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Background: Endomyocardial biopsy (EMB) is currently considered the gold standard for diagnosing cardiac allograft rejection. However, significant limitations related to histological interpretation variability are well-recognized. We sought to develop a methodology to evaluate EMB solely based on gene expression, without relying on histology interpretation., Methods: Sixty-four EMBs were obtained from 47 post-heart transplant recipients, who were evaluated for allograft rejection. EMBs were subjected to mRNA sequencing, in which an unsupervised classification algorithm was used to identify the molecular signatures that best classified the EMBs. Cytokine and natriuretic peptide peripheral blood profiling was also performed. Subsequently, we performed gene network analysis to identify the gene modules and gene ontology to understand their biological relevance. We correlated our findings with the unsupervised and histological classifications., Results: Our algorithm classifies EMBs into three categories based solely on clusters of gene expression: unsupervised classes 1, 2, and 3. Unsupervised and histological classifications were closely related, with stronger gene module-phenotype correlations for the unsupervised classes. Gene ontology enrichment analysis revealed processes impacting on the regulation of cardiac and mitochondrial function, immune response, and tissue injury response. Significant levels of cytokines and natriuretic peptides were detected following the unsupervised classification., Conclusion: We have developed an unsupervised algorithm that classifies EMBs into three distinct categories, without relying on histology interpretation. These categories were highly correlated with mitochondrial, immune, and tissue injury response. Significant cytokine and natriuretic peptide levels were detected within the unsupervised classification. If further validated, the unsupervised classification could offer a more objective EMB evaluation., (© 2023 The Authors. Clinical Transplantation published by John Wiley & Sons Ltd.)

Background: Crohn's diseases and ulcerative colitis, both of which are chronic immune-mediated disorders of the gastrointestinal tract are major contributors to the overarching Inflammatory bowel diseases. It has become increasingly evident that the pathological processes of IBDs results from interactions between genetic and environmental factors, which can skew immune responses against normal intestinal flora., Methods: The aim of this study is to assess and analyze the taxa diversity and relative abundances in CD and UC in the Saudi population. We utilized a sequencing strategy that targets all variable regions in the 16 S rRNA gene using the Swift Amplicon 16 S rRNA Panel on Illumina NovaSeq 6000., Results: The composition of stool 16 S rRNA was analyzed from 219 patients with inflammatory bowel disease and from 124 healthy controls. We quantified the abundance of microbial communities to examine any significant differences between subpopulations of samples. At the genus level, two genera in particular, Veillonella and Lachnoclostridium showed significant association with CD versus controls. There were significant differences between subjects with CD versus UC, with the top differential genera spanning Akkermansia, Harryflintia, Maegamonas and Phascolarctobacterium. Furthermore, statistically significant taxa diversity in microbiome composition was observed within the UC and CD groups., Conclusions: In conclusion we have shown that there are significant differences in gut microbiota between UC, CD and controls in a Saudi Arabian inflammatory bowel disease cohort. This reinforces the need for further studies in large populations that are ethnically and geographically diverse. In addition, our results show the potential to develop classifiers that may have add additional richness of context to clinical diagnosis of UC and CD with larger inflammatory bowel disease cohorts., (© 2023. The Author(s).)

