Schizophrenia is a severe condition that affects approximately 1% of the population. Certain elements of antipsychotic treatment can only be examined in large population, thus the need for ...population-based real-world analyses has been increasing.
Hungarian National Health Fund database includes all healthcare data of the population of Hungary. All patients diagnosed with schizophrenia between 01.01.2006 and 31.12.2015 were included in the study. We analyzed all patients with newly initiated second-generation antipsychotic during the inclusion period (01.01.2012-31.12.2013). Patients were followed for 2 years. All-cause treatment discontinuation served as the primary outcome of the study. Patients with newly initiated long-acting injectable treatments were further investigated in stratified analyses based on their previous treatment.
106,624 patients had schizophrenia diagnosis during the study period. 12,232 patients met the inclusion criteria for newly initiating second-generation antipsychotic during the inclusion period. The proportion of patients still on treatment after 1 year for oral treatments varied between 17% (oral risperidone) and 31% (oral olanzapine) while the analogous data for long acting injectables were between 32% (risperidone long acting) and 64% (paliperidone long acting one monthly). The 2-year data were similarly in favor of long-actings. Median time to discontinuation in the oral group varied between 57 days (clozapine) and 121 days (olanzapine). The median time to discontinuation for long-actings was significantly longer: between 176 and 287 days; in case of paliperidone long acting, median was not reached during the observation period. Patients receiving long-acting treatment switched from another long-acting remained on the newly initiated treatment significantly longer than those switched from orals.
Our results indicate the superiority of second generation long-acting antipsychotics with regard to rates of treatment discontinuation and periods of persistence to the assigned medication.
The half-life of short-lived 215Po was studied in a new experimental setup by means of liquid scintillation counting. The new value of 1.781 (5) ms was obtained by offline data analysis using the ...delayed coincidence method. Along with the half-life determination, a careful assessment of uncertainties was carried out. The result was compared with data available from the literature.
•The half-life of 215Po was measured in a new experiment using liquid scintillation counting.•Digitizer-based DAQ in combination with offline delayed coincidence analysis was used.•The derived half-life is in good agreement with previous determinations.
Glioblastoma (GBM) is the most common and malignant primary brain tumor, resulting in poor survival despite aggressive therapies. GBM is characterized in part by a highly heterogeneous and ...immunosuppressive tumor microenvironment (TME) made up predominantly of infiltrating peripheral immune cells. One significant immune cell type that contributes to glioma immune evasion is a population of immunosuppressive, hematopoietic cells, termed myeloid-derived suppressor cells (MDSCs). Previous studies suggest that a potent subset of myeloid cells, expressing monocytic (M)-MDSC markers, distinguished by dual expression of chemokine receptors CCR2 and CX3CR1, utilize CCR2 to infiltrate into the TME. This study evaluated the T cell suppressive function and migratory properties of CCR2
/CX3CR1
MDSCs. Bone marrow-derived CCR2
/CX3CR1
cells adopt an immune suppressive cell phenotype when cultured with glioma-derived factors. Recombinant and glioma-derived CCL2 and CCL7 induce the migration of CCR2
/CX3CR1
MDSCs with similar efficacy. KR158B-CCL2 and -CCL7 knockdown murine gliomas contain equivalent percentages of CCR2
/CX3CR1
MDSCs compared to KR158B gliomas. Combined neutralization of CCL2 and CCL7 completely blocks CCR2-expressing cell migration to KR158B cell conditioned media. CCR2
/CX3CR1
cells are also reduced within KR158B gliomas upon combination targeting of CCL2 and CCL7. High levels of CCL2 and CCL7 are also associated with negative prognostic outcomes in GBM patients. These data provide a more comprehensive understanding of the function of CCR2
/CX3CR1
MDSCs and the role of CCL2 and CCL7 in the recruitment of these immune suppressive cells and further support the significance of targeting this chemokine axis in GBM.
