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Enterohaemorrhagic E. coli cause major epidemics worldwide with significant organ damage and very high percentages of death. Due to the ability of enterohaemorrhagic E. coli to produce shiga toxin these bacteria damage the kidney leading to the hemolytic uremic syndrome. A therapy against this serious kidney disease has not been developed yet and the impact and mechanism of leukocyte activation and recruitment are unclear. Tissue-resident macrophages represent the main leukocyte population in the healthy kidney, but the role of this important cell population in shiga toxin-producing E. coli-hemolytic uremic syndrome is incompletely understood. Using state of the art microscopy and mass spectrometry imaging, our preclinical study demonstrated a phenotypic and functional switch of tissue-resident macrophages after disease induction in mice. Kidney macrophages produced the inflammatory molecule TNFα and depletion of tissue-resident macrophages via the CSF1 receptor abolished TNFα levels in the kidney and significantly diminished disease severity. Furthermore, macrophage depletion did not only attenuate endothelial damage and thrombocytopenia, but also activation of thrombocytes and neutrophils. Moreover, we observed that neutrophils infiltrated the kidney cortex and depletion of macrophages significantly reduced the recruitment of neutrophils and expression of the neutrophil-attracting chemokines CXCL1 and CXCL2. Intravital microscopy revealed that inhibition of CXCR2, the receptor for CXCL1 and CXCL2, significantly reduced the infiltration of neutrophils and reduced kidney injury. Thus, our study shows activation of tissue-resident macrophages during shiga toxin-producing E. coli-hemolytic uremic syndrome leading to the production of disease-promoting TNFα and CXCR2-dependent recruitment of neutrophils.

The aim of this study was to describe atypical dyskinesias (AtypDs) occurring during treatment with antipsychotic drugs (APDs). AtypDs are dyskinesias showing either an unusual temporal relationship between onset of treatment and start of the adverse drug reaction (ADR) or an unusual presentation of clinical symptoms.Data on the utilisation of APDs and reports of severe APD-induced AtypDs were collected using data from the observational pharmacovigilance programme - 'Arzneimittelsicherheit in der Psychiatrie (English: drug safety in psychiatry)' (AMSP) - from 1993 to 2016.A total of 495,615 patients were monitored, of which 333,175 were treated with APDs. Sixty-seven cases (0.020%) of severe AtypDs under treatment with APDs were registered. The diagnoses of schizophrenic disorders as well as organic mental disorders were related to significantly higher rates of AtypDs. Second-generation antipsychotic drugs (SGAs) showed slightly higher rates of AtypDs (0.024%) than high-potency (0.011%) or low-potency first-generation antipsychotic drugs (FGAs; 0.006%). In 41 cases (61.2%), two or more drugs were found to cause AtypDs.Our study indicates that AtypDs are rare ADRs. SGAs may have a higher risk for the occurrence of AtypDs than FGAs. Clinicians should be aware of this ADR and patients should be monitored and examined carefully.

Background: Currently available data on the prescription practice among patients with major depressive disorder (MDD) reflect the outpatient setting. This is the first study to provide information on time trends of psychotropic drug utilization in psychiatric inpatients. Method: Data stems from German-speaking psychiatric hospitals collected by the program “Drug Safety in Psychiatry” (Arzneimittelsicherheit in der Psychiatrie, AMSP) between 2001 and 2017. 44,418 psychiatric inpatients with MDD were included. Time trends in drug utilization were analyzed by comparing the first (2001–2003) and last time point (2015–2017) using risk ratios (RR). Results: Antidepressant drugs (ADD) were the most used psychotropic drug class with utilization decreasing slightly from 2001–2003 (89.7%) to 2015–2017 (85.5%). Use of tricyclic ADDs showed the greatest decline (RR 0.35), while use of selective serotonin-noradrenaline reuptake inhibitors (RR 1.72) and “other ADDs” increased the most. Use of antipsychotic drugs (APD), especially second-generation antipsychotic drugs (RR 1.46), increased. Use of tranquilizing (RR 0.71) and hypnotic drugs (RR 0.43) both decreased. Most patients were treated with more than one psychotropic drug, most often ADD + APD, which was utilized more often in 2015–2017 (51.1%) than in 2001–2003 (45.1%; RR 1.13). Combination of two ADDs increased from 2001–2003 (24.5%) to 2015–2017 (33.0%; RR 1.35). Limitations: The cross-sectional design does not allow conclusions to be drawn about causal relationship of findings. Further, only certain clinical and sociodemographic data was available. Conclusion: Treatment of MDD has shown significant changes from 2001 to 2017.

Rituximab and eculizumab, monoclonal antibodies that deplete most B cells and activate the terminal complement, respectively, are used to treat nonmalignant hematologic disorders (NMHDs), sometimes with unfavorable effects on the immune system. Hypogammaglobulinemia and neutropenia have been reported with variable prevalence in patients treated with rituximab. Neutropenia is mild and transient, and serious infectious complications are uncommon, so treatment is not indicated. Hypogammaglobulinemia is of greater concern. There is a lack of agreement on a standardized definition, and pre- and posttreatment immunoglobulin (Ig) levels are not routinely obtained. The association among low Ig levels, infectious risk, and mortality and morbidity in this population is unclear. There are also no formal guidelines on indication, risk factors, and threshold level of IgG to prompt Ig replacement therapy (IgRT). Among patients with NMHD, preexisting or persistent hypogammaglobulinemia (PH) after treatment with rituximab has been linked to underlying primary immunodeficiency disorders; therefore, a high index of suspicion should be maintained, and immunologic and genetic evaluation should be considered. Overall, important strategies in managing patients who are receiving rituximab include routine monitoring of pre- and posttreatment IgG levels, immune reconstitution (eg, B-cell subsets), assessment of vaccination status and optimization before treatment, and individualized consideration for IgRT. Accordingly, we discuss immunizations. Eculizumab, most commonly used in the treatment of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome, poses increased risk of meningococcal infections. To decrease the risk of infection, a meningococcal vaccination series is recommended before initiating therapy, and prophylactic antibiotics are preferred during the course of treatment.

