Publications by authors named "Jan Bauer"

238 Publications

The brain penetrant PPARγ agonist leriglitazone restores multiple altered pathways in models of X-linked adrenoleukodystrophy.

Sci Transl Med 2021 Jun;13(596)

Minoryx Therapeutics S.L., Barcelona 08302, Spain.

X-linked adrenoleukodystrophy (X-ALD), a potentially fatal neurometabolic disorder with no effective pharmacological treatment, is characterized by clinical manifestations ranging from progressive spinal cord axonopathy [adrenomyeloneuropathy (AMN)] to severe demyelination and neuroinflammation (cerebral ALD-cALD), for which molecular mechanisms are not well known. Leriglitazone is a recently developed brain penetrant full PPARγ agonist that could modulate multiple biological pathways relevant for neuroinflammatory and neurodegenerative diseases, and particularly for X-ALD. We found that leriglitazone decreased oxidative stress, increased adenosine 5'-triphosphate concentration, and exerted neuroprotective effects in primary rodent neurons and astrocytes after very long chain fatty acid-induced toxicity simulating X-ALD. In addition, leriglitazone improved motor function; restored markers of oxidative stress, mitochondrial function, and inflammation in spinal cord tissues from AMN mouse models; and decreased the neurological disability in the EAE neuroinflammatory mouse model. X-ALD monocyte-derived patient macrophages treated with leriglitazone were less skewed toward an inflammatory phenotype, and the adhesion of human X-ALD monocytes to brain endothelial cells decreased after treatment, suggesting the potential of leriglitazone to prevent the progression to pathologically disrupted blood-brain barrier. Leriglitazone increased myelin debris clearance in vitro and increased myelination and oligodendrocyte survival in demyelination-remyelination in vivo models, thus promoting remyelination. Last, leriglitazone was clinically tested in a phase 1 study showing central nervous system target engagement (adiponectin increase) and changes on inflammatory biomarkers in plasma and cerebrospinal fluid. The results of our study support the use of leriglitazone in X-ALD and, more generally, in other neuroinflammatory and neurodegenerative conditions.
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http://dx.doi.org/10.1126/scitranslmed.abc0555DOI Listing
June 2021

Fundamental mechanistic insights from rare but paradigmatic neuroimmunological diseases.

Nat Rev Neurol 2021 May 28. Epub 2021 May 28.

Infinity, Université Toulouse, CNRS, Inserm, Toulouse, France.

The pathophysiology of complex neuroimmunological diseases, such as multiple sclerosis and autoimmune encephalitis, remains puzzling - various mechanisms that are difficult to dissect seem to contribute, hampering the understanding of the processes involved. Some rare neuroimmunological diseases are easier to study because their presentation and pathogenesis are more homogeneous. The investigation of these diseases can provide fundamental insights into neuroimmunological pathomechanisms that can in turn be applied to more complex diseases. In this Review, we summarize key mechanistic insights into three such rare but paradigmatic neuroimmunological diseases - Susac syndrome, Rasmussen encephalitis and narcolepsy type 1 - and consider the implications of these insights for the study of other neuroimmunological diseases. In these diseases, the combination of findings in humans, different modalities of investigation and animal models has enabled the triangulation of evidence to validate and consolidate the pathomechanistic features and to develop diagnostic and therapeutic strategies; this approach has provided insights that are directly relevant to other neuroimmunological diseases and applicable in other contexts. We also outline how next-generation technologies and refined animal models can further improve our understanding of pathomechanisms, including cell-specific and antigen-specific CNS immune responses, thereby paving the way for the development of targeted therapeutic approaches.
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http://dx.doi.org/10.1038/s41582-021-00496-7DOI Listing
May 2021

Biodiversity conservation as a promising frontier for behavioural science.

Nat Hum Behav 2021 May 13;5(5):550-556. Epub 2021 May 13.

Department of Zoology, University of Cambridge, Cambridge, UK.

Human activities are degrading ecosystems worldwide, posing existential threats for biodiversity and humankind. Slowing and reversing this degradation will require profound and widespread changes to human behaviour. Behavioural scientists are therefore well placed to contribute intellectual leadership in this area. This Perspective aims to stimulate a marked increase in the amount and breadth of behavioural research addressing this challenge. First, we describe the importance of the biodiversity crisis for human and non-human prosperity and the central role of human behaviour in reversing this decline. Next, we discuss key gaps in our understanding of how to achieve behaviour change for biodiversity conservation and suggest how to identify key behaviour changes and actors capable of improving biodiversity outcomes. Finally, we outline the core components for building a robust evidence base and suggest priority research questions for behavioural scientists to explore in opening a new frontier of behavioural science for the benefit of nature and human wellbeing.
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http://dx.doi.org/10.1038/s41562-021-01109-5DOI Listing
May 2021

T cell numbers correlate with neuronal loss rather than with seizure activity in medial temporal lobe epilepsy.

Epilepsia 2021 Jun 6;62(6):1343-1353. Epub 2021 May 6.

Department of Neuroimmunology, Center for Brain Research, Medical University of Vienna, Vienna, Austria.

Objective: Medial temporal lobe epilepsy (MTLE) is a drug-resistant focal epilepsy that can be caused by a broad spectrum of different inciting events, including tumors, febrile seizures, and viral infections. In human epilepsy surgical resections as well as in animal models, an involvement of the adaptive immune system was observed. We here analyzed the presence of T cells in various subgroups of MTLE. We aimed to answer the question of how much inflammation was present and whether the presence of T cells was associated with seizures or associated with hippocampal neurodegeneration.

Methods: We quantified the numbers of CD3 T cells and CD8 cytotoxic T cells in the hippocampus of patients with gangliogliomas (GGs; intrahippocampal and extrahippocampal, with and without sclerosis), febrile seizures, and postinfectious encephalitic epilepsy and compared this with Rasmussen encephalitis, Alzheimer disease, and normal controls.

Results: We could show that T cell numbers were significantly elevated in MTLE compared to healthy controls. CD3 as well as CD8 T cell numbers, however, varied highly among MTLE subgroups. By comparing GG patients with and without hippocampal sclerosis (HS), we were able to show that T-cell numbers were increased in extrahippocampal GG patients with hippocampal neuronal loss and HS, whereas extrahippocampal GG cases without hippocampal neuronal loss (i.e., absence of HS) did not differ from healthy controls. Importantly, T cell numbers in MTLE correlated with the degree of neuronal loss, whereas no correlation with seizure frequency or disease duration was found. Finally, we found that in nearly all MTLE groups, T cell numbers remained elevated even years after the inciting event.

