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The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants threatens efforts to contain the coronavirus disease 2019 (COVID-19) pandemic. The number of COVID-19 cases and deaths in India has risen steeply, and a SARS-CoV-2 variant, B.1.617, is believed to be responsible for many of these cases. The spike protein of B.1.617 harbors two mutations in the receptor binding domain, which interacts with the angiotensin converting enzyme 2 (ACE2) receptor and constitutes the main target of neutralizing antibodies. Therefore, we analyze whether B.1.617 is more adept in entering cells and/or evades antibody responses. B.1.617 enters two of eight cell lines tested with roughly 50% increased efficiency and is equally inhibited by two entry inhibitors. In contrast, B.1.617 is resistant against bamlanivimab, an antibody used for COVID-19 treatment. B.1.617 evades antibodies induced by infection or vaccination, although less so than the B.1.351 variant. Collectively, our study reveals that antibody evasion of B.1.617 may contribute to the rapid spread of this variant., Graphical abstract, Between March and May 2021, India reported a steep increase in COVID-19 cases that was linked to SARS-CoV-2 variants, including B.1.617. Hoffmann et al. show that the B.1.617 spike protein mediates robust entry into human cells and evades neutralization by antibodies produced upon infection and vaccination.

Hepatitis B virus (HBV) from 76 adult immigrants in Australia from Myanmar was characterized to determine the prevalence of different HBV genotypes and subgenotypes. A mutational analysis was then performed to determine the presence of clinically significant mutations and correlate them to clinical outcomes. Initial genotyping revealed 68 patients with genotype C (89.5%) and eight patients with genotype B (10.5%). Phylogenetic analysis revealed the large majority of the genotype C infections were of subgenotype C1 (67/68). Sequencing of the HBV polymerase gene (and overlapping surface gene) revealed no mutations associated with antiviral resistance. HBV surface gene mutations were detected in 10 patients with subgenotype C1. HBV BCP/PC sequencing was obtained for 71/76 (93%) patients. BCP and/or PC mutations were identified in 57/71 (80%) of PCR positive patients. Treatment had been commenced for 15/76 (18%) patients, a further 26 untreated patients were in a stage of disease where HBV treatment would be considered standard of care. It was identified that genotype C1 is the predominant sub-genotype in this population. Genotype C is known to be associated with increased risk of development of HCC. This highlights the need for screening for HCC given the potential for the development of liver cancer. It was also identified that people with HBV were potentially not receiving optimal therapy in a timely fashion.

Patient-derived cancer xenografts (PDX) are widely used to identify and evaluate novel therapeutic targets, and to test therapeutic approaches in preclinical mouse avatar trials. Despite their widespread use, potential caveats of PDX models remain considerably underappreciated. Here, we demonstrate that EBV-associated B-lymphoproliferations frequently develop following xenotransplantation of human colorectal and pancreatic carcinomas in highly immunodeficient NOD.Cg-Prkdcscid Il2rgtm1Wjl /SzJ (NSG) mice (18/47 and 4/37 mice, respectively), and in derived cell cultures in vitro. Strikingly, even PDX with carcinoma histology can host scarce EBV-infected B-lymphocytes that can fully overgrow carcinoma cells during serial passaging in vitro and in vivo. As serial xenografting is crucial to expand primary tumor tissue for biobanks and cohorts for preclinical mouse avatar trials, the emerging dominance of B-lymphoproliferations in serial PDX represents a serious confounding factor in these models. Consequently, repeated phenotypic assessments of serial PDX are mandatory at each expansion step to verify "bona fide" carcinoma xenografts.

Due to high migration inflows to Europe, forensic age assessment of living persons has clearly gained importance. If there is a legal justification for X-ray examinations without a medical indication, the Study Group on Forensic Age Diagnostics (AGFAD) recommends the combination of a physical examination with anamnesis, an X-ray examination of the hand and a dental examination with evaluation of an orthopantomogram for age assessments of adolescents and young adults. If the development of the hand skeleton has been completed, an additional CT examination of the clavicles is to be performed. To demonstrate the outcome of forensic age assessments according to AGFAD recommendations with regard to migrants of doubtful minority declaration, this study analyzes the expert reports carried out at the Institute of Legal Medicine, Münster, from 2009 to 2018. A total of 597 age assessments were performed during the study period. A total of 227 age assessments were issued on behalf of youth welfare offices in the legal area of social law, 282 in family law proceedings, 76 in criminal proceedings, and 12 age assessments in immigration law proceedings. In 211 out of 597 cases, the stated age was compatible with the findings of the age assessment. In the remaining 386 cases, the average difference between the stated age and the minimum age was 1.9 years. The average difference between stated age and most probable age was 5.1 years. Of the 521 age assessments carried out outside criminal proceedings, 197 unaccompanied minors with questionable age minority (37.8%) have reached the age of majority beyond doubt. A total of 388 unaccompanied minors (74.5%) have most probably reached the age of majority. Forensic age assessments with the AGFAD methodology make an important contribution to legal certainty, the welfare of the child, and the fair distribution of resources.

