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BACKGROUND Living donor renal transplantation is widely performed in Switzerland with a superior long-term outcome and lower waiting time compared with deceased renal transplantation. However the chances of receiving a living donor kidney transplant are not the same for all transplant candidates. The current study aimed to identify psychosocial and demographic characteristics that predict lower access to living kidney donation in Switzerland. METHODS The study was a nationwide multicentre study nested within the Swiss Transplant Cohort Study. Pre-transplant demographic, psychosocial and health characteristics of 1126 deceased and 859 living renal transplant recipients were compared using logistic regression analysis. RESULTS Transplant candidates with higher age (odds ratio [OR] per 10 years 0.67, 95% confidence interval [CI] 0.60–0.74), lower education (OR 0.46, 95% CI 0.36–0.59), a work capacity of less than 50% (OR 0.48, 95% CI 0.35–0.66), single or formerly married (OR 0.38, 95% CI 0.26–0.53 / OR 0.37, 95% CI 0.26–0.53) or with a higher hospital depression score (OR per 5 points 0.61, 95% CI 0.50–0.74) were less likely to receive an allograft from a living donor. In some regions of Switzerland candidates were more likely to undergo living transplantation than in other regions. No association was found with gender or income. CONCLUSIONS Interventions to increase access to kidney transplantation from living donors should target transplant candidates of older age, lower education, lower working capacity and not living in a committed relationship. The observed regional differences suggest that additional determinants of living donation may play a role such as population and health professional attitudes toward living donation.

Private water supply systems consisting of a domestic well and septic system are used throughout the world where households lack access to public water supply and sewers. In residential areas with high housing density, septic contamination of private wells is common and associated with multiple health concerns. This situation can give rise to social dilemmas, where individual costs dis-incentivize homeowners from investing in enhanced septic systems that would reduce well contamination and bring communal benefits. We combine a stylized game-theoretical model with a probabilistic groundwater model to characterize how economic and hydrogeological conditions interact to produce misaligned incentives conducive to social dilemmas. The occurrence of social dilemmas depends on the relative costs of well contamination versus the cost of installing an enhanced septic treatment system, and the relative probabilities of cross-contamination versus self-contamination. The game reveals three three types of social dilemmas that occur in such systems, with each calling for distinct policy solutions. We demonstrate how the model can be applied to existing systems using a case study of St Joseph County, Indiana, where high nitrate contamination rates have raised public health concerns. This analysis represents a step towards identifying alternative policy solutions for a problem that has remained difficult to address for decades.

Metastatic spread of a cancer to secondary sites is a coordinated, non-random process. Cancer cell-secreted vesicles, especially exosomes, have recently been implicated in the guidance of metastatic dissemination, with specific surface composition determining some aspects of organ-specific localization. Nevertheless, whether the tumor microenvironment influences exosome biodistribution has yet to be investigated. Here, we show that microenvironmental cytokines, particularly CCL2, decorate cancer exosomes via binding to surface glycosaminoglycan side chains of proteoglycans, causing exosome accumulation in specific cell subsets and organs. Exosome retention results in changes in the immune landscape within these organs, coupled with a higher metastatic burden. Strikingly, CCL2-decorated exosomes are directed to a subset of cells that express the CCL2 receptor CCR2, demonstrating that exosome-bound cytokines are a crucial determinant of exosome-cell interactions. In addition to the finding that cytokine-conjugated exosomes are detected in the blood of cancer patients, we discovered that healthy subjects derived exosomes are also associated with cytokines. Although displaying a different profile from exosomes isolated from cancer patients, it further indicates that specific combinations of cytokines bound to exosomes could likewise affect other physiological and disease settings., Cancer derived exosomes are reported to promote metastatic dissemination. Here the authors show that cytokines in the tumor microenvironment bind to exosomes via glycosaminoglycan side chains of proteoglycans, and these exosomes are preferentially taken up by specific cell lineages and organs to promote metastasis.

The structured coalescent allows inferring migration patterns between viral sub-populations from genetic sequence data. However, these analyses typically assume that no genetic recombination process impacted the sequence evolution of pathogens. For segmented viruses, such as influenza, that can undergo reassortment this assumption is broken. Reassortment reshuffles the segments of different parent lineages upon a coinfection event, which means that the shared history of viruses has to be represented by a network instead of a tree. Therefore, full genome analyses of such viruses is complex or even impossible. While this problem has been addressed for unstructured populations, it is still impossible to account for population structure, such as induced by different host populations, while also accounting for reassortmentWe address this by extending the structured coalescent to account for reassortment and present a framework for investigating possible ties between reassortment and migration (host jump) events. This method can accurately estimate sub-population dependent effective populations sizes, reassortment and migration rates from simulated data. Additionally, we apply the new model to avian influenza A/H5N1 sequences, sampled from two avian host types, Anseriformes and Galliformes. We contrast our results with a structured coalescent without reassortment inference, which assumes independently evolving segments. This reveals that taking into account segment reassortment and using sequencing data from several viral segments for joint phylodynamic inference leads to different estimates for effective population sizes, migration and clock rates.This new model is implemented as the Structured Coalescent with Reassortment (SCoRe) package for BEAST 2.5 and is available at https://github.com/jugne/SCORE.

To investigate renal pelvic pressures during percutaneous nephrolithotomy (PCNL) in the standard, mini, and ultramini PCNL systems.We studied an ultramini PCNL system (UMP, outer shaft diameter 13F), a mini PCNL system (MPCNL, shaft 18F, nephroscope 12F), and a standard PCNL system (SPCNL, shaft 27F, nephroscope 24F). Pressure profiles were first investigated in an open model setup, subsequently in a closed model, and finally in an ex vivo porcine kidney. Measurements were determined with the nephroscope in an advanced and pulled-back position for all models.In the advanced position, maximum pressures of 41.61 ± 0.20 mmHg (UMP), 15.61 ± 0.15 mmHg (MPCNL), and 15.46 ± 0.14 mmHg (SPCNL) were measured in the closed model. In the pulled-back position, maximum pressures were 16.04 ± 0.22 mmHg (UMP), 17.02 ± 0.11 mmHg (MPCNL), and 20.50 ± 0.11 mmHg (SPCNL). In the ex vivo porcine kidney model, maximum pressures were 13.81 ± 6.04 mmHg (UMP), 5.64 ± 0.21 (MPCNL), and 9.21 ± 0.52 (SPCNL) with the nephroscope pushed to end position. After retracting the nephroscope from the outer shaft, pressures in all systems did not exceed 10 mmHg.The maximum pressures achieved with the three PCNL systems in all three models were kept below the 30 mmHg critical threshold value. High pressures were only determined for the UMP system with the nephroscope pushed to its end position. This was attributed to the conical shape of the nephroscope, which occupies the space between the nephroscope and outer shaft, resulting in outflow obstruction.

BackgroundLack of functional evidence hampers variant interpretation, leaving a large proportion of cases with a suspected Mendelian disorder without genetic diagnosis after genome or whole exome sequencing (WES). Research studies advocate to further sequence transcriptomes to directly and systematically probe gene expression defects. However, collection of additional biopsies, and establishment of lab workflows, analytical pipelines, and defined concepts in clinical interpretation of aberrant gene expression are still needed for adopting RNA-sequencing (RNA-seq) in routine diagnostics.MethodsWe implemented an automated RNA-seq protocol and a computational workflow with which we analyzed skin fibroblasts of 303 individuals with a suspected mitochondrial disease which previously underwent WES.ResultsWe detected on average 12,500 genes per sample including around 60% disease genes - a coverage substantially higher than with whole blood, supporting the use of skin biopsies. We prioritized genes demonstrating aberrant expression, aberrant splicing, or mono-allelic expression. The pipeline required less than one week from sample preparation to result reporting and provided a median of eight disease-associated genes per patient for inspection. A genetic diagnosis was established for 16% of the 205 WES-inconclusive cases. Detection of aberrant expression was a major contributor to diagnosis including instances of 50% reduction, which, together with mono-allelic expression, allowed for the diagnosis of dominant disorders caused by haploinsufficiency. Moreover, calling aberrant splicing and variants from RNA-seq data enabled detecting and validating splice-disrupting variants, of which the majority fell outside WES-covered regions.ConclusionTogether, these results show that streamlined experimental and computational processes can accelerate the implementation of RNA-seq in routine diagnostics.One sentence summaryImplementation of RNA-seq as a complementary tool in standard diagnostics achieves a 16% in diagnosis rate over whole exome sequencing.