Significance: We here provide a detailed histopathological investigation of the involvement of T cells in various subgroups of MTLE, which suggests that T cell influx correlates to neuronal loss rather than seizure activity.
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http://dx.doi.org/10.1111/epi.16914DOI Listing
June 2021

Rewarding behavior with a sweet food strengthens its valuation.

PLoS One 2021 14;16(4):e0242461. Epub 2021 Apr 14.

Department of Economics, Cornell University, Ithaca, New York, United States of America.

Sweet foods are commonly used as rewards for desirable behavior, specifically among children. This study examines whether such practice may contribute to reinforce the valuation of these foods. Two experiments were conducted, one with children, the other with rats. The first study, conducted with first graders (n = 214), shows that children who receive a food reward for performing a cognitive task subsequently value the food more compared to a control group who received the same food without performing any task. The second study, conducted on rats (n = 64), shows that rewarding with food also translates into higher calorie intake over a 24-hour period. These results suggest that the common practice of rewarding children with calorie-dense sweet foods is a plausible contributing factor to obesity and might therefore be ill advised.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0242461PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046216PMC
April 2021

Histone deacetylase 1 controls CD4 T cell trafficking in autoinflammatory diseases.

J Autoimmun 2021 May 20;119:102610. Epub 2021 Feb 20.

Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria. Electronic address:

CD4 T cell trafficking is a fundamental property of adaptive immunity. In this study, we uncover a novel role for histone deacetylase 1 (HDAC1) in controlling effector CD4 T cell migration, thereby providing mechanistic insight into why a T cell-specific deletion of HDAC1 protects against experimental autoimmune encephalomyelitis (EAE). HDAC1-deficient CD4 T cells downregulated genes associated with leukocyte extravasation. In vitro, HDAC1-deficient CD4 T cells displayed aberrant morphology and migration on surfaces coated with integrin LFA-1 ligand ICAM-1 and showed an impaired ability to arrest on and to migrate across a monolayer of primary mouse brain microvascular endothelial cells under physiological flow. Moreover, HDAC1 deficiency reduced homing of CD4 T cells into the intestinal epithelium and lamina propria preventing weight-loss, crypt damage and intestinal inflammation in adoptive CD4 T cell transfer colitis. This correlated with reduced expression levels of LFA-1 integrin chains CD11a and CD18 as well as of selectin ligands CD43, CD44 and CD162 on transferred circulating HDAC1-deficient CD4 T cells. Our data reveal that HDAC1 controls T cell-mediated autoimmunity via the regulation of CD4 T cell trafficking into the CNS and intestinal tissues.
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http://dx.doi.org/10.1016/j.jaut.2021.102610DOI Listing
May 2021

Acute and non-resolving inflammation associate with oxidative injury after human spinal cord injury.

Brain 2021 02;144(1):144-161

Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna, Austria.

Traumatic spinal cord injury is a devastating insult followed by progressive cord atrophy and neurodegeneration. Dysregulated or non-resolving inflammatory processes can disturb neuronal homeostasis and drive neurodegeneration. Here, we provide an in-depth characterization of innate and adaptive inflammatory responses as well as oxidative tissue injury in human traumatic spinal cord injury lesions compared to non-traumatic control cords. In the lesion core, microglia were rapidly lost while intermediate (co-expressing pro- as well as anti-inflammatory molecules) blood-borne macrophages dominated. In contrast, in the surrounding rim, TMEM119+ microglia numbers were maintained through local proliferation and demonstrated a predominantly pro-inflammatory phenotype. Lymphocyte numbers were low and mainly consisted of CD8+ T cells. Only in a subpopulation of patients, CD138+/IgG+ plasma cells were detected, which could serve as candidate cellular sources for a developing humoral immunity. Oxidative neuronal cell body and axonal injury was visualized by intracellular accumulation of amyloid precursor protein (APP) and oxidized phospholipids (e06) and occurred early within the lesion core and declined over time. In contrast, within the surrounding rim, pronounced APP+/e06+ axon-dendritic injury of neurons was detected, which remained significantly elevated up to months/years, thus providing mechanistic evidence for ongoing neuronal damage long after initial trauma. Dynamic and sustained neurotoxicity after human spinal cord injury might be a substantial contributor to (i) an impaired response to rehabilitation; (ii) overall failure of recovery; or (iii) late loss of recovered function (neuro-worsening/degeneration).
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http://dx.doi.org/10.1093/brain/awaa360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880675PMC
February 2021

Development of unmanned aerial vehicle (UAV) networks delivering early defibrillation for out-of-hospital cardiac arrests (OHCA) in areas lacking timely access to emergency medical services (EMS) in Germany: a comparative economic study.

BMJ Open 2021 01 22;11(1):e043791. Epub 2021 Jan 22.

Institute of Occupational Medicine, Social Medicine and Environmental Medicine, Goethe-Universitat Frankfurt am Main, Frankfurt am Main, Hessen, Germany.

Objectives: This study wants to assess the cost-effectiveness of unmanned aerial vehicles (UAV) equipped with automated external defibrillators (AED) in out-of-hospital cardiac arrests (OHCA). Especially in rural areas with longer response times of emergency medical services (EMS) early lay defibrillation could lead to a significant higher survival in OHCA.

Participants: 3296 emergency medical stations in Germany.

Setting: Rural areas in Germany.

Primary And Secondary Outcome Measures: Three UAV networks providing 80%, 90% or 100% coverage for rural areas lacking timely access to EMS (ie, time-to-defibrillation: >10 min) were developed using a location allocation analysis. For each UAV network, primary outcome was the cost-effectiveness using the incremental cost-effectiveness ratio (ICER) calculated by the ratio of financial costs to additional life years gained compared with current EMS.