Background: Postthrombotic syndrome (PTS) is a significant complication of pediatric deep venous thrombosis (DVT). There is a gap in the understanding of the risk factors associated with the development of pediatric PTS preventing the early identification of those patients at greatest risk, and the development of risk-stratified interventions. Objectives: To conduct a systematic review and meta-analysis of the literature on prognostic factors for PTS development in pediatric patients. Methods: A systematic search of MEDLINE, EMBASE, and the Cochrane Library from 1960 to December 2018 was performed. Eligible studies reported at least one prognostic factor for PTS development in patients < 21 years of age with a radiographically confirmed DVT. To be included in the meta-analysis, prognostic factors had to be reported in at least three published studies. Results and conclusions: Twelve studies (n = 1160 patients) met criteria for inclusion. Ninety-three percent of patients with an extremity DVT (n = 1076) were assessed for PTS. PTS developed in 40% (n = 434) of these patients. Central venous catheter-associated DVT (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.08-2.98), complete veno-occlusion (OR, 1.89; 95% CI, 1.04-3.46), and incomplete DVT resolution (OR, 2.07; 95% CI, 1.4-3.07) were identified as candidate prognostic factors for pediatric PTS. These findings should be interpreted in the context of the heterogeneity of the included studies and the limitations of current pediatric PTS assessment tools. Further, the predictive value of these prognostic factors will need to be validated in future collaborative prospective multicenter studies that maximize the homogeneity of pediatric DVT patients.

Objectives Drug-induced liver injury (DILI) has been associated with various antipsychotic drugs (APDs). Comparative studies between individual APDs are largely not available. Methods Antipsychotic drug utilisation data and reports of severe antipsychotic DILI were assessed by using data from an observational pharmacovigilance programme-Arzneimittelsicherheit in der Psychiatrie (AMSP)-during the period 1993-2016. Results Of the 333,175 patients treated with APDs, a total of 246 (0.07%) events of severe DILI were identified. Phenothiazines were associated with significantly higher rates of severe DILI (0.03%, 95% CI = 0.02-0.04) than thioxanthenes (0.01%, 95% CI = 0.00-0.02) or butyrophenones (0.01%, 95% CI = 0.00-0.01). Among individual drugs, olanzapine (0.12%, 95% CI = 0.10-0.16), perazine (0.09%, 95% CI = 0.05-0.15) and clozapine (0.09%, 95% CI = 0.10-0.12 ranked highest. In 78 cases (31.7%), combination therapies with antipsychotic and antidepressant drugs or with two or more APDs were considered responsible. Male sex and a diagnosis of mania were associated with significantly higher rates of severe DILI while older patients (≥65 years old) were significantly less often affected. Conclusions In the present analysis of a representative psychiatric inpatient cohort, olanzapine, perazine, and clozapine were the most common individual APDs associated with severe DILI.

The urothelium of the urinary bladder represents the first line of defense. However, uropathogenic E. coli (UPEC) damage the urothelium and cause acute bacterial infection. Here, we demonstrate the crosstalk between macrophages and the urothelium stimulating macrophage migration into the urothelium. Using spatial proteomics by MALDI-MSI and LC-MS/MS, a novel algorithm revealed the spatial activation and migration of macrophages. Analysis of the spatial proteome unravelled the coexpression of Myo9b and F4/80 in the infected urothelium, indicating that macrophages have entered the urothelium upon infection. Immunofluorescence microscopy additionally indicated that intraurothelial macrophages phagocytosed UPEC and eliminated neutrophils. Further analysis of the spatial proteome by MALDI-MSI showed strong expression of IL-6 in the urothelium and local inhibition of this molecule reduced macrophage migration into the urothelium and aggravated the infection. After IL-6 inhibition, the expression of matrix metalloproteinases and chemokines, such as CX3CL1 was reduced in the urothelium. Accordingly, macrophage migration into the urothelium was diminished in the absence of CX3CL1 signaling in Cx3cr1gfp/gfp mice. Conclusively, this study describes the crosstalk between the infected urothelium and macrophages through IL-6-induced CX3CL1 expression. Such crosstalk facilitates the relocation of macrophages into the urothelium and reduces bacterial burden in the urinary bladder.

The terricolous species Cladonia foliacea (Cladoniaceae, lichenised Ascomycota) widely distributed in open, dry lowland steppe and rocky mountain grassland vegetation in Europe was chosen as a potential test organism for ecological experiments, since their thalli are producing cortical solar radiation-protective and UV screening pigment dibenzofuran usnic acid and medullary secondary substance depsidone fumarprotocetraric acid. Significant seasonal differences were found in the amounts of lichen secondary metabolites analysed by HPTLC and HPLC-PDA between summer and winter collected thalli in sandy grassland area in Hungary. The concentrations of usnic acid varied between 7.34 and 15.52 mg/g in summer collected samples and 13.90 and 21.61 mg/g in winter collected ones. A comparable amount (11.61±0.29 mg/g) was measured in pulverised samples. The concentrations of fumarprotocetraric acid varied between 0.60 and 3.01 mg/g in summer collected samples and 2.26 and 5.81 mg/g in winter collected thalli. A comparable amount (2.45±0.21 mg/g) was found in pulverised samples. The range of concentration values is comparable with data known from lichens. A higher amount of usnic acid is produced in winter probably to ensure sufficient protection also for summer. The fumarprotocetraric acid content of the medulla might contribute to the solar irradiation reflecting role of the pale lower surface lobes turning upwards in dry condition.

