Unraveling the drivers of regional variation in healthcare spending by analyzing prevalent chronic diseases.

To indicate inefficiencies in health systems, previous studies examined regional variation in healthcare spending by analyzing the entire population. As a result, population heterogeneity is taken into account to a limited extent only. Furthermore, it clouds a detailed interpretation which could be used to inform regional budget allocation decisions to improve quality of care of one chronic disease over another. Therefore, we aimed to gain insight into the drivers of regional variation in healthcare spending by studying prevalent chronic diseases

Analysis of regulation of pentose utilisation in Aspergillus niger reveals evolutionary adaptations in Eurotiales

Aspergilli are commonly found in soil and on decaying plant material. D-xylose and L-arabinose are highly abundant components of plant biomass. They are released from polysaccharides by fungi using a set of extracellular enzymes and subsequently converted intracellularly through the pentose catabolic pathway (PCP)

Lost but not forgotten: finding pages on the unarchived web

Web archives attempt to preserve the fast changing web, yet they will always be incomplete. Due to restrictions in crawling depth, crawling frequency, and restrictive selection policies, large parts of the Web are unarchived and, therefore, lost to posterity. In this paper, we propose an approach to uncover unarchived web pages and websites and to reconstruct different types of descriptions for these pages and sites, based on links and anchor text in the set of crawled pages. We experiment with this approach on the Dutch Web Archive and evaluate the usefulness of page and host-level representations of unarchived content. Our main findings are the following: First, the crawled web contains evidence of a remarkable number of unarchived pages and websites, potentially dramatically increasing the coverage of a Web archive. Second, the link and anchor text have a highly skewed distribution: popular pages such as home pages have more links pointing to them and more terms in the anchor text, but the richness tapers off quickly. Aggregating web page evidence to the host-level leads to significantly richer representations, but the distribution remains skewed. Third, the succinct representation is generally rich enough to uniquely identify pages on the unarchived web: in a known-item search setting we can retrieve unarchived web pages within the first ranks on average, with host-level representations leading to further improvement of the retrieval effectiveness for websites

Cyclooxygenase-2 inhibition prevents renal toxicity but not hypertension during sunitinib treatment

Background: Anticancer angiogenesis inhibitors cause hypertension and renal injury. Previously we observed in rats that high-dose aspirin (capable of blocking cyclooxygenase (COX)-1 and-2) was superior to low-dose aspirin (blocking COX-1 only) to prevent these side-effects during treatment with the angiogenesis inhibitor sunitinib, suggesting a role for COX-2. High-dose aspirin additionally prevented the rise in COX-derived prostacyclin (PGI2). Therefore, we studied the preventive effects of selective COX-2 inhibition and the hypothesized contributing role of PGI2 during angiogenesis inhibition. Methods: Male WKY rats received vehicle, sunitinib ((SU), 14 mg/kg/day) alone or combined with COX-2 inhibition (celecoxib, 10 mg/kg/day) or a PGI2 analogue (iloprost, 100 μg/kg/day) for 8 days (n = 8–9 per group). Mean arterial pressure (MAP) was measured via radiotelemetry, biochemical measurements were performed via ELISA and vascular function was assessed via wire myography. Results: SU increased MAP (17±1mmHg versus 3±1mmHg after vehicle on day 4, P &lt; 0.002), which could not be significantly blunted by celecoxib (+12±3mmHg on day 4, P = 0.247), but was temporarily attenuated by iloprost (treatment days 1 + 2 only). Urinary PGI2 (996 ± 112 versus 51 ± 11ng/24h after vehicle, P &lt; 0.001), but not circulating PGI2 increased during SU, which remained unaffected by celecoxib and iloprost. Celecoxib reduced sunitinib-induced albuminuria (0.36 ± 0.05 versus 0.58 ± 0.05mg/24h after SU, P = 0.005). Wire myography demonstrated increased vasoconstriction to endothelin-1 after SU (Emax P = 0.005 versus vehicle), which remained unaffected by celecoxib or iloprost. Conclusion: Selective COX-2 inhibition ameliorates albuminuria during angiogenesis inhibition with sunitinib, which most likely acts independently of PGI2. To combat angiogenesis inhibitor-induced hypertension, dual rather than selective COX-1/2 blockade seems preferential.</p

Acquisition of N-Glycosylation Sites in Immunoglobulin Heavy Chain Genes During Local Expansion in Parotid Salivary Glands of Primary Sjogren Patients

Previous studies revealed high incidence of acquired N-glycosylation sites acquired N-glycosylation sites in RNA transcripts encoding immunoglobulin heavy variable region (IGHV) 3 genes from parotid glands of primary Sjogren's syndrome (pSS) patients. In this study, next generation sequencing was used to study the extent of ac-Nglycs among clonally expanded cells from all IGVH families in the salivary glands of pSS patients. RNA was isolated from parotid gland biopsies of five pSS patients and five non-pSS sicca controls. IGHV sequences covering all functional IGHV genes were amplified, sequenced, and analyzed. Each biopsy recovered 1,800-4,000 unique IGHV sequences. No difference in IGHV gene usage was observed between pSS and non-pSS sequences. Clonally related sequences with more than 0.3% of the total number of sequences per patient were referred to as dominant clone. Overall, 70 dominant clones were found in pSS biopsies, compared to 15 in non-pSS. No difference in percentage mutation in dominant clone-derived IGHV sequences was seen between pSS and non-pSS. In pSS, no evidence for antigen-driven selection in dominant clones was found. We observed a significantly higher amount of ac-Nglycs among pSS dominant clone-derived sequences compared to non-pSS. Ac-Nglycs were, however, not restricted to dominant clones or IGHV gene. Most ac-Nglycs were detected in the framework 3 region. No stereotypic rheumatoid factor rearrangements were found in dominant clones. Lineage tree analysis showed in four pSS patients, but not in non-pSS, the presence of the germline sequence from a dominant clone. Presence of germline sequence and mutated IGHV sequences in the same dominant clone provide evidence that this clone originated from a naive B-cell recruited into the parotid gland to expand and differentiate locally into plasma cells. The increased presence of ac-Nglycs in IGHV sequences, due to somatic hypermutation, might provide B-cells an escape mechanism to survive during immune response. We speculate that glycosylation of the B-cell receptor makes the cell sensitive to environmental lectin signals to contribute to aberrant B-cell selection in pSS parotid glands