Results: Current EMS with 3926 emergency stations was able to gain 1224 life years on annual average in the study area. The UAV network providing 100% coverage consisted of 1933 UAV with average annual costs of €43.5 million and 1845 additional life years gained on annual average (ICER: €23 568). The UAV network providing 90% coverage consisted of 1074 UAV with average annual costs of €24.2 million and 1661 additional life years gained on annual average (ICER: €14 548). The UAV network providing 80% coverage consisted of 798 UAV with average annual costs of €18.0 million and 1477 additional life years gained on annual average (ICER: €12 158).

Conclusion: These results reveal the relevant life-saving potential of all modelled UAV networks. Furthermore, all analysed UAV networks could be deemed cost-effective. However, real-life applications are needed to validate the findings.
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http://dx.doi.org/10.1136/bmjopen-2020-043791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825255PMC
January 2021

Nudging healthier food choices in a cafeteria setting: A sequential multi-intervention field study.

Appetite 2021 05 7;160:105106. Epub 2021 Jan 7.

Copenhagen Business School, Department of Management, Society and Communication, Dalgas Have 15, 2000, Frederiksberg, Denmark; Zeppelin University, Center for Consumer, Markets and Politics, Am Seemooser Horn 20, 88045, Friedrichshafen, Germany. Electronic address:

Creating more health-fostering environments is high on the agenda of public and private actors. The behavioral approach to nudge people towards healthier food choices is gaining popularity despite limited understanding about where, and for whom, which specific nudges work. This study contributes by reporting on three different nudging interventions in the same setting and presents effects on different sub-populations. We find overall small effects that are heterogeneous, ranging from robustly more to even less healthy choices. We discuss the importance of transparency and reactance to health interventions and the potential interplay of interventions with habitual behavior among different sub-populations.
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http://dx.doi.org/10.1016/j.appet.2021.105106DOI Listing
May 2021

Quality of Life Improves Following Laparoscopic Hemifundoplication in Neurologically Non-Impaired Children with Gastroesophageal Reflux Disease: A Propensity Score-Matched Analysis.

J Invest Surg 2020 Nov 29:1-6. Epub 2020 Nov 29.

Division of Pediatric Surgery, Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany.

Background: Quality of life (QOL) data following pediatric fundoplication for gastroesophageal reflux disease (GERD) are rare. Present study assessed the QOL in neurologically non-impaired children before and after laparoscopic hemifundoplication (LHF) in comparison to healthy controls.

Methods: PedsQL™ questionnaires assessed data on gastrointestinal symptoms (GIS) and general well-being (GWB) were compared in a propensity score-matched analysis (60 patients' pairs for time-point of surgery and 51 for follow-up).

Results: Preoperatively, the LHF group had more GIS (72.2 ± 53.9 vs. 38.8 ± 31.6;  < 0.001) and a lower GWB (16.7 ± 5.5 vs. 23.8 ± 3.5,  < 0.001) compared with controls. Postoperatively, GIS decreased significantly (74.3 ± 52.9 vs. 36.3 ± 33.5;  < 0.001) and the GWB was significantly higher (16.2 ± 6.0 vs. 20.8 ± 5.8;  < 0.001). GIS were similar in the LHF and control groups (39.1 ± 36.4 vs. 40.1 ± 31.0;  = 0.885) but GWB was lower in the LHF group than the control group (20.5 ± 6.3 vs. 23.4 ± 3.9;  = 0.009).

Conclusions: QOL significantly improves after LHF in neurologically non-impaired children.
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http://dx.doi.org/10.1080/08941939.2020.1850943DOI Listing
November 2020

Spatial accessibility of general inpatient care in Germany: an analysis of surgery, internal medicine and neurology.

Sci Rep 2020 11 5;10(1):19157. Epub 2020 Nov 5.

Division of Health Services Research, Institute of Occupational Medicine, Social Medicine and Environmental Medicine, Goethe University Frankfurt, Theodor Stern Kai 7, 60590, Frankfurt/Main, Germany.

Improving spatial accessibility to hospitals is a major task for health care systems which can be facilitated using recent methodological improvements of spatial accessibility measures. We used the integrated floating catchment area (iFCA) method to analyze spatial accessibility of general inpatient care (internal medicine, surgery and neurology) on national level in Germany determining an accessibility index (AI) by integrating distances, hospital beds and morbidity data. The analysis of 358 million distances between hospitals and population locations revealed clusters of lower accessibility indices in areas in north east Germany. There was a correlation of urbanity and accessibility up to r = 0.31 (p < 0.001). Furthermore, 10% of the population lived in areas with significant clusters of low spatial accessibility for internal medicine and surgery (neurology: 20%). The analysis revealed the highest accessibility for heart failure (AI = 7.33) and the lowest accessibility for stroke (AI = 0.69). The method applied proofed to reveal important aspects of spatial accessibility i.e. geographic variations that need to be addressed. However, for the majority of the German population, accessibility of general inpatient care was either high or at least not significantly low, which suggests rather adequate allocation of hospital resources for most parts of Germany.
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http://dx.doi.org/10.1038/s41598-020-76212-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645718PMC
November 2020

Access to intensive care in 14 European countries: a spatial analysis of intensive care need and capacity in the light of COVID-19.

Intensive Care Med 2020 11 4;46(11):2026-2034. Epub 2020 Sep 4.

Division of Health Services Research, Institute of Occupational Medicine, Social Medicine and Environmental Medicine, Goethe University Frankfurt, Theodor Stern Kai 7, 60590, Frankfurt, Germany.

Purpose: The coronavirus disease 2019 (COVID-19) poses major challenges to health-care systems worldwide. This pandemic demonstrates the importance of timely access to intensive care and, therefore, this study aims to explore the accessibility of intensive care beds in 14 European countries and its impact on the COVID-19 case fatality ratio (CFR).

Methods: We examined access to intensive care beds by deriving (1) a regional ratio of intensive care beds to 100,000 population capita (accessibility index, AI) and (2) the distance to the closest intensive care unit. The cross-sectional analysis was performed at a 5-by-5 km spatial resolution and results were summarized nationally for 14 European countries. The relationship between AI and CFR was analyzed at the regional level.

Results: We found national-level differences in the levels of access to intensive care beds. The AI was highest in Germany (AI = 35.3), followed by Estonia (AI = 33.5) and Austria (AI = 26.4), and lowest in Sweden (AI = 5) and Denmark (AI = 6.4). The average travel distance to the closest hospital was highest in Croatia (25.3 min by car) and lowest in Luxembourg (9.1 min). Subnational results illustrate that capacity was associated with population density and national-level inventories. The correlation analysis revealed a negative correlation of ICU accessibility and COVID-19 CFR (r = - 0.57; p < 0.001).