AimsThe Hamilton Depression Rating Scale (HAMD) and the Beck Depression Inventory (BDI) are the most frequently used observer-rated and self-report scales of depression, respectively. It is important to know what a given total score or a change score from baseline on one scale means in relation to the other scale.MethodsWe obtained individual participant data from the randomised controlled trials of psychological and pharmacological treatments for major depressive disorders. We then identified corresponding scores of the HAMD and the BDI (369 patients from seven trials) or the BDI-II (683 patients from another seven trials) using the equipercentile linking method.ResultsThe HAMD total scores of 10, 20 and 30 corresponded approximately with the BDI scores of 10, 27 and 42 or with the BDI-II scores of 13, 32 and 50. The HAMD change scores of −20 and −10 with the BDI of −29 and −15 and with the BDI-II of −35 and −16.ConclusionsThe results can help clinicians interpret the HAMD or BDI scores of their patients in a more versatile manner and also help clinicians and researchers evaluate such scores reported in the literature or the database, when scores on only one of these scales are provided. We present a conversion table for future research.

Coordination polymers, including metal–organic frameworks, are a diverse class of materials with myriad properties and potential applications. However, a number of drawbacks have hindered the scaling up of such materials towards commercial applications. These include health and safety risks, environmental hazards, poor cost efficiency and sustainability shortfalls. In contrast to the systematic progress of organic green chemistry, which has contributed to improvements in the sustainability of chemical processing, the development of green chemistry in the context of coordination polymers has been fragmented and sporadic. This review describes advances in the use of green components: benign sustainable ligands and non-hazardous earth abundant metals. Additionally, solvent considerations, synthesis strategies for improved sustainability and the performance of coordination polymers relative to alternative competing materials are discussed.

The mass composition is one of the key observables to understand the nature and origin of ultra-high energy cosmic rays.The study of hadronic interactions at energies well beyond human-made accelerators is a fundamental probe of elementary particle physics. In previous analyses, the properties of the hadronic interactions were estimated under the assumption of a certain mass composition, typically proton-dominated, and the cross sections were calculated by fitting the tail of the $X_{max}$ distribution. In such an analysis, the impact of a possible He-contamination on the cross section measurement is quoted as a systematic uncertainty. Vice versa, the cosmic-ray mass composition is typically determined using air shower simulations by assuming the validity of the considered hadronic interaction models. In this contribution, we present a fully self-consistent approach of varying the proton-proton cross sections, with the nucleus-nucleus cross sections being predicted via the Glauber theory, and making a full $X_{max}$ distribution fit to get an independent and simultaneous estimation of the interaction cross sections and cosmic-ray primary composition. We will discuss the degeneracy between mass composition and hadronic interactions and compare the sensitivity of the proposed method to one of the previous approaches.

The astrophysical journal / 2 930, L24 (2022). doi:10.3847/2041-8213/ac67d8, We present the first comprehensive search for high-energy neutrino emission from high- and low-mass X-ray binaries conducted by IceCube. Galactic X-ray binaries are long-standing candidates for the source of Galactic hadronic cosmic rays and neutrinos. The compact object in these systems can be the site of cosmic-ray acceleration, and neutrinos can be produced by interactions of cosmic rays with radiation or gas, in the jet of a microquasar, in the stellar wind, or in the atmosphere of the companion star. We study X-ray binaries using 7.5 yr of IceCube data with three separate analyses. In the first, we search for periodic neutrino emission from 55 binaries in the Northern Sky with known orbital periods. In the second, the X-ray light curves of 102 binaries across the entire sky are used as templates to search for time-dependent neutrino emission. Finally, we search for time-integrated emission of neutrinos for a list of 4 notable binaries identified as microquasars. In the absence of a significant excess, we place upper limits on the neutrino flux for each hypothesis and compare our results with theoretical predictions for several binaries. In addition, we evaluate the sensitivity of the next generation neutrino telescope at the South Pole, IceCube-Gen2, and demonstrate its power to identify potential neutrino emission from these binary sources in the Galaxy., Published by Institute of Physics Publ., London

Saccharomyces cerevisiae is used to provide fundamental understanding of eukaryotic genetics, gene product function, and cellular biological processes. Saccharomyces Genome Database (SGD) has been supporting the yeast research community since 1993, serving as its de facto hub. Over the years, SGD has maintained the genetic nomenclature, chromosome maps, and functional annotation, and developed various tools and methods for analysis and curation of a variety of emerging data types. More recently, SGD and six other model organism focused knowledgebases have come together to create the Alliance of Genome Resources to develop sustainable genome information resources that promote and support the use of various model organisms to understand the genetic and genomic bases of human biology and disease. Here we describe recent activities at SGD, including the latest reference genome annotation update, the development of a curation system for mutant alleles, and new pages addressing homology across model organisms as well as the use of yeast to study human disease.

We present characteristics of hadronic cascades from interactions of cosmic rays in the atmosphere, simulated by the novel CORSIKA 8 framework. The simulated spectra of secondaries, such as pions, kaons, baryons and muons, are compared with the cascade equations solvers MCEq in air shower mode, and full 3D air shower Monte Carlo simulations using the legacy CORSIKA 7. A novel capability of CORSIKA 8 is the simulation of cascades in media other than air, widening the scope of potential applications. We demonstrate this by simulating cosmic ray showers in the Mars atmosphere, as well as simulating a shower traversing from air into water. The CORSIKA 8 framework demonstrates good accuracy and robustness in comparison with previous results, in particular in those relevant for the production of muons in air showers. Furthermore, the impact of forward $\rho^0$ production on air showers is studied and illustrated.