Background: Surveillance of surgical site infections (SSI) relies on access to data from various sources. Insights into the practices of German hospitals conducting SSI surveillance and their information technology (IT) infrastructures are scarce. The aim of this study was to evaluate current SSI surveillance practices in German hospitals with a focus on employed IT infrastructures., Methods: German surgical departments actively participating in the national SSI surveillance module "OP-KISS" were invited in August 2020 to participate in a questionnaire-based online survey. Depending on whether departments entered all data manually or used an existing feature to import denominator data into the national surveillance database, departments were separated into different groups. Selected survey questions differed between groups., Results: Of 1,346 invited departments, 821 participated in the survey (response rate: 61%). Local IT deficits (n = 236), incompatibility of import specifications and hospital information system (n = 153) and lack of technical expertise (n = 145) were cited as the most frequent reasons for not using the denominator data import feature. Conversely, reduction of workload (n = 160) was named as the main motivation to import data. Questions on data availability and accessibility in the electronic hospital information system (HIS) and options to export data from the HIS for the purpose of surveillance, yielded diverse results. Departments utilizing the import feature tended to be from larger hospitals with a higher level of care., Conclusions: The degree to which digital solutions were employed for SSI surveillance differed considerably between surgical departments in Germany. Improving availability and accessibility of information in HIS and meeting interoperability standards will be prerequisites for increasing the amount of data exported directly from HIS to national databases and laying the foundation for automated SSI surveillance on a broad scale., (© 2023. The Author(s).)

This position paper, developed by an interdisciplinary expert group of neonatologists, paediatric infectious disease physicians, clinical pharmacists and specialists for the prevention and control of nosocomial infections, describes the "Good handling practice of medicines parenterally administered to patients on NICUs". It takes equal account of patient safety and the specialties of neonatal intensive care regarding feasibility and proportionality. The overall concept is perceived as a "learning system", in which open communication within the health-care team relating to medication errors and critical incidents enables continuous development and improvement to ensure patient safety. In our opinion, pharmacists, who are responsible for the supply of ready-to-administer parenteral medicinal products for neonatal intensive care patients, as well as the hygiene staff responsible on site are integral parts of the interdisciplinary treatment team. Risks of the current clinical practice of parenteral treatment of NICU patients are discussed in detail and recommendations for safety-relevant procedures are given., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2023 Krämer et al.)

Most detailed patient information in real-world data (RWD) is only consistently available in free-text clinical documents. Manual curation is expensive and time consuming. Developing natural language processing (NLP) methods for structuring RWD is thus essential for scaling real-world evidence generation. We propose leveraging patient-level supervision from medical registries, which are often readily available and capture key patient information, for general RWD applications. We conduct an extensive study on 135,107 patients from the cancer registry of a large integrated delivery network (IDN) comprising healthcare systems in five western US states. Our deep-learning methods attain test area under the receiver operating characteristic curve (AUROC) values of 94%-99% for key tumor attributes and comparable performance on held-out data from separate health systems and states. Ablation results demonstrate the superiority of these advanced deep-learning methods. Error analysis shows that our NLP system sometimes even corrects errors in registrar labels., Competing Interests: The scope of this work is strictly within research exploration and does not involve any Microsoft product or commercial sponsorship. However, by way of disclosure, S.P., M.W., R.R., R.T., N.U., M.L., Y.G., N.V., T.N., and H.P. are employees of Microsoft, as denoted in the authorship., (© 2023 The Authors.)

Inflammatory myofibroblastic tumor (IMT) of the uterus is a rare mesenchymal tumor with largely benign behavior; however, a small subset demonstrate aggressive behavior. While clinicopathologic features have been previously associated with aggressive behavior, these reports are based on small series, and these features are imperfect predictors of clinical behavior. IMTs are most commonly driven by ALK fusions, with additional pathogenic molecular alterations being reported only in rare examples of extrauterine IMTs. In this study, a series of 11 uterine IMTs, 5 of which demonstrated aggressive behavior, were evaluated for clinicopathologic variables and additionally subjected to capture-based next-generation sequencing with or without whole-transcriptome RNA sequencing. In the 6 IMTs without aggressive behavior, ALK fusions were the sole pathogenic alteration. In contrast, all 5 aggressive IMTs harbored pathogenic molecular alterations and numerous copy number changes in addition to ALK fusions, with the majority of the additional alterations present in the primary tumors. We combined our series with cases previously reported in the literature and performed statistical analyses to propose a novel clinicopathologic risk stratification score assigning 1 point each for: age above 45 years, size≥5 cm,≥4 mitotic figures per 10 high-power field, and infiltrative borders. No tumors with 0 points had an aggressive