Conclusion: Geographical access to intensive care beds varies significantly across European countries and low ICU accessibility was associated with a higher proportion of COVID-19 deaths to cases (CFR). Important differences in access are due to the sizes of national resource inventories and the distribution of health-care facilities relative to the human population. Our findings provide a resource for officials planning public health responses beyond the current COVID-19 pandemic, such as identifying potential locations suitable for temporary facilities or establishing logistical plans for moving severely ill patients to facilities with available beds.
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http://dx.doi.org/10.1007/s00134-020-06229-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7472675PMC
November 2020

Information Capturing in Pre-Hospital Emergency Medical Settings (EMS).

Stud Health Technol Inform 2020 Jun;270:613-617

Bern University of Applied Sciences, Bern Switzerland.

Emergency medical situations are characterized by high physical, cognitive and mental demands on the paramedics on the ground. Studies suggest that crucial information such as treatments administered to patients is often documented retrospectively, during patient transport or once a patient is handed over to an emergency department. Information access may also be surprisingly difficult (e.g. patient medical history). In this paper, we focus on supporting in situ information capturing and report on a realistic laboratory-based study involving experienced paramedics that we used to explore the specific requirements and constraints of supporting in situ information capturing. Specifically, we focused on ways to use audio and visual data capture methods and how they need to be designed to better support paramedics without interfering with their work. We then use the resulting information centric perspective to argue for a roadmap towards smart emergency medical services.
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http://dx.doi.org/10.3233/SHTI200233DOI Listing
June 2020

Vorinostat in the acute neuroinflammatory form of X-linked adrenoleukodystrophy.

Ann Clin Transl Neurol 2020 05 2;7(5):639-652. Epub 2020 May 2.

Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Vienna, Austria.

Objective: To identify a pharmacological compound targeting macrophages, the most affected immune cells in inflammatory X-linked adrenoleukodystrophy (cerebral X-ALD) caused by ABCD1 mutations and involved in the success of hematopoietic stem cell transplantation and gene therapy.

Methods: A comparative database analysis elucidated the epigenetic repressing mechanism of the related ABCD2 gene in macrophages and identified the histone deacetylase (HDAC) inhibitor Vorinostat as a compound to induce ABCD2 in these cells to compensate for ABCD1 deficiency. In these cells, we investigated ABCD2 and pro-inflammatory gene expression, restoration of defective peroxisomal β-oxidation activity, accumulation of very long-chain fatty acids (VLCFAs) and their differentiation status. We investigated ABCD2 and pro-inflammatory gene expression, restoration of defective peroxisomal ß-oxidation activity, accumulation of very long-chain fatty acids (VLCFA) and differentiation status. Three advanced cerebral X-ALD patients received Vorinostat and CSF and MRI diagnostics was carried out in one patient after 80 days of treatment.

Results: Vorinostat improved the metabolic defects in X-ALD macrophages by stimulating ABCD2 expression, peroxisomal ß-oxidation, and ameliorating VLCFA accumulation. Vorinostat interfered with pro-inflammatory skewing of X-ALD macrophages by correcting IL12B expression and further reducing monocyte differentiation. Vorinostat normalized the albumin and immunoglobulin CSF-serum ratios, but not gadolinium enhancement upon 80 days of treatment.

Interpretation: The beneficial effects of HDAC inhibitors on macrophages in X-ALD and the improvement of the blood-CSF/blood-brain barrier are encouraging for future investigations. In contrast with Vorinostat, less toxic macrophage-specific HDAC inhibitors might improve also the clinical state of X-ALD patients with advanced inflammatory demyelination.
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http://dx.doi.org/10.1002/acn3.51015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261758PMC
May 2020

Pre-migration socioeconomic status and post-migration health satisfaction among Syrian refugees in Germany: A cross-sectional analysis.

PLoS Med 2020 03 31;17(3):e1003093. Epub 2020 Mar 31.

Leibniz Institute for Prevention Research and Epidemiology-BIPS, Bremen, Germany.

Background: The large increase in numbers of refugees and asylum seekers in Germany and most of Europe has put the issue of migration itself, the integration of migrants, and also their health at the top of the political agenda. However, the dynamics of refugee health are not yet well understood. From a life-course perspective, migration experience is associated with various risks and changes, which might differ depending on the socioeconomic status (SES) of refugees in their home country. The aim of this paper was to analyze the relationship between pre-migration SES and self-reported health indicators after migration among Syrian refugees. Specifically, we wanted to find out how their SES affects the change in health satisfaction from pre- to post-migration.

Methods And Findings: We used data from the 2016 refugee survey, which was part of the German Socio-Economic Panel (GSOEP). Although cross-sectional by design, this survey collected information referring to the current situation as a refugee in Germany as well as to their situation before migration. Using a sample of 2,209 adult Syrian refugees who had entered Germany between 2013 and 2016, we conducted a cross-sectional and a quasi-longitudinal (retrospective) analysis. The mean ± SD age was 35 ± 11 years, with 64% of the participants being male. Our results showed a positive association between pre-migration self-reported SES and several subjective health indicators (e.g., health satisfaction, self-reported health, mental health) in the cross-sectional analysis. However, the quasi-longitudinal analysis revealed that the socioeconomic gradient in health satisfaction before migration was strongly attenuated after migration (SES-by-time interaction: -0.48, 95% CI -0.61 to -0.35, p < 0.001; unstandardized regression coefficients, 5-point SES scale and 11-point health outcome scale). Similar results were produced after controlling for sociodemographic characteristics, experiences during the migration passage, and the current situation in Germany. A sex-stratified analysis showed that while there was some improvement in health satisfaction among men from the lowest SES over time, no improvement was found among women. A limitation of this study is that it considers only the first months or years after migration. Thus, we cannot preclude that the socioeconomic gradient regains importance in the longer run.