Genetic improvement in apomictic forage species has been restricted because of the absence of genetic variability in sexual germplasm with the same ploidy level. Following a new breeding scheme, a sexual synthetic tetraploid population (SSTP) of Paspalum notatum has been generated. The objectives of this work were: (a) to evaluate the genetic variability in SSTP by means of molecular markers, morphologic and agronomic traits, and seed fertility and quality traits and (b) to assess the transference of genetic variability from the apomictic germplasm to the sexual one. Molecular markers revealed a twofold higher level of variability in the SSTP in comparison with the sexual germplasm utilised for its generation, and similar levels with the apomictic ones; moreover, markers showed that most of the variability was inherited from theapomictic germplasm. Morphologic and agronomic traits and seed fertility and quality traits showed high levels of variation in the three groups of genotypes indicating that the new breeding scheme was effective in transferring variability from the apomictic germplasm to the SSTP. This new population will be useful in breeding of P. notatum, and the breeding scheme used for its generation may be used in other apomictic species. Fil: Zilli, Alex Leonel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Botánica del Nordeste. Universidad Nacional del Nordeste. Facultad de Ciencias Agrarias. Instituto de Botánica del Nordeste; Argentina Fil: Acuña, Carlos Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Botánica del Nordeste. Universidad Nacional del Nordeste. Facultad de Ciencias Agrarias. Instituto de Botánica del Nordeste; Argentina Fil: Schulz, Roberto R.. Universidad Nacional del Nordeste; Argentina Fil: Marcón, Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Botánica del Nordeste. Universidad Nacional del Nordeste. Facultad de Ciencias Agrarias. Instituto de Botánica del Nordeste; Argentina Fil: Brugnoli, Elsa Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Botánica del Nordeste. Universidad Nacional del Nordeste. Facultad de Ciencias Agrarias. Instituto de Botánica del Nordeste; Argentina Fil: Novo, Sabina F.. Universidad Nacional del Nordeste. Facultad de Ciencias Agrarias; Argentina Fil: Quarin, Camilo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Botánica del Nordeste. Universidad Nacional del Nordeste. Facultad de Ciencias Agrarias. Instituto de Botánica del Nordeste; Argentina Fil: Martínez, Eric Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Botánica del Nordeste. Universidad Nacional del Nordeste. Facultad de Ciencias Agrarias. Instituto de Botánica del Nordeste; Argentina

Pilot testing of direct potable reuse (DPR) using multi-stage ozone and biological filtration as an alternative treatment train without reverse osmosis (RO) was investigated. This study examined four blending ratios of advanced treated reclaimed water from the F. Wayne Hill Water Resources Center (FWH WRC) in Gwinnett County, Georgia, combined with the existing drinking water treatment plant raw water supply, Lake Lanier, for potable water production. Baseline testing with 100 percent (%) Lake Lanier water was initially conducted; followed by testing blends of 15, 25, 50, and 100% reclaimed water from FWH WRC. Finished water quality from the DPR pilot was compared to drinking water standards, and emerging microbial and chemical contaminants were also evaluated. Results were benchmarked against a parallel indirect potable reuse (IPR) pilot receiving 100% of the raw water from Lake Lanier. Finished water quality from the DPR pilot at the 15% blend complied with the United States primary and secondary maximum contaminant levels (MCLs and SMCLs, respectively). However, exceedances of one or more MCLs or SMCLs were observed at higher blends. Importantly, reclaimed water from FWH WRC was of equal or better quality for all microbiological targets tested compared to Lake Lanier, indicating that a DPR scenario could lower acute risks from microbial pathogens compared to current practices. Finished water from the DPR pilot had no detections of microorganisms, even at the 100% FWH WRC effluent blend. Microbiological targets tested included heterotrophic plate counts, total and fecal coliforms, Escherichia coli, somatic and male-specific coliphage, Clostridium perfringens, Enterococci, Legionella, Cryptosporidium, and Giardia. There were water quality challenges, primarily associated with nitrate originating from incomplete denitrification and bromate formation from ozonation at the FWH WRC. These challenges highlight the importance of upstream process monitoring and control at the advanced wastewater treatment facility if DPR is considered. This research demonstrated that ozone with biological filtration could achieve potable water quality criteria, without the use of RO, in cases where nitrate is below the MCL of 10 mg nitrogen per liter and total dissolved solids are below the SMCL of 500 mg per liter.

Background Zebrafish (Danio rerio) are growing in popularity as a vertebrate model organism for the study of spinal neurocircuitry and locomotion. While many studies have used the zebrafish model system for electrophysiological analyses in embryonic and larval stages, there is a growing interest in studying spinal circuits and neurons from adult fish. New Method To expand upon the existing toolset available to the zebrafish research community, we have developed the first primary cell culture system of adult zebrafish spinal neurons. The intact spinal cord is dissected, and neurons are isolated through enzymatic digestion and mechanical dissociation. Identifiable neurons are viable for electrophysiological analyses after two days in culture. Results Spinal neurons in culture were confirmed by immunofluorescence labeling and found to exhibit distinct morphologies from other cell types, allowing neurons to be identified based on morphology alone. Neurons were suitable for calcium imaging and whole cell patch clamp recordings, which revealed excitable cells with voltage-gated whole cell currents, including tetrodotoxin-sensitive sodium currents. Comparison with Existing Methods This primary cell culture system is the only methodology available to isolate neurons from the adult zebrafish spinal cord. Other methods rely on keeping the spinal cord intact or the utilization of embryonic or larval stage fish. This method provides a robust platform for use in neurophysiological and pharmacological studies. Conclusions The novel primary cell culture system described here provides the first in vitro methodology available to isolate and culture neurons from the adult zebrafish spinal cord for use in electrophysiological analyses.