outcome, while 21% of tumors with 1 to 2 points and all tumors with ≥3 points had aggressive outcomes. We propose a 2-step classification model that first uses the clinicopathologic risk stratification score to identify low-risk and high-risk tumors, and recommend molecular testing to further classify intermediate-risk tumors., Competing Interests: Conflicts of Interest and Source of Funding: This study was funded by the UCSF Department of Pathology Clinical Research Endowment awards granted to N.R.L., K.G., and S.E.U. J.T.R. reports that his spouse receives salary and stock options from Merck and Co. For the remaining authors none were declared., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Tumor mutational burden (TMB), a surrogate for tumor neoepitope burden, is used as a pan-tumor biomarker to identify patients who may benefit from anti-program cell death 1 (PD1) immunotherapy, but it is an imperfect biomarker. Multiple additional genomic characteristics are associated with anti-PD1 responses, but the combined predictive value of these features and the added informativeness of each respective feature remains unknown. We evaluated whether machine learning (ML) approaches using proposed determinants of anti-PD1 response derived from whole exome sequencing (WES) could improve prediction of anti-PD1 responders over TMB alone. Random forest classifiers were trained on publicly available anti-PD1 data (n = 104), and subsequently tested on an independent anti-PD1 cohort (n = 69). Both the training and test datasets included a range of cancer types such as non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), melanoma, and smaller numbers of patients from other tumor types. Features used include summaries such as TMB and number of frameshift mutations, as well as more gene-level features such as counts of mutations associated with immune checkpoint response and resistance. Both ML algorithms demonstrated area under the receiver-operator curves (AUC) that exceeded TMB alone (AUC 0.63 "human-guided," 0.64 "cluster," and 0.58 TMB alone). Mutations within oncogenes disproportionately modulate anti-PD1 responses relative to their overall contribution to tumor neoepitope burden. The use of a ML algorithm evaluating multiple proposed genomic determinants of anti-PD1 responses modestly improves performance over TMB alone, highlighting the need to integrate other biomarkers to further improve model performance., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

Introduction: Parenteral nutrition, usually indicated for preterm infants with a birthweight<1500 g and sick newborns, enables the supply with critical nutrients. As a high degree of therapy safety is required, a European guideline provides recommendations for safe therapy procedures. The present project aimed to evaluate the implementation of the European guideline in German perinatal centers and to identify possible barriers that impede its implementation. A further goal was to develop solution approaches to overcome possible barriers., Methods and Results: A multidisciplinary cooperation conducted an online survey questioning the current implementation procedures of the European guideline among pediatricians and hospital pharmacists. Results show barriers in the provisioning process of parenteral nutrition that hinder a guideline-compliant implementation in practice. Based on results of this survey, an expert network developed an interactive toolkit with simplified guideline recommendations, guideline-compliant advice for practice, best-practice examples, forms, and handouts. It seeks to encourage critical reflection of routine processes and provides concrete solutions to overcome barriers in practice., Conclusion: The current procedures related to parenteral nutrition deviate from guideline recommendations. The developed toolkit provides practice-oriented support aiming to enhance the guideline-compliant implementation of parenteral nutrition in perinatal centers., Competing Interests: EFCNI erhielt einen Educational Grant von Baxter zur Projektdurchführung. Es bestehen keine weiteren Interessenskonflikte., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Objectives: To determine the influence of a national surveillance system for neonates (NEO-KISS) in neonatal intensive care units (NICUs) on consumption of antibacterial and to identify risk factors for prescriptions., Methods: Data on antibacterial use between 2013 and 2019 from 231 NICUs in Germany was analyzed in this longitudinal study after introduction of a mandatory module for surveillance of antibacterial consumption in preterm infants. 59,411 newborns with a birth weight under 1500 gs were under surveillance in NEO-KISS during the study period. We report the development of antibacterial consumption during the days of treatment (DOT)/1000 patient days (PD) including the name of the substance administered. Risk factors for antibacterial treatment over time were analyzed., Results: A total, 2,090,341 surveillance patient days were monitored. Antibacterial consumption was 430.4 DOT/1000PD (Median 380.3; IQR: 284.2-502.7). Antibacterial use significantly decreased by 19.5% from 2013, 474.3 DOT/1000PD to 382.1 DOT/1000PD in 2019. Use of penicillins with extended spectrum (J01CA), other aminoglycosides (J01GB), glycopeptide antibacterials (J01XA and J01DH), and third-generation cephalosporins (J01DD) decreased, while use of macrolides (J01FA) and combinations of penicillins, including beta-lactamase inhibitors (J01CR), increased over time. Regression analysis identified year of birth as an independent protective factor for the prescription of antibacterials in general., Conclusion: The implementation of a national mandatory surveillance system was associated with a reduction in antibacterial consumption in preterm infants with VLBW. Surveillance of antibacterial use is an integral part of targeting antimicrobial stewardship efforts., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2022. Published by Elsevier Ltd.)