Conclusions: Our findings suggest that the pre-migration socioeconomic gradient in health satisfaction is strongly attenuated in the first years after migration among Syrian refugees. Hence, a high SES before crisis and migration provides limited protection against the adverse health effects of migration passage.
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http://dx.doi.org/10.1371/journal.pmed.1003093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108713PMC
March 2020

A 64-Year-Old Patient With a Mesiotemporal Mass and Symptomatic Epilepsy.

Brain Pathol 2020 03;30(2):413-414

Department of Neurology, Ulm University, Ulm, Germany.

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http://dx.doi.org/10.1111/bpa.12818DOI Listing
March 2020

Treatment of experimental autoimmune encephalomyelitis with engineered bi-specific Foxp3+ regulatory CD4+ T cells.

J Autoimmun 2020 03 13;108:102401. Epub 2020 Jan 13.

Centre de Physiopathologie Toulouse-Purpan (CPTP), Université de Toulouse, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (Inserm), Université Paul Sabatier (UPS), Toulouse, France. Electronic address:

The use of autoantigen-specific regulatory T cells (Tregs) as a cellular therapy for autoimmune diseases is appealing. However, it is challenging to isolate and expand large quantity of Tregs expressing disease-relevant T-cell receptors (TCR). To overcome this problem, we used an approach aiming at redirecting the specificity of polyclonal Tregs through autoreactive TCR gene transfer technology. In this study, we examined whether Tregs engineered through retroviral transduction to express a TCR cross-reactive to two CNS autoantigens, myelin oligodendrocyte glycoprotein (MOG) and neurofilament-medium (NF-M), had a superior protective efficacy compared with Tregs expressing a MOG mono-specific TCR. We observed that engineered Tregs (engTregs) exhibited in vitro regulatory effects related to the antigenic specificity of the introduced TCR, and commensurate in potency with the avidity of the transduced TCR. In experimental autoimmune encephalomyelitis (EAE), adoptively transferred engTregs proliferated, and migrated to the CNS, while retaining FoxP3 expression. EngTregs expressing MOG/NF-M cross-reactive TCR had superior protective properties over engTregs expressing MOG-specific TCR in MOG-induced EAE. Remarkably, MOG/NF-M bi-specific TCR-engTregs also improved recovery from EAE induced by an unrelated CNS autoantigen, proteolipid protein (PLP). This study underlines the benefit of using TCRs cross-reacting towards multiple autoantigens, compared with mono-reactive TCR, for the generation of engTregs affording protection from autoimmune disease in adoptive cell therapy.
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http://dx.doi.org/10.1016/j.jaut.2020.102401DOI Listing
March 2020

CD8 T cell-mediated endotheliopathy is a targetable mechanism of neuro-inflammation in Susac syndrome.

Nat Commun 2019 12 18;10(1):5779. Epub 2019 Dec 18.

Institute of Clinical Neuroimmunology, Biomedical Center and Hospital of the Ludwig-Maximilians-University Munich, Großhaderner Straße 9, Martinsried, 82152, Munich, Germany.

Neuroinflammation is often associated with blood-brain-barrier dysfunction, which contributes to neurological tissue damage. Here, we reveal the pathophysiology of Susac syndrome (SuS), an enigmatic neuroinflammatory disease with central nervous system (CNS) endotheliopathy. By investigating immune cells from the blood, cerebrospinal fluid, and CNS of SuS patients, we demonstrate oligoclonal expansion of terminally differentiated activated cytotoxic CD8 T cells (CTLs). Neuropathological data derived from both SuS patients and a newly-developed transgenic mouse model recapitulating the disease indicate that CTLs adhere to CNS microvessels in distinct areas and polarize granzyme B, which most likely results in the observed endothelial cell injury and microhemorrhages. Blocking T-cell adhesion by anti-α4 integrin-intervention ameliorates the disease in the preclinical model. Similarly, disease severity decreases in four SuS patients treated with natalizumab along with other therapy. Our study identifies CD8 T-cell-mediated endotheliopathy as a key disease mechanism in SuS and highlights therapeutic opportunities.
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http://dx.doi.org/10.1038/s41467-019-13593-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6920411PMC
December 2019

Gender and workforce in urology - use of the BG Index to Assess Female Career Promotion in Academic Urology.

Urol J 2020 01 26;17(1):86-90. Epub 2020 Jan 26.

Department of Social Medicine, The Institute of Occupational Medicine, Social Medicine and Environmental Medicine, Goethe-University, Frankfurt, Germany.

Purpose: Today, the majority of medical graduates in countries such as the UK, the US or Germany are female. This poses a major problem for workforce planning especially in urology. We here use first the first time the previously established Brüggmann Groneberg (BG) index to assess if female academic career options advance in urology.

Methods: Different operating parameters (student population, urology specialist population, urology chair female:male (f:m) ratio) were collected from the Federal Office of Statistics, the Federal Chamber of Physicians and the medical faculties of 36 German universities. Four time points were monitored (2000, 2005, 2010 and 2015). From these data, female to male (f:m) ratios and the recently established career advancement (BG) index have been calculated.

Results: The German hospital urology specialists' f:m ratios were 0.257 (499 female vs. 1944 male) for 2015, 0.195 for 2010, 0.133 for 2005 and 0.12 for 2000. The career advancement (BG) index was 0.0007 for 2000, 0,0005 for 2005, 0.094 for 2010 and 0.073 for 2015. The decrease from 2010 to 2015 was due to an increase in the f:m ratio of hospital urologists and female medical students.

Conclusion: The BG index clearly illustrated that there is an urgent need for special academic career funding programs to counteract gender problems in urology. The BG index has been shown to be an excellent tool to assess female academic career options and will be very helpful to assess and document positive or negative changes in the next decades.
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http://dx.doi.org/10.22037/uj.v0i0.4116DOI Listing
January 2020

A world map of evidence-based medicine: Density equalizing mapping of the Cochrane database of systematic reviews.

PLoS One 2019 13;14(12):e0226305. Epub 2019 Dec 13.

The Institute of Occupational, Social and Environmental Medicine, Goethe University Frankfurt, Frankfurt, Germany.

