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Predicting outcome after transplantation of marginal kidneys is a challenging task. Donor creatinine or estimated glomerular filtration rate (eGFR) are integral components of the respective risk scores. However, there is uncertainty on which of their values obtained successively during procurement is the most suitable.This is a retrospective study of 221 adult brain death donors with marginal kidneys, transplanted in 223 recipients. We applied logistic regression analysis to investigate the association between initial (at hospital admission), nadir (lowest), zenith (highest) and terminal (at recovery) donor eGFR with primary non-function (PNF), delayed graft function (DGF), 3- and 12-month graft function and 1- and 3-year patient- and death-censored graft survival.In the multivariate analysis, admission, terminal, and the lowest donor eGFR could most accurately predict DGF. The respective ORs [95% CI] were: 0.875 [0.771-0.993], 0.818 [95% CI: 0.726-0.922] and 0.793 [0.689-0.900]. Although not being significant for DGF (OR 0.931 [95% CI: 0.817-1.106]), the highest eGFR was the best predictor of 3-month graft function (adjusted b coefficient 1.161 [95% CI: 0.355-1.968]). Analysis of primary nonfunction showed that determination of initial and the highest eGFR proved to be the best predictors. The respective ORs [95% CI] were: 0.804 [0.667-0.968] and 0.750 [0.611-0.919]. There were no differences in the risk associations of each of the four eGFR recordings with patient- and graft survival.The various eGFR recordings determined during the procurement process of marginal donors can predict PNF, DGF and 3- and 12-month graft function. Regarding short-term patient- and graft survival, there appears to be impacted by recipient factors rather than donor kidney function.

Background Deceased donor kidneys with acute kidney injury (AKI) are often discarded because of concerns about inferior transplant outcomes. A means of grading the quality of such kidneys is the performance of procurement biopsies. Methods This is a retrospective study of 221 brain death donors with marginal kidneys transplanted in 223 recipients in Germany. Marginal kidneys were defined as kidneys with procurement biopsies done exceptionally to assess suitability for transplantation in otherwise potentially discarded organs. The impact of deceased donor AKI on patient survival and death-censored graft survival at 1, 3 and 5 years and graft function at 1 and 3 years after transplantation was investigated. Results Recipients of kidneys with stage 3 AKI had a greater incidence of delayed graft function [DGF; ORStage 1: 1.435 (95% CI 0.438–0.702), ORStage 2: 2.463 (95% CI 0.656–9.245), ORStage 3: 4.784 (95% CI 1.421–16.101)] but a similar graft and patient survival compared to recipients of donors without AKI and with AKI stage 1 and 2 as well. The coexistence of recipient DGF and donor AKI was associated with the lowest graft survival and function rates. Conclusion The transplantation of deceased donor marginal kidneys with AKI confers a higher risk for DGF but is associated with acceptable graft and patient outcomes, which do not differ in comparison with marginal donor kidneys without AKI. Graft prognosis is especially poor if donor AKI and recipient DGF concur. Donor AKI was a risk factor independent of the histological lesions of procurement biopsies.

Background. Transcriptome analysis could be an additional diagnostic parameter in diagnosing kidney transplant (KTx) rejection. Here, we assessed feasibility and potential of NanoString nCounter analysis of KTx biopsies to aid the classification of rejection in clinical practice using both the Banff-Human Organ Transplant (B-HOT) panel and a customized antibody-mediated rejection (AMR)-specific NanoString nCounter Elements (Elements) panel. Additionally, we explored the potential for the classification of KTx rejection building and testing a classifier within our dataset. Methods. Ninety-six formalin-fixed paraffin-embedded KTx biopsies were retrieved from the archives of the ErasmusMC Rotterdam and the University Hospital Cologne. Biopsies with AMR, borderline or T cell-mediated rejections (BLorTCMR), and no rejection were compared using the B-HOT and Elements panels. Results. High correlation between gene expression levels was found when comparing the 2 chemistries pairwise (r = 0.76-0.88). Differential gene expression (false discovery rate; P < 0.05) was identified in biopsies diagnosed with AMR (B-HOT: 294; Elements: 76) and BLorTCMR (B-HOT: 353; Elements: 57) compared with no rejection. Using the most predictive genes from the B-HOT analysis and the Element analysis, 2 least absolute shrinkage and selection operators-based regression models to classify biopsies as AMR versus no AMR (BLorTCMR or no rejection) were developed achieving an receiver-operating-characteristic curve of 0.994 and 0.894, sensitivity of 0.821 and 0.480, and specificity of 1.00 and 0.979, respectively, during cross-validation. Conclusions. Transcriptomic analysis is feasible on KTx biopsies previously used for diagnostic purposes. The B-HOT panel has the potential to differentiate AMR from BLorTCMR or no rejection and could prove valuable in aiding kidney transplant rejection classification.

Background Globally, half of all years of life lost is due to emergency medical conditions, with low- and middle-income countries (LMICs) facing a disproportionate burden of these conditions. There is an urgent need to train the future physicians in LMICs in the identification and stabilization of patients with emergency medical conditions. Little research focuses on the development of effective emergency medicine (EM) medical education resources in LMICs and the perspectives of the students themselves. One emerging tool is the use of electronic learning (e-learning) and blended learning courses. We aimed to understand Uganda medical trainees’ use of learning materials, perception of current e-learning resources, and perceived needs regarding EM skills acquisition during participation in an app-based EM course. Methods We conducted semi-structured interviews and focus groups of medical students and EM residents. Participants were recruited using convenience sampling. All sessions were audio recorded and transcribed verbatim. The final codebook was approved by three separate investigators, transcripts were coded after reaching consensus by all members of the coding team, and coded data were thematically analyzed. Results Twenty-six medical trainees were included in the study. Analysis of the transcripts revealed three major themes: [1] medical trainees want education in EM and actively seek EM training opportunities; [2] although the e-learning course supplements knowledge acquisition, medical students are most interested in hands-on EM-related training experiences; and [3] medical students want increased time with local physician educators that blended courses provide. Conclusions Our findings show that while students lack access to structured EM education, they actively seek EM knowledge and practice experiences through self-identified, unstructured learning opportunities. Students value high quality, easily accessible EM education resources and employ e-learning resources to bridge gaps in their learning opportunities. However, students desire that these resources be complemented by in-person educational sessions and executed in collaboration with local EM experts who are able to contextualize materials, offer mentorship, and help students develop their interest in EM to continue the growth of the EM specialty.