An aqueous solution of 99mTc was standardized by means of 4πce(LS)-γ and 4πce(PC)-γ coincidence counting. The activity concentration was obtained by efficiency extrapolation relying on four different ...variation techniques. In both setups, fast digitizers were used for data acquisition. Detected events were recorded in list mode format, and their coincidence relationship was analyzed in the subsequent offline analysis. The combined result was used to participate in an international comparison using the Transfer Instrument of the International Reference System.
•99mTc was standardized by 4πce(LS)-γ and 4πce(PC)-γ coincidence counting.•Digitizer-based DAQ in combination with offline coincidence analysis was used.•Activity concentration was derived by various efficiency variation methods.•The results from different methods are in good agreement with each other.
Summary
1. Quantifying the relative importance of environmental filtering versus regional spatial structuring has become an intensively studied area in the context of metacommunity ecology. However, ...most studies have evaluated the role of environmental and spatial processes using taxonomic data sets of single snapshot surveys.
2. Here, we examined temporal changes in patterns and possible processes behind the functional metacommunity organization of stream fishes in a human‐modified landscape. Specifically, we (i) studied general changes in the functional composition of fish assemblages among 40 wadeable stream sites during a 3‐year study period in the catchment area of Lake Balaton, Hungary, (ii) quantified the relative importance of spatial and environmental factors as determinants of metacommunity structure and (iii) examined temporal variability in the relative role of spatial and environmental processes for this metacommunity.
3. Partial triadic analysis showed that assemblages could be effectively ordered along a functional gradient from invertebrate consuming species dominated by the opportunistic life‐history strategy, to assemblages with a diverse array of functional attributes. The analysis also revealed that functional fish assemblage structure was moderately stable among the sites between the sampling periods.
4. Despite moderate stability, variance partitioning using redundancy analyses (RDA) showed considerable temporal variability in the contribution of environmental and spatial factors to this pattern. The analyses also showed that environmental variables were, in general, more important than spatial ones in determining metacommunity structure. Of these, natural environmental variables (e.g. altitude, velocity) proved to be more influential than human‐related effects (e.g. pond area, % inhabited area above the site, nutrient enrichment), even in this landscape with relatively low variation in altitude and stream size.
5. Pond area was, however, the most important human stressor variable that was positively associated with the abundance of non‐native species with diverse functional attributes. The temporal variability in the relative importance of environmental and spatial factors was probably shaped by the release of non‐native fish from fish ponds to the stream system during flood events.
6. To conclude, both spatial processes and environmental control shape the functional metacommunity organization of stream fish assemblages in human‐modified landscapes, but their importance can vary in time. We argue, therefore, that metacommunity studies should better consider temporal variability in the ecological mechanisms (e.g. dispersal limitation, species sorting) that determine the dynamics of landscape‐level community organization.
Most studies characterize metacommunities based on a single snapshot of the spatial structure, which may be inadequate for taxa with high migratory behavior (e.g., fish). Here, we applied elements of ...metacommunity structure to examine variations in the spatial distributions of stream fishes over time and to explore possible structuring mechanisms. Although the major environmental gradients influencing species distributions remained largely the same in time, the best-fit pattern of metacommunity structure varied according to sampling occasion and whether or not we included non-native species in the analyses. Quasi-Clementsian and Clementsian structures were the predominant best-fit structures, indicating the importance of species turnover among sites and the existence of more or less discrete community boundaries. The environmental gradient most correlated with metacommunity structure was defined by altitude, area of artificial ponds in the catchment, and dissolved oxygen content. Our results suggest that the best-fit metacommunity structure of the native species can change in time in this catchment due to seasonal changes in distribution patterns. However, the distribution of non-native species throughout the landscape homogenizes the temporal variability in metacommunity structure of native species. Further studies are necessary from other regions to examine best-fit metacommunity structures of stream fishes within relatively short environmental gradients.