Mass cytometry is increasingly employed in larger immune profiling studies involving data acquisitions across several days and multiple sites. For gaining a maximum of information from respective data by computational analyses, several techniques have been developed to minimize noise in mass cytometric data sets, such as sample banking, standardized instrument setup, sample barcoding, and signal normalization. However, the repeated preparation of cocktails composed of isotope-tagged antibodies remained a significant source of error. We here show that premixed antibody cocktails fail to deliver expected staining patterns when stored at 4°C for 4 weeks. As a solution, we developed and tested a cryopreservation method for highly multiplexed antibody cocktails for mass cytometry including lanthanide, palladium, and platinum conjugates that yielded stable staining patterns for at least 9 months when stored at temperatures below -80°C. Using frozen aliquots of antibody cocktails is an economic and flexible approach to significantly improve data consistency in large mass cytometry studies with repetitive staining/measurement cycles spanning several days or involving multiple data acquisition sites. © 2019 International Society for Advancement of Cytometry.

Polystyrene beads are broadly applied in flow cytometry. Implementing bead-based assays in mass cytometry is desired but hampered by the lack of an elemental label required for their detection. In this study, we introduce stable osmium tetroxide labeling as a universal approach for generating functionalized beads readily detectable by mass cytometry. We demonstrate the utility of osmium-labeled beads for signal spillover compensation in mass cytometry, and, strikingly, their application in quantitative Ab-binding capacity assays combined with high-dimensional profiling of human PBMC enabled the systematic assessment of receptor expression profiles across large numbers of cellular phenotypes. This analysis confirmed increased monocytic Siglec-1 expression in active systemic lupus erythematosus patients and, additionally, revealed interrelated reductions of CD4 expression by regulatory and memory CD4 T cells and HLA-DR expression by myeloid dendritic cells, pointing toward defective cross-talk at the immunological synapse that may limit immune responses in systemic lupus erythematosus. By converting conventional flow cytometry beads into beads suitable for mass cytometry, our approach paves the way toward the broad implementation of bead-based assays in high-dimensional cell profiling studies by mass cytometry in biomedical research.

Objective/Background: The Clinical Global Impression scale (CGI) reflects the clinician's assessment of the disease impact on patient's global functioning. We assessed predictors of CGI scale rating in patients with obstructive sleep apnea (OSA). Patients/Methods: Consecutive patients with suspected OSA (n = 7581) were identified in the European Sleep Apnea Database (ESADA). Anthropometrics, comorbidities, apnea severity obtained by polygraphy or polysomnography, and daytime sleepiness [Epworth Sleepiness Scale (ESS)] were assessed. The CGI 7-point scale was completed at the end of the diagnostic process (CGI-severity, ie, CGI-S) and, in a sub-population, at treatment follow-up (CGI-Improvement). Results: CGI-S was rated mild to moderate in 44% of patients. CGI rating at any given apnea intensity was worse in women than in men (p < 0.01). Patients undergoing polygraphy (n = 5075) were more frequently rated as severely ill compared to those studied with polysomnography (19.0% vs 13.0%, p < 0.001). In patients aged

Population-based studies on Staphylococcus aureus nasal colonization are scarce. We examined the prevalence, resistance, and molecular diversity of S. aureus in the general population in Northeast Germany. Nasal swabs were obtained from 3,891 adults in the large-scale population-based Study of Health in Pomerania (SHIP-TREND). Isolates were characterized using spa genotyping, as well as antibiotic resistance and virulence gene profiling. We observed an S. aureus prevalence of 27.2%. Nasal S. aureus carriage was associated with male sex and inversely correlated with age. Methicillin-resistant S. aureus (MRSA) accounted for 0.95% of the colonizing S. aureus strains. MRSA carriage was associated with frequent visits to hospitals, nursing homes, or retirement homes within the previous 24 months. All MRSA strains were resistant to multiple antibiotics. Most MRSA isolates belonged to the pandemic European hospital-acquired MRSA sequence type 22 (HA-MRSA-ST22) lineage. We also detected one livestock-associated MRSA ST398 (LA-MRSA-ST398) isolate, as well as six livestock-associated methicillin-susceptible S. aureus (LA-MSSA) isolates (clonal complex 1 [CC1], CC97, and CC398). spa typing revealed a diverse but also highly clonal S. aureus population structure. We identified a total of 357 spa types, which were grouped into 30 CCs or sequence types. The major seven CCs (CC30, CC45, CC15, CC8, CC7, CC22, and CC25) included 75% of all isolates. Virulence gene patterns were strongly linked to the clonal background. In conclusion, MSSA and MRSA prevalences and the molecular diversity of S. aureus in Northeast Germany are consistent with those of other European countries. The detection of HA-MRSA and LA-MRSA within the general population indicates possible transmission from hospitals and livestock, respectively, and should be closely monitored.

Purpose: Visual impairment presents significant risks for occupational injuries among farmworkers, a vulnerable population with limited access to vision care. Although previous research has noted farmworkers’ low lifetime experience with vision screening and high rates of complaints of eye ailments and poor vision, there have been few screening data collected to evaluate these self-reports. The objectives of this analysis are to (1) describe farmworker visual health using standardized visual acuity screening data and self-reported visual function, and (2) to compare the screening and self-report data. Methods: Data are from a cross-sectional study of eye health among Latino migrant farmworkers in North Carolina with uncorrected vision (n = 289). Workers were recruited using methods to achieve a representative sample of a hard-to-reach population. Visual acuity data were collected using Snellen Tumbling E charts for nearsightedness and farsightedness. Binocular data are reported here. Interviews were conducted to obtain personal characteristics and self-assessed visual function. Results: About 75% of farmworkers reported never having had a vision screening. Based on binocular screening, 1.7% (distance vision) and 6.9% (near vision) had moderate to severe visual impairment (>20/40). Farmworkers self-reported poorer visual function, compared with screening results; only 36.4% reported good or very good vision. Sensitivity of distance and near vision self-reports were 60 and 20%, respectively, but specificity was high. Conclusions: This study confirms past reports of little vision screening among farmworkers. Visual impairment for distance is comparable to other studies of Latinos in the US, though these studies have not reported near vision. Self-reports of vision problems are not a sensitive measure of visual acuity among farmworkers. Screening is needed to identify visual impairment that can create occupational safety risks in this health disparate population.