Signaling pathways of regulated necrosis, such as necroptosis and ferroptosis, contribute to acute kidney injury (AKI), but the role of pyroptosis is unclear. Pyroptosis is mediated by the pore-forming protein gasdermin D (GSDMD). Here, we report a specific pattern of GSDMD-protein expression in the peritubular compartment of mice that underwent bilateral ischemia and reperfusion injury (IRI). Along similar lines, the GSDMD-protein expression in whole kidney lysates increased during the first 84 h following cisplatin-induced AKI. Importantly, unlike whole kidney lysates, no GSDMD-protein expression was detectable in isolated kidney tubules. In IRI and cisplatin-induced AKI, GSDMD-deficient mice exhibited hypersensitivity to injury as assessed by tubular damage, elevated markers of serum urea, and serum creatinine. This hypersensitivity was reversed by a combined deficiency of GSDMD and the necroptosis mediator mixed lineage kinase domain-like (MLKL). In conclusion, we demonstrate a non-cell autonomous role for GSDMD in protecting the tubular compartment from necroptosis-mediated damage in IRI.

Property regimes are based on fundamental values of the society or group that designs and reproduces them. This paper analyses the ethical underpinnings of Progressive Commons in comparison to the ...

Over the past 2 decades, scoring systems for multiple glomerular diseases have emerged, as have consortia of pathologists and nephrologists for the study of glomerular diseases, including correlation of pathologic findings with clinical features and outcomes. However, one important limitation faced by members of these consortia and other renal pathologists and nephrologists in both investigative work and routine practice remains a lack of uniformity and precision in clearly defining the morphologic lesions on which the scoring systems are based. In response to this issue, the Renal Pathology Society organized a working group to identify the most frequently identified glomerular lesions observed by light microscopy and electron microscopy, review the literature to capture the published definitions most often used for each, and determine consensus terms and definitions for each lesion in a series of online and in-person meetings. The defined lesions or abnormal findings are not specific for any individual disease or subset of diseases, but rather can be applied across the full spectrum of glomerular diseases and within the context of the different scoring systems used for evaluating and reporting these diseases. In addition to facilitating glomerular disease research, standardized terms and definitions should help harmonize reporting of medical kidney diseases worldwide and lead to more-precise diagnoses and improved patient care.

This conceptual paper addresses the role the individual plays in sustainability against the backdrop of the ethical dimensions of sustainability. We discuss the relevance of moral personhood as a basis for sustainability and develop a model of personhood for sustainability. The paper outlines the ethical dimensions of sustainability and discusses the role of individual morality for sustainability from a virtue ethics perspective. We employ a Buddhist virtue ethical approach for conceptualizing a model of the sustainable person that is characterized by sustainability virtues, interdependent personhood, and an inherent concern for the wellbeing of others, nature, and future beings. In contrast to many Western-based conceptions of the individual actor, our model of sustainable personhood conceptualizes and explains a coherent and inherent individual motivation for sustainability. The paper contributes to the methodological question of how to best consider the individual in sustainability research and sustainability approaches and suggests a conceptual basis for integrating individual, institutional, and systemic aspects of sustainability.

In recent years, service providers have identified the proactive postsales service (PPS) as a viable measure for preempting service failures and their negative consequences. Due to the high costs associated with PPSs, companies are looking for ways to increase their efficiency. To understand how companies can increase their revenues and lower their costs, this study investigates how cross-selling activities and different media types affect the impact of a PPS on inbound service calls and customer churn. Based on a large-scale field experiment in the telecommunications industry, as well as a controlled lab experiment, the results demonstrate the overall effectiveness of the PPS and indicate two mediating effects. While the effect of cross-selling on customer churn and service calls is mediated by the customers’ uncertainty regarding the company’s motives, it is the customers’ perception of privacy invasion that mediates the influence of the contact medium on the effectiveness of the PPS. Our finding that PPS contacts have to be clear in their message and should not be perceived as invasive is an indication of the importance of service-(post)sales ambidexterity.

Wir berichten uber den Fall einer 73-jahrigen Patientin bosnischer Herkunft, die mit einem akuten Nierenversagen aufgenommen wurde. Die Nierenbiopsie erbrachte die Diagnose einer infektassoziierten nekrotisierenden sowie extrakapillar proliferativen Glomerulonephritis. Die Patientin berichtete, etwa zwei Wochen zuvor einen fieberhaften Infekt gehabt zu haben. Unsere Diagnostik ergab keinen Hinweis auf einen aktuellen floriden Infekt. Es erfolgte eine systemische Steroidtherapie mit gutem Ansprechen. Sechs Wochen spater erfolgte die erneute stationare Aufnahme der Patientin in einem schwer kranken Zustand. Wir konnten bioptisch in der Magenschleimhaut eine Strongyloides-stercoralis-Infestation nachweisen. Unter der Steroidtherapie hatte sich ein sogenanntes Hyperinfektionssyndrom entwickelt, an dem die Patientin trotz intensivmedizinischer Bemuhungen verstarb. Dieser Fall illustriert, dass insbesondere bei Patienten aus Endemiegebieten auch hierzulande an diese Parasitose gedacht werden muss. Wir diskutieren eine wahrscheinliche kausale Verknupfung mit der Glomerulonephritis und geben eine Ubersicht uber die Diagnostik, den Krankheitsverlauf und die Therapie dieser Parasitose.

