Evaluating the risk for Usutu virus circulation in Europe: comparison of environmental niche models and epidemiological models

Background

Usutu virus (USUV) is a mosquito-borne flavivirus, reported in many countries of Africa and Europe, with an increasing spatial distribution and host range. Recent outbreaks leading to regional declines of European common blackbird (Turdus merula) populations and a rising number of human cases emphasize the need for increased awareness and spatial risk assessment.

Methods

Modelling approaches in ecology and epidemiology differ substantially in their algorithms, potentially resulting in diverging model outputs. Therefore, we implemented a parallel approach incorporating two commonly applied modelling techniques: (1) Maxent, a correlation-based environmental niche model and (2) a mechanistic epidemiological susceptible-exposed-infected-removed (SEIR) model. Across Europe, surveillance data of USUV-positive birds from 2003 to 2016 was acquired to train the environmental niche model and to serve as test cases for the SEIR model. The SEIR model is mainly driven by daily mean temperature and calculates the basic reproduction number R₀. The environmental niche model was run with long-term bio-climatic variables derived from the same source in order to estimate climatic suitability.

Results

Large areas across Europe are currently suitable for USUV transmission. Both models show patterns of high risk for USUV in parts of France, in the Pannonian Basin as well as northern Italy. The environmental niche model depicts the current situation better, but with USUV still being in an invasive stage there is a chance for under-estimation of risk. Areas where transmission occurred are mostly predicted correctly by the SEIR model, but it mostly fails to resolve the temporal dynamics of USUV events. High R₀ values predicted by the SEIR model in areas without evidence for real-life transmission suggest that it may tend towards over-estimation of risk.

Conclusions

The results from our parallel-model approach highlight that relying on a single model for assessing vector-borne disease risk may lead to incomplete conclusions. Utilizing different modelling approaches is thus crucial for risk-assessment of under-studied emerging pathogens like USUV.

     

Integration von Geschlecht in die Forschung zu umweltbezogener Gesundheit. Ergebnisse des interdisziplinären Forschungsnetzwerks Geschlecht – Umwelt – Gesundheit (GeUmGe-NET)

Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz - Die umfassende Berücksichtigung von Geschlecht (biologische und soziale Dimensionen) in der Gesundheitsforschung ist...     

Combining informal care and paid work: The use of work arrangements by working adult‐child caregivers in the Netherlands

An increasing number of people combine paid work with the provision of informal care for a loved one. This combination of work and care may cause difficulties, necessitating adaptations at work, i.e. work arrangements. The present study explores what types of work arrangements are used by working caregivers, and which caregiver, care and work characteristics are associated with the use of these work arrangements. Within the Lifelines Informal Care Add‐on Study (Lifelines ICAS), data on 965 Dutch informal caregivers in the North of the Netherlands were collected between May 2013 and July 2014 (response rate 48%), and data on 333 working adult‐child caregivers (aged 26–68 years, 82% female) were used in this study. A small majority (56%) of the working caregivers used one or more work arrangement(s): taking time off (41%), individual agreements with supervisor (30%), formal care leave arrangement (13%), and reduction in paid work hours (6%). Logistic regression analyses showed that long working hours (OR 1.06, 95% CI 1.01–1.08), and the experience of more health problems (OR 2.54, 95% CI 1.56–4.05) or a disrupted schedule due to caregiving (OR 2.50, 95% CI 1.66–3.78) increased the chance to have used one or more work arrangements. Lower educated working caregivers were less likely to have used a formal care leave arrangement (tertiary vs. primary education OR 2.75, 95% CI 1.13–6.67; tertiary vs. secondary education OR 1.27, 95% CI 1.27–5.09). Policy makers should inform working caregivers about the availability of the different work arrangements, with specific attention for low educated working caregivers. Employers need to consider a more caregiver‐friendly policy, as almost half of the working adult‐child caregivers did not use any work arrangement.     

The Work Role Functioning Questionnaire v2.0 Showed Consistent Factor Structure Across Six Working Samples

Objective The Work Role Functioning Questionnaire v2.0 (WRFQ) is an outcome measure linking a persons’ health to the ability to meet work demands in the twenty-first century. We aimed to examine the construct validity of the WRFQ in a heterogeneous set of working samples in the Netherlands with mixed clinical conditions and job types to evaluate the comparability of the scale structure. Methods Confirmatory factor and multi-group analyses were conducted in six cross-sectional working samples (total N?=?2433) to evaluate and compare a five-factor model structure of the WRFQ (work scheduling demands, output demands, physical demands, mental and social demands, and flexibility demands). Model fit indices were calculated based on RMSEA?≤?0.08 and CFI?≥?0.95. After fitting the five-factor model, the multidimensional structure of the instrument was evaluated across samples using a second order factor model. Results The factor structure was robust across samples and a multi-group model had adequate fit (RMSEA?=?0.63, CFI?=?0.972). In sample specific analyses, minor modifications were necessary in three samples (final RMSEA 0.055–0.080, final CFI between 0.955 and 0.989). Applying the previous first order specifications, a second order factor model had adequate fit in all samples. Conclusion A five-factor model of the WRFQ showed consistent structural validity across samples. A second order factor model showed adequate fit, but the second order factor loadings varied across samples. Therefore subscale scores are recommended to compare across different clinical and working samples.     