Measurements of KASCADE-Grande on the muon size in high energy extensive air showers (EAS) have provided evidence that the actual attenuation length of shower muons in the atmosphere is larger than the expectations from the hadronic interaction models QGSJET-II-04, EPOS-LHC and SIBYLL 2.3. This discrepancy is related with a deficient description of the shower muon content with atmospheric depth by MC models. To further explore the origin of the above anomaly, we have investigated the muon size as a function of the primary energy at different zenith angles using data from the KASCADE-Grande experiment. The procedure consisted in comparing the measured muon number flux against the predictions of a reference cosmic ray energy spectrum and from the observed difference to estimate the data/MC muon ratio that best describe the measurements. The ratio is then applied to the MC simulations and from here, we estimate the wanted muon content versus the primary energy. As a reference model, we employed the energy spectrum measured from the Pierre Auger observatory, while, for the different cosmic ray abundances, the GSF model. Results are presented using the QGSJET-II-04, EPOS-LHC, SIBYLL 2.3 and SIBYLL 2.3c models in the analysis procedure.

We use the Monte Carlo simulation package FLUKA to study the production of neutrons in extensive air showers. In contrast to typical shower simulations, we consider the full range of neutron energies extending down to thermal neutrons. The importance of different neutron production mechanisms and their impact on the predicted neutron distributions in energy, lateral distance, and arrival time are discussed and compared with those of muons. In addition, the dependence of the predictions on the primary particle is studied.

We report the results of the second measurement campaign of the Karlsruhe Tritium Neutrino (KATRIN) experiment. KATRIN probes the effective electron anti-neutrino mass, mν, via a high-precision measurement of the tritium β-decay spectrum close to its endpoint at 18.6 keV. In the second physics run presented here, the source activity was increased by a factor of 3.8 and the background was reduced by 25% with respect to the first campaign. A sensitivity on mν of 0.7 eV/c2 at 90% confidence level (CL) was reached. This is the first sub-eV sensitivity from a direct neutrino-mass experiment. The best fit to the spectral data yields mν2=(0.26±0.34) eV2/c4, resulting in an upper limit of mν2 (90% CL). By combining this result with the first neutrino mass campaign, we find an upper limit of mν2 (90% CL).

Epithelioid hemangioendothelioma (EHE) is a rare malignant vascular tumor with no standardized treatment. The mammalian target of rapamycin inhibitor, sirolimus, has been used successfully in adult EHE and other vascular tumors in children but has not been studied in pediatric EHE. The aim of this retrospective case series is to discuss the results of sirolimus for treatment in 6 pediatric patients with EHE. Four of 6 patients demonstrated partial response or disease stabilization with sirolimus treatment. No treatment dosing, trough goals, or duration of treatment recommendations can be made. Prospective studies are warranted to further investigate the use of sirolimus in treatment of EHE.

The Saccharomyces Genome Database (SGD; www.yeastgenome.org) maintains the official annotation of all genes in the Saccharomyces cerevisiae reference genome and aims to elucidate the function of these genes and their products by integrating manually curated experimental data. Technological advances have allowed researchers to profile RNA expression and identify transcripts at high resolution. These data can be configured in web-based genome browser applications for display to the general public. Accordingly, SGD has incorporated published transcript isoform data in our instance of JBrowse, a genome visualization platform. This resource will help clarify S. cerevisiae biological processes by furthering studies of transcriptional regulation, untranslated regions, genome engineering, and expression quantification in S. cerevisiae.

The Alliance of Genome Resources (Alliance) is a consortium of the major model organism databases and the Gene Ontology that is guided by the vision of facilitating exploration of related genes in human and well-studied model organisms by providing a highly integrated and comprehensive platform that enables researchers to leverage the extensive body of genetic and genomic studies in these organisms. Initiated in 2016, the Alliance is building a central portal (www.alliancegenome.org) for access to data for the primary model organisms along with gene ontology data and human data. All data types represented in the Alliance portal (e.g. genomic data and phenotype descriptions) have common data models and workflows for curation. All data are open and freely available via a variety of mechanisms. Long-term plans for the Alliance project include a focus on coverage of additional model organisms including those without dedicated curation communities, and the inclusion of new data types with a particular focus on providing data and tools for the non-model-organism researcher that support enhanced discovery about human health and disease. Here we review current progress and present immediate plans for this new bioinformatics resource.

Photomultiplier tubes (PMTs) are widely used in astroparticle physics experiments to detect light flashes (e.g. fluorescence or Cherenkov light) from extensive air showers (EASs) initiated by statistically rare very high energy cosmic particles when travelling through the atmosphere. Their high amplification factor (gain) allows the detection of very low photon fluxes down to single photons. At the same time this sensitivity causes the gain and signal-to-noise ratio to decrease with collected charge over the lifetime of the PMT (referred to as “ageing”). To avoid fast ageing, many experiments limit the PMT operation to reasonably low night sky background (NSB) conditions. However, in order to collect more event statistics at the highest energies, it is desirable to extend the measurement cycle into (part of) nights with higher NSB levels. In case the signal-to-noise ratio remains large enough in the subsequent reconstruction of the EAS events, lowering the PMT gain in such conditions can be an option to avoid faster ageing. In this paper, performance studies under high NSB with Photonis XP3062 PMTs, as used in the fluorescence detector of the Pierre Auger Observatory, are presented. The results suggest that lowering the PMT gain by a factor of 10 while increasing the NSB level by a similar factor does not significantly affect the PMT performance and ageing behaviour so that detection and offline reconstruction of EASs are still possible. Adjusting the PMT gain according to a changing NSB level throughout a night has been shown to be possible and it follows a predictable behaviour. This allows to extend the measurement cycles of experiments, based on PMTs of type Photonis XP3062 or comparable and exposed to the NSB, to enhance the sensitivity especially at the highest energies where events are very rare.