Background: One possible transmission route for nosocomial pathogens is contaminated medical devices. Formation of biofilms can exacerbate the problem. We report on a carbapenemase-producing Klebsiella pneumoniae that had caused an outbreak linked to contaminated duodenoscopes. To determine whether increased tolerance to disinfectants may have contributed to the outbreak, we investigated the susceptibility of the outbreak strain to disinfectants commonly used for duodenoscope reprocessing. Disinfection efficacy was tested on planktonic bacteria and on biofilm., Methods: Disinfectant efficacy testing was performed for planktonic bacteria according to EN standards 13727 and 14561 and for biofilm using the Bead Assay for Biofilms. Disinfection was defined as ≥ 5log 10 reduction in recoverable colony forming units (CFU)., Results: The outbreak strain was an OXA-48 carbapenemase-producing K. pneumoniae of sequence type 101. We found a slightly increased tolerance of the outbreak strain in planktonic form to peracetic acid (PAA), but not to other disinfectants tested. Since PAA was the disinfectant used for duodenoscope reprocessing, we investigated the effect of PAA on biofilm of the outbreak strain. Remarkably, disinfection of biofilm of the outbreak strain could not be achieved by the standard PAA concentration used for duodenoscope reprocessing at the time of outbreak. An increased tolerance to PAA was not observed in a K. pneumoniae type strain tested in parallel., Conclusions: Biofilm of the K. pneumoniae outbreak strain was tolerant to standard disinfection during duodenoscope reprocessing. This study establishes for the first time a direct link between biofilm formation, increased tolerance to disinfectants, reprocessing failure of duodenoscopes and nosocomial transmission of carbapenem-resistant K. pneumoniae., (© 2022. The Author(s).)

Tumor-infiltrating neoantigen-reactive T cells can mediate regression of metastatic gastrointestinal cancers yet remain poorly characterized. We performed immunological screening against personalized neoantigens in combination with single-cell RNA sequencing on tumor-infiltrating lymphocytes from bile duct and pancreatic cancer patients to characterize the transcriptomic landscape of neoantigen-reactive T cells. We found that most neoantigen-reactive CD8 + T cells displayed an exhausted state with significant CXCL13 and GZMA co-expression compared with non-neoantigen-reactive bystander cells. Most neoantigen-reactive CD4 + T cells from a patient with bile duct cancer also exhibited an exhausted phenotype but with overexpression of HOPX or ADGRG1 while lacking IL7R expression. Thus, neoantigen-reactive T cells infiltrating gastrointestinal cancers harbor distinct transcriptomic signatures, which may provide new opportunities for harnessing these cells for therapy., Competing Interests: Declaration of interests E.T. is on the scientific advisory board of PACT Pharma, Genocea Biosciences, and Turnstone Biologics. C.B.B. reports a consultant/advisory relationship with BMS, has stock ownership in and is on the scientific board of PrimeVax, and is on the scientific board of BioAI and LunaPhore. Other authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Cancer heterogeneity is a result of genetic mutations within the cancer cells. Their proliferation is not only driven by autocrine functions but also under the influence of cancer microenvironment, which consists of normal stromal cells such as infiltrating immune cells, cancer-associated fibroblasts, endothelial cells, pericytes, vascular and lymphatic channels. The relationship between cancer cells and cancer microenvironment is a critical one and we are just on the verge to understand it on a molecular level. Cancer microenvironment may serve as a selective force to modulate cancer cells to allow them to evolve into more aggressive clones with ability to invade the lymphatic or vascular channels to spread to regional lymph nodes and distant sites. It is important to understand these steps of cancer evolution within the cancer microenvironment towards invasion so that therapeutic strategies can be developed to control or stop these processes., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Factors contributing to the spread of SARS-CoV-2 outside the acute care hospital setting