BACKGROUND: Transcriptome sequencing (RNA-seq) improves diagnostic rates in individuals with suspected Mendelian conditions to varying degrees, primarily by directing the prioritization of candidate DNA variants identified on exome or genome sequencing (ES/GS). Here we implemented an RNA-seq–guided method to diagnose individuals across a wide range of ages and clinical phenotypes. METHODS: One hundred fifteen undiagnosed adult and pediatric patients with diverse phenotypes and 67 family members (182 total individuals) underwent RNA-seq from whole blood and skin fibroblasts at the Baylor College of Medicine (BCM) Undiagnosed Diseases Network clinical site from 2014 to 2020. We implemented a workflow to detect outliers in gene expression and splicing for cases that remained undiagnosed despite standard genomic and transcriptomic analysis. RESULTS: The transcriptome-directed approach resulted in a diagnostic rate of 12% across the entire cohort, or 17% after excluding cases solved on ES/GS alone. Newly diagnosed conditions included Koolen–de Vries syndrome (KANSL1), Renpenning syndrome (PQBP1), TBCK-associated encephalopathy, NSD2- and CLTC-related intellectual disability, and others, all with negative conventional genomic testing, including ES and chromosomal microarray (CMA). Skin fibroblasts exhibited higher and more consistent expression of clinically relevant genes than whole blood. In solved cases with RNA-seq from both tissues, the causative defect was missed in blood in half the cases but none from fibroblasts. CONCLUSIONS: For our cohort of undiagnosed individuals with suspected Mendelian conditions, transcriptome-directed genomic analysis facilitated diagnoses, primarily through the identification of variants missed on ES and CMA. TRIAL REGISTRATION: Not applicable. FUNDING: NIH Common Fund, BCM Intellectual and Developmental Disabilities Research Center, Eunice Kennedy Shriver National Institute of Child Health & Human Development.

Within the framework of the German pediatric screening examinations, the checks include visual functions. There is no ophthalmological screening examination in childhood in Germany. This study investigated whether participation in the pediatric screening examinations U8 (at the end of the fourth year of life) and U9 (at the beginning of the sixth year of life) is associated with the results of visual acuity, which are compiled at the school entry examinations (SEU).This study evaluated data of the SEU for school the enrollment years 2009/2010-2014/2015 of the State of Rhineland-Palatinate. In these years visual acuity was assessed using the Rodenstock visual testing device (E-hooks; Rodenstock intruments GmbH, Ottobrunn, Deutschland) wearing glasses if present. The association between participation in the U8 and U9 screening examinations and the presence of unilateral and bilateral visual acuity0.7 was investigated using multiple logistic regression adjusted for important disturbance variables.Data from 189,704 children (91,041 girls, 98,663 boys) from 35 out of 36 districts were included. A visual acuity0.7 was measured in 8416 (4.4%) children and in both eyes in 4345 (2.3%) children. The participation rates in the U8 and U9 were 93.9% and 93.3%, respectively. There was a negative association between participation in the U8 and U9 and a unilateral or bilateral SEU visual acuity0.7 (adjusted odds ratio, OR 0.68, 95% confidence interval, CI 0.61-0.75; p 0.01, N = 124,467/adjusted OR 0.57, 95% CI 0.51-0.65; p 0.01, N = 121,496).The proportion of children with visual acuity0.7 at the SEU was high. Children who were examined in the U8 and U9 had a better chance for a good visual acuity in the school entry examination.HINTERGRUND: Im Rahmen der kinderärztlichen Vorsorgeuntersuchungen U1 bis U9 von der Geburt bis zum Beginn des sechsten Lebensjahres wird unter anderem das Sehvermögen getestet – eine augenärztliche Vorsorgeuntersuchung im Kindesalter gibt es in Deutschland nicht. Diese Studie untersucht, ob eine Teilnahme an der U8 (am Ende des vierten Lebensjahres) und der U9 (zu Beginn des sechsten Lebensjahres) mit Sehschärfeergebnissen assoziiert ist, die im Rahmen der Schuleingangsuntersuchungen (SEU) erhoben werden.Ausgewertet wurden Daten der SEU des Landes Rheinland-Pfalz der Einschulungsjahrgänge 2009/2010 bis 2014/2015. In diesen Jahrgängen wurde die Sehschärfe mittels Rodenstock-Sehtestgerät (E-Haken; Rodenstock Instrumente GmbH, Ottobrunn, Deutschland) und eigener Korrektur geprüft. Festgehalten wurden reduzierte Sehschärfen von0,7. Der Zusammenhang zwischen der Teilnahme an den Vorsorgeuntersuchungen U8 bzw. U9 und dem Vorliegen einer ein- und beidseitigen Sehschärfe0,7 bei SEU wurde mithilfe von multipler logistischer Regressionsanalyse untersucht und für wichtige Störgrößen adjustiert.Daten von 189.704 Kindern (91.041 Mädchen und 98.663 Jungen) aus 35 von 36 Landkreisen konnten eingeschlossen werden. Eine Sehschärfe0,7 wurde bei 8416 Kindern (4,4 %) ermittelt, in beiden Augen bei 4345 (2,3 %) Kindern. Die Teilnahmequote an der U8 bzw. U9 betrug 93,9 % bzw. 93,3 %. Es bestand eine negative Assoziation zwischen der Teilnahme an der U8 bzw. U9 und einem ein- oder beidseitigen SEU-Visus0,7 (adjustierte OR: 0,68; 95 %-KI: 0,61–0,75; p 0,01; N = 124.467/adjustierte OR: 0,57; 95 %-KI: 0,51–0,65; p 0,01; N = 121.496).Es zeigt sich ein hoher Anteil an Kindern mit verminderter Sehschärfe bei der Schuleingangsuntersuchung. Kinder, die in der U8 und U9 untersucht worden waren, hatten eine bessere Chance für eine gute Sehschärfe bei der Schuleingangsuntersuchung.

Background Coronavirus disease 2019 (COVID-19) results in debilitating long-term symptoms, often referred to as Post-Acute Sequelae of SARS-CoV-2 Infection (PASC), in a substantial subgroup of patients. One of the most prevalent symptoms following COVID-19 is severe fatigue. Prompt delivery of cognitive behavioural therapy (CBT), an evidence-based treatment that has shown benefit in reducing severe fatigue in other conditions, may reduce post-COVID-19 fatigue. Based on an existing CBT protocol, a blended intervention of 17 weeks, Fit after COVID, was developed to treat severe fatigue after the acute phase of infection with SARS-CoV-2. Method The ReCOVer study is a multicentre 2-arm randomised controlled trial (RCT) to test the efficacy of Fit after COVID on severe post-infectious fatigue. Participants are eligible if they report severe fatigue 3 up to and including 12 months following COVID-19. One hundred and fourteen participants will be randomised to either Fit after COVID or care as usual (ratio 1:1). The primary outcome, the fatigue severity subscale of the Checklist Individual Strength (CIS-fatigue), is assessed in both groups before randomisation (T0), directly post CBT or following care as usual (T1), and at follow-up 6 months after the second assessment (T2). In addition, a long-term follow-up (T3), 12 months after the second assessment, is performed in the CBT group only. The primary objective is to investigate whether CBT will lead to a significantly lower mean fatigue severity score measured with the CIS-fatigue across the first two follow-up assessments (T1 and T2) as compared to care as usual. Secondary objectives are to determine the proportion of participants no longer being severely fatigued (operationalised in different ways) at T1 and T2 and to investigate changes in physical and social functioning, in the number and severity of somatic symptoms and in problems concentrating across T1 and T2. Discussion This is the first trial testing a cognitive behavioural intervention targeting severe fatigue after COVID-19. If Fit after COVID is effective in reducing fatigue severity following COVID-19, this intervention could contribute to alleviating the long-term health consequences of COVID-19 by relieving one of its most prevalent and distressing long-term symptoms. Trial registration Netherlands Trial Register NL8947. Registered on 14 October 2020.