The Toxicity of a Novel Antifungal Compound Is Modulated by Endoplasmic Reticulum-Associated Protein Degradation Components

In a search for new antifungal compounds, we screened a library of 4,454 chemicals for toxicity against the human fungal pathogen Aspergillus fumigatus. We identified sr7575, a molecule that inhibits growth of the evolutionary distant fungi A. fumigatus, Cryptococcus neoformans, Candida albicans, and Saccharomyces cerevisiae but lacks acute toxicity for mammalian cells. To gain insight into the mode of inhibition, sr7575 was screened against 4,885 S. cerevisiae mutants from the systematic collection of haploid deletion strains and 977 barcoded haploid DAmP (decreased abundance by mRNA perturbation) strains in which the function of essential genes was perturbed by the introduction of a drug resistance cassette downstream of the coding sequence region. Comparisons with previously published chemogenomic screens revealed that the set of mutants conferring sensitivity to sr7575 was strikingly narrow, affecting components of the endoplasmic reticulum-associated protein degradation (ERAD) stress response and the ER membrane protein complex (EMC). ERAD-deficient mutants were hypersensitive to sr7575 in both S. cerevisiae and A. fumigatus, indicating a conserved mechanism of growth inhibition between yeast and filamentous fungi. Although the unfolded protein response (UPR) is linked to ERAD regulation, sr7575 did not trigger the UPR in A. fumigatus and UPR mutants showed no enhanced sensitivity to the compound. The data from this chemogenomic analysis demonstrate that sr7575 exerts its antifungal activity by disrupting ER protein quality control in a manner that requires ERAD intervention but bypasses the need for the canonical UPR. ER protein quality control is thus a specific vulnerability of fungal organisms that might be exploited for antifungal drug development.     

Determination of itraconazole and hydroxyitraconazole in plasma by use of liquid chromatography-tandem mass spectrometry with on-line solid-phase extraction.

In this paper a method for the simultaneous quantification of the anti-fungal drug itraconazole and its co-active metabolite hydroxyitraconazole in plasma employing liquid chromatography tandem-mass spectrometry and automated solid-phase extraction is described. The method proved rugged, enables short turn-around times and is highly specific. Since there is growing evidence for the importance of therapeutic drug monitoring of itraconazole in the prophylaxis and treatment of invasive fungal infections, the method described here is of interest for a large number of tertiary care hospital laboratories.     

Inhibition of O6-methylguanine-DNA methyltransferase by glucose-conjugated inhibitors: comparison with nonconjugated inhibitors and effect on fotemustine and temozolomide-induced cell death

The DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT) is an important suicide enzyme involved in the defense against O(6)-alkylating mutagens. It also plays a role in the resistance of tumors to anticancer drugs targeting the O(6)-position of guanine, such as temozolomide and fotemustine. Several potent MGMT inhibitors have been developed sensitizing cells to O(6)-alkylating agents. Aimed at targeting MGMT inhibitors to tumor cells, we synthesized MGMT inhibitory compounds conjugated with glucose to improve uptake in tumor cells. Here, we compared O(6)-benzylguanine, O(6)-2-fluoropyridinylmethylguanine (O(6)FPG), O(6)-3-iodobenzylguanine, O(6)-4-bromothenylguanine, and O(6)-5-iodothenylguanine with the corresponding C8-linker beta-d-glucose derivatives. All glucose conjugated inhibitors were 3- to 5-fold less effective than the corresponding nonconjugated drugs as to MGMT inhibition that was measured in cell extracts (in vitro) and cultivated HeLaS3 cells (in vivo). Except for O(6)FPG, IC(50) values of the guanine derivatives applied in vitro and in vivo were correlated. A similar correlation was not obvious for the corresponding glucosides, indicating differences in cellular uptake. C8-alpha-d-glucosides were less effective than beta-glucosides. From the newly developed glucose-conjugated inhibitors tested, O(6)-4-bromothenylguanine-C8-beta-d-glucoside (O(6)BTG-C8-betaGlu) was most potent in inhibiting MGMT both in vitro and in vivo. At a concentration of 0.1 microM, it inhibited cellular MGMT to completion. It was not toxic, even when applied chronically to cells at high dose (up to 20 microM). O(6)BTG-C8-betaGlu strongly potentiated the killing effect of fotemustine and temozolomide, causing reversal from MGMT+ to MGMT- phenotype. Therefore, O(6)BTG-C8-betaGlu seems to be especially suitable for approaching MGMT inhibitor targeting in tumor therapy.     