have been described in detail. However, data concerning risk factors for nosocomial SARS-CoV-2 infections in hospitalized patients remain scarce. To close this research gap and inform targeted measures for the prevention of nosocomial SARS-CoV-2 infections, we analyzed nosocomial SARS-CoV-2 cases in our hospital during a defined time period., Methods: Data on nosocomial SARS-CoV-2 infections in hospitalized patients that occurred between May 2020 and January 2021 at Charité university hospital in Berlin, Germany, were retrospectively gathered. A SARS-CoV-2 infection was considered nosocomial if the patient was admitted with a negative SARS-CoV-2 reverse transcription polymerase chain reaction test and subsequently tested positive on day five or later. As the incubation period of SARS-CoV-2 can be longer than five days, we defined a subgroup of "definite" nosocomial SARS-CoV-2 cases, with a negative test on admission and a positive test after day 10, for which we conducted a matched case-control study with a one to one ratio of cases and controls. We employed a multivariable logistic regression model to identify factors significantly increasing the likelihood of nosocomial SARS-CoV-2 infections., Results: A total of 170 patients with a nosocomial SARS-CoV-2 infection were identified. The majority of nosocomial SARS-CoV-2 patients (n = 157, 92%) had been treated at wards that reported an outbreak of nosocomial SARS-CoV-2 cases during their stay or up to 14 days later. For 76 patients with definite nosocomial SARS-CoV-2 infections, controls for the case-control study were matched. For this subgroup, the multivariable logistic regression analysis revealed documented contact to SARS-CoV-2 cases (odds ratio: 23.4 (95% confidence interval: 4.6-117.7)) and presence at a ward that experienced a SARS-CoV-2 outbreak (odds ratio: 15.9 (95% confidence interval: 2.5-100.8)) to be the principal risk factors for nosocomial SARS-CoV-2 infection., Conclusions: With known contact to SARS-CoV-2 cases and outbreak association revealed as the primary risk factors, our findings confirm known causes of SARS-CoV-2 infections and demonstrate that these also apply to the acute care hospital setting. This underscores the importance of rapidly identifying exposed patients and taking adequate preventive measures., (© 2022. The Author(s).)

Background: Early detection of clusters of pathogens is crucial for infection prevention and control (IPC) in hospitals. Conventional manual cluster detection is usually restricted to certain areas of the hospital and multidrug resistant organisms. Automation can increase the comprehensiveness of cluster surveillance without depleting human resources. We aimed to describe the application of an automated cluster alert system (CLAR) in the routine IPC work in a hospital. Additionally, we aimed to provide information on the clusters detected and their properties., Methods: CLAR was continuously utilized during the year 2019 at Charité university hospital. CLAR analyzed microbiological and patient-related data to calculate a pathogen-baseline for every ward. Daily, this baseline was compared to data of the previous 14 days. If the baseline was exceeded, a cluster alert was generated and sent to the IPC team. From July 2019 onwards, alerts were systematically categorized as relevant or non-relevant at the discretion of the IPC physician in charge., Results: In one year, CLAR detected 1,714 clusters. The median number of isolates per cluster was two. The most common cluster pathogens were Enterococcus faecium (n = 326, 19 %), Escherichia coli (n = 274, 16 %) and Enterococcus faecalis (n = 250, 15 %). The majority of clusters (n = 1,360, 79 %) comprised of susceptible organisms. For 906 alerts relevance assessment was performed, with 317 (35 %) alerts being classified as relevant., Conclusions: CLAR demonstrated the capability of detecting small clusters and clusters of susceptible organisms. Future improvements must aim to reduce the number of non-relevant alerts without impeding detection of relevant clusters. Digital solutions to IPC represent a considerable potential for improved patient care. Systems such as CLAR could be adapted to other hospitals and healthcare settings, and thereby serve as a means to fulfill these potentials., (© 2021. The Author(s).)