In 2016/2017, Washington State experienced a mumps outbreak despite high childhood vaccination rates, with cases more frequently detected among school-aged children and members of the Marshallese community. We sequenced 166 mumps virus genomes collected during outbreaks in Washington and other US states, and apply phylodynamic approaches to trace mumps introductions and transmission within Washington. We uncover that mumps was introduced into Washington at least 13 times, primarily from Arkansas, sparking multiple co-circulating transmission chains. Neither vaccination status nor age were strong determinants of transmission. Instead, the outbreak in Washington was overwhelmingly sustained by transmission within the Marshallese community. Our findings underscore the utility of genomic data to clarify epidemiologic factors driving transmission, and pinpoint contact networks as critical determinants of mumps transmission. These results imply that contact structures and historic disparities may leave populations at increased risk for respiratory virus disease even when a vaccine is effective and widely used.

Background The tumor microenvironment (TME) is composed of various cell types which closely interact via cell cell contacts and cytokines leading to tumor promotion, immune cell inhibition and drug resistance. TME is increasingly recognized for its role in cancer immunotherapies. In B-cell malignancies, myeloid cells play a central role in supporting tumor growth and immune suppression (Roussel et al., 2017, Cancer Immunol Immunother). Despite the importance of a syngeneic TME, preclinical studies with novel drugs have mainly been performed in models lacking a functional immune system. Therefore, we developed an immune competent murine lymphoma model transgenic to human CD22 to study effects of targeted therapies on TME. Materials and Methods A chimeric CD22 consisting of human extracellular and murine intracellular CD22 (h/mCD22) was introduced in BL6 mice (BL6h/mCD22). Crossbreeding with BL6λ-myc lead to spontaneous development of murine lymphoma that were serially transplanted. Tumor infiltration and TME was characterized by flow cytometry. Mice were treated with Moxetumomab pasudotox, a CD22 targeted immunotoxin and Doxorubicin. Results Spontaneously developed tumors in lymphoid organs from BL6h/mCD22 x λ-myc consist of a monomorphic population of h/mCD22+ murine B cells. Three primary lymphoma subclones were isolated from distinct mice and serially transplanted in syngeneic mice. Stable tumor growth was established after subcutaneous (sc) and intravenous (iv) injection. However, TME of sc tumors was infiltrated by less than 1% immune cells, while myc-driven lymphoma in humans usually show substantial immune infiltration. In contrast to sc tumors, systemically growing lymphoma in murine bone marrow (BM) are infiltrated by 30% myeloid cells and 1% T-cells and in murine spleen by 10% and 30%, respectively. Myeloid cells found in these tumors were shown to suppress T cell proliferation in vitro. To test functionality of the h/mCD22 transgene, lymphoma-bearing mice were treated with Moxetumomab, which reduced BM lymphoma infiltration by 20 to 100-fold and infiltration in spleen by 5 to 20-fold in the three lymphoma models. Effects of treatment on TME were analyzed after treatment with Doxorubicin which is known to activate myeloid cells in vivo. Compared to untreated controls, Doxorubicin increased CD11b+ cells in spleen by 1.5-fold. Among these cells, Ly6G+ granulocytic cells increased most substantially. Conclusions We established primary, myc-driven h/mCD22+ B-cell lymphoma which stably engraft in syngeneic mice with a TME mimicking myc-driven lymphoma in men. The model responds well to CD22-targeted therapy and Doxorubicin induces expected immunologic changes. Therefore, our unique model provides a platform to test CD22-targeting treatment strategies in an immune competent background. Disclosure Information F. Gsottberger: None. C. Brandl: None. S. Petkovic: None. L. Nitschke: None. A. Mackensen: None. F. Muller: None.

Spaceborne NO2 column observations from two high‐resolution instruments, TROPOMI onboard Sentinel‐5 Precursor and OMI on Aura, reveal unprecedented NO2 decreases over China, South Korea, Western Europe and the U.S. as a result of public health measures enforced to contain the coronavirus disease outbreak (Covid‐19) in January‐April 2020. The average NO2 column drop over all Chinese cities amounts to ‐40% relative to the same period in 2019, and reaches up to a factor of ~2 at heavily hit cities, e.g. Wuhan, Jinan, while the decreases in Western Europe and the U.S. are also significant (‐20 to ‐38%). In contrast with this, although Iran is also strongly affected by the disease, the observations do not show evidence of lower emissions, reflecting more limited health measures., Key Points Satellite NO2 data show substantial decreases by 40% on average over Chinese cities due to lockdown measures against the Covid‐19 outbreakWestern Europe and U.S. display robust NO2 decreases in 2020, 20‐38% relative to the same period in 2019Satellite NO2 observations above Iran, a region strongly affected by coronavirus, do not show clear evidence of lower emissions

A series of unfortunate events The history of how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spread around the planet has been far from clear. Several narratives have been propagated by social media and, in some cases, national policies were forged in response. Now that many thousands of virus sequences are available, two studies analyzed some of the key early events in the spread of SARS-CoV-2. Bedford et al. found that the virus arrived in Washington state in late January or early February. The viral genome from the first case detected had mutations similar to those found in Chinese samples and rapidly spread and dominated subsequent undetected community transmission. The other viruses detected had origins in Europe. Worobey et al. found that early introductions into Germany and the west coast of the United States were extinguished by vigorous public health efforts, but these successes were largely unrecognized. Unfortunately, several major travel events occurred in February, including repatriations from China, with lax public health follow-up. Serial, independent introductions triggered the major outbreaks in the United States and Europe that still hold us in the grip of control measures. Science, this issue p. 571, p. 564, The first case of SARS-CoV-2 in Washington state occurred at the end of January and, by going undetected, sparked community transmission., After its emergence in Wuhan, China, in late November or early December 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus rapidly spread globally. Genome sequencing of SARS-CoV-2 allows the reconstruction of its transmission history, although this is contingent on sampling. We analyzed 453 SARS-CoV-2 genomes collected between 20 February and 15 March 2020 from infected patients in Washington state in the United States. We find that most SARS-CoV-2 infections sampled during this time derive from a single introduction in late January or early February 2020, which subsequently spread locally before active community surveillance was implemented.

With two-thirds of the global population projected to be living in urban areas by 2050, understanding the transmission patterns of viral pathogens within cities is crucial for effective prevention strategies. Here, in unprecedented spatial resolution, we analysed the socioeconomic determinants of influenza transmission in a European city. We combined geographical and epidemiological data with whole genome sequencing of influenza viruses at the scale of urban quarters and statistical blocks, the smallest geographic subdivisions within a city. We observed annually re-occurring geographic clusters of influenza incidences, mainly associated with net income, and independent of population density and living space. Vaccination against influenza was also mainly associated with household income and was linked to the likelihood of influenza-like illness within an urban quarter. Transmissions patterns within and between quarters were complex. High-resolution city-level epidemiological studies combined with social science surveys such as this will be essential for understanding seasonal and pandemic transmission chains and delivering tailored public health information and vaccination programs at the municipal level.