Background Podocyte infolding glomerulopathy (PIG) is a rare histopathologic finding with global infolding of the podocytes into the glomerular basement membrane (GBM), accompanied by microstructures underneath. Described in 2002 for the first time, PIG was proposed as a new pathological entity in 2008 based on the largest case series so far. Yet all of the described cases derive from Asian countries. We report a case from Germany fulfilling the diagnostic criteria of PIG. Considering the scarcity of data on this entity especially in Western countries, collecting cases like ours and multicentric meta-analyses will be crucial to obtain a better understanding of PIG, its causes, clinical course and potential treatment options. Case presentation A 56-year-old Caucasian woman with a history of rheumatoid arthritis (RA), no other comorbidities and no known renal disease was admitted to the hospital with acute kidney injury (AKI) and nephrotic syndrome. Physical examination was unremarkable except for anasarca. Renal ultrasound revealed no abnormalities. Laboratory and urine analyses were consistent with the nephrotic syndrome and renal failure. Serological studies regarding ANA, ANCA, anti-PLA2R autoantibodies, complement, virus infections, immunofixation and quantitative light chain analysis were unremarkable. A renal biopsy was performed. Light microscopic examination showed flattened tubular epithelium consistent with acute tubular damage, no infiltrates and unremarkable glomeruli except diffuse and global holes in the GBM (Fig. 1a) and negative staining for immunoglobulin heavy-chains, light-chains and complement split products. Electron microscopy revealed a rare correlate for these holes: global peculiar infolding of podocyte cytoplasm into the GBM. Most of these infoldings were accompanied by condensation of the GBM underneath. No such condensation or electron dense deposits were found without these infoldings or outside the GBM. Conclusion Here we report the first case of PIG outside of Asia. Since there are only few reports about this specific finding, we feel there is a need to share information in an attempt to accumulate knowledge about this possible new entity and potential treatment options.

Die Ladedruckregelung ist ein wichtiger Bestandteil der Steuerung moderner Ottomotoren. Die Umsetzung moderner Regelungsverfahren fur diese nichtlineare Strecke ist seit Jahren Gegenstand wissenschaftlicher Publikationen. Stand der Technik fur den Serienbetrieb ist dagegen eine verhaltnismasig einfache Gain-Scheduling-Struktur basierend auf PID-Reglern und stationarer Vorsteuerung. Diese Arbeit prasentiert ein serientaugliches Konzept zur Regelung des Ladedrucks und dessen experimentelle Erprobung an einem Prufstand. Die verwendete Reglerstruktur entspricht weitgehend dem Stand der Technik, wobei die Vorsteuerung signifikant vereinfacht und ein Anti-Windup-Konzept zur systematischen Berucksichtigung von Stellgrosenbeschrankungen erganzt wurden. Hervorzuheben ist das verwendete systematische modellbasierte Vorgehen zur $$\text{H}_{\infty}$$-optimalen Auslegung der strukturierten Arbeitspunktregler. Der Einsatz $$\text{H}_{\infty}$$-optimaler Regler erlaubt die a priori Einbeziehung quantitativer Forderungen an das Verhalten der resultierenden lokalen Regelkreise in den Entwurfsprozess. Das zugrundeliegende Reglerentwurfsverfahren erlaubt lineare Regler beliebiger Struktur. Damit eroffnet sich die Moglichkeit im Einsatz befindliche, von anwendungsorientierten Ingenieuren akzeptierte Reglerstrukturen $$\text{H}_{\infty}$$-optimal zu parametrieren. Die Berechnung der Parameter erfolgt zuverlassig durch die Losung nichtkonvexer und nichtglatter Optimierungsprobleme unter Verwendung veroffentlichter Verfahren. Die Gewinnung der fur den modellbasierten Reglerentwurf erforderlichen mathematischen Systembeschreibungen geschieht durch Identifikation linearer zeitinvarianter Arbeitspunktsysteme. Die experimentell erzielten Resultate zeigen im Vergleich zu einer konventionell parametrierten Ladedruckregelung deutlich die Leistungsfahigkeit des vorgeschlagenen Regelungskonzeptes. Gegenuber dem konventionellen Vorgehen zur Parametrierung auf Basis von Expertenwissen und Fahrversuchen zeichnet sich der aufgezeigte Entwurfsprozess durch das strukturierte, methodische und theoretisch fundierte Vorgehen aus. Der resultierende Entwurfsprozess ist weitestgehend automatisiert und weist einen signifikant reduzierten Ressourcen- und Zeitbedarf auf.