It is essential to reveal the associations between various omics data for a comprehensive understanding of the altered biological process in human wellness and disease. To date, very few studies have focused on collecting and exhibiting multi-omics associations in a single database. Here, we present iNetModels, an interactive database and visualization platform of Multi-Omics Biological Networks (MOBNs). This platform describes the associations between the clinical chemistry, anthropometric parameters, plasma proteomics, plasma metabolomics, as well as metagenomics for oral and gut microbiome obtained from the same individuals. Moreover, iNetModels includes tissue- and cancer-specific Gene Co-expression Networks (GCNs) for exploring the connections between the specific genes. This platform allows the user to interactively explore a single feature's association with other omics data and customize its particular context (e.g. male/female specific). The users can also register their data for sharing and visualization of the MOBNs and GCNs. Moreover, iNetModels allows users who do not have a bioinformatics background to facilitate human wellness and disease research. iNetModels can be accessed freely at https://inetmodels.com without any limitation., (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Pancreatic ductal adenocarcinoma (PDAC) has traditionally been thought of as an immunologically quiescent tumor type presumably because of a relatively low tumor mutational burden (TMB) and poor responses to checkpoint blockade therapy. However, many PDAC tumors exhibit T cell inflamed phenotypes. The presence of tertiary lymphoid structures (TLS) has recently been shown to be predictive of checkpoint blockade response in melanomas and sarcomas, and are prognostic for survival in PDAC. In order to more comprehensively understand tumor immunity in PDAC patients with TLS, we performed RNA-seq, single and multiplex IHC, flow cytometry and predictive genomic analysis on treatment naïve, PDAC surgical specimens. Forty-six percent of tumors contained distinct T and B cell aggregates reflective of "early-stage TLS" (ES-TLS), which correlated with longer overall and progression-free survival. These tumors had greater CD8 + T cell infiltration but were not defined by previously published TLS gene-expression signatures. ES-TLS + tumors were enriched for IgG1 class-switched memory B cells and memory CD4 + T cells, suggesting durable immunological memory persisted in these patients. We also observed the presence of active germinal centers (mature-TLS) in 31% of tumors with lymphocyte clusters, whose patients had long-term survival (median 56 months). M-TLS-positive tumors had equivalent overall T cell infiltration to ES-TLS, but were enriched for activated CD4 + memory cells, naive B cells and NK cells. Finally, using a TCGA-PDAC dataset, ES-TLS + tumors harbored a decreased TMB, but M-TLS with germinal centers expressed significantly more MHCI-restricted neoantigens as determined by an in silico neoantigen prediction method. Interestingly, M-TLS + tumors also had evidence of increased rates of B cell somatic hypermutation, suggesting that germinal centers form in the presence of high-quality tumor neoantigens leading to increased humoral immunity that confers improved survival for PDAC patients. Abbreviations TLS: tertiary lymphoid structures; GC: germinal center(s); PDAC: pancreatic ductal adenocarcinoma; RNA-seq: RNA sequencing; BCRseq: B cell receptor sequencing; HEV: high endothelial venule; PNAd: peripheral node addressin; TMB: tumor mutational burden; TCGA: the cancer genome atlas; PAAD: pancreatic adenocarcinoma; FFPE: formalin fixed paraffin embedded; TIME: tumor immune microenvironment., (© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Background: Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) represents an unprecedented healthcare