Tributary confluences play an important role in the dispersal of organisms, and consequently, in shaping regional scale diversity in stream networks. Despite their importance in dispersal processes, ...little is known about how ecological assemblages are organized in these habitats. We studied the scales of variability of stream fish assemblages over three seasons using a hierarchical sampling design, which incorporated three tributaries, three sites at the mouth of each tributary and using four sampling units at each site. We found strong scale dependent variability in species richness, composition and relative abundance. Most of the variation was accounted for by the interactive effect of season, between stream and between site effects, while habitat structure of the sampling units had a relatively minor role. Species richness showed a continuous decrease from the mainstem river in most cases, while species composition and relative abundance changed less consistently along the longitudinal profile. Consequently, we found that not only the junctions presented a strong filter on the species pool, but some species were filtered out if they passed this critical habitat bottleneck. In addition, spatial position of the tributaries along the river also contributed to assemblage variability in the confluences. Overall, our results suggest high variability in fish assemblages across multiple scales at tributary confluences. Environmental management should take a more critical care on the filtering role of tributary confluences in species dispersal, for better understanding patterns and processes in the branches of dendritic stream networks.
Refractory disease is a major challenge in treating patients with acute myeloid leukemia (AML). Whereas the armamentarium has expanded in the past few years for treating AML, long-term survival ...outcomes have yet to be proven. To further expand the arsenal for treating AML, we searched for druggable gene targets in AML by analyzing screening data from a lentiviral-based genome-wide pooled CRISPR-Cas9 library and gene knockout (KO) dependency scores in 15 AML cell lines (HEL, MV411, OCIAML2, THP1, NOMO1, EOL1, KASUMI1, NB4, OCIAML3, MOLM13, TF1, U937, F36P, AML193, P31FUJ). Ninety-four gene KOs met the criteria of (A) specifically essential to AML cell survival, (B) non-essential in non-AML cells, and (C) druggable according to three-dimensional (3D) modeling or ligand-based druggability scoring. Forty-four of 94 gene-KOs (47%) had an already-approved drug match and comprised a drug development list termed "deKO." Fifty of 94 gene-KOs (53%) had no drug in development and comprised a drug discovery list termed "disKO." STRING analysis and gene ontology categorization of the disKO targets preferentially cluster in the metabolic processes of UMP biosynthesis, IMP biosynthesis, dihydrofolate metabolism, pyrimidine nucleobase biosynthesis, vitellogenesis, and regulation of T cell differentiation and hematopoiesis. Results from this study serve as a testable compendium of AML drug targets that, after validation, may be translated into new therapeutics.
We conducted a matched-cohort study to assess mortality in schizophrenia and the relationship of mortality with comorbid somatic conditions and suicide attempts.
A full-population register-based ...prospective matched-cohort study was performed including all eligible patients with schizophrenia in Hungary between 01/01/2005 and 31/12/2013. Control subjects were individually matched to patients with schizophrenia at a 5:1 ratio. The principal outcome measure was death due to any reason. A non-parametric approach was used for descriptive statistical purposes, the Kaplan-Meier model for survival analysis, and the Cox proportional-hazards regression model for inferential statistics.
Patients with schizophrenia (n=65,169) had substantially higher risk of all-cause mortality than the control subjects (n=325,435) (RR=2.4; P<0.0001). Comorbidities and suicide attempts were associated with significantly increased mortality in both groups. As compared to the controls, 20-year old males with schizophrenia had a shorter life expectancy by 11.5years, and females by 13.7years; the analogous numbers for 45-year old schizophrenics were 8.1 and 9.6years, respectively.
A significant mortality gap – mainly associated with somatic comorbidities – was detected between patients with schizophrenia and individually matched controls. Improved medical training to address the disparity in mortality, and many other factors including lack of resources, access to and model of medical care, lifestyle, medication side effects, smoking, stigma, need for early intervention and adequate health care organization could help to better address the physical health needs of patients with schizophrenia.
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