Mass cytometry has pioneered >40-parameter single-cell analyses that allow for the characterization of complex cellular networks at unprecedented depth. Up to 135 parameters can be simultaneously detected, but limited availability of metal tags suitable for labeling of specific probes prevents optimal exploitation of the analytical capacity of mass cytometers. To this end, we here establish the application of elemental silver nanoparticles (AgNP) of different size for reporting cell surface antigens on human leukocytes in mass cytometry assays. The mass channels at 107 Da and 109 Da are uniquely occupied by silver isotopes and do not interfere with other mass cytometry reagents. Streptavidin-coated AgNP (SA-AgNP) facilitated distinct and specific detection of various antigens, such as CD8, CD244 and CD294 on peripheral blood leukocytes pre-incubated with respective biotinylated primary antibodies. Signal intensities elicited by 40 nm-sized AgNP allowed specific detection of the low abundance antigen CD25 on both, peripheral blood regulatory T cells and CD25lo CD127+ CD4+ T cells, enabling their distinct clustering in viSNE plots. SA-AgNP were of high elemental purity, showed minor background binding to cells in immunoassays, and were compatible with previously established staining protocols for PBMC and leukocytes, facilitating their use in complex mass cytometry panels. Considering the synthesis of AgNP from isotopically purified silver, the usage of AgNP extends the analytical capacity of mass cytometry panels by one, prospectively two, additional parameters, suitable for the detection of cellular targets of low abundance. © 2016 International Society for Advancement of Cytometry.

Zusammenfassung Hintergrund: Daten aus der kassenärztlichen Versorgung werden u. a. in der Gesundheitsberichterstattung und der Versorgungsforschung auf Kreisebene genutzt. Für eine korrekte Ratenbildung müsste die Zahl der GKV-Versicherten im Nenner zugrunde gelegt werden, diese steht aber in einigen Bundesländern auf Kreisebene nicht zur Verfügung. Die Raten werden daher im kassenärztlichen System mit einer Surrogatgröße (definiert über die Arztkontakte) gebildet. Dies führt zu Unschärfen, sodass kleinräumige Regionalvergleiche nur bedingt möglich sind. Ziel der vorliegenden Arbeit ist ein besseres Schätzmodell für die Zahl der GKV-Versicherten auf Kreisebene. Methodik: Der Anteil der GKV-Versicherten in den bayerischen Kreisen wird durch ein multiples lineares Regressionsmodell geschätzt. Im Modell wird der Anteil der GKV-Versicherten in den Anpassungsschichten des Mikrozensus (einer Zusammenfassung von mehreren Kreisen) erklärt durch Einflussfaktoren auf den Versicherungsstatus, die auf Kreisebene vorliegen (verfügbares Einkommen, Beamten- und Selbständigenanteil). Die durch das Modell berechneten GKV-Versichertenzahlen werden mit der Surrogatgröße verglichen. Eine konkrete Anwendung erfolgt am Beispiel der regionalen Diabetesdiagnosen aus den Daten der Kassenärztlichen Vereinigung Bayerns. Ergebnisse: Durch das Regressionsmodell werden für die bayerischen Kreise GKV-Versichertenanteile zwischen 74,7 und 91,6% geschätzt. Der Unterschied zu der bisher genutzten Ersatzgröße beträgt bis zu 18,6 Prozentpunkte. Dies spiegelt sich dementsprechend in den Behandlungsprävalenzen wider, hier am Beispiel des Diabetes mellitus veranschaulicht. Schlussfolgerung: Die vorliegende Analyse zeigt, mit welchen Unsicherheiten die Ratenbildung bei Daten aus der kassenärztlichen Versorgung derzeit behaftet ist und was daraus für kleinräumige Vergleiche, etwa in der Gesundheitsberichterstattung, folgt. Die Aufbereitung valider Nennerdaten im Rahmen der Datentransparenzregelung nach SGB V ist anzustreben.

In the first part of this article, we extend the formal upscaling of a diffusion–precipitation model through a two-scale asymptotic expansion in a level set framework to three dimensions. We obtain upscaled partial differential equations, more precisely, a non-linear diffusion equation with effective coefficients coupled to a level set equation. As a first step, we consider a parametrization of the underlying pore geometry by a single parameter, e.g. by a generalized “radius” or the porosity. Then, the level set equation transforms to an ordinary differential equation for the parameter. For such an idealized setting, the degeneration of the diffusion tensor with respect to porosity is illustrated with numerical simulations. The second part and main objective of this article is the analytical investigation of the resulting coupled partial differential equation–ordinary differential equation model. In the case of non-degenerating coefficients, local-in-time existence of at least one strong solution is shown by applying Schauder's fixed point theorem. Additionally, non-negativity, uniqueness, and global existence or existence up to possible closure of some pores, i.e. up to the limit of degenerating coefficients, is guaranteed.