Thomas Borsch, Hilda Flores-Olvera, Silvia Zumaya, Kai Müller (2018): Pollen characters and DNA sequence data converge on a monophyletic genus Iresine (Amaranthaceae, Caryophyllales) and help to elucidate its species diversity. Taxon 67 (5): 944-976, DOI: https://doi.org/10.12705/675.7

By considering the debilitating outcome of co-occurring of bipolar disorder (BD) and substance abuse, determination of risk factors of substance use disorders (SUD: abuse or dependence of drugs and/or alcohol) is essential to identify the susceptible patients. The purpose of this study was to clarify the major determinant factors of SUD among adults with BD by reviewing the relevant literature. We systematically searched electronic databases including PubMed (MEDLINE), EMBASE, OVID, Cochrane and Scopus for human studies addressing the co-existence of bipolar disorder and SUD. All potential published papers up to September 2016 have been reviewed. The statistical analysis was performed using Comprehensive Meta-analysis version 2. Male gender (Odds ratio: 2.191 (95% CI: 1.121-4.281), P 0.022), number of manic episodes (P: 0.001) and previous history of suicidality (Odds ratio: 1.758 (95% CI: 1.156-2.674), P: 0.008) were associated to SUD in patients with BD. SUD was not related to age, subtype of BD, hospitalization and co-existence of anxiety disorders or psychotic symptoms. SUD affects many aspects of BD regarding clinical course, psychopathology and prognosis. Our study demonstrates that male gender, history of higher number of manic episodes and suicidality are associated to higher susceptibility to SUD. Thus, assignment of more intensive therapeutic interventions should be considered in patients with increased risk of drug abuse to prevent development of SUD.

The characterization of the functional network of the brain dynamics has become a prominent tool to illuminate novel aspects of brain functioning. Due to its excellent time resolution, such research is oftentimes based on electroencephalographic recordings (EEG). However, a particular EEG-reference might cause crucial distortions of the spatiotemporal interrelation pattern and may induce spurious correlations as well as diminish genuine interrelations originally present in the dataset. Here we investigate in which manner correlation patterns are affected by a chosen EEG reference. To this end we evaluate the influence of 7 popular reference schemes on artificial recordings derived from well controlled numerical test frameworks. In this respect we are not only interested in the deformation of spatial interrelations, but we test additionally in which way the time evolution of the functional network, estimated via some bi-variate interrelation measures, gets distorted. It turns out that the median reference as well as the global average show the best performance in most situations considered in the present study. However, if a collective brain dynamics is present, where most of the signals get correlated, these schemes may also cause crucial deformations of the functional network, such that the parallel use of different reference schemes seems advisable.

Model-based phylodynamic approaches recently employed generalized linear models (GLMs) to uncover potential predictors of viral spread. Very recently some of these models have allowed both the predictors and their coefficients to be time-dependent. However, these studies mainly focused on predictors that are assumed to be constant through time. Here we inferred the phylodynamics of avian influenza A virus H9N2 isolated in 12 Asian countries and regions under both discrete trait analysis (DTA) and structured coalescent (MASCOT) approaches. Using MASCOT we applied a new time-dependent GLM to uncover the underlying factors behind H9N2 spread. We curated a rich set of time-series predictors including annual international live poultry trade and national poultry production figures. This time-dependent phylodynamic prediction model was compared to commonly employed time-independent alternatives. Additionally the time-dependent MASCOT model allowed for the estimation of viral effective sub-population sizes and their changes through time, and these effective population dynamics within each country were predicted by a GLM. International annual poultry trade is a strongly supported predictor of virus migration rates. There was also strong support for geographic proximity as a predictor of migration rate in all GLMs investigated. In time-dependent MASCOT models, national poultry production was also identified as a predictor of virus genetic diversity through time and this signal was obvious in mainland China. Our application of a recently introduced time-dependent GLM predictors integrated rich time-series data in Bayesian phylodynamic prediction. We demonstrated the contribution of poultry trade and geographic proximity (potentially unheralded wild bird movements) to avian influenza spread in Asia. To gain a better understanding of the drivers of H9N2 spread, we suggest increased surveillance of the H9N2 virus in countries that are currently under-sampled as well as in wild bird populations in the most affected countries., PLoS Computational Biology, 15 (8), ISSN:1553-734X, ISSN:1553-7358

Background: Osteonecrosis of the lunate, Kienbock's disease, can lead to fragmentation of the lunate, carpal collapse, and severe osteoarthritis. Since the etiology of Kienbock's disease is impaired circulation, a diagnostic method capable of assessing perfusion would be valuable. Recent studies have suggested that dynamic contrast-enhanced (DCE) MR examinations at 3 T can assess perfusion in healthy carpal bones. Purpose: To evaluate the use of DCE-MR for assessing perfusion in the lunate bone in patients with Kienbock's disease. Furthermore, to compare perfusion with histopathology with a focus on bone viability. Study Type: Prospective case–control study. Population: Fourteen patients with Kienbock's disease and a control group of 19 healthy subjects. Field Strength: 3 T with T1-weighted fat-saturated contrast-enhanced gradient echo series. Assessment: Features of the enhancement curves from the DCE-MR examinations, time to peak (TTP), maximum slope (MS), and maximum enhancement (ME) assessed by a radiologist. Six of 14 patients were surgerized with lunate excision, allowing comparison between features of the enhancement curves and histopathology. Statistical Tests: Mann–Whitney U-test. P < 0.05 was considered a statistically significant difference. Results: Patients with Kienbock's disease showed significantly higher and faster perfusion parameters compared with the control group, the mean value of the TTP in patients was 126.73 sec, in controls 189.79 sec (P = 0.024), ME in patients 173.55 AU, in controls 28.46 AU (P < 0.001), and MS in patients 5.04 AU, in controls 1.06 AU (P < 0.001). When compared with histopathology, increased perfusion was seen in areas of bone formation but also in necrosis. Areas of normal bone showed low perfusion. Data Conclusion: DCE-MRI at 3 T can diagnose altered perfusion in patients with Kienbock's disease. Increased perfusion cannot definitely be used as a marker of bone viability. Level of Evidence: 1. Technical Efficacy: Stage 3. J. Magn. Reson. Imaging 2018. (Less)

Skrjabingylus nasicola (Leuckart, 1842) are geographically widespread nematodes that parasitize the nasal and frontal sinus cavities of smaller mustelids. As most prior work was solely based on the analysis of bone injuries of museum skull, little is known about the determinants and effects of infestation in the host species. Working on fresh skulls, we aimed to analyze infestation patterns in American mink (Neovison vison Schreber, 1777) from nine study areas in northern Germany and to identify factors that explained infestation prevalence and intensity in the host species. The prevalence (46.7-62.9 %) and infestation intensity values (4.5-10.89 nematodes) reported here were relatively large, especially compared to other American mink populations in Europe. Considering mink diet, our study sites probably harbored a larger number of infested paratenic hosts and climate did not have a substantial negative influence on survival of S. nasicola larvae. We did not observe any significant sex-age differences in either prevalence or intensity of S. nasicola infestation. We did not find a negative impact of an infestation on the host animals' body weight, confirming prior results that the parasite is not a significant mortality factor in mustelids. Our study suggests that this holds even outside the native distributional range where the host's defenses might not be optimally adapted to an autochthonous parasite.