challenge. Various SARS-CoV-2 outbreaks in healthcare facilities have been reported. Healthcare workers (HCWs) may play a critical role in the spread of the virus, particularly when asymptomatic. We examined four healthcare-associated outbreaks of SARS-CoV-2 infections that occurred at a university hospital in Berlin, Germany. We aimed to describe and analyze the spread of the virus in order to draw conclusions for effective containment of SARS-CoV-2 in healthcare facilities., Methods: Healthcare-associated outbreaks of SARS-CoV-2 infections were defined as two or more laboratory confirmed infections with SARS-CoV-2 where an epidemiological link within the healthcare setting appeared likely. We focused our analysis on one of three sites of the Charité-University Medicine hospital within a 2 month period (March and April 2020)., Results: We observed four healthcare-associated outbreaks of SARS-CoV-2 infections, with a total of 24 infected persons (23 HCWs and one patient). The outbreaks were detected in the departments of nephrology and dialysis (n = 9), anesthesiology (n = 8), surgical pediatrics (n = 4), and neurology (n = 3). Each outbreak showed multiple unprotected contacts between infected HCWs. A combination of contact tracing, testing, physical distancing and mandatory continuous wearing of face masks by all HCWs was able to contain all four outbreaks., Conclusions: HCW to HCW transmission represented the likely source of the four outbreaks. Ensuring proper physical distancing measures and wearing of protective equipment, also when interacting with colleagues, must be a key aspect of fighting COVID-19 in healthcare facilities.

Objective: In Berlin, the first public severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing site started 1 day after the first case in the city occurred. We describe epidemiological and clinical characteristics and aim at identifying risk factors for SARS-CoV-2 detection during the first 6 weeks of operation., Methods: Testing followed national recommendations, but was also based on the physician's discretion. We related patient characteristics to SARS-CoV-2 test positivity for exploratory analyses using a cross-sectional, observational study design., Results: Between 3 March and 13 April 2020, 5179 individuals attended the site (median age 34 years; interquartile range 26-47 years). The median time since disease onset was 4 days (interquartile range 2-7 days). Among 4333 persons tested, 333 (7.7%) were positive. Test positivity increased up to 10.3% (96/929) during the first 3 weeks and then declined, paralleling Germany's lock-down and the course of the epidemic in Berlin. Strict adherence to testing guidelines resulted in 10.4% (262/2530) test positivity, compared with 3.9% (71/1803) among individuals tested for other indications. A nightclub was a transmission hotspot; 27.7% (26/94) of one night's visitors were found positive. Smell and/or taste dysfunction indicated coronavirus disease 2019 (COVID-19) with 85.6% specificity (95% CI 82.1%-88.1%). Four per cent (14/333) of those infected were asymptomatic. Risk factors for detection of SARS-CoV-2 infection were recent contact with a positive case (second week after contact, OR 3.42; 95% CI 2.48-4.71), travel to regions of high pandemic activity (e.g. Austria, OR 4.16; 95% CI 2.48-6.99), recent onset of symptoms (second week, OR 3.61; 95% CI 1.87-6.98) and an impaired sense of smell/taste (4.08; 95% CI 2.36-7.03)., Conclusions: In this young population, early-onset presentation of COVID-19 resembled flu-like symptoms, except for smell and/or taste dysfunction. Risk factors for SARS-CoV-2 detection were return from regions with high incidence and contact with confirmed SARS-CoV-2 cases, particularly when tests were administered within the first 2 weeks after contact and/or onset of symptoms., (Copyright © 2020. Published by Elsevier Ltd.)