BACKGROUND: Evaluation of an outreach programme using a mobile transient elastography (TE) device (FibroScan) to improve liver disease assessment in different clinical settings. AIMS: To evaluate a programme of liver fibrosis assessment by TE and to compare fibrosis scores between different sites and patient groups. METHODS: Prospective cohort study. TE was conducted at a tertiary hospital and during outreach clinics in three different settings: community clinics, clinics for people who use drugs (PWUD) and regional clinics in rural Victoria. All patients referred for TE at the participating locations were eligible during the study period. RESULTS: A total of 200 of 623 patients was assessed and evaluated during outreach sessions (regional 100; PWUD 18; community 82). While the majority of patients in community centres were infected with hepatitis B (68%), most patients in regional clinics and in PWUD settings had hepatitis C virus (HCV) (81 and 100%, respectively). Significantly more patients assessed at regional clinics and PWUD settings presented with severe fibrosis (F3-F4, F4): regional clinics 39%; PWUD 31%; tertiary 11%; community 7%, (P

Context. Flares in radio-loud active galactic nuclei are thought to be associated with the injection of fresh plasma into the compact jet base. Such flares are usually strongest and appear earlier at shorter radio wavelengths. Hence, very long baseline interferometry (VLBI) at millimeter(mm)-wavelengths is the best-suited technique for studying the earliest structural changes of compact jets associated with emission flares. Aims. We study the morphological changes of the parsec-scale jet in the nearby (z = 0.049) γ-ray bright radio galaxy 3C 111 following a flare that developed into a major radio outburst in 2007. Methods. We analyse three successive observations of 3C 111 at 86 GHz with the Global mm-VLBI Array (GMVA) between 2007 and 2008 which yield a very high angular resolution of ∼45 μas. In addition, we make use of single-dish radio flux density measurements from the F-GAMMA and POLAMI programmes, archival single-dish and VLBI data. Results. We resolve the flare into multiple plasma components with a distinct morphology resembling a bend in an otherwise remarkably straight jet. The flare-associated features move with apparent velocities of ∼4.0c to ∼4.5c and can be traced also at lower frequencies in later epochs. Near the base of the jet, we find two bright features with high brightness temperatures up to ∼1011 K, which we associate with the core and a stationary feature in the jet. Conclusions. The flare led to multiple new jet components indicative of a dynamic modulation during the ejection. We interpret the bend-like feature as a direct result of the outburst which makes it possible to trace the transverse structure of the jet. In this scenario, the components follow different paths in the jet stream consistent with expectations for a spine-sheath structure, which is not seen during intermediate levels of activity. The possibility of coordinated multiwavelength observations during a future bright radio flare in 3C 111 makes this source an excellent target for probing the radio-γ-ray connection. © ESO 2020., We would like to thank the anonymous referee for helpful comments that improved the manuscript. We would like to thank the internal MPIfR referee N. MacDonald for insightful comments that helped improve the manuscript. RS gratefully acknowledge support from the European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013)/ERC Advanced Grant RADIOLIFE-320745 and support by Deutsche Forschungsgemeinschaft grant WI 1860/10-1. MP acknowledges financial support from the Spanish Ministry of Science through Grants PID2019-105510GB-C31, PID2019-107427GB-C33 and AYA2016-77237-C3-3-P, and from the Generalitat Valenciana through grant PROMETEU/2019/071. I.A. acknowledges support by a Ramon y Cajal grant (RYC-2013-14511) of the "Ministerio de Ciencia e Innovacion (MICINN)" of Spain. He also acknowledges financial support from MCINN through the "Center of Excellence Severo Ochoa" award for the Instituto de Astrofisica de Andalucia-CSIC (SEV-2017-0709). Acquisition and reduction of the POLAMI data was supported in part by MICINN through grant AYA2016-80889-P. IRAM is supported by INSU/CNRS (France), MPG (Germany) and IGN (Spain). This research has made use of data obtained with the Global Millimeter VLBI Array (GMVA), which consists of telescopes operated by the MPIfR, IRAM, Onsala, Metsahovi, Yebes, the Korean VLBI Network, the Green Bank Observatory and the Very Long Baseline Array (VLBA). The VLBA is a facility of the National Science Foundation operated under cooperative agreement by Associated Universities, Inc. The data were correlated at the correlator of the MPIfR in Bonn, Germany. This study makes use of 43 GHz VLBA data from the Boston University gamma-ray blazar monitoring program (http://www.bu.edu/blazars/VLBAproject.html), funded by NASA through the Fermi Guest Investigator Program. This research has made use of data from the MOJAVE database that is maintained by the MOJAVE team (Lister et al. 2009). The Very Long Baseline Array (VLBA) is an instrument of the National Radio Astronomy Observatory (NRAO). NRAO is a facility of the National Science Foundation, operated by Associated Universities Inc. This research made use of the Interactive Spectral Interpretation System (ISIS) (Houck & Denicola 2000) and a collection of ISIS scripts provided by the Dr. Karl Remeis observatory, Bamberg, Germany at http://www.sternwarte.uni-erlangen.de/isis/. This research made use of the NASA/IPAC Extragalactic Database (NED), which is operated by the Jet Propulsion Laboratory, California Institute of Technology, under contract with the National Aeronautics and Space Administration and of the VizieR catalogue access tool, CDS, Strasbourg, France.