The aim of the study was to assess rates of severe parkinsonism related to different antipsychotic drugs (APDs) using data from an observational pharmacovigilance programme in German-speaking countries—Arzneimittelsicherheit in der Psychiatrie (AMSP). Data on APD utilization and reports of severe APD-induced parkinsonism were collected in 99 psychiatric hospitals in Austria, Germany and Switzerland during the period 2001–2016. Of 340,099 patients under surveillance, 245,958 patients were treated with APDs for the main indications of schizophrenic disorders, depression, mania and organic mental disorders. A total of 200 events of severe APD-induced parkinsonism were identified (0.08%). First-generation low-potency APDs were significantly less often implicated (0.02%) than second-generation APDs (0.07%) and first-generation high-potency APDs (0.16%). Among the second-generation APDs, amisulpride and risperidone ranked highest. The phenothiazines were associated with significantly lower rates of severe parkinsonism (0.02%) than those of the butyrophenones (0.11%) and thioxanthenes (0.12%). In 71 cases (35.5%), more than 1 drug was considered responsible for the induction of severe parkinsonism. In 44 patients (22.0%), the symptoms were extremely severe, leading to complete immobility and/or massive complications such as pneumonia and severe injuries due to falls. Higher age (> 60 years) was associated with significantly higher rates of severe parkinsonism, as were the diagnoses of schizophrenic disorder or mania. The large number of patients included in the present survey allows for the comparison of severe parkinsonism rates related to different APD classes and single APDs. The first-generation low-potency APDs had significantly reduced risk of severe parkinsonism compared not only to high potency but also to second-generation APDs.

Background Cardiovascular diseases are still the leading cause of global mortality. Some antipsychotic agents can show severe cardiovascular side effects and are also associated with metabolic syndrome. Methods This observational study was based on data of AMSP (Arzneimittelsicherheit in der Psychiatrie), a multicenter drug surveillance program in Austria, Germany and Switzerland, that recorded severe drug reactions in psychiatric inpatients. Results A total of 404 009 inpatients were monitored between 1993 and 2013, whereas 291 510 were treated with antipsychotics either in combination or alone. There were 376 cases of severe cardiovascular adverse reactions reported in the given timespan, yielding a relative frequency of 0.13%. The study revealed that incidence rates of cardiovascular adverse reactions were highest during treatment with ziprasidone (0.35%), prothipendyl (0.32%), and clozapine (0.23%). The lowest rate of cardiovascular symptoms occurred during treatment with promethazine (0.03%) as well as with aripiprazole (0.06%). The most common clinical symptoms were orthostatic collapse and severe hypotonia, sinustachycardia, QTc prolongation, myocarditis, and different forms of arrhythmia. The dosage at the timepoint when severe cardiovascular events occurred was not higher in any of the given antipsychotics than in everyday clinical practice and was in average therapeutic ranges. In terms of subclasses of antipsychotics, no significant statistical difference was seen in the overall frequencies of adverse reactions cases, when first-generation high potency, first-generation low potency, and second-generation antipsychotics were compared. Thirty percent of adverse events among second-generation antipsychotics were induced by clozapine. Conclusions Our findings on cardiovascular adverse reactions contribute to a better understanding of cardiovascular risk profiles of antipsychotic agents in inpatients.

Thrombocytopenia and other hematologic manifestations related to HIV are not uncommon. Treatment of HIV-related thrombocytopenia is challenging: treatment options are not effective in all patients, or less well studied, particularly in the pediatric population. We aim to present and discuss the case of a 13-year-old with HIV and persistent thrombocytopenia who, after failing monthly IVIG infusions, showed normalization of platelet count on the novel thrombopoietin receptor agonist, eltrombopag. A retrospective chart review of the case patient's medical record was conducted. Additionally, a thorough literature review was performed on this topic, including the pathophysiology of underlying HIV-related thrombocytopenia and its treatment modalities. The patient was treated initially with monthly IVIG infusions for about 1 year but did not show a sustained response, particularly in between infusions. After initiation with eltrombopag 50 mg daily, the patient showed a sustained increase in his platelet count. During a brief lapse in eltrombopag treatment, his platelet count dropped, which then increased upon his reinitiation of therapy. He has continued to show a sustained platelet response and has not been symptomatic or required IVIG for more than 1 year. To our knowledge, this is the first report of a pediatric patient with HIV-related thrombocytopenia who has benefited from the use of eltrombopag.