Background Serum oxalate levels suddenly increase with certain dietary exposures or ethylene glycol poisoning and are a well known cause of AKI. Established contributors to oxalate crystal–induced renal necroinflammation include the NACHT, LRR and PYD domains-containing protein-3 (NLRP3) inflammasome and mixed lineage kinase domain-like (MLKL) protein–dependent tubule necroptosis. These studies examined the role of a novel form of necrosis triggered by altered mitochondrial function. Methods To better understand the molecular pathophysiology of oxalate-induced AIK, we conducted in vitro studies in mouse and human kidney cells and in vivo studies in mice, including wild-type mice and knockout mice deficient in peptidylprolyl isomerase F (Ppif) or deficient in both Ppif and Mlkl. Results Crystals of calcium oxalate, monosodium urate, or calcium pyrophosphate dihydrate, as well as silica microparticles, triggered cell necrosis involving PPIF–dependent mitochondrial permeability transition. This process involves crystal phagocytosis, lysosomal cathepsin leakage, and increased release of reactive oxygen species. Mice with acute oxalosis displayed calcium oxalate crystals inside distal tubular epithelial cells associated with mitochondrial changes characteristic of mitochondrial permeability transition. Mice lacking Ppif or Mlkl or given an inhibitor of mitochondrial permeability transition displayed attenuated oxalate-induced AKI. Dual genetic deletion of Ppif and Mlkl or pharmaceutical inhibition of necroptosis was partially redundant, implying interlinked roles of these two pathways of regulated necrosis in acute oxalosis. Similarly, inhibition of mitochondrial permeability transition suppressed crystal-induced cell death in primary human tubular epithelial cells. PPIF and phosphorylated MLKL localized to injured tubules in diagnostic human kidney biopsies of oxalosis-related AKI. Conclusions Mitochondrial permeability transition–related regulated necrosis and necroptosis both contribute to oxalate-induced AKI, identifying PPIF as a potential molecular target for renoprotective intervention.

Necrosis of a cell is defined by the loss of its plasma membrane integrity. Morphologically, necrosis occurs in several forms such as coagulative necrosis, colliquative necrosis, caseating necrosis, fibrinoid necrosis, and others. Biochemically, necrosis was demonstrated to represent a number of genetically determined signalling pathways. These include (i) kinase-mediated necroptosis, which depends on receptor interacting protein kinase 3 (RIPK3)-mediated phosphorylation of the pseudokinase mixed lineage kinase domain like (MLKL); (ii) gasdermin-mediated necrosis downstream of inflammasomes, also referred to as pyroptosis; and (iii) an iron-catalysed mechanism of highly specific lipid peroxidation named ferroptosis. Given the molecular understanding of the nature of these pathways, specific antibodies may allow direct detection of regulated necrosis and correlation with morphological features. Necroptosis can be specifically detected by immunohistochemistry and immunofluorescence employing antibodies to phosphorylated MLKL. Likewise, it is possible to generate cleavage-specific antibodies against epitopes in gasdermin protein family members. In ferroptosis, however, specific detection requires quantification of oxidative lipids by mass spectrometry (oxylipidomics). Together with classical cell death markers, such as TUNEL staining and detection of cleaved caspase-3 in apoptotic cells, the extension of the arsenal of necrosis markers will allow pathological detection of specific molecular pathways rather than isolated morphological descriptions. These novel pieces of information will be extraordinarily helpful for clinicians as inhibitors of necroptosis (necrostatins), ferroptosis (ferrostatins), and inflammasomes have emerged in clinical trials. Anatomical pathologists should embrace these novel ancillary tests and the concepts behind them and test their impact on diagnostic precision, prognostication, and the prediction of response to the upcoming anti-necrotic therapies. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Background Endothelial Progenitor Cells have been shown as effective tool in experimental AKI. Several pharmacological strategies for improving EPC-mediated AKI protection were identified in recent years. Aim of the current study was to analyze consequences of constitutive Atg5 activation in murine EPCs, utilized for AKI therapy. Methods Ischemic AKI was induced in male C57/Bl6N mice. Cultured murine EPCs were systemically injected post-ischemia, either natively or after Atg5 transfection (Adenovirus-based approach). Mice were analyzed 48 h and 6 weeks later. Results Both, native and transfected EPCs (EPCsAtg5) improved persisting kidney dysfunction at week 6, such effects were more pronounced after injecting EPCsAtg5. While matrix deposition and mesenchymal transdifferentiation of endothelial cells remained unaffected by cell therapy, EPCs, particularly EPCsAtg5 completely prevented the post-ischemic loss of peritubular capillaries. The cells finally augmented the augophagocytic flux in endothelial cells. Conclusions Constitutive Atg5 activation augments AKI-protective effects of murine EPCs. The exact clinical consequences need to be determined.

Artificial intelligence (AI) for the purpose of this review is an umbrella term for technologies emulating a nephropathologist's ability to extract information on diagnosis, prognosis, and therapy responsiveness from native or transplant kidney biopsies. Although AI can be used to analyze a wide variety of biopsy-related data, this review focuses on whole slide images traditionally used in nephropathology. AI applications in nephropathology have recently become available through several advancing technologies, including (i) widespread introduction of glass slide scanners, (ii) data servers in pathology departments worldwide, and (iii) through greatly improved computer hardware to enable AI training. In this review, we explain how AI can enhance the reproducibility of nephropathology results for certain parameters in the context of precision medicine using advanced architectures, such as convolutional neural networks, that are currently the state of the art in machine learning software for this task. Because AI applications in nephropathology are still in their infancy, we show the power and potential of AI applications mostly in the example of oncopathology. Moreover, we discuss the technological obstacles as well as the current stakeholder and regulatory concerns about developing AI applications in nephropathology from the perspective of nephropathologists and the wider nephrology community. We expect the gradual introduction of these technologies into routine diagnostics and research for selective tasks, suggesting that this technology will enhance the performance of nephropathologists rather than making them redundant.