Krüppel-Like-Factor 2 (KLF2) is a transcription factor that controls organ development, differentiation and trafficking of cells. In the immune system, KLF2 fosters the egress of T lymphocytes from the thymus via S1PR1 and promotes quiescent states of B lymphocytes as well as homing of antigen-specific IgG plasmablasts (PB) and plasma cells (PC) to the bone marrow (BM) via the α4β7 receptor. To investigate the PC-specific role of KLF2, we analyzed CD138+/TACI+ PB/PC subpopulations and isotype changes in various organs such as spleen (SP), BM, gut associated lymphoid tissues (GALT) and blood of KLF2-deficient mice in comparison to their mb1cre+ KLF2wt/wt controls. Therefore, FACS and Elispot analyses showed a striking reduction of IgA+ PB/PC in SP, BM and blood of non-immunized mice. Elisa and multiplex data revealed a strong reduction in serum IgA as well as (s)IgA in the feces of KLF2-deficient mice. However, frequencies of IgA+ PB/PC were not changed in GALT but total PB/PC accumulated in mesenteric lymph nodes (mLN) and Peyer’s Patches. In addition, IgA secretion of these cells was not effected. Based on these data, we conclude that the observed IgA-deficiency in KLF2-deficient mice can in part be explained by impaired egress of class switched PB/PC from their organ of generation to survival niches in the bone marrow and gut by controlling the expression of integrins. To address the consequences of a dysregulated PB/PC migration during infection, we are analyzing a GALT-dependent immunization with recombinant Flagellin which is known to trigger a systemic IgG as well as an mucosal IgA response. Furthermore, we are identifying KLF2 target genes that control PC egress and trafficking by RNAseq of IgA+ PB/PC from the mLN of KLF2-deficient mice.

Plasma cells provide humoral protection by secreting large amounts of antibodies. The heterogeneity of the plasma cell compartment has recently been demonstrated by functional studies and subpopulation markers, but the distinct properties of long-lived plasma cells (LLPC) are still unresolved. B Cell Maturation Antigen (BCMA) has been described as an essential receptor for LLPC survival. To elucidate the mechanisms of BCMA-mediated survival we established a reporter mouse line that expresses a tdTomato fluorescent protein together with BCMA under the control of the promoter of Tnfrsf17, the gene that encodes BCMA. In this reporter model, we could demonstrate the restricted expression of Tomato and BCMA in plasma cells making this an ideal system for the identification and tracking of plasma cells. Importantly, we observed an increase in the abundance of BCMA:Tomato along with a gradual loss of CD19 expression, delineating a developmental progression from plasmablasts to mature plasma cell subsets. In contrast, plasmablasts generated in vitro display only minimal BCMA induction, confirming the independence of BCMA expression from the Blimp1 master regulator of PC differentiation. In summary, we have developed a new plasma cell-specific reporter model that, together with an inducible BCMA-KO mouse, will allow us to investigate the BCMA-dependent signals of the generation and maintenance of LLPC. This work was supported, in part, by the Deutsche Forschungsgemeinschaft (DFG) through research grants TRR130 to H.-M.J. and W.S. and GRK1660 to H.-M.J.

ObjectiveThe aim of this study was to explore the features of sustainable antimicrobial stewardship (AMS) programs in Australian rural hospitals and develop recommendations on incorporating these features into rural hospitals’ AMS programs. MethodsLead AMS clinicians with knowledge of at least one AMS program sustained for >2 years in a health service in rural Australia were recruited to the study. A series of interviews was conducted and the transcripts analysed thematically using a framework method. ResultsFifteen participants from various professional disciplines were interviewed. Key features that positively affected the sustainability of AMS programs in rural hospitals included a hospital executive who provided strong governance and accountability, dedicated resources, passionate local champions, area-wide arrangements and adaptability to engage in new partnerships. Challenges to building AMS programs with these features were identified, particularly in engaging hospital executive to allocate AMS resources, managing the burn out of passionate champions and formalising network arrangements. ConclusionsStrategies to increase the sustainability of AMS programs in rural hospitals include using accreditation as a mechanism to drive direct resource allocation, explicit staffing recommendations for rural hospitals, greater support to develop formal network arrangements and a framework for integrated AMS programs across primary, aged and acute care. What is known about the topic?AMS programs facilitate the responsible use of antimicrobials. Implementation challenges have been identified for rural hospitals, but the sustainability of AMS programs has not been explored. What does this paper add?Factors that positively affected the sustainability of AMS programs in rural hospitals were a hospital executive that provided strong governance and accountability, dedicated resources, network or area-wide arrangements and adaptability. Challenges to building AMS programs with these features were identified. What are the implications for practitioners?Recommended actions to boost the sustainability of AMS programs in rural hospitals are required. These include using accreditation as a mechanism to drive direct resource allocation, explicit staffing recommendations for rural hospitals, greater support to develop network arrangements and support to create integrated AMS programs across acute, aged and primary care.

The interaction of our immune system with breast cancer (BC) cells prompted the investigation of tumor-infiltrating lymphocytes (TILs) and targeted, tumor antigen-specific immunotherapy.Correlation between TILs and pathological complete response (pCR) after neoadjuvant systemic therapy (NACT). Tumor-specific antigens (TSAs) in HER2+ and triple negative BC and establishment of TSA-specific therapies within the interdisciplinary TILGen study.Illustration of the TILGen study design. Assessment of TILs and correlation with pCR within this BC study.pCR was achieved in 38.4% (56/146) and associated with estrogen receptor/progesterone receptor negative (ER-/PR-) and HER2+ tumors. Lymphocytic predominant BC (LPBC) was found in 16.4% (24/146), particularly in ER-/PR- (ER-: 27.3% vs. ER+: 9.9%, PR-: 22.3% vs. PR+: 8.2%), large, and poorly differentiated BC. TILs were significantly correlated with pCR in multivariate analysis. In LPBC, pCR was achieved in 66.7%, whereas it was 32.8% in non-LPBC.First results confirm the influence of the human immune system on the response to NACT in HER2+ and triple negative BC. TSA-specific immunotherapy might improve the outcome in BC patients but there is an urgent need for comprehensive studies to further investigate this issue.