Aims: Radiation-induced normal tissue toxicity often precludes the application of curative radiation doses. Here we investigated the therapeutic potential of chemokine C-C motif ligand 2 (Ccl2) signaling inhibition to protect normal lung tissue from radiotherapy (RT)-induced injury. Results: RT-induced vascular dysfunction and associated adverse effects can be efficiently antagonized by inhibition of Ccl2 signaling using either the selective Ccl2 inhibitor bindarit (BIN) or mice deficient for the main Ccl2 receptor CCR2 (KO). BIN-treatment efficiently counteracted the RT-induced expression of Ccl2, normalized endothelial cell (EC) morphology and vascular function, and limited lung inflammation and metastasis early after irradiation (acute effects). A similar protection of the vascular compartment was detected by loss of Ccl2 signaling in lungs of CCR2-KO mice. Long-term Ccl2 signaling inhibition also significantly limited EC loss and accompanied fibrosis progression as adverse late effect. With respect to the human situation, we further confirmed that Ccl2 secreted by RT-induced senescent epithelial cells resulted in the activation of normally quiescent but DNA-damaged EC finally leading to EC loss in ex vivo cultured human normal lung tissue. Innovation: Abrogation of certain aspects of the secretome of irradiated resident lung cells, in particular signaling inhibition of the senescence-associated secretory phenotype-factor Ccl2 secreted predominantly by RT-induced senescent epithelial cells, resulted in protection of the endothelial compartment. Conclusions: Radioprotection of the normal tissue via Ccl2 signaling inhibition without simultaneous protection or preferable radiosensitization of tumor tissue might improve local tumor control and survival, because higher doses of radiation could be used.

Sea mines are one of the most cost-effective weapons of naval warfare. Underwater mine-disposal vehicles are used to identify and neutralise this threat. In order to localise the position of the vehicle in a shallow water scenario, it needs to surface and update its internal navigation system using a global navigation satellite system. This paper presents the design and prototype of an antenna that can be integrated in the mine-disposal vehicle SeaFox. Simulation and measurement results suggest that the antenna design can cover all major GNSS bands. However, the radiation pattern strongly depends on the water level.

Data on drug prescription for outpatients with major depressive disorder (MDD) suggest women are more likely to be treated with psychotropic drugs, while data on sex differences regarding pharmacological treatment of psychiatric inpatients are currently not available. Drug utilization data from the program “Drug Safety in Psychiatry” (German: Arzneimittelsicherheit in der Psychiatrie, AMSP) of 44,418 psychiatric inpatients with MDD were analyzed for sex differences between 2001 and 2017. Sex differences were analyzed using relative risks (RR) and 95% confidence intervals (95% CI). Time trends were analyzed by comparing the first (2001–2003) with the last time period (2015–2017). In general, men and women were equally likely to use psychotropic drugs. Monotherapy was more common in men. Women were more likely to utilize ≥ 4 psychotropic drugs. Antidepressant drugs (ADDs) were the most prescribed drug class. Men had a higher utilization of noradrenergic and specific serotonergic antidepressants (RR 1.15; 95% CI 1.12–1.19), especially mirtazapine (RR 1.16; 95% CI 1.12–1.19), but also of other ADDs such as bupropion (RR 1.50; 95% CI 1.35–1.68). Males had a slightly higher utilization of second-generation antipsychotic drugs (RR 1.06; 95% CI 1.03–1.09) and were less often treated with low-potency first-generation antipsychotic drugs (RR 0.86; 95% CI 0.83–0.90). Tranquilizing (e.g., benzodiazepines; RR 0.89; 95% CI 0.86–0.92) and hypnotic drugs (e.g., Z-drugs; RR 0.85; 95% CI 0.81–0.89) were less utilized in the treatment of male patients. Not all sex differences were stable over time. More sex differences were detectable in 2015–2017 than in 2001–2003. Findings suggest that certain psychotropic drugs are preferred in the treatment of men vs. women, however, sex differences found in this study are not as large as in ambulatory settings. To make evidence-based sex-specific recommendations in the treatment of MDD, differences in drug response and tolerability need to be further researched.

The production cross section of 30.92 GeV/c protons on carbon is measured by the NA61/SHINE spectrometer at the CERN SPS by means of beam attenuation in a copy (replica) of the 90-cm-long target of the T2K neutrino oscillation experiment. The employed method for direct production cross-section estimation minimizes model corrections for elastic and quasi-elastic interactions. The obtained production cross section is σ$_{prod}$ = 227.6 ± 0.8(stat)$\frac{+1.9}{−3.2}$(sys) − 0.8(mod) mb. It is in agreement with previous NA61/SHINE results obtained with a thin carbon target, while providing improved precision with a total fractional uncertainty of less than 2%. This direct measurement is performed to reduce the uncertainty on the T2K neutrino flux prediction associated with the re-weighting of the interaction rate of neutrino-yielding hadrons.

BackgroundIn contrast with the setting of acute myocardial infarction, there are limited data regarding the impact of diabetes mellitus on clinical outcomes in contemporary cohorts of patients with chronic coronary syndromes. We aimed to investigate the prevalence and prognostic impact of diabetes according to geographical regions and ethnicity.Methods and resultsCLARIFY is an observational registry of patients with chronic coronary syndromes, enrolled across 45 countries in Europe, Asia, America, Middle East, Australia, and Africa in 2009–2010, and followed up yearly for 5 years. Chronic coronary syndromes were defined by ≥1 of the following criteria: prior myocardial infarction, evidence of coronary stenosis >50%, proven symptomatic myocardial ischaemia, or prior revascularization procedure.Among 32 694 patients, 9502 (29%) had diabetes, with a regional prevalence ranging from below 20% in Northern Europe to ∼60% in the Gulf countries. In a multivariable-adjusted Cox proportional hazards model, diabetes was associated with increased risks for the primary outcome (cardiovascular death, myocardial infarction, or stroke) with an adjusted hazard ratio of 1.28 (95% confidence interval 1.18, 1.39) and for all secondary outcomes (all-cause and cardiovascular mortality, myocardial infarction, stroke, heart failure, and coronary revascularization). Differences on outcomes according to geography and ethnicity were modest.ConclusionIn patients with chronic coronary syndromes, diabetes is independently associated with mortality and cardiovascular events, including heart failure, which is not accounted by demographics, prior medical history, left ventricular ejection fraction, or use of secondary prevention medication. This is observed across multiple geographic regions and ethnicities, despite marked disparities in the prevalence of diabetes.ClinicalTrials identifierISRCTN43070564