Understanding why certain patients with IgA nephropathy progress to kidney failure while others maintain normal kidney function remains a major unanswered question. To help answer this, we performed miRNome profiling by next generation sequencing of kidney biopsies in order to identify microRNAs specifically associated with the risk of IgA nephropathy progression. Following sequencing and validation in independent cohorts, four microRNAs (-150-5p, -155-5p, -146b-5p, -135a-5p) were found to be differentially expressed in IgA nephropathy progressors compared to non-progressors, and patients with thin membrane nephropathy, lupus nephritis and membranous nephropathy, and correlated with estimated glomerular filtration rate, proteinuria, and the Oxford MEST-C scores (five histological features that are independent predictors of clinical outcome). Each individual microRNA increased the discrimination score of the International IgAN Prediction Tool, although due to the small number of samples the results did not reach statistical significance. miR-150-5p exhibited the largest amplitude of expression between cohorts and displayed the best discrimination between IgA nephropathy progressors and non-progressors by receiver operating curve analysis (AUC: 0.8). However, expression was similarly upregulated in kidneys with established fibrosis and low estimated glomerular filtration rates at the time of biopsy. Consistent with a more generic role in kidney fibrosis, in situ hybridization revealed that miR-150-5p was found in lymphoid infiltrates, and areas of proliferation and fibrosis consistent with the known drivers of progression. Thus, miR-150-5p may be a potential functional mediator of kidney fibrosis that may add value in predicting risk of progression in IgA nephropathy and other kidney diseases.

This conceptual paper addresses the role the individual plays in sustainability against the backdrop of the ethical dimensions of sustainability. We discuss the relevance of moral personhood as a basis for sustainability and develop a model of personhood for sustainability. The paper outlines the ethical dimensions of sustainability and discusses the role of individual morality for sustainability from a virtue ethics perspective. We employ a Buddhist virtue ethical approach for conceptualizing a model of the sustainable person that is characterized by sustainability virtues, interdependent personhood, and an inherent concern for the wellbeing of others, nature, and future beings. In contrast to many Western-based conceptions of the individual actor, our model of sustainable personhood conceptualizes and explains a coherent and inherent individual motivation for sustainability. The paper contributes to the methodological question of how to best consider the individual in sustainability research and sustainability approaches and suggests a conceptual basis for integrating individual, institutional, and systemic aspects of sustainability.

The classification of Antibody Mediated Rejection (AMR) in kidney transplant remains challenging even for experienced nephropathologists; this is partly because histological tissue stain analysis is often characterized by low inter-observer agreement and poor reproducibility. One of the implicated causes for inter-observer disagreement is the variability of tissue stain quality between (and within) pathology labs, coupled with the gradual fading of archival sections. Variations in stain colors and intensities can make tissue evaluation difficult for pathologists, ultimately affecting their ability to describe relevant morphological features. Being able to accurately predict the AMR status based on kidney histology images is crucial for improving patient treatment and care. We propose a novel pipeline to build robust deep neural networks for AMR classification based on StyPath, a histological data augmentation technique that leverages a light weight style-transfer algorithm as a means to reduce sample-specific bias. Each image was generated in \(1.84 \pm 0.03\) s using a single GTX TITAN V gpu and pytorch, making it faster than other popular histological data augmentation techniques. We evaluated our model using a Monte Carlo (MC) estimate of Bayesian performance and generate an epistemic measure of uncertainty to compare both the baseline and StyPath augmented models. We also generated Grad-CAM representations of the results which were assessed by an experienced nephropathologist; we used this qualitative analysis to elucidate on the assumptions being made by each model. Our results imply that our style-transfer augmentation technique improves histological classification performance (reducing error from 14.8% to 11.5%) and generalization ability.

The paper explores ethical aspects of design from a normative perspective. It develops a set of ethical principles for design against the theoretical backdrop of moral philosophy and the specific characteristics of design as a creative, function-oriented field. The paper provides a systematic ethical approach and critically reflects on ethical assumptions of prominent design approaches, such as user-centred design, green or sustainability design, and design addressing societal issues. The paper develops an encompassing perspective on the complex ethical aspects of modern design and considers users, stakeholders, society, nature, people around the world, and future generations. It specifically focuses on the role of design for addressing crucial challenges of the 21st century, such as sustainability, globalization, and inclusion, and proposes a reconstruction of professional responsibilities for functionality and creativity in this context.

In the service literature, churn is primarily attributed to customers who are dissatisfied with a service. However, in several industries, such as health care, weight loss services, and online dating, satisfied customers also churn because the service delivers on its promise, for example, by providing a cure, facilitating weight loss, or creating the circumstances that allow a person to meet their partner. Considering these dual churn pathways, it is necessary for companies in these markets to create awareness of what drives positive and negative churn to address the corresponding challenges for managing customer relationships. This study defines and theoretically discusses the concept of positive churn and outlines its consequences for companies in the short- and long term. Based on an analysis of combined observational and survey data from 1,369 customers, we empirically demonstrate the necessity of accounting for positive and negative churn by analyzing this phenomenon in online dating. Furthermore, this article discusses opportunities for future research on positive churn.

Eine akzidentielle oder (para)suizidale Intoxikation mit Ethylenglykol kann zu einer schweren Acidose, zu verschiedenen Organsystemschaden und zum Tod fuhren. Wirksame Therapien stellen die Hamodialyse und die sofortige Gabe von Fomepizol bzw. von Ethanol dar. Wir beschreiben einen Patienten nach wiederholter Ethylenglykolintoxikation mit einer schweren metabolischen Acidose und einem akuten Nierenversagen. Durch Hamodialyse mit ethanolhaltigem Dialysat und i. v.-Gabe von Ethanol konnten wir gravierende Folgeschaden verhindern.

The Journal of Media Economics is a leading journal for the media discipline. It publishes relevant insights from rigorous original research on the economics and policy of mediated communication, f...

