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Post-injury dysfunction of humoral immunity accounts for infections and poor outcomes in cardiovascular diseases. Among immunoglobulins (Ig), IgA, the most abundant mucosal antibody, is produced by plasma B cells in intestinal Peyer's patches (PP) and lamina propria. Here we show that patients with stroke and myocardial ischemia (MI) had strongly reduced IgA blood levels. This was phenocopied in experimental mouse models where decreased plasma and fecal IgA were accompanied by rapid loss of IgA-producing plasma cells in PP and lamina propria. Reduced plasma IgG was detectable in patients and experimental mice 3-10 d after injury. Stroke/MI triggered the release of neutrophil extracellular traps (NETs). Depletion of neutrophils, NET degradation or blockade of NET release inhibited the loss of IgA + cells and circulating IgA in experimental stroke and MI and in patients with stroke. Our results unveil how tissue-injury-triggered systemic NET release disrupts physiological Ig secretion and how this can be inhibited in patients., (© 2024. The Author(s).)

Background: Recent advances in hardware and software enabled the use of artificial intelligence (AI) algorithms for analysis of complex data in a wide range of daily-life use cases. We aim to explore the benefits of applying AI to a specific use case in transplant nephrology: risk prediction for severe posttransplant events. For the first time, we combine multinational real-world transplant data, which require specific legal and technical protection measures., Objective: The German-Canadian NephroCAGE consortium aims to develop and evaluate specific processes, software tools, and methods to (1) combine transplant data of more than 8000 cases over the past decades from leading transplant centers in Germany and Canada, (2) implement specific measures to protect sensitive transplant data, and (3) use multinational data as a foundation for developing high-quality prognostic AI models., Methods: To protect sensitive transplant data addressing the first and second objectives, we aim to implement a decentralized NephroCAGE federated learning infrastructure upon a private blockchain. Our NephroCAGE federated learning infrastructure enables a switch of paradigms: instead of pooling sensitive data into a central database for analysis, it enables the transfer of clinical prediction models (CPMs) to clinical sites for local data analyses. Thus, sensitive transplant data reside protected in their original sites while the comparable small algorithms are exchanged instead. For our third objective, we will compare the performance of selected AI algorithms, for example, random forest and extreme gradient boosting, as foundation for CPMs to predict severe short- and long-term posttransplant risks, for example, graft failure or mortality. The CPMs will be trained on donor and recipient data from retrospective cohorts of kidney transplant patients., Results: We have received initial funding for NephroCAGE in February 2021. All clinical partners have applied for and received ethics approval as of 2022. The process of exploration of clinical transplant database for variable extraction has started at all the centers in 2022. In total, 8120 patient records have been retrieved as of August 2023. The development and validation of CPMs is ongoing as of 2023., Conclusions: For the first time, we will (1) combine kidney transplant data from nephrology centers in Germany and Canada, (2) implement federated learning as a foundation to use such real-world transplant data as a basis for the training of CPMs in a privacy-preserving way, and (3) develop a learning software system to investigate population specifics, for example, to understand population heterogeneity, treatment specificities, and individual impact on selected posttransplant outcomes., International Registered Report Identifier (irrid): DERR1-10.2196/48892., (©Matthieu-P Schapranow, Mozhgan Bayat, Aadil Rasheed, Marcel Naik, Verena Graf, Danilo Schmidt, Klemens Budde, Héloïse Cardinal, Ruth Sapir-Pichhadze, Franz Fenninger, Karen Sherwood, Paul Keown, Oliver P Günther, Konstantin D Pandl, Florian Leiser, Scott Thiebes, Ali Sunyaev, Matthias Niemann, Andreas Schimanski, Thomas Klein. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 22.12.2023.)

Researchers increasingly turn to explainable artificial intelligence (XAI) to analyze omics data and gain insights into the underlying biological processes. Yet, given the interdisciplinary nature of the field, many findings have only been shared in their respective research community. An overview of XAI for omics data is needed to highlight promising approaches and help detect common issues. Toward this end, we conducted a systematic mapping study. To identify relevant literature, we queried Scopus, PubMed, Web of Science, BioRxiv, MedRxiv and arXiv. Based on keywording, we developed a coding scheme with 10 facets regarding the studies' AI methods, explainability methods and omics data. Our mapping study resulted in 405 included papers published between 2010 and 2023. The inspected papers analyze DNA-based (mostly genomic), transcriptomic, proteomic or metabolomic data by means of neural networks, tree-based methods, statistical methods and further AI methods. The preferred post-hoc explainability methods are feature relevance (n = 166) and visual explanation (n = 52), while papers using interpretable approaches often resort to the use of transparent models (n = 83) or architecture modifications (n = 72). With many research gaps still apparent for XAI for omics data, we deduced eight research directions and discuss their potential for the field. We also provide exemplary research questions for each direction. Many problems with the adoption of XAI for omics data in clinical practice are yet to be resolved. This systematic mapping study outlines extant research on the topic and provides research directions for researchers and practitioners., (© The Author(s) 2023. Published by Oxford University Press.)

