the literature and to add missing items (Phase II). Ultimately, AA/PNH-specific patient-reported outcome (PRO) questionnaires including the selected measures were designed (Phase III).; AA symptoms from 62 and PNH symptoms from 45 observational studies were extracted from the literature. Twenty-four patients and seven medical experts identified 11 core symptoms including HRQoL issues after three consensus rounds. Significant differences in the symptom ranking of patients versus medical experts could be observed. Therefore, patient- as well as expert-centered PRO questionnaires in AA and PNH were created following the concepts of validated instruments.; The development of symptom self-reporting questionnaires for AA and PNH was feasible and the disease-specific PRO questionnaires can now be validated within a web-based workflow in a subsequent feasibility study

Prediction results.

<p>Variance explained (Nagelkerke pseudo-<i>R</i>² from logistic regression) vs. <i>p</i>-value threshold <i>p</i>_T for including SNPs in the score calculation.</p

Q–Q plots of the self-employment discovery meta-analyses.

<p>Q–Q plot of the self-employment discovery meta-analysis for (A) pooled males and females, (B) males only, and (C) females only. The grey shaded areas in the Q–Q plots represent the 95% confidence bands around the <i>p</i>-values.</p

Variance in the tendency to engage in self-employment explained by all autosomal SNPs in a combined sample of RS-I and STR for pooled males and females, males only, and females only.

<p>The genetic relationships were estimated from 301,115 directly genotyped autosomal SNPs that were available in both studies. All analyses controlled for age, study, and the first 10 principal components of the genetic similarity matrix of the combined sample of RS-I and STR. In the pooled sample we also controlled for sex. The results did not change markedly when 4 or 20 principal components were included; <i>σ_g</i>²/<i>σ_P</i>²: proportion of phenotypic variance explained by the variance of the total additive genetic effects of the 301,115 autosomal SNPs; s.e.: standard error; <i>p</i>-value: <i>p</i>-value from a likelihood ratio (LR) test assuming that the LR is distributed as a 50∶50 mixture of zero and <i>χ</i>₁².</p