Summary Background No treatment has consistently shown efficacy in slowing disability progression in patients with secondary progressive multiple sclerosis (SPMS). We assessed the effect of siponimod, a selective sphingosine 1-phosphate (S1P) receptor 1,5 modulator, on disability progression in patients with SPMS. Methods This event-driven and exposure-driven, double-blind, phase 3 trial was done at 292 hospital clinics and specialised multiple sclerosis centres in 31 countries. Using interactive response technology to assign numbers linked to treatment arms, patients (age 18–60 years) with SPMS and an Expanded Disability Status Scale score of 3·0–6·5 were randomly assigned (2:1) to once daily oral siponimod 2 mg or placebo for up to 3 years or until the occurrence of a prespecified number of confirmed disability progression (CDP) events. The primary endpoint was time to 3-month CDP. Efficacy was assessed for the full analysis set (ie, all randomly assigned and treated patients); safety was assessed for the safety set. This trial is registered with ClinicalTrials.gov, number NCT01665144. Findings 1651 patients were randomly assigned between Feb 5, 2013, and June 2, 2015 (1105 to the siponimod group, and 546 to the placebo group). One patient did not sign the consent form, and five patients did not receive study drug, all of whom were in the siponimod group. 1645 patients were included in the analyses (1099 in the siponimod group and 546 in the placebo). At baseline, the mean time since first multiple sclerosis symptoms was 16·8 years (SD 8·3), and the mean time since conversion to SPMS was 3·8 years (SD 3·5); 1055 (64%) patients had not relapsed in the previous 2 years, and 918 (56%) of 1651 needed walking assistance. 903 (82%) patients receiving siponimod and 424 (78%) patients receiving placebo completed the study. 288 (26%) of 1096 patients receiving siponimod and 173 (32%) of 545 patients receiving placebo had 3-month CDP (hazard ratio 0·79, 95% CI 0·65–0·95; relative risk reduction 21%; p=0·013). Adverse events occurred in 975 (89%) of 1099 patients receiving siponimod versus 445 (82%) of 546 patients receiving placebo; serious adverse events were reported for 197 (18%) patients in the siponimod group versus 83 (15%) patients in the placebo group. Lymphopenia, increased liver transaminase concentration, bradycardia and bradyarrhythmia at treatment initiation, macular oedema, hypertension, varicella zoster reactivation, and convulsions occurred more frequently with siponimod than with placebo. Initial dose titration mitigated cardiac first-dose effects. Frequencies of infections, malignancies, and fatalities did not differ between groups. Interpretation Siponimod reduced the risk of disability progression with a safety profile similar to that of other S1P modulators and is likely to be a useful treatment for SPMS. Funding Novartis Pharma AG.

Geographic proximity has become increasingly relevant due to the growing number of marketing services that use consumers’ geographic locations, thus increasing the importance of gaining insights from this information. In five studies (both field and experimental), the authors analyze the effect of geographic proximity on social influence and demonstrate that not only social proximity but also perceived homophily can trigger social influence. They find that this effect holds under alternative representations of geographic distance and is confirmed for a range of different services and even for physical goods. Furthermore, the authors show that geographic proximity has a relative effect because the social influence of a closer sender is stronger than that of a more distant sender, regardless of the absolute distances. They present managerially relevant conditions under which the influence of geographic proximity not only is comparable to other types of information such as age or gender but also prov...

Rewarding existing customers for the recruitment of new ones has become an increasingly popular acquisition tool for companies. However, when a company rewards the recruitment of a new customer, managers are unaware of whether the rewarded referral was actually necessary or whether “reward-scrounging” has occurred because the referral receiver would have converted anyway. As a consequence, companies risk overestimating the effectiveness of their referral programs, which is why gaining insights into how and when reward-scrounging occurs is crucial. In this study, we employ a large data set from the telecommunications industry to analyze the drivers of reward-scrounging. The results indicate that reward-scrounging reduces the effectiveness of referral reward programs over time and that its likelihood depends on both the referral sender's network position and the company's marketing activities. The findings are used to develop managerial means to alleviate the negative effects of reward-scrounging.

Ethical leadership has so far mainly been featured in the organizational behavior domain and, as such, treated as an intra-organizational phenomenon. The present study seeks to highlight the relevance of ethical leadership for extra-organizational phenomena by combining the organizational behavior perspective on ethical leadership with a classical marketing approach. In particular, we demonstrate that customers may use perceived ethical leadership cues as additional reference points when forming purchasing intentions. In two experimental studies (N = 601 and N = 336), we find that ethical leadership positively affects purchasing intentions because of customers’ concerns for moral self-congruence. We show this by means of both mediation and moderation analyses. Interestingly, the effect of perceived ethical leadership on purchasing intentions holds over and above the ethical advertising claims (e.g., cause-related marketing) that are commonly used in marketing. We conclude by discussing the possible ramifications of ethical leadership beyond its effects on immediate employees.

Immunosuppressive strategies applied in renal transplantation traditionally focus on T-cell inhibition. B cells were mainly examined in the context of antibody-mediated rejection, whereas the impact of antibody-independent B-cell functions has only recently entered the field of transplantation. Similar to T cells distinct B-cell subsets can enhance or inhibit immune responses. In this study, we prospectively analyzed the evolution of B-cell subsets in peripheral blood of AB0-compatible (n=27) and AB0-incompatible (n=10) renal transplant recipients. Activated B cells were transiently and plasmablasts were permanently decreased in patients without signs of rejection throughout the first year. In patients with histologically confirmed renal allograft rejection, activated B cells and plasmablasts were significantly elevated on day 365. Rituximab treatment in AB0-incompatible patients resulted in long-lasting B-cell depletion and in a naive phenotype of repopulating B cells one year following transplantation. Acute allograft rejection was correlated with an increase of activated B cells and plasmablasts and with a significant reduction of regulatory B-cell subsets. Taken together, our study demonstrates remarkable effects of standard immunosuppression on circulating B-cell subsets. Furthermore the B-cell compartment was significantly altered in rejecting patients. A specific targeting of deleterious B-cell subsets could be of clinical benefit in renal transplantation. This article is protected by copyright. All rights reserved.