A recent time-integrated analysis of a catalog of 110 candidate neutrino sources revealed a cumulative neutrino excess in the data collected by IceCube between April 6, 2008 and July 10, 2018. This excess, inconsistent with the background hypothesis in the Northern hemisphere at the $3.3~\sigma$ level, is associated with four sources: NGC 1068, TXS 0506+056, PKS 1424+240 and GB6 J1542+6129. This letter presents two time-dependent neutrino emission searches on the same data sample and catalog: a point-source search that looks for the most significant time-dependent source of the catalog by combining space, energy and time information of the events, and a population test based on binomial statistics that looks for a cumulative time-dependent neutrino excess from a subset of sources. Compared to previous time-dependent searches, these analyses enable a feature to possibly find multiple flares from a single direction with an unbinned maximum-likelihood method. M87 is found to be the most significant time-dependent source of this catalog at the level of $1.7~\sigma$ post-trial, and TXS 0506+056 is the only source for which two flares are reconstructed. The binomial test reports a cumulative time-dependent neutrino excess in the Northern hemisphere at the level of $3.0~\sigma$ associated with four sources: M87, TXS 0506+056, GB6 J1542+6129 and NGC 1068.

An optical parametric oscillator (OPO) is developed and characterized for the simultaneous generation of ultraviolet (UV) and near-UV nanosecond laser pulses for the single-shot Rayleigh scattering and planar laser-induced-fluorescence (PLIF) imaging of methylidyne (CH) and nitric oxide (NO) in turbulent flames. The OPO is pumped by a multichannel, 8-pulse Nd:YAG laser cluster that produces up to 225 mJ/pulse at 355 nm with pulse spacing of 100 µs. The pulsed OPO has a conversion efficiency of 9.6% to the signal wavelength of ∼ 430 n m when pumped by the multimode laser. Second harmonic conversion of the signal, with 3.8% efficiency, is used for the electronic excitation of the A-X (1,0) band of NO at ∼ 215 n m , while the residual signal at 430 nm is used for direct excitation of the A-X (0,0) band of the CH radical and elastic Rayleigh scattering. The section of the OPO signal wavelength for simultaneous CH and NO PLIF imaging is performed with consideration of the pulse energy, interference from the reactant and product species, and the fluorescence signal intensity. The excitation wavelengths of 430.7 nm and 215.35 nm are studied in a laminar, premixed C H 4 − H 2 − N H 3 –air flame. Single-shot CH and NO PLIF and Rayleigh scatter imaging is demonstrated in a turbulent C H 4 − H 2 − N H 3 diffusion flame using a high-speed intensified CMOS camera. Analysis of the complementary Rayleigh scattering and CH and NO PLIF enables identification and quantification of the high-temperature flame layers, the combustion product zones, and the fuel-jet core. Considerations for extension to simultaneous, 10-kHz-rate acquisition are discussed.

Introduction Partial anomalous pulmonary venous connection (PAPVC) is a rare congenital heart disease, characterized by one or some but not all pulmonary veins anomalously connected to the right atrium or a systemic vein. PAPVC is either an isolated shunt lesion or associated with an atrial septal defect (ASD). This study compares the arrhythmic outcome of patients treated surgically with those clinically monitored. Method Clinical, surgical, imaging and invasive data of PAPVC patients were retrospectively reviewed from 7 centers from the Swiss Adult Congenital HEart disease Registry (SACHER) and one French center. Results A total of 168 patients with PAPVC were identified. Most (77%) patients underwent surgery, while the remaining (23%) ones were treated conservatively with clinical monitoring. The operated group (OG) had a significantly higher number of associated ASD (N=106, 82%) (p Age did not differ at latest follow-up (table). Holter recordings revealed a higher prevalence of arrhythmia in the OG (p=0.031), mainly of supraventricular tachyarrhythmias (table). The occurrence of ventricular non-sustained tachycardia and of bradyarrhythmia did not statistically differ between groups. Patients in the OG required more often medical treatment for arrhythmias: 12 (9%) needed electrophysiological study in the OG and none in the NOG (p=0.057). The amount of patients requiring a pacemaker implantation in the OG (11%) was significantly higher than that of NOG (0%) (p=0.039). Conclusion Patients after PAPVC repair present with a significant higher burden of arrhythmia than conservatively treated patients, either due to a larger shunt pre-operatively and/or as a late complication of the corrective surgery itself. Funding Acknowledgement Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): Unrestricted grant from Actelion, Switzerland