Systematic reviews represent the core and backbone of evidence-based medicine (EBM) strategies in all fields of medicine. In order to depict a first global sketch of the international efforts in the Cochrane database systematic reviews (CDSR), we analyzed the systematic reviews of the Cochrane database. Our global maps of systematic reviewing offer intriguing structural insights into the world of EBM strategies. They demonstrate that for the CDSR, the UK and Commonwealth countries take the lead position. Since patients, care providers and health systems all over the world benefit from systematic reviewing, institutions in other countries should increase their commitment.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0226305PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6910692PMC
April 2020

Identification of influenza urban transmission patterns by geographical, epidemiological and whole genome sequencing data: protocol for an observational study.

BMJ Open 2019 08 20;9(8):e030913. Epub 2019 Aug 20.

Human Geography, Department of Environmental Science, University of Basel, Basel, Switzerland.

Introduction: Urban transmission patterns of influenza viruses are complex and poorly understood, and multiple factors may play a critical role in modifying transmission. Whole genome sequencing (WGS) allows the description of patient-to-patient transmissions at highest resolution. The aim of this study is to explore urban transmission patterns of influenza viruses in high detail by combining geographical, epidemiological and immunological data with WGS data.

Methods And Analysis: The study is performed at the University Hospital Basel, University Children's Hospital Basel and a network of paediatricians and family doctors in the Canton of Basel-City, Switzerland. The retrospective study part includes an analysis of PCR-confirmed influenza cases from 2013 to 2018. The prospective study parts include (1) a household survey regarding influenza-like illness (ILI) and vaccination against influenza during the 2015/2016 season; (2) an analysis of influenza viruses collected during the 2016/2017 season using WGS-viral genomic sequences are compared with determine genetic relatedness and transmissions; and (3) measurement of influenza-specific antibody titres against all vaccinated and circulated strains during the 2016/2017 season from healthy individuals, allowing to monitor herd immunity across urban quarters. Survey data and PCR-confirmed cases are linked to data from the Statistics Office of the Canton Basel-City and visualised using geo-information system mapping. WGS data will be analysed in the context of patient epidemiological data using phylodynamic analyses, and the obtained herd immunity for each quarter. Profound knowledge on the key geographical, epidemiological and immunological factors influencing urban influenza transmission will help to develop effective counter measurements.

Ethics And Dissemination: The study is registered and approved by the regional ethics committee as an observational study (EKNZ project ID 2015-363 and 2016-01735). It is planned to present the results at conferences and publish the data in scientific journals.

Trial Registration Number: NCT03010007.
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http://dx.doi.org/10.1136/bmjopen-2019-030913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6707652PMC
August 2019

Paraneoplastic neuromyelitis optica and ovarian teratoma: A case series.

Mult Scler Relat Disord 2019 Jun 1;31:97-100. Epub 2019 Apr 1.

Center for pathophysiology Toulouse Purpan, INSERM U1043, CNRS 5282, Université Toulouse III, 31024 Toulouse, France; CRC-SEP, Pôle Neurosciences, CHU de Toulouse, 31059 Toulouse, France.

Neuromyelitis optica spectrum disorder (NMOSD) is a rare inflammatory disease of the central nervous system, characterized by the presence of auto-antibodies directed against aquaporin-4 (AQP4) expressed on astrocyte end-feet. Despite NMOSD does not primarily belong to the spectrum of paraneoplastic neurological syndromes, rare cases of association with neoplasia have been outlined. Here, we report the association of NMOSD with ovarian teratoma in 3 cases. Pathological analysis of teratomas revealed glial component strongly expressing AQP4 and closely localized to immune infiltrates. Our series highlight the rare association of teratoma with NMOSD and the possible paraneoplastic mechanism.
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http://dx.doi.org/10.1016/j.msard.2019.03.031DOI Listing
June 2019

IFN-γ is a therapeutic target in paraneoplastic cerebellar degeneration.

JCI Insight 2019 04 4;4(7). Epub 2019 Apr 4.

Centre de Physiopathologie Toulouse-Purpan (CPTP), Université de Toulouse, CNRS, Inserm, UPS, Toulouse, France.

Paraneoplastic neurological disorders result from an autoimmune response against neural self-antigens that are ectopically expressed in neoplastic cells. In paraneoplastic disorders associated to autoantibodies against intracellular proteins, such as paraneoplastic cerebellar degeneration (PCD), current data point to a major role of cell-mediated immunity. In an animal model, in which a neo-self-antigen was expressed in both Purkinje neurons and implanted breast tumor cells, immune checkpoint blockade led to complete tumor control at the expense of cerebellum infiltration by T cells and Purkinje neuron loss, thereby mimicking PCD. Here, we identify 2 potential therapeutic targets expressed by cerebellum-infiltrating T cells in this model, namely α4 integrin and IFN-γ. Mice with PCD were treated with anti-α4 integrin antibodies or neutralizing anti-IFN-γ antibodies at the onset of neurological signs. Although blocking α4 integrin had little or no impact on disease development, treatment using the anti-IFN-γ antibody led to almost complete protection from PCD. These findings strongly suggest that the production of IFN-γ by cerebellum-invading T cells plays a major role in Purkinje neuron death. Our successful preclinical use of neutralizing anti-IFN-γ antibody for the treatment of PCD offers a potentially new therapeutic opportunity for cancer patients at the onset of paraneoplastic neurological disorders.
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http://dx.doi.org/10.1172/jci.insight.127001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6483638PMC
April 2019

Microglial nodules provide the environment for pathogenic T cells in human encephalitis.

Acta Neuropathol 2019 04 20;137(4):619-635. Epub 2019 Jan 20.

Department of Neuroimmunology, Center for Brain Research, Medical University of Vienna, Spitalgasse 4, 1090, Vienna, Austria.

Microglia nodule formation is a common feature in inflammatory brain diseases mediated by T lymphocytes such as viral and paraneoplastic encephalitis, multiple sclerosis, and Rasmussen encephalitis (RE). However, its role has not been fully understood yet. We hypothesized that, in RE, microglial nodules provide an environment for the initiation of the later dominating T-cell cytotoxicity. In RE stage 0, small primary microglia nodules could be identified in the absence of T cells. These primary nodules showed inflammasome activation and endosomal Toll-like receptor upregulation. In stage 1, T cells migrate into the parenchyma and intermingle with microglial cells, thereby forming secondary nodules in which neurons are destroyed. Whole-genome transcriptome analysis at this point showed upregulation of several inflammatory pathways including interferon signaling and major histocompatibility complex-I signaling. Inflammatory profiles, like the ones observed in RE, could be induced upon TLR3 stimulation in neonatal microglial cell cultures. Taken together, our results point towards activation of endosomal TLRs, resulting in increased interferon signaling, inflammasome activation, and chemokine upregulation as early steps in RE pathogenesis. This activity sets the scene for subsequent infiltration of T cells and destruction of neurons. Similar to RE, this microglial microenvironment might be a crucial step in other T-cell-mediated inflammatory brain diseases.
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http://dx.doi.org/10.1007/s00401-019-01958-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6426829PMC
April 2019

Targeted Diet Modification Reduces Multiple Sclerosis-like Disease in Adult Marmoset Monkeys from an Outbred Colony.