Combining domain knowledge (DK) and machine learning is a recent research stream to overcome multiple issues like limited explainability, lack of data, and insufficient robustness. Most approaches applying informed machine learning (IML), however, are customized to solve one specific problem. This study analyzes the status of IML in medicine by conducting a scoping literature review based on an existing taxonomy. We identified 177 papers and analyzed them regarding the used DK, the implemented machine learning model, and the motives for performing IML. We find an immense role of expert knowledge and image data in medical IML. We then provide an overview and analysis of recent approaches and supply five directions for future research. This review can help develop future medical IML approaches by easily referencing existing solutions and shaping future research directions., Competing Interests: Declaration of competing interest The authors do not have any conflicts of interest to disclose., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: Streptococcus pneumoniae is one of the main causes of community-acquired infections in the lung alveoli in children and the elderly. Alveolar macrophages (AM) patrol alveoli in homeostasis and under infectious conditions. However, the molecular adaptations of AM upon infections with Streptococcus pneumoniae are incompletely resolved., Methods: We used a comparative transcriptomic and proteomic approach to provide novel insights into the cellular mechanism that changes the molecular signature of AM during lung infections. Using a tandem mass spectrometry approach to murine cell-sorted AM, we revealed significant proteomic changes upon lung infection with Streptococcus pneumoniae., Results: AM showed a strong neutrophil-associated proteomic signature, such as expression of CD11b, MPO, neutrophil gelatinases, and elastases, which was associated with phagocytosis of recruited neutrophils. Transcriptomic analysis indicated intrinsic expression of CD11b by AM. Moreover, comparative transcriptomic and proteomic profiling identified CD11b as the central molecular hub in AM, which influenced neutrophil recruitment, activation, and migration., Discussion: In conclusion, our study provides novel insights into the intrinsic molecular adaptations of AM upon lung infection with Streptococcus pneumoniae and reveals profound alterations critical for effective antimicrobial immunity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zec, Thiebes, Bottek, Siemes, Spangenberg, Trieu, Kirstein, Subramaniam, Christ, Klein, Jendrossek, Loose, Wagenlehner, Jablonska, Bracht, Sitek, Budeus, Klein-Hitpass, Theegarten, Shevchuk and Engel.)

Background: With direct-to-consumer (DTC) genetic testing enabling self-responsible access to novel information on ancestry, traits, or health, consumers often turn to social media for assistance and discussion. YouTube, the largest social media platform for videos, offers an abundance of DTC genetic testing-related videos. Nevertheless, user discourse in the comments sections of these videos is largely unexplored., Objective: This study aims to address the lack of knowledge concerning user discourse in the comments sections of DTC genetic testing-related videos on YouTube by exploring topics discussed and users' attitudes toward these videos., Methods: We employed a 3-step research approach. First, we collected metadata and comments of the 248 most viewed DTC genetic testing-related videos on YouTube. Second, we conducted topic modeling using word frequency analysis, bigram analysis, and structural topic modeling to identify topics discussed in the comments sections of those videos. Finally, we employed Bing (binary), National Research Council Canada (NRC) emotion, and 9-level sentiment analysis to identify users' attitudes toward these DTC genetic testing-related videos, as expressed in their comments., Results: We collected 84,082 comments from the 248 most viewed DTC genetic testing-related YouTube videos. With topic modeling, we identified 6 prevailing topics on (1) general genetic testing, (2) ancestry testing, (3) relationship testing, (4) health and trait testing, (5) ethical concerns, and (6) YouTube video reaction. Further, our sentiment analysis indicates strong positive emotions (anticipation, joy, surprise, and trust) and a neutral-to-positive attitude toward DTC genetic testing-related videos., Conclusions: With this study, we demonstrate how to identify users' attitudes on DTC genetic testing by examining topics and opinions based on YouTube video comments. Shedding light on user discourse on social media, our findings suggest that users are highly interested in DTC genetic testing and related social media content. Nonetheless, with this novel market constantly evolving, service providers, content providers, or regulatory authorities may still need to adapt their services to users' interests and desires., Competing Interests: Conflicts of Interest: None declared., (©Philipp A Toussaint, Maximilian Renner, Sebastian Lins, Scott Thiebes, Ali Sunyaev. Originally published in JMIR Infodemiology (https://infodemiology.jmir.org), 15.09.2022.)

Objective: Rising interests in distributed ledger technology (DLT) and genomics have sparked various interdisciplinary research streams with a proliferating number of scattered publications investigating the application of DLT in genomics. This review aims to uncover the current state of research on DLT in genomics, in terms of focal research themes and directions for future research., Materials and Methods: We conducted a scoping review and thematic analysis. To identify the 60 relevant papers, we queried Scopus, Web of Science, PubMed, ACM Digital Library, IEEE Xplore, arXiv, and BiorXiv., Results: Our analysis resulted in 7 focal themes on DLT in genomics discussed in literature, namely: (1) Data economy and sharing; (2) Data management; (3) Data protection; (4) Data storage; (5) Decentralized data analysis; (6) Proof of useful work; and (7) Ethical, legal, and social implications., Discussion: Based on the identified themes, we present 7 future research directions: (1) Investigate opportunities for the application of DLT concepts other than Blockchain; (2) Explore people's attitudes and behaviors regarding the commodification of genetic data through DLT-based genetic data markets; (3) Examine opportunities for joint consent management via DLT; (4) Investigate and evaluate data storage models appropriate for DLT; (5) Research the regulation-compliant use of DLT in healthcare information systems; (6) Investigate alternative consensus mechanisms based on Proof of Useful Work; and (7) Explore DLT-enabled approaches for the protection of genetic data ensuring user privacy., Conclusion: While research on DLT in genomics is currently growing, there are many unresolved problems. This literature review outlines extant research and provides future directions for researchers and practitioners., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