Einleitung: Der Zuwachs des Wissens in der HNO-Heilkunde ubersteigt, wie in den anderen Disziplinen auch, seit langem die individuellen Moglichkeiten, dieses Wissen adaquat aufzunehmen und einen entsprechenden Uberblick zu behalten. Somit konnen tatsachliche oder vermeintliche Wissenslucken entstehen, die der Weiterentwicklung des Faches und einer evidenzbasierten Behandlung von Patienten entgegenstehen. Zudem gibt es in Kliniken und Praxen traditionelle Lehrmeinungen, die den medizinischen Alltag pragen, ohne dass diese Schulen je hinsichtlich ihrer Evidenz hinterfragt wurden. Methode: Zwischen Februar und Juni 2015 wurde unter 160 HNO-Kliniken, davon 34 Lehrstuhlinhaber, und 2 670 HNO-Praxen eine 2-armige Online-Umfrage zu vorhandenen oder empfundenen Evidenzlucken im Fachgebiet der HNO-Heilkunde mittels eines zuvor entwickelten Fragebogens durchgefuhrt. Dabei erfolgte die Befragung zur einen Halfte in offener Form, zur anderen Halfte wurde eine Systematik des Fachgebietes den Befragten als Orientierung zur Verfugung gestellt. Erganzt wurde die Befragung durch Zusatzangaben, wie der Anzahl von Publikationen und Forschungsschwerpunkten bei den Kliniken und dem Lebensalter und der Praxisform bei den niedergelassenen Kolleginnen und Kollegen. Ergebnisse: Bei den Kliniken gab es eine Rucklauferquote von 39,7%, bei der geschlossenen von 29,3%. Bei den Praxen antworteten 14,6% der geschlossen und 18,6% der offen befragten Arztinnen und Arzte. Grose Unterschiede ergaben sich zwischen den beiden Befragungsformen nicht. Bei den Kliniken fuhrten mit je etwa 30% otologische und onkologische Themen die Liste der Antworten an. Hierbei wurden zu aktuellen diagnostischen und therapeutischen Problemen, wie z. B. der stadiengerechten Tumortherapie oder bei implantierbaren Horhilfen, entsprechende Fragen formuliert. Der Schwerpunkt der aus den Praxen stammenden Fragestellungen lag bei diagnostischen Verfahren, z. B. bei speziellen, neuen Verfahren der Audiologie und Vestibulogie. Sowohl Kliniken als auch Praxen benannten aber auch alltagsrelevante Randgebiete des Faches. Diskussion: Im folgenden mussten die benannten Wissenslucken verifiziert bzw. falsifiziert werden und durch eine entsprechende Literaturrecherche geklart werden, ob die vorhandene Evidenz tatsachlich bei den Behandlern durch Leitlinien, Publikationen, Kongresse und Fortbildungen im Alltag ankommt. Weitere Schritte waren die Priorisierung der kunftigen Forschung, ein Evidenz-Mapping, die Entscheidung fur weitere systematische Reviews und gezielte Studien in Verbindung mit der Einwerbung von Drittmitteln und bei der Zusammenarbeit mit Patientenverbanden. Das so gewonnene Wissen sollte schlieslich in einer verbesserten Form in den klinischen Alltag transferiert werden. Hierzu sollten fur die Bereiche der Kliniken und Praxen jeweils die 10 wichtigsten Fragestellungen formuliert werden.

Korrektur zu 10.1038/s41375-020-0826-9

Purpose Driveline associated infections (DLI) are common in patients supported with ventricular assist devices (VAD). Patients with infections and wound healing disorder are often hospital bound and morbidity and mortality are elevated. The risk for severe bloodstream infection is high as foreign material colonization and multiresistant pathogen are omnipresent. Furthermore, DLI represent an imminent threat to survival and outcome after heart transplantation. Previous studies on the antimicrobial activity of cold atmospheric pressure argon plasma (CAP) showed promising effects against a wide range of pathogens in other fields. This is the first study to analyze the safety and efficiency of CAP in the treatment of DLI. Methods Between 04/2019 and 09/2019 15 male patients with DLI were included. 5 patients with a HVAD and 10 patients with a HeartMate3 LVAD. Bacterial species were detected by standard bacterial swabs. 4 patients were treated in our outpatient VAD clinic. Concomitant antibiotic treatment was administered according to wound swabs. Results Analysis of 120 CAP treatments in 15 patients for DLI was performed in addition to an extended wound care. The average number of CAP sessions was 7.7 (1-17 sessions/patient). We found a reduction of bacterial load in treated wounds in 9 patients, regardless of the pathogen. The wounds were treated with a mean of 368.5 (120-480) seconds CAP in each session. There was a significant reduction in UTAH wound classification before and after CAP treatment (UTAH 2.80 vs. 1.18; p Conclusion CAP treatment is a potent, safe and painless supplemental technique to treat DLI without need for repeating surgical interventions. Further studies may support this pilot trial to evaluate details of the applied CAP and outcome measures need to be defined.

Model-based phylodynamic approaches recently employed generalized linear models (GLMs) to uncover potential predictors of viral spread. Very recently some of these models have allowed both the predictors and their coefficients to be time-dependent. However, these studies mainly focused on predictors that are assumed to be constant through time. Here we inferred the phylodynamics of H9N2 viruses isolated in 12 Asian countries and regions under both discrete trait analysis (DTA) and structured coalescent (MASCOT) approaches. Using MASCOT we applied a new time-dependent GLM to uncover the underlying factors behind H9N2 spread. We curated a rich set of time-series predictors including annual international live poultry trade and national poultry production figures. This time-dependent phylodynamic prediction model was compared to commonly employed time-independent alternatives. Additionally the time-dependent MASCOT model allowed for the estimation of viral effective sub-population sizes and their changes through time and these effective population dynamics within each country were predicted by a GLM. International annual poultry trade is a strongly supported predictor of virus migration rates. There was also strong support for geographic proximity as a predictor of migration rate in all GLMs investigated. In time-dependent MASCOT models, national poultry production was also identified as a predictor of virus genetic diversity through time and this signal was obvious in mainland China and Bangladesh. Our application of a recently introduced time-dependent GLM predictors integrated rich time-series data in Bayesian phylodynamic prediction. We demonstrated the contribution of poultry trade and geographic proximity (potentially unheralded wild bird movements) to avian influenza spread in Asia. To gain a better understanding of the drivers of H9N2 spread, we suggest increased surveillance of the H9N2 virus in countries that are currently under-sampled as well as in wild bird populations in the most affected countries.Author summaryWhat drives the geographic dispersal and genetic diversity of H9N2 avian influenza virus in Asia? We used two model-based approaches, DTA and MASCOT, to reconstruct the phylogeographic dynamics of the virus. Further, multiple potential predictors were used to inform the virus spread and population dynamics by GLMs. Here, we maximised the power of time-series predictors in Bayesian phylodynamic prediction. For the first time, we were able to quantify the contribution of both time-series and constant predictors to both migration rates and effective population sizes in a structured population. We identified a positive association of international poultry trade and national poultry production time-series with virus migration rates and effective population sizes respectively. We also identify geographic proximity as a strongly supported driver to virus migration rates and this points to the potential role of wild bird populations in virus dispersal across countries. Our study is a practical exemplar of the use of temporal information in predictors to model heterogeneous spatial diffusion and population dynamic processes and provides direction to H9N2 control efforts in Asia.

