Multiscale quantification of morphological heterogeneity with creation of a predictor of longer survival in glioblastoma

Intratumor heterogeneity is a main cause of the dismal prognosis of glioblastoma (GBM). Yet, there remains a lack of a uniform assessment of the degree of heterogeneity. With a multiscale approach, we addressed the hypothesis that intratumor heterogeneity exists on different levels comprising traditional regional analyses, but also innovative methods including computer-assisted analysis of tumor morphology combined with epigenomic data. With this aim, 157 biopsies of 37 patients with therapy-naive IDH-wildtype GBM were analyzed regarding the intratumor variance of protein expression of glial marker GFAP, microglia marker Iba1 and proliferation marker Mib1. Hematoxylin and eosin stained slides were evaluated for tumor vascularization. For the estimation of pixel intensity and nuclear profiling, automated analysis was used. Additionally, DNA methylation profiling was conducted separately for the single biopsies. Scoring systems were established to integrate several parameters into one score for the four examined modalities of heterogeneity (regional, cellular, pixel-level and epigenomic). As a result, we could show that heterogeneity was detected in all four modalities. Furthermore, for the regional, cellular and epigenomic level, we confirmed the results of earlier studies stating that a higher degree of heterogeneity is associated with poorer overall survival. To integrate all modalities into one score, we designed a predictor of longer survival, which showed a highly significant separation regarding the OS. In conclusion, multiscale intratumor heterogeneity exists in glioblastoma and its degree has an impact on overall survival. In future studies, the implementation of a broadly feasible heterogeneity index should be considered.     

Association of Early Kidney Allograft Failure with Preformed IgA Antibodies to β2-Glycoprotein I

In the current immunosuppressive therapy era, vessel thrombosis is the most common cause of early graft loss after renal transplantation. The prevalence of IgA anti–β₂-glycoprotein I antibodies (IgA-aB2GPI-ab) in patients on dialysis is elevated (>30%), and these antibodies correlate with mortality and cardiovascular morbidity. To evaluate the effect of IgA-aB2GPI-ab in patients with transplants, we followed all patients transplanted from 2000 to 2002 in the Hospital 12 de Octubre prospectively for 10 years. Presence of IgA-aB2GPI-ab in pretransplant serum was examined retrospectively. Of 269 patients, 89 patients were positive for IgA-aB2GPI-ab (33%; group 1), and the remaining patients were negative (67%; group 2). Graft loss at 6 months post-transplant was significantly higher in group 1 (10 of 89 versus 3 of 180 patients in group 2; P=0.002). The most frequent cause of graft loss was thrombosis of the vessels, which was observed only in group 1 (8 of 10 versus 0 of 3 patients in group 2; P=0.04). Multivariate analysis showed that the presence of IgA-aB2GPI-ab was an independent risk factor for early graft loss (P=0.04) and delayed graft function (P=0.04). There were no significant differences regarding patient survival between the two groups. Graft survival was similar in both groups after 6 months. In conclusion, patients with pretransplant IgA-aB2GPI-ab have a high risk of early graft loss caused by thrombosis and a high risk of delayed graft function. Therefore, pretransplant IgA-aB2GPI-ab may have a detrimental effect on early clinical outcomes after renal transplantation.     

SEROPOSITIVITY FOR ASCARIOSIS AND TOXOCARIOSIS AND CYTOKINE EXPRESSION AMONG THE INDIGENOUS PEOPLE IN THE VENEZUELAN DELTA REGION

The present study aimed at measuring seropositivities for infection by Ascaris suum and Toxocara canis using the excretory/secretory (E/S) antigens from Ascaris suum (AES) and Toxocara canis (TES) within an indigenous population. In addition, quantification of cytokine expressions in peripheral blood cells was determined. A total of 50 Warao indigenous were included; of which 43 were adults and seven children. In adults, 44.1% were seropositive for both parasites; whereas children had only seropositivity to one or the other helminth. For ascariosis, the percentage of AES seropositivity in adults and children was high; 23.3% and 57.1%, respectively. While that for toxocariosis, the percentage of TES seropositivity in adults and children was low; 9.3% and 14.3%, respectively. The percentage of seronegativity was comparable for AES and TES antigens in adults (27.9%) and children (28.6%). When positive sera were analyzed by Western blotting technique using AES antigens; three bands of 97.2, 193.6 and 200.2 kDas were mostly recognized. When the TES antigens were used, nine major bands were mostly identified; 47.4, 52.2, 84.9, 98.2, 119.1, 131.3, 175.6, 184.4 and 193.6 kDas. Stool examinations showed that Blastocystis hominis, Hymenolepis nana and Entamoeba coli were the most commonly observed intestinal parasites. Quantification of cytokines IFN-γ, IL-2, IL-6, TGF-β, TNF-α, IL-10 and IL-4 expressions showed that there was only a significant increased expression of IL-4 in indigenous with TES seropositivity (p < 0.002). Ascaris and Toxocara seropositivity was prevalent among Warao indigenous.     

Work hazards and workers’ mental health: an investigation based on the fifth European Working Conditions Survey

Background:Workplace hazards are a significant source of health impairment for workers and of financial losses for firms. EU directives on workers’ health and safety standards significantly contributed to reduce reported occupational injuries, yet the incidence and prevalence of work-related mental illness is still very high.Objectives:We investigated the association between work-related hazards and individuals’ perceived mental health. We reviewed the existing evidence on the channels through which task-related factors, adverse agents and psychosocial factors are expected to affect workers’ health, with specific regard to mental health.Methods:We used data from the fifth wave of the European Working Conditions Survey, covering over 40,000 face-to-face interviews with workers in 34 countries, which includes information on socio-demographic characteristics, firms and jobs attributes, employment status, as well as working conditions and health status. We carried out an empirical analysis with multivariate regression models in order to estimate the relationship between workers’ mental health problems and workplace risk factors.Results:21,020 interviews were used in the multivariate analysis. We found strong correlations between hazards and various indicators of mental health. Among hazardous agents, low temperatures (β=0.0287) and contact with infectious materials (β=0.0394) were positively associated with mental health outcomes. Among task/sequence-related factors, tiring or painful positions (β=0.0713), repetitive hand/arm movements (β=0.0255), working with VDUs (β=0.0301), repetitive tasks <10 min (β=0.0859) and working in evenings (β=0.00754) were positively associated with mental health. Various psychosocial risk factors related to both the content of the job (for example, frequent disruptive interruptions: β=0.219, working in free time: β=0.0759, poor work-life balance: β=0.228) as well as the job context (for example, bad employment prospects: β=0.177, low decisional autonomy: β=0.245, bad social relations: β=0.186, workplace violence: β=0.411) were positively associated with mental health. The main results of the decomposition show that an important contribution to workers’ overall mental distress at work is associated with psychosocial risk factors (up to 60% for depression/anxiety symptoms and sleep disorders), while the contribution of somatic factors is on average lower (up to 20% for overall fatigue).Conclusions:We argue that action is needed to improve workers’ mental well-being, and reduce the economic costs for both the national health system and employers. Regulations and traditional economic measures are unlikely to prove successful in providing adequate standards of primary and secondary preventive measures in the work place without an appropriate and reliable Risk Assessment Procedure.Key words: Work hazards, risk assessment, job content, mental health