Although consumers and experts often express concerns regarding the questionable business practices of direct-to-consumer (DTC) genetic testing services (e.g., reselling of consumers' genetic data), the DTC genetic testing market keeps expanding rapidly. We employ retail fairness as our theoretical lens to address this seeming paradox and conduct a discrete choice experiment with 16 attributes to better understand consumers' fairness perceptions of DTC genetic testing business models. Our results suggest that, while consumers perceive privacy-preserving DTC genetic testing services fairer, price is the main driver for fairness perception. We contribute to research on consumer perceptions of DTC genetic testing by investigating consumer preferences of DTC genetic testing business models and respective attributes. Further, this research contributes to knowledge about disruptive business models in healthcare and retail fairness by contextualizing the concept of retail fairness in the DTC genetic testing market. We also demonstrate how to utilize discrete choice experiments to elicit perceived fairness., Supplementary Information: The online version contains supplementary material available at 10.1007/s12525-022-00571-x., (© The Author(s) 2022.)

Cerebral malaria is a potentially lethal disease, which is caused by excessive inflammatory responses to Plasmodium parasites. Here we use a newly developed transgenic Plasmodium berghei ANKA ( PbA Ama1 OVA ) parasite that can be used to study parasite-specific T cell responses. Our present study demonstrates that Ifnar1 -/- mice, which lack type I interferon receptor-dependent signaling, are protected from experimental cerebral malaria (ECM) when infected with this novel parasite. Although CD8 + T cell responses generated in the spleen are essential for the development of ECM, we measured comparable parasite-specific cytotoxic T cell responses in ECM-protected Ifnar1 -/- mice and wild type mice suffering from ECM. Importantly, CD8 + T cells were increased in the spleens of ECM-protected Ifnar1 -/- mice and the blood-brain-barrier remained intact. This was associated with elevated splenic levels of CCL5, a T cell and eosinophil chemotactic chemokine, which was mainly produced by eosinophils, and an increase in eosinophil numbers. Depletion of eosinophils enhanced CD8 + T cell infiltration into the brain and increased ECM induction in PbA Ama1 OVA -infected Ifnar1 -/- mice. However, eosinophil-depletion did not reduce the CD8 + T cell population in the spleen or reduce splenic CCL5 concentrations. Our study demonstrates that eosinophils impact CD8 + T cell migration and proliferation during PbA Ama1 OVA -infection in Ifnar1 -/- mice and thereby are contributing to the protection from ECM., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Scheunemann, Reichwald, Korir, Kuehlwein, Jenster, Hammerschmidt-Kamper, Lewis, Klocke, Borsche, Schwendt, Soun, Thiebes, Limmer, Engel, Mueller, Hoerauf, Hübner and Schumak.)

Background: In health care, the use of game-based interventions to increase motivation, engagement, and overall sustainability of health behaviors is steadily becoming more common. The most prevalent types of game-based interventions in health care research are gamification and serious games. Various researchers have discussed substantial conceptual differences between these 2 concepts, supported by empirical studies showing differences in the effects on specific health behaviors. However, researchers also frequently report cases in which terms related to these 2 concepts are used ambiguously or even interchangeably. It remains unclear to what extent existing health care research explicitly distinguishes between gamification and serious games and whether it draws on existing conceptual considerations to do so., Objective: This study aims to address this lack of knowledge by capturing the current state of conceptualizations of gamification and serious games in health care research. Furthermore, we aim to provide tools for researchers to disambiguate the reporting of game-based interventions., Methods: We used a 2-step research approach. First, we conducted a systematic literature review of 206 studies, published in the Journal of Medical Internet Research and its sister journals, containing terms related to gamification, serious games, or both. We analyzed their conceptualizations of gamification and serious games, as well as the distinctions between the two concepts. Second, based on the literature review findings, we developed a set of guidelines for researchers reporting on game-based interventions and evaluated them with a group of 9 experts from the field., Results: Our results show that less than half of the concept mentions are accompanied by an explicit definition. To distinguish between the 2 concepts, we identified four common approaches: implicit distinction, synonymous use of terms, serious games as a type of gamified system, and distinction based on the full game dimension. Our Game-Based Intervention Reporting Guidelines (GAMING) consist of 25 items grouped into four topics: conceptual focus, contribution, mindfulness about related concepts, and individual concept definitions., Conclusions: Conceptualizations of gamification and serious games in health care literature are strongly heterogeneous, leading to conceptual ambiguity. Following the GAMING can support authors in rigorous reporting on study results of game-based interventions., (©Simon Warsinsky, Manuel Schmidt-Kraepelin, Sascha Rank, Scott Thiebes, Ali Sunyaev. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 10.09.2021.)