"Please tell me what happened":A descriptive study on prevalence, disclosure and characteristics of victimization in people with a psychotic disorder

IntroductionAlthough people with a psychotic disorder are approximately four to six times more often victimized than the general population, victimization is not routinely assessed in mental healthcare. This study investigates prevalence, context and risk factors of victimization in patients with a psychotic disorder in the Northern, relatively rural region of the Netherlands. Moreover, disclosure rates and awareness of psychiatrists are examined.MethodInformation on personal crime (threats, assaults and sexual violence), property and other forms of crime, the context of victimization and disclosure was routinely assessed in 353 patients with a psychotic disorder who received care at a mental health facility. In addition, involved psychiatrists reported on last year's victimization incidents in their patients.ResultsOne third of the patients reported victimization in the previous year. More than half of the crimes were committed by someone acquainted and took place in the victim's own home or a place familiar to the victim. Younger age, having a comorbid disorder, drug use and perpetration of a crime were all positively associated with victimization. Approximately half of the reported personal crimes were disclosed to a health care professional but only in 16% of the cases the involved psychiatrist report to know about the incident.ConclusionThis study confirms that people with a history of psychosis have an increased risk of becoming the victim of a crime. Although our results suggest that in fifty percent of cases the patients did share the information with professionals, a substantial proportion of incidents appear to go still unnoticed

A Bayesian network to simulate macroinvertebrate responses to multiple stressors in lowland streams

Aquatic ecosystems are affected by multiple environmental stressors across spatial and temporal scales. Yet the nature of stressor interactions and stressor-response relationships is still poorly understood. This hampers the selection of appropriate restoration measures. Hence, there is a need to understand how ecosystems respond to multiple stressors and to unravel the combined effects of the individual stressors on the ecological status of waterbodies. Models may be used to relate responses of ecosystems to environmental changes as well as to restoration measures and thus provide valuable tools for water management. Therefore, we aimed to develop and test a Bayesian Network (BN) for simulating the responses of stream macroinvertebrates to multiple stressors. Although the predictive performance may be further improved, the developed model was shown to be suitable for scenario analyses. For the selected lowland streams, an increase in macroinvertebrate-based ecological quality (EQR) was predicted for scenarios where the streams were relieved from single and multiple stressors. Especially a combination of measures increasing flow velocity and enhancing the cover of coarse particulate organic matter showed a significant increase in EQR compared to current conditions. The use of BNs was shown to be a promising avenue for scenario analyses in stream restoration management. BNs have the capacity for clear visual communication of model dependencies and the uncertainty associated with input data and results and allow the combination of multiple types of knowledge about stressor-effect relations. Still, to make predictions more robust, a deeper understanding of stressor interactions is required to parametrize model relations. Also, sufficient training data should be available for the water type of interest. Yet, the application of BNs may now already help to unravel the contribution of individual stressors to the combined effect on the ecological quality of water bodies, which in turn may aid the selection of appropriate restoration measures that lead to the desired improvements in macroinvertebrate-based ecological quality

NDUFS4 deletion triggers loss of NDUFA12 in Ndufs4−/− mice and Leigh syndrome patients: A stabilizing role for NDUFAF2

Mutations in NDUFS4, which encodes an accessory subunit of mitochondrial oxidative phosphorylation (OXPHOS) complex I (CI), induce Leigh syndrome (LS). LS is a poorly understood pediatric disorder featuring brain-specific anomalies and early death. To study the LS pathomechanism, we here compared OXPHOS proteomes between various Ndufs4−/− mouse tissues. Ndufs4−/− animals displayed significantly lower CI subunit levels in brain/diaphragm relative to other tissues (liver/heart/kidney/skeletal muscle), whereas other OXPHOS subunit levels were not reduced. Absence of NDUFS4 induced near complete absence of the NDUFA12 accessory subunit, a 50% reduction in other CI subunit levels, and an increase in specific CI assembly factors. Among the latter, NDUFAF2 was most highly increased. Regarding NDUFS4, NDUFA12 and NDUFAF2, identical results were obtained in Ndufs4−/− mouse embryonic fibroblasts (MEFs) and NDUFS4-mutated LS patient cells. Ndufs4−/− MEFs contained active CI in situ but blue-native-PAGE highlighted that NDUFAF2 attached to an inactive CI subcomplex (CI-830) and inactive assemblies of higher MW. In NDUFA12-mutated LS patient cells, NDUFA12 absence did not reduce NDUFS4 levels but triggered NDUFAF2 association to active CI. BN-PAGE revealed no such association in LS patient fibroblasts with mutations in other CI subunit-encoding genes where NDUFAF2 was attached to CI-830 (NDUFS1, NDUFV1 mutation) or not detected (NDUFS7 mutation). Supported by enzymological and CI in silico structural analysis, we conclude that absence of NDUFS4 induces near complete absence of NDUFA12 but not vice versa, and that NDUFAF2 stabilizes active CI in Ndufs4−/− mice and LS patient cells, perhaps in concert with mitochondrial inner membrane lipids