J Immunol 2018 12 19;201(11):3229-3243. Epub 2018 Oct 19.

Department of Immunobiology, Biomedical Primate Research Centre, 2280 GH Rijswijk, the Netherlands.

Experimental autoimmune encephalomyelitis (EAE) in common marmosets is a translationally relevant model of the chronic neurologic disease multiple sclerosis. Following the introduction of a new dietary supplement in our purpose-bred marmoset colony, the percentage of marmosets in which clinically evident EAE could be induced by sensitization against recombinant human myelin oligodendrocyte glycoprotein in IFA decreased from 100 to 65%. The reduced EAE susceptibility after the dietary change coincided with reduced expression in the colony, an EBV-related γ1-herpesvirus associated with EAE. We then investigated, in a controlled study in marmoset twins, which disease-relevant parameters were affected by the dietary change. The selected twins had been raised on the new diet for at least 12 mo prior to the study. In twin siblings reverted to the original diet 8 wk prior to EAE induction, 100% disease prevalence (eight out of eight) was restored, whereas in siblings remaining on the new diet the EAE prevalence was 75% (six out of eight). Spinal cord demyelination, a classical hallmark of the disease, was significantly lower in new-diet monkeys than in monkeys reverted to the original diet. In new-diet monkeys, the proinflammatory T cell response to recombinant human myelin oligodendrocyte glycoprotein was significantly reduced, and RNA-sequencing revealed reduced apoptosis and enhanced myelination in the brain. Systematic typing of the marmoset gut microbiota using 16S rRNA sequencing demonstrated a unique, Bifidobacteria-dominated composition, which changed after disease induction. In conclusion, targeted dietary intervention exerts positive effects on EAE-related parameters in multiple compartments of the marmoset's gut-immune-CNS axis.
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http://dx.doi.org/10.4049/jimmunol.1800822DOI Listing
December 2018

Does livestock protect from malaria or facilitate malaria prevalence? A cross-sectional study in endemic rural areas of Indonesia.

Malar J 2018 Aug 20;17(1):302. Epub 2018 Aug 20.

Faculty of Medicine, Institute of Occupational Medicine, Social Medicine and Environmental Medicine, Goethe University, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.

Background: Ever since it was discovered that zoophilic vectors can transmit malaria, zooprophylaxis has been used to prevent the disease. However, zoopotentiation has also been observed. Thus, the presence of livestock has been widely accepted as an important variable for the prevalence and risk of malaria, but the effectiveness of zooprophylaxis remained subject to debate. This study aims to critically analyse the effects of the presence of livestock on malaria prevalence using a large dataset from Indonesia.

Methods: This study is based on data from the Indonesia Basic Health Research ("Riskesdas") cross-sectional survey of 2007 organized by the National Institute of Health Research and Development of Indonesia's Ministry of Health. The subset of data used in the present study included 259,885 research participants who reside in the rural areas of 176 regencies throughout the 15 provinces of Indonesia where the prevalence of malaria is higher than the national average. The variable "existence of livestock" and other independent demographic, social and behavioural variables were tested as potential determinants for malaria prevalence by multivariate logistic regressions.

Results: Raising medium-sized animals in the house was a significant predictor of malaria prevalence (OR = 2.980; 95% CI 2.348-3.782, P < 0.001) when compared to keeping such animals outside of the house (OR = 1.713; 95% CI 1.515-1.937, P < 0.001). After adjusting for gender, age, access to community health facility, sewage canal condition, use of mosquito nets and insecticide-treated bed nets, the participants who raised medium-sized animals inside their homes were 2.8 times more likely to contract malaria than respondents who did not (adjusted odds ratio = 2.809; 95% CI 2.207-3.575; P < 0.001).

Conclusions: The results of this study highlight the importance of livestock for malaria transmission, suggesting that keeping livestock in the house contributes to malaria risk rather than prophylaxis in Indonesia. Livestock-based interventions should therefore play a significant role in the implementation of malaria control programmes, and focus on households with a high proportion of medium-sized animals in rural areas. The implementation of a "One Health" strategy to eliminate malaria in Indonesia by 2030 is strongly recommended.
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http://dx.doi.org/10.1186/s12936-018-2447-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6102806PMC
August 2018

The compartmentalized inflammatory response in the multiple sclerosis brain is composed of tissue-resident CD8+ T lymphocytes and B cells.

Brain 2018 07;141(7):2066-2082

Department of Neuroimmunology, Center for Brain Research, Medical University of Vienna, Vienna, Austria.

Multiple sclerosis is an inflammatory demyelinating disease in which active demyelination and neurodegeneration are associated with lymphocyte infiltrates in the brain. However, so far little is known regarding the phenotype and function of these infiltrating lymphocyte populations. In this study, we performed an in-depth phenotypic characterization of T and B cell infiltrates in a large set of multiple sclerosis cases with different disease and lesion stages and compared the findings with those seen in inflammatory, non-inflammatory and normal human controls. In multiple sclerosis lesions, we found a dominance of CD8+ T cells and a prominent contribution of CD20+ B cells in all disease courses and lesion stages, including acute multiple sclerosis cases with very short disease duration, while CD4+ T cells were sparse. A dominance of CD8+ T cells was also seen in other inflammatory controls, such as Rasmussen's encephalitis and viral encephalitis, but the contribution of B cells in these diseases was modest. Phenotypic analysis of the CD8+ T cells suggested that part of the infiltrating cells in active lesions proliferate, show an activated cytotoxic phenotype and are in part destroyed by apoptosis. Further characterization of the remaining cells suggest that CD8+ T cells acquire features of tissue-resident memory cells, which may be focally reactivated in active lesions of acute, relapsing and progressive multiple sclerosis, while B cells, at least in part, gradually transform into plasma cells. The loss of surface molecules involved in the egress of leucocytes from inflamed tissue, such as S1P1 or CCR7, and the upregulation of CD103 expression may be responsible for the compartmentalization of the inflammatory response in established lesions. Similar phenotypic changes of tissue-infiltrating CD8+ T cells were also seen in Rasmussen's encephalitis. Our data underline the potential importance of CD8+ T lymphocytes and B cells in the inflammatory response in established multiple sclerosis lesions. Tissue-resident T and B cells may represent guardians of previous inflammatory brain disease, which can be reactivated and sustain the inflammatory response, when they are re-exposed to their specific antigen.
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http://dx.doi.org/10.1093/brain/awy151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6022681PMC
July 2018