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., (Copyright © 2021 International Society of Nephrology. All rights reserved.)

Disturbed functional connectivity is assumed to cause neurocognitive deficits in patients suffering from schizophrenia. A Glutamate N-methyl-D-aspartate receptor (NMDAR) dysfunction has been suggested as a possible mechanism underlying altered connectivity in schizophrenia, especially in the gamma- and theta-frequency range. The present study aimed to investigate the effects of the NMDAR-antagonist ketamine on resting-state power, functional connectivity, and schizophrenia-like psychopathological changes in healthy volunteers. In a placebo-controlled crossover design, 25 healthy subjects were recorded using resting-state 64-channel-electroencephalography (EEG) (eyes closed). The imaginary coherence-based Multivariate Interaction Measure (MIM) was used to measure gamma and theta connectivity across 80 cortical regions. The network-based statistic was applied to identify involved networks under ketamine. Psychopathology was assessed with the Positive and Negative Syndrome Scale (PANSS) and the 5-Dimensional Altered States of Consciousness Rating Scale (5D-ASC). Ketamine caused an increase in all PANSS ( p < 0.001) as well as 5D-ASC scores ( p < 0.01). Significant increases in resting-state gamma and theta power were observed under ketamine compared to placebo ( p < 0.05). The source-space analysis revealed two distinct networks with an increased mean functional gamma- or theta-band connectivity during the ketamine session. The gamma-network consisted of midline regions, the cuneus, the precuneus, and the bilateral posterior cingulate cortices, while the theta-band network involved the Heschl gyrus, midline regions, the insula, and the middle cingulate cortex. The current source density (CSD) within the gamma-band correlated negatively with the PANSS negative symptom score, and the activity within the gamma-band network correlated negatively with the subjective changed meaning of percepts subscale of the 5D-ASC. These results are in line with resting-state patterns seen in people who have schizophrenia and argue for a crucial role of the glutamate system in mediating dysfunctional gamma- and theta-band-connectivity in schizophrenia. Resting-state networks could serve as biomarkers for the response to glutamatergic drugs or drug development efforts within the glutamate system., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Curic, Andreou, Nolte, Steinmann, Thiebes, Polomac, Haaf, Rauh, Leicht and Mulert.)

To combat the COVID-19 pandemic, many countries around the globe have adopted digital contact tracing apps. Various technologies exist to trace contacts that are potentially prone to different types of tracing errors. Here, we study the impact of different proximity detection ranges on the effectiveness and efficiency of digital contact tracing apps. Furthermore, we study a usage stop effect induced by a false positive quarantine. Our results reveal that policy makers should adjust digital contact tracing apps to the behavioral characteristics of a society. Based on this, the proximity detection range should at least cover the range of a disease spread, and be much wider in certain cases. The widely used Bluetooth Low Energy protocol may not necessarily be the most effective technology for contact tracing.

Patients with chronic lymphocytic leukemia (CLL) typically suffer from frequent and severe bacterial infections. Although it is well known that neutrophils are critical innate immune cells facilitating the early defense, the underlying phenotypical and functional changes in neutrophils during CLL remain largely elusive. Using a murine adoptive transfer model of CLL, we demonstrate aggravated bacterial burden in CLL-bearing mice upon a urinary tract infection with uropathogenic Escherichia coli. Bioinformatic analyses of the neutrophil proteome revealed increased expression of proteins associated with interferon signaling and decreased protein expression associated with granule composition and neutrophil migration. Functional experiments validated these findings by showing reduced levels of myeloperoxidase and acidification of neutrophil granules after ex vivo phagocytosis of bacteria. Pathway enrichment analysis indicated decreased expression of molecules critical for neutrophil recruitment, and migration of neutrophils into the infected urinary bladder was significantly reduced. These altered migratory properties of neutrophils were also associated with reduced expression of CD62L and CXCR4 and correlated with an increased incidence of infections in patients with CLL. In conclusion, this study describes a molecular signature of neutrophils through proteomic, bioinformatic, and functional analyses that are linked to a reduced migratory ability, potentially leading to increased bacterial infections in patients with CLL., (© 2021 by The American Society of Hematology.)