Infection with human immunodeficiency virus type 1 (hereafter referred to as HIV) results in a progressive impairment of immune function, ultimately leading to opportunistic infections and malignancies of the acquired immunodeficiency syndrome (AIDS). The fundamental immunologic abnormality is a progressive impairment of the number and functions of CD4+ lymphocytes. Because the CD4+ lymphocytes are important immune regulatory cells, various immune functions are affected. In recent years, several reports have suggested that impaired antioxidant defense plays a role in the immunopathogenesis of HIV infection. 1–5 Several investigators have suggested that clinical trials with antioxidants, in particular with glutathione replenishing drugs, should be carried out. 6–9

Selenoprotein H (SELENOH) is supposed to be involved in redox regulation as well as in tumorigenesis. However, its role in healthy and transformed cells of the gastrointestinal tract remains elusive. We analyzed SELENOH expression in cells depending on their selenium supply and differentiation status and found that SELENOH expression was increased in tumor tissue, in undifferentiated epithelial cells from mice and in colorectal cancer lines as compared to more differentiated ones. Knockdown studies in human colorectal cancer cells revealed that repression of SELENOH decreased cellular differentiation and increased proliferation and migration. In addition, SELENOH knockdown cells have a higher competence to form colonies or tumor xenografts. In parallel, they show a faster cell cycle transition. The high levels of SELENOH in tumors as well as in undifferentiated, proliferative cells together with its inhibitory effects on proliferation and G1/S phase transition suggest SELENOH as a key regulator for cell cycle progression and for prevention of uncontrolled proliferation. As SELENOH expression is highly dependent on the selenium status, effects of selenium supplementation on cancer initiation and progression appear to involve SELENOH.

Clostridium difficile associated diarrhoea (CDAD) is the most common cause of health-care-associated infectious diarrhoea. In the context of the German health-care system, direct and indirect costs of an initial episode of CDAD and of CDAD recurrence are currently unknown.We defined CDAD as presence of diarrhoea (≥3 unformed stools/day) in association with detection of Clostridium difficile toxin in an unformed faecal sample. Patients treated with metronidazole (PO or IV) and/or vancomycin (PO) were included. Comprehensive data of patients were retrospectively documented into a database using the technology of the Cologne Cohort of Neutropenic Patients (CoCoNut). Patients with CDAD were matched to control patients in a 1:1 ratio. Analysis was split in three groups: incidence group (CDAD patients without recurrence), recurrence group (CDAD patients with ≥1 recurrence) and control group (matched non-CDAD patients).Between 02/2010 and 12/2011, 150 patients with CDAD (114 patients in the incidence and 36 (24 %) in the recurrence group) and 150 controls were analysed. Mean length of stay was: 32 (95 %CI: 30-37), 94 (95 %CI: 76-112) and 24 days (95 %CI: 22-27; P =0.001), resulting in mean overall direct treatment costs per patient of €18,460 (95 %CI: €14,660-€22,270), €73,900 (95 %CI: €50,340-€97,460) and €14,530 (95 %CI: €11,730-€17,330; P =0.001). In the incidence and recurrence group, the mean cumulative number of antibiotic CDAD treatment days was 11 (95 %CI: 10-12) and 36 (95 %CI: 27-45; P =0.001).Especially CDAD recurrence was associated with excessive costs, which were mostly attributable to a significantly longer overall length of stay. Innovative treatment strategies are warranted to reduce treatment costs and prevent recurrence of CDAD.

We surveyed European medical schools regarding teaching of prudent antibiotic prescribing in the undergraduate curriculum. We performed a cross-sectional survey in 13 European countries (Belgium, Croatia, Denmark, France, Germany, Italy, Netherlands, Norway, Serbia, Slovenia, Spain, Switzerland, United Kingdom) in 2013. Proportional sampling was used, resulting in the selection of two to four medical schools per country. A standardized questionnaire based on literature review and validated by a panel of experts was sent to lecturers in infectious diseases, medical microbiology and clinical pharmacology. In-depth interviews were conducted with four lecturers. Thirty-five of 37 medical schools were included in the study. Prudent antibiotic use principles were taught in all but one medical school, but only four of 13 countries had a national programme. Interactive teaching formats were used less frequently than passive formats. The teaching was mandatory for 53% of the courses and started before clinical training in 71%. We observed wide variations in exposure of students to important principles of prudent antibiotic use among countries and within the same country. Some major principles were poorly covered (e.g. reassessment and duration of antibiotic therapy, communication skills). Whereas 77% of the respondents fully agreed that the teaching of these principles should be prioritized, lack of time, mainly due to rigid curriculum policies, was the main reported barrier to implementation. Given the study design, these are probably optimistic results. Teaching of prudent antibiotic prescribing principles should be improved. National and European programmes for development of specific learning outcomes or competencies are urgently needed. Clinical Microbiology and Infection © 2014 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved

The High-Luminosity LHC will provide the unique opportunity to explore the nature of physics beyond the Standard Model of strong and electroweak interactions. Highly selective first level triggers are essential for the physics programme of the ATLAS experiment at the HL-LHC where the instantaneous luminosity will exceed the LHC Run 1 instantaneous luminosity by almost an order of magnitude. The ATLAS first level muon trigger rate is dominated by low momentum muons, selected due to the moderate momentum resolution of the resistive plate and thin gap trigger chambers. This limitation can be overcome by including the data of the precision muon drift tube (MDT) chambers in the first level trigger decision. This requires the fast continuous transfer of the MDT hits to the off-detector trigger logic and a fast track reconstruction algorithm performed in the trigger logic. In order to demonstrate the feasibility of reconstructing tracks in MDT chambers within the short available first-level trigger latency of about 3 μs we implemented a seeded Hough transform on the ARM Cortex A9 microprocessor of a Xilinx Zynq FPGA and studied its performance with test-beam data recorded in CERN's Gamma Irradiation Facility. We could show that by using the ARM processor's Neon Single Instruction Multiple Data Engine to carry out 4 floating point operations in parallel the challenging latency requirement can be matched. The High-Luminosity LHC will provide the unique opportunity to explore the nature of physics beyond the Standard Model of strong and electroweak interactions. Highly selective first level triggers are essential for the physics programme of the ATLAS experiment at the HL-LHC where the instantaneous luminosity will exceed the LHC Run 1 instantaneous luminosity by almost an order of magnitude. The ATLAS first level muon trigger rate is dominated by low momentum muons, selected due to the moderate momentum resolution of the resistive plate and thin gap trigger chambers. This limitation can be overcome by including the data of the precision muon drift tube (MDT) chambers in the first level trigger decision. This requires the fast continuous transfer of the MDT hits to the off-detector trigger logic and a fast track reconstruction algorithm performed in the trigger logic. In order to demonstrate the feasibility of reconstructing tracks in MDT chambers within the short available first-level trigger latency of about 3~$\mu$s we implemented a seeded Hough transform on the ARM Cortex A9 microprocessor of a Xilinx Zynq FPGA and studied its performance with test-beam data recorded in CERN's Gamma Irradiation Facility. We could show that by using the ARM processor's Neon Single Instruction Multiple Data Engine to carry out 4 floating point operations in parallel the challenging latency requirement can be matched.