Impact of a multidisciplinary pain program for the management of chronic low back pain in patients undergoing spine surgery and primary total hip replacement: a retrospective cohort study

Background

Low back pain is a very common disorder. In this field chronic low back pain represents a special challenge. The management of chronic low back pain consists of a range of different intervention strategies. Usually operative intervention should be avoided if possible. However, there are constellations were surgical therapy in patients with chronic low back pain seems to be meaningful.The aim of this study was to investigate the clinical outcomes after spine surgery and hip replacement in patients with chronic low back pain after undergoing a structured rehabilitation program including cognitive – behavioral therapy.

Methods

From January 1, 2007 to January 1, 2010 patients were indicated for total hip replacement (THA) or spine surgery after receiving inpatient multidisciplinary pain programs including cognitive – behavioral therapy at our orthopedic institute with a specialized unit for the rehabilitation of chronic pain patients. Indications for surgery were based on the synopsis of clinical and imaging findings and on positive effects after local injections during the multidisciplinary pain program. The tools for assessment included follow-up at 6 and 12 months and analyses of pain, chronicity, physical functioning and depression.

Results

Of the 256 patients admitted for multidisciplinary pain program, fifteen were indicated to benefit from a surgical intervention during multidisciplinary pain program. Ten patients received spine surgery. THA was indicated in five patients. In all cases, the peri- and postoperative clinical courses were uneventful. Only two of the patients subjected to spine surgery and three patients who had THA were improved after 12 months. One patient reported a worsened condition. All patients presented with good functional outcomes and normal radiological findings.

Conclusions

The indication for surgical intervention in patients with chronic low back pain and degenerative diseases must be critically assessed. THA in this cohort should focus on functional aspects, such as the improvement of range of motion, rather than the reduction of pain. Spine surgery in chronic low back pain patients after multidisciplinary pain program including cognitive – behavioral therapy cannot be recommended due to its questionable success.

     

Transplantation of cryopreserved human umbilical cord blood mononuclear cells does not induce sustained recovery after experimental stroke in spontaneously hypertensive rats

Previous studies have highlighted the enormous potential of cell-based therapies for stroke not only to prevent ischemic brain damage, but also to amplify endogenous repair processes. Considering its widespread availability and low immunogenicity human umbilical cord blood (HUCB) is a particularly attractive stem cell source. Our goal was to investigate the neurorestorative potential of cryopreserved HUCB mononuclear cells (MNC) after permanent middle cerebral artery occlusion (MCAO) in spontaneously hypertensive rats (SHR). Human umbilical cord blood MNC or vehicle solution was administered intravenously 24 hours after MCAO. Experimental groups were as follows: (1) quantitative polymerase chain reaction (PCR) of host-derived growth factors up to 48 hours after stroke; (2) immunohistochemical analysis of astroglial scarring; (3) magnetic resonance imaging (MRI) and weekly behavioral tests for 2 months after stroke. Long-term functional outcome and lesion development on MRI were not beneficially influenced by HUCB MNC therapy. Furthermore, HUCB MNC treatment did not change local growth factor levels and glial scarring extent. In summary, we could not demonstrate neurorestorative properties of HUCB MNC after stroke in SHR. Our results advise caution regarding a prompt translation of cord blood therapy into clinical stroke trials as long as deepened knowledge about its precise modes of action is missing.     

Cortical hypoplasia and ventriculomegaly of p73‐deficient mice: Developmental and adult analysis

Trp73, a member of the p53 gene family, plays a crucial role in neural development. We describe two main phenotypic variants of p73 deficiency in the brain, a severe one characterized by massive apoptosis in the cortex leading to early postnatal death and a milder, non‐/low‐apoptosis one in which 50% of pups may reach adulthood using an intensive‐care breeding protocol. Both variants display the core triad of p73 deficiency: cortical hypoplasia, hippocampal malformations, and ventriculomegaly. We studied the development of the neocortex in p73 KO mice from early embryonic life into advanced age (25 months). Already at E14.5, the incipient cortical plate of the p73 KO brains showed a reduced width. Examination of adult neocortex revealed a generalized, nonprogressive reduction by 10–20%. Area‐specific architectonic landmarks and lamination were preserved in all cortical areas. The surviving adult animals had moderate ventricular distension, whereas pups of the early lethal phenotypic variant showed severe ventriculomegaly. Ependymal cells of wild‐type ventricles strongly express p73 and are particularly vulnerable to p73 deficiency. Ependymal denudation by apoptosis and reduction of ependymal cilia were already evident in young mice, with complete absence of cilia in older animals. Loss of p73 function in the ependyma may thus be one determining factor for chronic hydrocephalus, which leads to atrophy of subcortical structures (striatum, septum, amygdala). p73 Is thus involved in a variety of CNS activities ranging from embryonic regulation of brain size to the control of cerebrospinal fluid homeostasis in the adult brain via maintenance of the ependyma. J. Comp. Neurol. 522:2663–2679, 2014. © 2014 Wiley Periodicals, Inc.