Background/Aims: Rheumatoid arthritis is a chronic autoimmune disease hallmarked by inflammation in synovial joints. Treatment is hampered by the lack of a cure and current disease-modifying drugs are associated with potentially severe toxicities. Methods: We investigated arthritis severity by measuring joint swelling and pro-inflammatory cytokine production in a murine experimental model of inflammatory arthritis (antigen-induced arthritis). We analyzed acid sphingomyelinase knock-out mice and wild-type littermates, as well as mice treated with the pharmacological acid sphingomyelinase inhibitor amitriptyline. Results: Genetic ablation or pharmacological inhibition of acid sphingomyelinase reduced joint swelling and levels of pro-inflammatory cytokines in the arthritic joint. Conclusion: We identified acid sphingomyelinase as a novel druggable target in rheumatoid arthritis. Functional inhibitors of acid sphingomyelinase have been clinically used for decades, are well tolerated and suitable for long-term treatment. They would be immediately available for clinical development as a novel rheumatoid arthritis therapy. (C) 2017 The Author(s) Published by S. Karger AG, Basel

Progressive renal diseases are associated with rarefaction of peritubular capillaries, but the ultrastructural and functional alterations of the microvasculature are not well described. To study this, we analyzed different time points during progressive kidney damage and fibrosis in 3 murine models of different disease etiologies. These models were unilateral ureteral obstruction, unilateral ischemia-reperfusion injury, and Col4a3 -deficient mice, we analyzed ultrastructural alterations in patient biopsy specimens. Compared with kidneys of healthy mice, we found a significant and progressive reduction of peritubular capillaries in all models analyzed. Ultrastructurally, compared with the kidneys of control mice, focal widening of the subendothelial space and higher numbers of endothelial vacuoles and caveolae were found in fibrotic kidneys. Quantitative analysis showed that peritubular capillary endothelial cells in fibrotic kidneys had significantly and progressively reduced numbers of fenestrations and increased thickness of the cell soma and lamina densa of the capillary basement membrane. Similar ultrastructural changes were also observed in patient's kidney biopsy specimens. Compared with healthy murine kidneys, fibrotic kidneys had significantly increased extravasation of Evans blue dye in all 3 models. The extravasation could be visualized using 2-photon microscopy in real time in living animals and was mainly localized to capillary branching points. Finally, fibrotic kidneys in all models exhibited a significantly greater degree of interstitial deposition of fibrinogen. Thus, peritubular capillaries undergo significant ultrastructural and functional alterations during experimental progressive renal diseases, independent of the underlying injury. Analyses of these alterations could provide read-outs for the evaluation of therapeutic approaches targeting the renal microvasculature.

Recent acquisitions involving Tumblr and Instagram have demonstrated that the takeover of an unlisted start-up company can offer enormous financial benefits to its (former) stakeholders. Considering the multimillion-dollar amounts paid for start-ups with no existing and highly uncertain future revenues, we investigate the process and outcome of negotiation dynamics in the context of takeovers. In a series of experiments, we show that even with a low level of uncertainty about a start-up's value and its financial resources, start-ups can influence bidders' behavior and consequently the start-ups' valuation. The results indicate that incumbents' bidding behavior is driven by the perceived threat level with respect to the start-up's business activities as well as by the uncertainty with respect to other incumbents' bidding behavior—drivers that are subject to activities by the start-ups' management. Interestingly, the effect even exists if incumbents clearly know that initiating a bidding process will very likely lead to losses.

This article reports about a 73-year-old woman of Bosnian descent who presented with acute renal failure. A renal biopsy was diagnostic for a postinfect necrotizing and extracapillary proliferative glomerulonephritis. The patient reported a febrile infection fever 2 weeks previously. The diagnostics did not reveal any indications of an ongoing infection. The glomerulonephritis responded to treatment with systemic steroids. The patient was readmitted to hospital 6 weeeks later in a severely ill condition. A gastric biopsy revealed a Strongyloides stercoralis infestation. Due to the systemic steroid therapy the patient had developed a so-called hyperinfection syndrome and died despite treatment on the intensive care unit. This case illustrates the need for awareness of this rare parasitosis, particularly in patients from endemic areas. A likely causal relationship with the glomerulonephritis is discussed and an overview of the diagnostics, course of the disease and treatment of this parasitosis is given.

Background Transplant failure requires the consideration of numerous potential causes including rejection, acute tubular necrosis, infection, and recurrence of the original kidney disease. Kidney biopsy is generally required to approach these differential diagnoses. However, the histopathological findings on their own do not always lead to a definite diagnosis. Consequently, it is crucial to integrate them with clinical findings and patient history when discussing histopathological patterns of injury. The histopathologic finding of a membranoproliferative glomerulonephritis (MPGN) is one of the most challenging constellations since it does not refer to a specific disease entity but rather reflects a pattern of injury that is the result of many different causes. Whilst MPGN is occasionally classified as immune complex mediated, careful evaluation usually reveals an underlying disorder such as chronic infection, plasma cell dyscrasia, complement disorders, and autoimmune disease. Case presentation We describe the case of a 43-year-old woman who was referred to us because of a slowly rising serum creatinine 4 years after kidney transplantation. As in the native kidney, the biopsy revealed an MPGN pattern of injury. The cause of this finding had not been established prior to transplantation leading to a classification as idiopathic MPGN in the past. Further workup at the time of presentation and allograft failure revealed chronic infection of a ventriculoatrial shunt as the most probable cause. Conclusion This case underlines the fact that MPGN is not a disease but a histopathological description. Consequently, the causative disorder needs to be identified to avoid kidney failure and recurrence after transplantation.