Background: Nowadays, numerous health-related mobile apps implement gamification in an attempt to draw on the motivational potential of video games and thereby increase user engagement or foster certain health behaviors. However, research on effective gamification is still in its infancy and researchers increasingly recognize methodological shortcomings of existing studies. What we actually know about the phenomenon today stems from fragmented pieces of knowledge, and a variety of different perspectives. Existing research primarily draws on conceptual knowledge that is gained from research prototypes, and isolated from industry best practices. We still lack knowledge on how gamification has been successfully designed and implemented within the industry and whether certain gamification approaches have shown to be particularly suitable for certain health behaviors., Objective: We address this lack of knowledge concerning best practices in the design and implementation of gamification for health-related mobile apps by identifying archetypes of gamification approaches that have emerged in pertinent health-related mobile apps and analyzing to what extent those gamification approaches are influenced by the underlying desired health-related outcomes., Methods: A 3-step research approach is employed. As a first step, a database of 143 pertinent gamified health-related mobile apps from the Apple App Store and Google Play Store is set up. Second, the gamification approach of each app within the database is classified based on an established taxonomy for gamification in health-related apps. Finally, a 2-step cluster analysis is conducted in order to identify archetypes of the most dominant gamification approaches in pertinent gamified health-related mobile apps., Results: Eight archetypes of gamification emerged from the analysis of health-related mobile apps: (1) competition and collaboration, (2) pursuing self-set goals without rewards, (3) episodical compliance tracking, (4) inherent gamification for external goals, (5) internal rewards for self-set goals, (6) continuous assistance through positive reinforcement, (7) positive and negative reinforcement without rewards, and (8) progressive gamification for health professionals. The results indicate a close relationship between the identified archetypes and the actual health behavior that is being targeted., Conclusions: By unveiling salient best practices and discussing their relationship to targeted health behaviors, this study contributes to a more profound understanding of gamification in mobile health. The results can serve as a foundation for future research that advances the knowledge on how gamification may positively influence health behavior change and guide practitioners in the design and development of highly motivating and effective health-related mobile health apps., (©Manuel Schmidt-Kraepelin, Philipp A. Toussaint, Scott Thiebes, Juho Hamari, Ali Sunyaev. Originally published in JMIR mHealth and uHealth (http://mhealth.jmir.org), 19.10.2020.)

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 CX 3 CL1 was reduced in the urothelium. Accordingly, macrophage migration into the urothelium was diminished in the absence of CX 3 CL1 signaling in Cx 3 cr1 gfp/gfp mice. Conclusively, this study describes the crosstalk between the infected urothelium and macrophages through IL-6-induced CX 3 CL1 expression. Such crosstalk facilitates the relocation of macrophages into the urothelium and reduces bacterial burden in the urinary bladder.

Background: Recent progress in genome data collection and analysis technologies has led to a surge of direct-to-consumer (DTC) genetic testing services. Owing to the clinical value and sensitivity of genomic data, as well as uncertainty and hearsay surrounding business practices of DTC genetic testing service providers, DTC genetic testing has faced significant criticism by researchers and practitioners. Research in this area has centered on ethical and legal implications of providing genetic tests directly to consumers, but we still lack a more profound understanding of how businesses in the DTC genetic testing markets work and provide value to different stakeholders., Objective: The aim of this study was to address the lack of knowledge concerning business models of DTC genetic testing services by systematically identifying the salient properties of various DTC genetic testing service business models as well as discerning dominant business models in the market., Methods: We employed a 3-phased research approach. In phase 1, we set up a database of 277 DTC genetic testing services. In phase 2, we drew on these data as well as conceptual models of DTC genetic testing services and iteratively developed a taxonomy of DTC genetic testing service business models. In phase 3, we used a 2-stage clustering method to cluster the 277 services that we identified during phase 1 and derived 6 dominant archetypes of DTC genetic testing service business models., Results: The contributions of this research are 2-fold. First, we provided a first of its kind, systematically developed taxonomy of DTC genetic testing service business models consisting of 15 dimensions in 4 categories. Each dimension comprises 2 to 5 characteristics and captures relevant aspects of DTC genetic testing service business models. Second, we derived 6 archetypes of DTC genetic testing service business models named as follows: (1) low-cost DTC genomics for enthusiasts, (2) high-privacy DTC genomics for enthusiasts, (3) specific information tests, (4) simple health tests, (5) basic low-value DTC genomics, and (6) comprehensive tests and low data processing., Conclusions: Our analysis paints a much more complex business landscape in the DTC genetic testing market than previously anticipated. This calls for further research on business models and their effects that underlie DTC genetic testing services and invites specific regulatory interventions to protect consumers and level the playing field., (©Scott Thiebes, Philipp A Toussaint, Jaehyeon Ju, Jae-Hyeon Ahn, Kalle Lyytinen, Ali Sunyaev. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 21.01.2020.)

Abnormal gamma-band oscillations (GBO) have been frequently associated with the pathophysiology of schizophrenia. GBO are modulated by glutamate, a neurotransmitter, which is continuously discussed to shape the complex symptom spectrum in schizophrenia. The current study examined the effects of ketamine, a glutamate N-methyl-D-aspartate receptor (NMDAR) antagonist, on the auditory-evoked gamma-band response (aeGBR) and psychopathological outcomes in healthy volunteers to investigate neuronal mechanisms of psychotic behavior. In a placebo-controlled, randomized crossover design, the aeGBR power, phase-locking factor (PLF) during a choice reaction task, the Positive and Negative Syndrome Scale (PANSS) and the Altered State of Consciousness (5D-ASC) Rating Scale were assessed in 25 healthy subjects. Ketamine was applied in a subanaesthetic dose. Low-resolution brain electromagnetic tomography was used for EEG source localization. Significant reductions of the aeGBR power and PLF were identified under ketamine administration compared to placebo (p < 0.01). Source-space analysis of aeGBR generators revealed significantly reduced current source density (CSD) within the anterior cingulate cortex during ketamine administration. Ketamine induced an increase in all PANSS (p < 0.001) as well as 5D-ASC scores (p < 0.01) and increased response times (p < 0.001) and error rates (p < 0.01). Only negative symptoms were significantly associated with an aeGBR power decrease (p = 0.033) as revealed by multiple linear regression. These findings argue for a substantial role of the glutamate system in the mediation of dysfunctional gamma band responses and negative symptomatology of schizophrenia and are compatible with the NMDAR hypofunction hypothesis of schizophrenia.