Introduction Total anomalous pulmonary venous connection is a rare cyanotic congenital heart disease, where all pulmonary veins aberrantly connect to a systemic vein or the right atrium. The only curative treatment is surgery allowing the patients to reach adulthood. This study describes the long-term outcome of these individuals focusing on arrhythmias. Methods Clinical, surgical, imaging and invasive data were retrospectively reviewed from 7 centers participating in the Swiss Adult Congenital Heart disease Registry (SACHER) and one French center. Results A total of 57 patients were identified and analyzed 22±8 years after surgery. At last follow-up, 21% of patients presented cardiac symptoms, mainly palpitations. No patient had pulmonary hypertension or a relevant valvulopathy. Echocardiography revealed in 5 (8.8%) patients a dilated right ventricle (RV) and in 3 (5.3%) patients a diminished RV systolic function. Exercise capacity was normal in most patients (table). Cardiac magnetic resonance imaging found in 2 (4%) had a residual shunt with an mean Qp:Qs of 1.25, due to a single anomalously connected pulmonary vein. Holter recordings revealed arrhythmias in 23% of patient. Ten (17.5%) had atrial fibrillation, flutter or tachycardia. Three (5%) patients presented ventricular arrhythmias: two patients showed non-sustained ventricular tachycardia and one patient complex ventricular extrasystoles. Four patients (7%) were on antiarrhythmic medication for supraventricular arrhythmias. Three patients (5%) underwent an electrophysiological study with a mean time since surgery of 20 years. Three (5%) patients underwent pacemaker implantation within 3 weeks to 36 months after surgical correction, which were removed in 2 patients after 7 years. Age and the presence of a valvulopathy at follow-up predicted tachyarrhythmia on binomial logistic regression analysis (p Conclusions In adult survivors after TAPVC repair, supraventricular but also ventricular arrhythmias are frequently observed which appears to be related to age and valvular lesions at follow-up. This study underlies the importance of long-term follow-up as some of the patients currently without arrhythmia will probably develop rhythm disorders in the future. Funding Acknowledgement Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): Unrestricted grant by Actelion SA, Switzerland

Introduction Partial anomalous pulmonary venous connection (PAPVC) is a rare congenital heart disease, which is characterized by one or some but not all pulmonary veins anomalously connected to the right atrium or a systemic vein. PAPVC is either an isolated shunt lesion or associated with an atrial septal defect (ASD). The only curative treatment is surgery, however the indication for surgery can be challenging. This study compares the outcome of patients treated surgically with those clinically monitored. Method Clinical, surgical, imaging and invasive data were retrospectively reviewed from 7 centers from the Swiss Adult Congenital HEart Registry (SACHER) and a French center. Results A total of 168 patients with partial anomalous pulmonary venous connection were identified. The majority (77%) of patients underwent surgery and the remaining (23%) were treated conservatively with clinical monitoring. The operated group (OG) had a significantly higher proportion of associated ASD (N=106, 82%) (p Latest follow-up was 12 years after surgery. Mean age was 40±17 years. Patients in the non-operated group (NOG) were significantly more dyspneic than the OG (p=0.002). However, the need for medical treatment did not differ between groups: 58% of the NOG and 48% in the OG (p=0.203). Right ventricular (RV) ejection fraction did not differ between groups despite a significantly larger RV end-diastolic volume and a higher Qp:Qs on cardiac magnetic resonance (CMR) in the NOG (table). On echocardiography, the NOG showed a significantly better right ventricular longitudinal function and a higher systolic pulmonary artery pressure than the OG (table). The prevalence of significant valvulopathies did not differ between groups (table). Both groups had normal exercise capacity and with no differences between groups (table). Eighteen (14%) OG patients required a re-intervention either for residual shunt and/or stenosis of the pulmonary veins, superior and inferior vena cava. Conclusion PAPVC patients after surgical correction, show a favorable outcome in terms of imaging parameters and exercise capacity, however, a significant number presents with symptoms. PAPVC patients treated conservatively with small left to right shunting, have similar outcome justifying a conservative approach. Funding Acknowledgement Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): Unrestricted grant from Actelion, Switzerland

Galactorrhea is a well-known adverse drug reaction (ADR) of numerous antipsychotic drugs (APD) and is often distressing for those affected. Methodological problems in the existing literature make it difficult to determine the prevalence of symptomatic hyperprolactinemia in persons treated with APDs. Consequently, a large sample of patients exposed to APDs is needed for more extensive evaluation. Data on APD utilization and reports of galactorrhea caused by APDs were analyzed using data from an observational pharmacovigilance program in German-speaking countries—Arzneimittelsicherheit in der Psychiatrie (AMSP)—from 1993 to 2015. 320,383 patients (175,884 female inpatients) under surveillance were treated with APDs for schizophrenia and other indications. A total of 170 events of galactorrhea caused by APDs were identified (0.97 cases in 1000 female inpatient admissions). Most cases occurred during the reproductive age with the highest incidence among patients between 16 and 30 years (3.81 cases in 1000 inpatients). The APDs that were most frequently imputed alone for inducing galactorrhea were risperidone (52 cases and 0.19% of all exposed inpatients), amisulpride (30 resp. 0.48%), and olanzapine (13 resp. 0.05%). In three cases, quetiapine had a prominent role as a probable cause for galactorrhea. High dosages of the imputed APDs correlated with higher rates of galactorrhea. Galactorrhea is a severe and underestimated condition in psychopharmacology. While some APDs are more likely to cause galactorrhea, we identified a few unusual cases. This highlights the importance of alertness in clinical practice and of taking a patient’s individual situation into consideration.

Biological processes are accomplished by the coordinated action of gene products. Gene products often participate in multiple processes, and can therefore be annotated to multiple Gene Ontology (GO) terms. Nevertheless, processes that are functionally, temporally, and/or spatially distant may have few gene products in common, and co-annotation to unrelated processes likely reflects errors in literature curation, ontology structure, or automated annotation pipelines. We have developed an annotation quality control workflow that uses rules based on mutually exclusive processes to detect annotation errors, based on and validated by case studies including the three we present here: fission yeast protein-coding gene annotations over time; annotations for cohesin complex subunits in human and model species; and annotations using a selected set of GO biological process terms in human and five model species. For each case study, we reviewed available GO annotations, identified pairs of biological processes which are unlikely to be correctly co-annotated to the same gene products (e.g., amino acid metabolism and cytokinesis), and traced erroneous annotations to their sources. To date we have generated 107 quality control rules, and corrected 289 manual annotations in eukaryotes and over 2.5 million automatically propagated annotations across all taxa.