Introduction One-third of the Australian population lives outside major cities and this group has worse health outcomes. Telehealth is becoming an accepted way to improve patient access to specialist healthcare. Over 200,000 Australian’s have hepatitis C virus (HCV) and new treatments are very effective and well tolerated. We aim to demonstrate that HCV treatment utilising telehealth support for care delivery has cure rates similar to onsite care in clinical trials. We also report length of consultation and calculate reductions in travel and carbon output. Methods Patient demographic, clinical, and treatment outcome data were collected prospectively from hospital software and analysed retrospectively. This was an audit of all patients treated for HCV in one year from a single tertiary hospital that included telehealth in their care delivery. Results Sustained virological response was achieved in 51/52 (98%) patients with completed treatment courses, and 51/58 (88%) of those who had a planned telehealth consultation as part of their management. A median of 634 km of patient travel was saved per telehealth consultation. Discussion We found that a telehealth-supported outreach programme for patients in regional Australia with HCV produced similar outcomes to clinical trials. There was a considerable saving in time and cost for the patients and significant environmental benefit through the reduction in carbon footprint associated with travel to distant specialist health services. We conclude that telehealth facilitated outreach is a feasible and effective way to access HCV treatment and cure in regional Australia.

Summary Background Many regional and remote (‘regional’) hospitals are without the specialist services that support antimicrobial stewardship (AMS) programmes in hospitals in major cities. This can impact their ability to implement AMS activities. Aim To identify factors that impact on the delivery of AMS programmes in regional hospitals. Methods Healthcare clinicians who have primary AMS responsibilities or provide AMS support to a health service or across health services with an Australian Statistical Geography Standard Remoteness classification of inner regional, outer regional, remote or very remote were recruited purposively and via snowballing. A series of focus groups and interviews were held, and the discussions were audiotaped and transcribed verbatim. The transcripts were coded by two researchers, and thematic analysis was undertaken using a framework method. Findings Four focus groups and one interview were conducted (22 participants). Six main themes that impacted on AMS programme delivery were identified: culture of independence and self-reliance by local clinicians, personal relationships, geographical location of the hospital influencing antimicrobial choice, local context, inability to meaningfully benchmark performance, and lack of resources. Possible strategies to support the delivery of AMS programmes in regional hospitals proposed by participants were categorized into two main themes: those that may be best developed or managed centrally, and those that should be a local responsibility. Conclusion AMS programme delivery in regional hospitals is influenced by factors that are not present in hospitals in major cities. These findings provide a strong basis for the development of strategies to support regional hospitals to implement sustainable AMS programmes.

INTRODUCTION: Antimicrobial resistance (AMR) has been recognised as an urgent health priority, both nationally and internationally. Australian hospitals are required to have an antimicrobial stewardship (AMS) program, yet the necessary resources may not be available in regional, rural or remote hospitals. This review will describe models for AMS programs that have been introduced in regional, rural or remote hospitals internationally and showcase achievements and key considerations that may guide Australian hospitals in establishing or sustaining AMS programs in the regional, rural or remote hospital setting. METHODS: A narrative review was undertaken based on literature retrieved from searches in Ovid Medline, Scopus, Web of Science and the grey literature. 'Cited' and 'cited by' searches were undertaken to identify additional articles. Articles were included if they described an AMS program in the regional, rural or remote hospital setting (defined as a bed size less than 300 and located in a non-metropolitan setting). RESULTS: Eighteen articles were selected for inclusion. The AMS initiatives described were categorised into models designed to address two different challenges relating to AMS program delivery in regional, rural and remote hospitals. This included models to enable regional, rural and remote hospital staff to manage AMS programs in the absence of on-site infectious diseases (ID) trained experts. Non-ID doctor-led, pharmacist-led and externally led initiatives were identified. Lack of pharmacist resources was recognised as a core barrier to the further development of a pharmacist-led model. The second challenge was access to timely off-site expert ID clinical advice when required. Examples where this had been overcome included models utilising visiting ID specialists, telehealth and hospital network structures. Formalisation of such arrangements is important to clarify the accountabilities of all parties and enhance the quality of the service. Information technology was identified as a facilitator to a number of these models. The variance in availability of information technology between hospitals and cost limits the adoption of uniform programs to support AMS. CONCLUSION: Despite known barriers, regional, rural and remote hospitals have implemented AMS programs. The examples highlighted show that difficulty recruiting ID specialists should not inhibit AMS programs in regional, rural and remote hospitals, as much of the day-to-day work of AMS can be done by non-experts. Capacity building and the strengthening of networks are core features of these programs. Descriptions of how Australian regional, rural and remote hospitals have structured and supported their AMS programs would add to the existing body of knowledge sourced from international examples. Research into AMS programs predominantly led by GPs and nursing staff will provide further possible models for regional, rural and remote hospitals.

Many regional and remote hospitals (RRHs) do not have the specialist services that usually support antimicrobial stewardship (AMS) programmes in major city hospitals. It is not known if this is associated with higher rates of inappropriate antimicrobial prescribing. The aim of this study was to identify similarities and differences in antimicrobial prescribing patterns between major city hospitals and RRHs in Australia. The Australian Hospital National Antimicrobial Prescribing Survey (H-NAPS) datasets from 2014, 2015 and 2016 (totalling 47,876 antimicrobial prescriptions) were analysed. The antimicrobial prescribed, indications for use, documentation of indication, recording of a review date and assessment of the appropriateness of prescribing were evaluated. Overall, inappropriate prescribing of antimicrobials was higher in RRHs than in major city hospitals (24.0% vs. 22.1%; P