[The gender gap in highest quality medical research - A scientometric analysis of the representation of female authors in highest impact medical journals].

Dtsch Med Wochenschr 2018 May 4;143(10):e85-e94. Epub 2018 May 4.

Abteilung für computergestützte Methoden in der Medizin, Institut für Arbeits-, Sozial- und Umweltmedizin, Goethe University Frankfurt, Germany.

Objective:  The study aims to elucidate the state of gender equality in high-impact medical research, analyzing the representation of female authorships from January, 2008 to September, 2017.

Methods:  133 893 male and female authorships from seven high-impact medical journals were analyzed. The key methodology was the combined analysis of the relative frequency, odds ratio and citations of female authorships. The Prestige Index measures the distribution of prestigious authorships between the two genders.

Results:  35.0 % of all authorships and 34.3 % of the first, 36.1 % of the co- and 24.2 % of the last authorships were held by women. Female authors have an odds ratio of 0.97 (KI: 0.93 - 1.01) for first, 1.36 (KI: 1.32 - 1.40) for co- und 0.57 (KI: 0.54 - 0.60) for last authorships compared to male authors. The proportion of female authorships exhibits an annual growth of 1.3 % overall, with 0.5 % for first, 1.2 % for co-, and 0.8 % for last authorships. Women are underrepresented at prestigious authorship compared to men (Prestige Index = -0.38). The underrepresentation accentuates in highly competitive articles attracting the highest citation rates, namely, articles with many authors and articles that were published in highest-impact journals. Multi-author articles with male key authors are more frequently cited than articles with female key authors. The gender-specific differences in citation rates increase the more authors contribute to an article. Women publish fewer articles compared to men (39.6 % female authors are responsible for 35.0 % of the authorships) and are underrepresented at productivity levels of more than 1 article per author. Distinct differences at the country level were revealed.

Conclusion:  High impact medical research is characterized by few female group leaders as last authors and many female researchers being first or co-authors early in their career. It is very likely that this gender-specific career dichotomy will persistent in the next decade.
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http://dx.doi.org/10.1055/s-0044-102267DOI Listing
May 2018

Immigration: analysis, trends and outlook on the global research activity.

J Glob Health 2018 Jun;8(1):010414

Goethe University Frankfurt, Department of Gynecology and Obstetrics, Frankfurt am Main, Germany.

Background: Immigration has a strong impact on the development of health systems, medicine and science worldwide. Therefore, this article provides a descriptive study on the overall research output.

Methods: Utilizing the scientific database Web of Science, data research was performed. The gathered bibliometric data was analyzed using the established platform NewQIS, a benchmarking system to visualize research quantity and quality indices.

Findings: Between 1900 and 2016 a total of 6763 articles on immigration were retrieved and analyzed. 86 different countries participated in the publications. Quantitatively the United States followed by Canada and Spain were prominent regarding the article numbers. On comparing by additionally taking the population size into account, Israel followed by Sweden and Norway showed the highest performance. The main releasing journals are the the and Over the decades, an increasing number of articles can be recognized which finally forms the mainly used subject area.

Conclusion: Considerably increasing scientific work on immigration cannot only be explained by the general increase of scientific work but is also owed to the latest development with increased mobility, worldwide crises and the need of flight and migration. Especially countries with a good economic situation are highly affected by immigrants and prominent in their publication output on immigration, since the countries' publication effort is connected with the appointed expenditures for research and development. Remarkable numbers of immigrants throughout Europe compel medical professionals to consider neglected diseases, requires the public health system to restructure itself and finally promotes science.
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http://dx.doi.org/10.7189/jogh.08.010414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5908396PMC
June 2018

Systematic evaluation of RNA quality, microarray data reliability and pathway analysis in fresh, fresh frozen and formalin-fixed paraffin-embedded tissue samples.

Sci Rep 2018 04 20;8(1):6351. Epub 2018 Apr 20.

Department of Neuroimmunology, Center for Brain Research, Medical University of Vienna, Vienna, Austria.

Formalin-fixed paraffin-embedded (FFPE) tissues are valuable resources commonly used in pathology. However, formalin fixation modifies nucleic acids challenging the isolation of high-quality RNA for genetic profiling. Here, we assessed feasibility and reliability of microarray studies analysing transcriptome data from fresh, fresh-frozen (FF) and FFPE tissues. We show that reproducible microarray data can be generated from only 2 ng FFPE-derived RNA. For RNA quality assessment, fragment size distribution (DV200) and qPCR proved most suitable. During RNA isolation, extending tissue lysis time to 10 hours reduced high-molecular-weight species, while additional incubation at 70 °C markedly increased RNA yields. Since FF- and FFPE-derived microarrays constitute different data entities, we used indirect measures to investigate gene signal variation and relative gene expression. Whole-genome analyses revealed high concordance rates, while reviewing on single-genes basis showed higher data variation in FFPE than FF arrays. Using an experimental model, gene set enrichment analysis (GSEA) of FFPE-derived microarrays and fresh tissue-derived RNA-Seq datasets yielded similarly affected pathways confirming the applicability of FFPE tissue in global gene expression analysis. Our study provides a workflow comprising RNA isolation, quality assessment and microarray profiling using minimal RNA input, thus enabling hypothesis-generating pathway analyses from limited amounts of precious, pathologically significant FFPE tissues.
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http://dx.doi.org/10.1038/s41598-018-24781-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5910432PMC
April 2018