Background: The massive amounts of data from next generation sequencing (NGS) methods pose various challenges with respect to data security, storage and metadata management. While there is a broad range of data analysis pipelines, these challenges remain largely unaddressed to date., Results: We describe the integration of the open-source metadata management system iRODS (Integrated Rule-Oriented Data System) with a cancer genome analysis pipeline in a high performance computing environment. The system allows for customized metadata attributes as well as fine-grained protection rules and is augmented by a user-friendly front-end for metadata input. This results in a robust, efficient end-to-end workflow under consideration of data security, central storage and unified metadata information., Conclusions: Integrating iRODS with an NGS data analysis pipeline is a suitable method for addressing the challenges of data security, storage and metadata management in NGS environments.

Background: Cloud computing is an innovative paradigm that provides users with on-demand access to a shared pool of configurable computing resources such as servers, storage, and applications. Researchers claim that information technology (IT) services delivered via the cloud computing paradigm (ie, cloud computing services) provide major benefits for health care. However, due to a mismatch between our conceptual understanding of cloud computing for health care and the actual phenomenon in practice, the meaningful use of it for the health care industry cannot always be ensured. Although some studies have tried to conceptualize cloud computing or interpret this phenomenon for health care settings, they have mainly relied on its interpretation in a common context or have been heavily based on a general understanding of traditional health IT artifacts, leading to an insufficient or unspecific conceptual understanding of cloud computing for health care., Objective: We aim to generate insights into the concept of cloud computing for health IT research. We propose a taxonomy that can serve as a fundamental mechanism for organizing knowledge about cloud computing services in health care organizations to gain a deepened, specific understanding of cloud computing in health care. With the taxonomy, we focus on conceptualizing the relevant properties of cloud computing for service delivery to health care organizations and highlighting their specific meanings for health care., Methods: We employed a 2-stage approach in developing a taxonomy of cloud computing services for health care organizations. We conducted a structured literature review and 24 semistructured expert interviews in stage 1, drawing on data from theory and practice. In stage 2, we applied a systematic approach and relied on data from stage 1 to develop and evaluate the taxonomy using 14 iterations., Results: Our taxonomy is composed of 8 dimensions and 28 characteristics that are relevant for cloud computing services in health care organizations. By applying the taxonomy to classify existing cloud computing services identified from the literature and expert interviews, which also serves as a part of the taxonomy, we identified 7 specificities of cloud computing in health care. These specificities challenge what we have learned about cloud computing in general contexts or in traditional health IT from the previous literature. The summarized specificities suggest research opportunities and exemplary research questions for future health IT research on cloud computing., Conclusions: By relying on perspectives from a taxonomy for cloud computing services for health care organizations, this study provides a solid conceptual cornerstone for cloud computing in health care. Moreover, the identified specificities of cloud computing and the related future research opportunities will serve as a valuable roadmap to facilitate more research into cloud computing in health care., (©Fangjian Gao, Scott Thiebes, Ali Sunyaev. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 11.07.2018.)

Auditory verbal hallucinations (AVH) are a common positive symptom of schizophrenia. Excitatory-to-inhibitory (E/I) imbalance related to disturbed N-methyl-D-aspartate receptor (NMDAR) functioning has been suggested as a possible mechanism underlying altered connectivity and AVH in schizophrenia. The current study examined the effects of ketamine, a NMDAR antagonist, on glutamate-related mechanisms underlying interhemispheric gamma-band connectivity, conscious auditory perception during dichotic listening (DL), and the emergence of auditory verbal distortions and hallucinations (AVD/AVH) in healthy volunteers. In a single-blind, pseudo-randomized, placebo-controlled crossover design, nineteen male, right-handed volunteers were measured using 64 channel electroencephalography (EEG). Psychopathology was assessed with the PANSS interview and the 5D-ASC questionnaire, including a subscale to detect auditory alterations with regard to AVD/AVH (AUA-AVD/AVH). Interhemispheric connectivity analysis was performed using eLORETA source estimation and lagged phase synchronization (LPS) in the gamma-band range (30-100 Hz). Ketamine induced positive symptoms such as hallucinations in a subgroup of healthy subjects. In addition, interhemispheric gamma-band connectivity was found to be altered under ketamine compared to placebo, and subjects with AUA-AVD/AVH under ketamine showed significantly higher interhemispheric gamma-band connectivity than subjects without AUA-AVD/AVH. These findings demonstrate a relationship between NMDAR functioning, interhemispheric connectivity in the gamma-band frequency range between bilateral auditory cortices and the emergence of AVD/AVH in healthy subjects. The result is in accordance with the interhemispheric miscommunication hypothesis of AVH and argues for a possible role of glutamate in AVH in schizophrenia.