This study investigated the impact of migration background on the health outcomes of preschool children from families of various social status levels.During the school entrance health examination (Schuleingangsuntersuchung (SEU)) from October 2012 to August 2013, the parents of 5052 preschool children (62% response rate) participated in a cross-sectional health survey within the framework of health-monitoring units (Gesundheits-Monitoring-Einheiten (GME)) in Bavaria, Germany. They were handed a self-administered questionnaire with questions relating to the language spoken at home and other socio-demographic characteristics. By applying the record linkage method, 3747 participants were correctly linked to the corresponding data of the SEU. Based on the merged dataset, 4 definitions of migration background were explored regarding demographic indicators, the parents' mother tongue, and the language spoken at home. The association between migration background and health outcomes of preschool children was analyzed using multivariable logistic regression models separately. The risk estimates were presented for the study population and stratified into high, medium, and low social status. The models were repeated for each of the 4 migration background variables.The results show significant associations between migration background and health outcomes of preschool children (except in pronunciation). A migration background had the strongest impact on the development of word/sentence formation disorder. Compared to non-migrant preschool children, migrant children had twice the chances for full vaccination coverage (OR [95% CI]: 2.4 [1.9-3.1]) but only half the chance to participate in all health examinations from U1 to U9 (0.5 [0.4-0.6]). These children were also at two-fold increased risk to be overweight/obese (2.2 [1.7-2.8]). Moreover, preschool children with double-sided migration from medium social status families faced the highest risk for word/sentence formation disorder (9.5 [5.6-16.1] with SEU definition and 23.3 [10.3-52.6] with GME definition of a migration background).Future prevention programs at the preschool level should focus on children with double-sided migration from medium social status families. With respect to social and cultural integration, the definition of migration background based on the language spoken at home should be appropriate for future SEUs.Die Studie untersucht den Einfluss des Migrationshintergrundes auf den Gesundheitszustand von Vorschulkindern aus Familien mit unterschiedlichem Sozialstatus.Während der Schuleingangsuntersuchungen (SEU) von 10/2012 bis 08/2013 nahmen Eltern von 5052 Vorschulkindern (Teilnahmerate: 62%) an einer Querschnittsstudie im Rahmen der Gesundheits-Monitoring-Einheiten (GME) in Bayern, Deutschland teil. Sie wurden nach der zu Hause gesprochenen Sprache und anderen soziodemografischen Merkmalen befragt. Die Daten der 3747 Vorschulkinder wurden nach der deterministischen Record-Linkage-Methode mit den entsprechenden Daten aus der SEU verknüpft. Anhand dieses Datensatzes wurden 4 Definitionen von Migrationshintergrund basierend auf demografischen Indikatoren, der Muttersprache der Eltern und der zu Hause gesprochenen Sprache untersucht. Die Assoziation zwischen Migrationshintergrund und den Gesundheitszustand von Vorschulkindern wurde separat mittels multivariabler logistischer Regression analysiert. Die Risikoschätzungen wurden für die gesamte Studienpopulation und getrennt nach hohem, mittlerem und niedrigem Sozialstatus vorgenommen. Die Modelle wurden für jede Definition des Migrationshintergrundes wiederholt.Der Migrationshintergrund hat einen signifikanten Einfluss auf Gesundheitszustand von Vorschulkindern (ausgenommen Lautbildungsstörung) und den stärksten Effekt auf eine Wort-/Satzbildungsstörung. Vorschulkinder mit Migrationshintergrund haben eine doppelt so hohe Chance für vollständige Impfungen wie Kinder ohne Migrationshintergrund (OR [95% KI]: 2,4 [1,9–3,1]), aber nur die Hälfte der Chance an allen U-Untersuchungen teilzunehmen (0,5 [0,4–0,6]). Sie haben ein doppelt so hohes Risiko für Übergewicht/Adipositas (2,2 [1,7–2,8]). Vorschulkinder mit beidseitigem Migrationshintergrund aus Familien mit mittlerem Sozialstatus weisen das höchste Risiko für Wort-/Satzbildungsstörung auf (9,5 [5,6–16,1] mit SEU-Definition und 23,3 [10,3–52,6] mit GME-Definition des Migrationshintergrundes).Eine wichtige Zielgruppe für zukünftige Präventionsprogramme im Vorschulalter stellt die Gruppe der Kinder mit beidseitigem Migrationshintergrund aus Familien mit mittlerem Sozialstatus dar. In Hinsicht auf die soziale und kulturelle Integration erscheint die Definition des Migrationshintergrunds bzgl. der zu Hause gesprochenen Sprache am geeignetsten für die SEU.

Background Combinations *Equal contributors. of different imaging techniques in fusion devices appear to be associated with improvements in diagnostic assessment. Purpose The aim of this study was to test the feasibility of using an automated standard three-dimensional (3D) ultrasound (US) device fused with standard mammography for the first time in breast cancer patients. Material and Methods Digital mammograms and 3D automated US images were obtained in 23 patients with highly suspicious breast lesions. A recently developed fusion machine consisting of an ABVS 3D US transducer from an Acuson S2000 machine and a conventional Mammomat Inspiration device (both Siemens Healthcare GmbH, Erlangen, Germany) were used for the purpose. The feasibility of the examinations, imaging coverage, and patients' experience of the procedure were examined. Results In 15 out of 19 patients, the region of interest (ROI) with the tumor marked in the mammogram was visible on US. The examination was experienced positively by the patients, with no unexpected pain or injury. The examination was time-saving and well tolerated. Conclusion In conclusion, we have shown initial clinical feasibility of an US/radiography fusion prototype with good localization and evaluation of the ROIs. The combined examination was well tolerated. The simultaneous evaluation with mammography and US imaging may be able to improve detection and reduce examiner-related variability.