To determine the natural history of left ventricular function at rest and during exercise and to assess the impact of this variable on subsequent mortality, 165 patients were studied with radionuclide angiography within 24 hours of acute myocardial infarction. The ejection fraction of the 19 patients who died during the 6 month follow-up was lower than that of the 146 survivals: 41±16% vs 50±13% (P

Objective: To provide a comprehensive review of robot-assisted surgery in urolithiasis and to consider the future prospects of robotic approaches in stone surgery. Materials and methods: We performed a systematic PubMed© literature search using predefined Medical Subject Headings search terms to identify PubMed-listed clinical research studies on robotic stone surgery. All authors screened the results for eligibility and two independent reviewers performed the data extraction. Results: The most common approach in robotic stone surgery is a robot-assisted pyelolithotomy using the da Vinci™ system (Intuitive Surgical Inc., Sunnyvale, CA, USA). Several studies show this technique to be comparable to classic laparoscopic and open surgical interventions. One study that focused on ureteric stones showed a similar result. In recent years, promising data on robotic intrarenal surgery have been reported (Roboflex Avicenna™; Elmed Medical Systems, Ankara, Turkey). Initial studies have shown its feasibility and high stone-free rates and prove that this novel endoscopic approach is safe for the patient and comfortable for the surgeon. Conclusions: The benefits of robotic devices in stone surgery in existing endourological, laparoscopic, and open treatment strategies still need elucidation. Although recent data are promising, more prospective randomised controlled studies are necessary to clarify the impact of this technique on patient safety and stone-free rates. Keywords: Robotic stone surgery, Urolithiasis, Nephrolithiasis, Stone disease, Endourology

Background The management of patients with rheumatic diseases is guided in part by asking patients about their medical history at each clinic visit. Patients often find it difficult to accurately remember the course of their symptoms between these appointments as they are often months apart. Regular app-based patients9 self-monitoring of disease activity (with our without feedback to the rheumatologist) between clinic visits might provide a possible solution for this. The COmPASS I study [1] demonstrated that RA patients9 self-assessments of disease activity via App correlate strongly with rheumatologists9 assessments. Following up on this, the Swiss based COmPASS II study is embedded in the Swiss rheumatology registry (SCQM) and hence allows the linkage of data obtained via the COmPASS II App from the patients with routine clinical data collected in the registry. The main aims of the COmPASS II study are to assess if continuous self-monitoring of the disease by patients optimises disease management and outcome in rheumatic diseases, and to assess the fluctuation of disease activity between clinic visits. Objectives The objectives of this abstract are to describe the set-up and the recruitment of the COmPASS II study in the first 11 months. Methods The COmPASS II App questionnaire consists of the RAPID3 score, a validated, commonly used PRO to self-assess disease activity. Additionally, patients are asked about their therapy compliance and cortisone dose. At inclusion, interested patients with RA, axSpA and PsA are electronically randomized into 3 study arms (Figure 1). In arm 1 patients and rheumatologist are displayed the self-assessed disease activity over time, the patient directly via the App and the rheumatologist via the SCQM registry. In arm 2 only the patients are displayed their disease activity chart and in study arm 3 neither sees the recorded data. Patients are encouraged to fill in the App weekly. Results The COmPASS II App went online on the 15/02/2016. In the first 11 months of COmPASS II, 272 patients were enrolled by their rheumatologist. 64% of patients used the WebApp (32% in arm 1, 38% in arm 2 and 30% in arm 3); 82% of patients filled in the questionnaires for longer than a months, the longest follow-up was 11 months. On average patients use the App every 2 weeks. Patients found the App easy to use “The COmPASS II WebApp is so easy to use. It doesn9t even take me 2 min.” and received feedback included “Now my rheumatologist sees how I was since the last appointment instead of me trying to remember how I was half a year ago.”. Conclusions The COmPASS II study will validate the utility of app-based patients9 self-assessments in enhancing disease control in a treat to target approach and deliver numerous additional scientific data. References Mueller R et al. Patient9s Self-Monitoring Via Smartphone: The Compass Study - COrrelation between PAtient self-ASSessment of rheumatoid arthritis disease activity via smartphone technology and physicians9 validated scores [abstract]. Arthritis Rheumatol. 2014;66(S10). Acknowledgements COmPASS II is supported by an unrestricted grant from AbbVie. Disclosure of Interest None declared

WOS: 000415165200027, PubMed ID: 28603052, BACKGROUND & AIMS: Predniso(lo) ne, alone or in combination with azathioprine, is the standard-of-care (SOC) therapy for autoimmune hepatitis (AIH). However, the SOC therapy is poorly tolerated or does not control disease activity in up to 20% of patients. We assessed the efficacy of mycophenolate mofetil (MMF) and tacrolimus as second-line therapy for patients with AIH. METHODS: We performed a retrospective study of data (from 19 centers in Europe, the United States, Canada, and China) from 201 patients with AIH who received second-line therapy (121 received MMF and 80 received tacrolimus), for a median of 62 months (range, 6-190 mo). Patients were categorized according to their response to SOC. Patients in group 1 (n = 108) had a complete response to the SOC, but were switched to second-line therapy as a result of side effects of predniso(lo) ne or azathioprine, whereas patients in group 2 (n = 93) had not responded to SOC. RESULTS: There was no significant difference in the proportion of patients with a complete response to MMF (69.4%) vs tacrolimus (72.5%) (P = .639). In group 1, MMF and tacrolimus maintained a biochemical remission in 91.9% and 94.1% of patients, respectively (P = .682). Significantly more group 2 patients given tacrolimus compared with MMF had a complete response (56.5% vs 34%, respectively; P = .029) There were similar proportions of liver-related deaths or liver transplantation among patients given MMF (13.2%) vs tacrolimus (10.3%) (log-rank, P = .472). Ten patients receiving MMF (8.3%) and 10 patients receiving tacrolimus (12.5%) developed side effects that required therapy withdrawal. CONCLUSIONS: Long-term therapy with MMF or tacrolimus generally was well tolerated by patients with AIH. The agents were equally effective in previous complete responders who did not tolerate SOC therapy. Tacrolimus led to a complete response in a greater proportion of previous nonresponder patients compared with MMF.

Ground-based multi-axis differential optical absorption spectroscopy (MAX-DOAS) measurements of sulfur dioxide (SO2) have been performed at the Xianghe station (39.8° N, 117.0° E) located at ~ 50 km southeast of Beijing from March 2010 to February 2013. Tropospheric SO2 vertical profiles and corresponding vertical column densities (VCDs), retrieved by applying the optimal estimation method to the MAX-DOAS observations, have been used to study the seasonal and diurnal cycles of SO2, in combination with correlative measurements from in situ instruments, as well as meteorological data. A marked seasonality was observed in both SO2 VCD and surface concentration, with a maximum in winter (February) and a minimum in summer (July). This can be explained by the larger emissions in winter due to the domestic heating and, in case of surface concentration, by more favorable meteorological conditions for the accumulation of SO2 close to the ground during this period. Wind speed and direction are also found to be two key factors in controlling the level of the SO2-related pollution at Xianghe. In the case of east or southwest wind, the SO2 concentration does not change significantly with the wind speed, since the city of Tangshan and heavy polluting industries are located to the east and southwest of the station, respectively. In contrast, when wind comes from other directions, the stronger the wind, the less SO2 is observed due to a more effective dispersion. Regarding the diurnal cycle, the SO2 amount is larger in the early morning and late evening and lower at noon, in line with the diurnal variation of pollutant emissions and atmospheric stability. A strong correlation with correlation coefficients between 0.6 and 0.9 is also found between SO2 and aerosols in winter, suggesting that anthropogenic SO2, through the formation of sulfate aerosols, contributes significantly to the total aerosol content during this season. The observed diurnal cycles of MAX-DOAS SO2 surface concentration are also in very good agreement (correlation coefficient close to 0.9) with those from collocated in situ data, indicating the good reliability and robustness of our retrieval.