Antibody-mediated rejection (AMR) is the major cause of allograft loss after solid organ transplantation. Circulating donor-specific antibodies against human leukocyte antigen (HLA), in particular HLA class II antibodies are critical for the pathogenesis of AMR via interactions with endothelial cells (ECs). To investigate the effects of HLA class II antibody ligation to the graft endothelium, a model of HLA-DR antibody-dependent stimulation was utilized in primary human ECs. Antibody ligation of HLA class II molecules in interferon-γ-treated ECs caused necrotic cell death without complement via a pathway that was independent of apoptosis and necroptosis. HLA-DR-mediated cell death was blocked by specific neutralization of antibody ligation with recombinant HLA class II protein and by lentiviral knockdown of HLA-DR in ECs. Importantly, HLA class II-mediated cytotoxicity was also induced by relevant native allele-specific antibodies from human allosera. Necrosis of ECs in response to HLA-DR ligation was mediated via hyperactivation of lysosomes, lysosomal membrane permeabilization (LMP), and release of cathepsins. Notably, LMP was caused by reorganization of the actin cytoskeleton. This was indicated by the finding that LMP and actin stress fiber formation by HLA-DR antibodies were both downregulated by the actin polymerization inhibitor cytochalasin D and inhibition of Rho GTPases, respectively. Finally, HLA-DR-dependent actin stress fiber formation and LMP led to mitochondrial stress, which was revealed by decreased mitochondrial membrane potential and generation of reactive oxygen species in ECs. Taken together, ligation of HLA class II antibodies to ECs induces necrotic cell death independent of apoptosis and necroptosis via a LMP-mediated pathway. These findings may enable novel therapeutic approaches for the treatment of AMR in solid organ transplantation.

C3-dominance by immunofluorescence is a defining feature in the diagnosis of C3 glomerulopathy. Most pathologists stain for C3c, which has been reported as a trace/negative even in otherwise clear-cut cases of dense deposit disease. We investigated the usefulness of C3d immunohistochemistry in biopsies with C3 glomerulopathy as an ancillary diagnostic tool. All biopsies from patients diagnosed with C3 glomerulopathy in the period January 2005 to June 2017 in the Erasmus MC, Rotterdam were included (n = 14; 10 C3 glomerulonephritis, 4 dense deposit disease). The staining pattern of C3d and C4d by immunohistochemistry was analyzed. As controls, biopsies from patients with immune complex membranoproliferative glomerulonephritis (n = 2), infection-associated glomerulonephritis (n = 6), pauci-immune crescentic glomerulonephritis (n = 7), tubulointerstitial nephritis (n = 7) and chronic-active antibody-mediated rejection (n = 9) were included. All 14 biopsies with C3 glomerulopathy showed a C3d score of ≥2, including two clear-cut biopsies with C3 glomerulopathy originally showing a trace/negative staining for C3c. In the control group, a C3d score ≥2 was observed in 11 biopsies (35%; 2 with immune complex membranoproliferative glomerulonephritis (100%), 6 with infection-associated glomerulonephritis (100%), 1 with pauci-immune crescentic glomerulonephritis (14%), 1 with tubulointerstitial nephritis (14%) and 1 with chronic-active antibody-mediated rejection (11%)). C4d was positive in 71% of the biopsies with C3 glomerulopathy (10/14). In conclusion, C3d immunohistochemistry is a valuable tool in the diagnosis of C3 glomerulopathy, especially in cases in which C3c immunofluorescence shows a trace/negative. We recommend the use of C3d in addition to C3c in cases suspicious for C3 glomerulopathy.

Acute kidney injury (AKI) leads to significant morbidity and mortality; unfortunately, strategies to prevent or treat AKI are lacking. In recent years, several preconditioning protocols have been shown to be effective in inducing organ protection in rodent models. Here, we characterized two of these interventions—caloric restriction and hypoxic preconditioning—in a mouse model of cisplatin-induced AKI and investigated the underlying mechanisms by acquisition of multi-layered omic data (transcriptome, proteome, N-degradome) and functional parameters in the same animals. Both preconditioning protocols markedly ameliorated cisplatin-induced loss of kidney function, and caloric restriction also induced lipid synthesis. Bioinformatic analysis revealed mRNA-independent proteome alterations affecting the extracellular space, mitochondria, and transporters. Interestingly, our analyses revealed a strong dissociation of protein and RNA expression after cisplatin treatment that showed a strong correlation with the degree of damage. N-degradomic analysis revealed that most posttranscriptional changes were determined by arginine-specific proteolytic processing. This included a characteristic cisplatin-activated complement signature that was prevented by preconditioning. Amyloid and acute-phase proteins within the cortical parenchyma showed a similar response. Extensive analysis of disease-associated molecular patterns suggested that transcription-independent deposition of amyloid P-component serum protein may be a key component in the microenvironmental contribution to kidney damage. This proof-of-principle study provides new insights into the pathogenesis of cisplatin-induced AKI and the molecular mechanisms underlying organ protection by correlating phenotypic and multi-layered omics data.

Physical review letters 122(4), 041102 (2019). doi:10.1103/PhysRevLett.122.041102, Published by APS, College Park, Md.