The hemolytic uremic syndrome (HUS) is a life-threatening disease of the kidney that is induced by shiga toxin-producing E.coli. Major changes in the monocytic compartment and in CCR2-binding chemokines have been observed. However, the specific contribution of CCR2-dependent Gr1 high monocytes is unknown. To investigate the impact of these monocytes during HUS, we injected a combination of LPS and shiga toxin into mice. We observed an impaired kidney function and elevated levels of the CCR2-binding chemokine CCL2 after shiga toxin/LPS- injection, thus suggesting Gr1 high monocyte infiltration into the kidney. Indeed, the number of Gr1 high monocytes was strongly increased one day after HUS induction. Moreover, these cells expressed high levels of CD11b suggesting activation after tissue entry. Non-invasive PET-MR imaging revealed kidney injury mainly in the kidney cortex and this damage coincided with the detection of Gr1 high monocytes. Lack of Gr1 high monocytes in Ccr2-deficient animals reduced neutrophil gelatinase-associated lipocalin and blood urea nitrogen levels. Moreover, the survival of Ccr2-deficient animals was significantly improved. Conclusively, this study demonstrates that CCR2-dependent Gr1 high monocytes contribute to the kidney injury during HUS and targeting these cells is beneficial during this disease., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Ly6C + monocytes are important components of the innate immune defense against infections. These cells have been shown to proliferate in the bone marrow of mice with systemic infections. However, the proliferative capacity of Ly6C + monocytes in infected peripheral tissues as well as the associated regulatory mechanisms remain unclear. In this study, we analyzed the proliferative capacity of Ly6C + monocytes in the urinary bladder after infection with uropathogenic E. coli, one of the most prevalent pathogen worldwide, and in LPS-induced peritonitis. We show that Ly6C + monocytes proliferated in the bladder after infection with uropathogenic E. coli and in the peritoneum after intraperitoneal injection of LPS. We identified IL-6, a molecule that is highly expressed in infections, as a crucial regulator of Ly6C + monocyte proliferation. Inhibition of IL-6 via administration of antibodies against IL-6 or gp130 impeded Ly6C + monocyte proliferation. Furthermore, repression of IL-6 trans-signaling via administration of soluble gp130 markedly reduced the proliferation of Ly6C + monocytes. Overall, this study describes the proliferation of Ly6C + monocytes using models of urinary tract infection and LPS-induced peritonitis. IL-6 trans-signaling was identified as the regulator of Ly6C + monocyte proliferation., (©2017 Society for Leukocyte Biology.)

Objective: Postoperative ileus (POI), the most frequent complication after intestinal surgery, depends on dendritic cells (DCs) and macrophages. Here, we have investigated the mechanism that activates these cells and the contribution of the intestinal microbiota for POI induction., Design: POI was induced by manipulating the intestine of mice, which selectively lack DCs, monocytes or macrophages. The disease severity in the small and large intestine was analysed by determining the distribution of orally applied fluorescein isothiocyanate-dextran and by measuring the excretion time of a retrogradely inserted glass ball. The impact of the microbiota on intestinal peristalsis was evaluated after oral antibiotic treatment., Results: We found that Cd11c-Cre + Irf4 flox/flox mice lack CD103 + CD11b + DCs, a DC subset unique to the intestine whose function is poorly understood. Their absence in the intestinal muscularis reduced pathogenic inducible nitric oxide synthase (iNOS) production by monocytes and macrophages and ameliorated POI. Pathogenic iNOS was produced in the jejunum by resident Ly6C - macrophages and infiltrating chemokine receptor 2-dependent Ly6C + monocytes, but in the colon only by the latter demonstrating differential tolerance mechanisms along the intestinal tract. Consistently, depletion of both cell subsets reduced small intestinal POI, whereas the depletion of Ly6C + monocytes alone was sufficient to prevent large intestinal POI. The differential role of monocytes and macrophages in small and large intestinal POI suggested a potential role of the intestinal microbiota. Indeed, antibiotic treatment reduced iNOS levels and ameliorated POI., Conclusions: Our findings reveal that CD103 + CD11b + DCs and the intestinal microbiome are a prerequisite for the activation of intestinal monocytes and macrophages and for dysregulating intestinal motility in POI., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Targeting the N -methyl-D-aspartate receptor (NMDAR) is a major translational approach for treating negative symptoms of schizophrenia. Ketamine comprehensively produces schizophrenia-like symptoms, such as positive, cognitive and negative symptoms in healthy volunteers. The amplitude of the mismatch negativity (MMN) is known to be significantly reduced not only in patients with schizophrenia, but also in healthy controls receiving ketamine. Accordingly, it was the aim of the present study to investigate whether changes of MMN amplitudes during ketamine administration are associated with the emergence of schizophrenia-like negative symptoms in healthy volunteers., Methods: We examined the impact of ketamine during an MMN paradigm with 64-channel electroencephalography (EEG) and assessed the psychopathological status using the Positive and Negative Syndrome Scale (PANSS) in healthy male volunteers using a single-blind, randomized, placebo-controlled crossover design. Low-resolution brain electromagnetic tomography was used for source localization., Results: Twenty-four men were included in our analysis. Significant reductions of MMN amplitudes and an increase in all PANSS scores were identified under the ketamine condition. Smaller MMN amplitudes were specifically associated with more pronounced negative symptoms. Source analysis of MMN generators indicated a significantly reduced current source density (CSD) under the ketamine condition in the primary auditory cortex, the posterior cingulate and the middle frontal gyrus., Limitations: The sample included only men within a tight age range of 20-32 years., Conclusion: The MMN might represent a biomarker for negative symptoms in schizophrenia related to an insufficient NMDAR system and could be used to identify patients with schizophrenia with negative symptoms due to NMDAR dysfunction.