Endometriosis is one of the most frequent benign diseases in women of child-bearing age. The main symptoms are chronic upper abdominal pain and infertility. However, the aetiology and pathogenesis of endometriosis are as yet insufficiently clarified. Thus, therapy is mainly symptomatic with laparoscopic surgery being the gold standard. The aim of drug therapy is to achieve a hypo-oestrogenic condition. In cases of severe endometriosis and a desire to have children there is often an indication for assisted reproduction. The present article illustrates almost all current aspects on the diagnosis of and therapy of endometriosis. From the clinical viewpoint, emphasis is placed on the rare cases of deeply infiltrating endometriosis that are, however, accompanied with a high morbidity. Current therapeutic options in cases of infertility are also presented in more detail. Furthermore, special attention is paid to the latest research results from both clinical and basic research fields in order to demonstrate our current knowledge on the pathogenesis and, where possible, potentially related therapeutic options.Die Endometriose ist eine der häufigsten gutartigen Erkrankungen der Frau im reproduktionsfähigen Alter. Hauptsymptome sind chronische Unterbauchschmerzen und Infertilität. Ätiologie und Pathogenese der Endometriose sind jedoch bisher unzulänglich geklärt. Es erfolgt daher eine vornehmlich symptomatische Therapie, wobei die laparoskopische Entfernung als operativer „Goldstandard“ gilt. Ziel der medikamentösen Therapie ist das Erreichen eines hypoöstrogenen Zustands. Bei schwerer Endometriose und Kinderwunsch ergibt sich häufig die Indikation für eine assistierte Reproduktion. Die vorliegende Arbeit fasst alle aktuellen Aspekte zur Diagnostik und Therapie der Endometriose zusammen. Dabei wird klinisch ein Schwerpunkt auch auf die zwar seltenere, jedoch mit hoher Morbidität verbundene tief infiltrierende Endometriose gesetzt. Auch zeitgemäße Therapieoptionen bei Infertilität werden näher dargestellt. Zudem wird ein Schwerpunkt auf neueste Forschungsansätze gelegt, um sowohl Klinikern als auch Wissenschaftlern aktuelle Erkenntnisse zur Pathogenese und ggf. daraus resultierenden Therapieoptionen darzustellen.

To apply and compare magnetic resonance imaging (MRI) metal artifact reducing sequences (MARS) including subtraction imaging after contrast application in patients with metal-on-metal (MoM) hip prostheses, investigate the prevalence and characteristics of periprosthetic abnormalities, as well as their relation with pain and risk factors. Fifty-two MoM prostheses (35 cases with pain and or risk factors, and 17 controls) in 47 patients were examined in a 1.5-T MR scanner using MARS: turbo spin echo (TSE) with high readout bandwidth with and without view angle tilting (VAT), TSE with VAT and slice encoding for metal artifact correction (SEMAC), short tau inversion recovery (STIR) with matched RF pulses, and post-contrast imaging. The relations of MRI findings to pain and risk factors were analyzed and in five revised hips findings from operation, histology, and MRI were compared. TSE VAT detected the highest number of osteolyses. Soft tissue mass, effusion, and capsular thickening were common, whereas osteolysis in acetabulum and femur were less frequent. Contrast enhancement occurred in bone, synovia, joint capsule, and the periphery of soft tissue mass. There was no significant relation between MRI findings and pain or risk factors. MARS and gadolinium subtraction imaging are useful for evaluation of complications to MoM prosthesis. TSE VAT had the highest sensitivity for osteolysis. Contrast enhancement might indicate activation of aseptic lymphocyte-dominated vasculitis-associated lesion (ALVAL). Pain, small head, or steep prosthesis inclination angle are not useful predictors of periprosthetic abnormalities, and wide indications for MR follow-up are warranted.

Objectives There is convergent evidence for an important role of interleukin-16 (IL-16) in the pathogenesis of multiple sclerosis (MS). IL-16 serves as a chemoattractant for different immune cells that are involved in developing lesions. Here, we compared IL-16 levels of MS patients and controls and addressed the long-term effect of IFN-β, the most common immunomodulatory MS therapy, on IL-16 serum levels in MS patients over 2 years. Beyond this, we analysed the expression of IL-16 in two CD4+ T-cell subsets, Th1 and Th17 cells, which are important autoimmune mediators and affected by IFN-β treatment, derived from myelin-specific T-cell transgenic mice. Materials and methods IL-16 serum levels of 17 controls and of 16 MS patients before therapy and at months 1, 2, 3, 6, 9, 12 and 24 during IFN-β1a therapy were determined by ELISA. MRI was performed before therapy, at months 12 and 24. IL-16 expression of in vitro differentiated murine myelin oligodendrocyte glycoprotein (MOG)-specific Th1 and Th17 cells was quantified by real-time PCR. Results Before therapy, MS patients showed significantly elevated IL-16 levels compared with controls irrespective of disease activity determined by MRI. Therapy with IFN-β1a led to a significant linear decrease in IL-16 serum levels beginning after 2 months. MOG-specific Th17 cells expressed more IL-16 than Th1 cells. Conclusions Reduction in increased IL-16 levels may be of relevance for the therapeutic effect of IFN-β1a in MS. Easily accessible IL-16 serum levels hold a potential as biomarker of treatment efficacy in MS.

Aim Applications of transcranial direct current stimulation (tDCS) aim at targeting specific cognitive domains. Optimization of tDCS protocols is therefore crucial. It has been suggested to combine tDCS with a cognitive task aiming at the networks related to the targeted cognitive domain. The present study investigates (1) the timing of tDCS in relation to the target task (working memory). (2) Specificity of DLPFC-stimulation on executive functions. Methods A total of 80 subjects aged 18–30 participated in the study; eight were excluded for IQ above 130 (40 female; age M = 22.0, SD = 3.2; IQ M = 107.2, SD = 11.1). Twenty-four hours after baseline examination (T0), participants were randomly allocated to one of four different conditions of tDCS timing: Verum stimulation (1) before, (2) during and (3) after performing an adaptive n-back task (T1) as well as (4) sham stimulation during the n-back task. 1.5 mA anodal tDCS was delivered through the Starstim system for 17 min (Neuroelectrics, Barcelona, Spain). The size of the circular active electrode (left DLPFC) was 8 cm2 and of the reference electrode 25 cm2 (contralateral mastoid). Cognitive examination covered attention, executive functions (working memory, cognitive flexibility, inhibitory control), verbal and non-verbal memory, and visuo-spatial functioning. Repeated measurement ANOVA was performed to compare each verum condition to sham stimulation. Results Concerning executive functions, participants in the conditions ‘before’ and ‘after’ didn’t improve as much as the sham group at T1 in a Go-NoGo task (median reaction time). Regarding memory, participants in the condition ‘before’ didn’t improve as much as the sham group at T1 in non-verbal delayed recall (Rey-Osterrieth Complex Figure Test). Participants in the ‘during’ condition improved at T1 compared to the sham group in verbal delayed recall (Rey Auditory Verbal Learning Test). Discussion These preliminary results show that anodal tDCS over the left DLPFC can selectively modulate single functions from executive functions and memory. (1) Stimulation before and after an executive target task showed similar negative effects on inhibitory control, while stimulation during the target task did not show any effect on executive functioning. Yet, we only saw changes in one out of seven conducted executive tasks. Therefore, we cannot conclude a preferred timing of stimulation in relation to a working memory task aiming at the networks of executive functions through DLPFC stimulation. Interestingly, the only positive effects on cognition were seen with stimulation during the target task. (2) Stimulation during the target task had a positive impact on delayed recall in verbal memory, which is known to be hippocampus-dependent. Together with the negative effect on non-verbal delayed recall in the ‘before’ condition, these results indicate a wider, impact of tDCS on cognition, possibly related to electrode montage and subsequently activated brain networks.

In cases of permanent immobility of both vocal folds patients have difficulties with breathing but rarely with voicing. However, clinical experience shows that the shape of the larynx (voice box) seems to have a significant influence on the degree of airflow and breathing pattern. In order to find an optimal geometry of the larynx in terms of easiness for breathing after the surgical change of vocal folds or false vocal cords (ventricular folds), a set of numerical simulations of glottal flow for weakly compressible Navier-Stokes equations has been performed. We compare airflow resistance and volumetric flow rate for several geometry concepts for inspiration as well as expiration. Finally, we discuss the optimal geometry with respect to the quality of breathing.