Innate immune responses by myeloid cells decisively contribute to perpetuation of central nervous system (CNS) autoimmunity and their pharmacologic modulation represents a promising strategy to prevent disease progression in Multiple Sclerosis (MS). Based on our observation that peripheral immune cells from relapsing-remitting and primary progressive MS patients exhibited strongly decreased levels of the bile acid receptor FXR (farnesoid-X-receptor, NR1H4), we evaluated its potential relevance as therapeutic target for control of established CNS autoimmunity. Pharmacological FXR activation promoted generation of anti-inflammatory macrophages characterized by arginase-1, increased IL-10 production, and suppression of T cell responses. In mice, FXR activation ameliorated CNS autoimmunity in an IL-10-dependent fashion and even suppressed advanced clinical disease upon therapeutic administration. In analogy to rodents, pharmacological FXR activation in human monocytes from healthy controls and MS patients induced an anti-inflammatory phenotype with suppressive properties including control of effector T cell proliferation. We therefore, propose an important role of FXR in control of T cell-mediated autoimmunity by promoting anti-inflammatory macrophage responses.

The antibacterial defense against infections depends on the cooperation between distinct phagocytes of the innate immune system, namely macrophages and neutrophils. However, the mechanisms driving this cooperation are incompletely understood. In this study we describe the crosstalk between Ly6C⁺ and Ly6C(-) macrophage-subtypes and neutrophils in the context of urinary tract infection (UTI) with uropathogenic E. coli (UPEC). Ly6C(-) macrophages acted as tissue resident sentinels and attracted circulating phagocytes by chemokines. Ly6C⁺ macrophages produced tumor necrosis factor (TNF) that licensed Ly6C(-) macrophages to release preformed CXCL2, which in turn caused matrix metalloproteinases (MMP-9) secretion by neutrophils to enable transepithelial migration.

A dense network of macrophages and dendritic cells (DC) expressing the chemokine receptor CX3CR1 populates most tissues. We recently reported that CX3CR1 regulates the abundance of CD11c(+) DC in the kidney and thereby promotes renal inflammation in glomerulonephritis. Given that chronic inflammation usually causes fibrosis, we hypothesized that CX3CR1 deficiency should attenuate renal fibrosis. However, when we tested this hypothesis using the DC-independent murine fibrosis model of unilateral ureteral obstruction, kidney fibrosis was unexpectedly more severe, despite less intrarenal inflammation. Two-photon imaging and flow cytometry revealed in kidneys of CX3CR1-deficient mice more motile Ly6C/Gr-1(+) macrophages. Flow cytometry verified that renal macrophages were more abundant in the absence of CX3CR1 and produced more of the key profibrotic mediator, TGF-β. Macrophages accumulated because of higher intrarenal proliferation, despite reduced monocyte recruitment and higher signs of apoptosis within the kidney. These findings support the theory that tissue macrophage numbers are regulated through local proliferation and identify CX3CR1 as a regulator of such proliferation. Thus, CX3CR1 inhibition should be avoided in DC-independent inflammatory diseases because it may promote fibrosis., (Copyright © 2015 by The American Association of Immunologists, Inc.)

The phagocytes of the innate immune system, macrophages and neutrophils, contribute to antibacterial defense, but their functional specialization and cooperation is unclear. Here, we report that three distinct phagocyte subsets play highly coordinated roles in bacterial urinary tract infection. Ly6C(-) macrophages acted as tissue-resident sentinels that attracted circulating neutrophils and Ly6C(+) macrophages. Such Ly6C(+) macrophages played a previously undescribed helper role: once recruited to the site of infection, they produced the cytokine TNF, which caused Ly6C(-) macrophages to secrete CXCL2. This chemokine activated matrix metalloproteinase-9 in neutrophils, allowing their entry into the uroepithelium to combat the bacteria. In summary, the sentinel macrophages elicit the powerful antibacterial functions of neutrophils only after confirmation by the helper macrophages, reminiscent of the licensing role of helper T cells in antiviral adaptive immunity. These findings identify helper macrophages and TNF as critical regulators in innate immunity against bacterial infections in epithelia., (Copyright © 2014 Elsevier Inc. All rights reserved.)