Pancreatic adenocarcinoma is characterized by a complex tumor environment with a wide diversity of infiltrating stromal and immune cell types that impact the tumor response to conventional treatments. However, even in this poorly responsive tumor the extent of T cell infiltration as determined by quantitative immunohistology is a candidate prognostic factor for patient outcome. As such, even more comprehensive immunophenotyping of the tumor environment, such as immune cell type deconvolution via inference models based on gene expression profiling, holds significant promise. We hypothesized that RNA-Seq can provide a comprehensive alternative to quantitative immunohistology for immunophenotyping pancreatic cancer. We performed RNA-Seq on a prospective cohort of pancreatic tumor specimens and compared multiple approaches for gene expression-based immunophenotyping analysis compared to quantitative immunohistology. Our analyses demonstrated that while gene expression analyses provide additional information on the complexity of the tumor immune environment, they are limited in sensitivity by the low overall immune infiltrate in pancreatic cancer. As an alternative approach, we identified a set of genes that were enriched in highly T cell infiltrated pancreatic tumors, and demonstrate that these can identify patients with improved outcome in a reference population. These data demonstrate that the poor immune infiltrate in pancreatic cancer can present problems for analyses that use gene expression-based tools; however, there remains enormous potential in using these approaches to understand the relationships between diverse patterns of infiltrating cells and their impact on patient treatment outcomes., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: MJG and MRC have research support from Bristol Myers Squibb, Mavupharma, and Jounce that is not relevant to the subject of this manuscript. Funding for this manuscript was provided by NIH R01CA182311 (MJG), NIH R01CA244142 (MJG), NIH R01CA208644 (MRC), and the Providence Opportunity Fund. The authors declare that these do not represent competing interests relevant to the subject of this manuscript.

Background: The extensive use of antibiotics is reflected by an increasing prevalence of infections with multidrug-resistant bacteria, including third-generation cephalosporin-resistant bacteria (3GCRB). For neonatal intensive care units screening and enhanced barrier precautions are recommended to control the spread of multidrug-resistant Gram-negative bacteria, while evidence for efficacy of barrier precautions remains scarce in a non-outbreak setting., Objective: To determine the impact of a screening program for maternal 3GCRB colonization and the effects of contact precautions and cohort nursing, concerning the risk of neonatal late-onset sepsis (LOS) and antibiotic use rates (AURs)., Study Design: In a retrospective matched-pair cohort study, data of neonates exposed to maternal 3GCRB colonization were compared with findings in non-exposed neonates., Results: Of 3,144 neonates admitted, 184 neonates born to 3GCRB-positive mothers were eligible. Among them, 37 (20%) became 3GCRB positive during hospital stay. 3GCRB-exposed infants had a lower rate of LOS (6.5 vs. 14.1%, p=0.03) and lower AURs in that time period compared to controls (mean 0.009 vs. 0.025, p=0.006). When started within the first 72h after birth, days of therapy with meropenem were significantly lower in non-exposed vs. 3GCRB-exposed infants (mean 0.13 vs. 0.42; p=0.002). No invasive infections with 3GCRB occurred., Conclusions: Neonates of 3GCRB-positive mothers do not have an increased a priori risk for invasive 3GCRB infection and may benefit from enhanced contact precautions measures., Hintergrund: Der zunehmende Einsatz von Antibiotika führt zu einem Anstieg von Infektionen mit multiresistenten Erregern wie z. B. Drittgeneration Cephalosporin-resistenten Bakterien (3GCRB). Empfehlungen zu Screening- und Kohortierungsmaßnahmen auf neonatologischen Intensivstationen zielen auf die Prävention von horizontaler Transmission und invasiven Infektionen ab. Für Nicht-Ausbruchssituationen ist die Evidenz für Hygienemaßnahmen und Screeningprogrammen unzureichend. ZIEL: Evaluation eines Screening für mütterliche 3GCRB-Besiedlung mit nachfolgender Isolation bzw. Kohortenpflege des Neugeborenen (NG) unter Bezug auf das Risiko einer Late-Onset-Sepsis (LOS) und die Anzahl der Antibiotika-Tage (AUR)., Studiendesign: In einer retrospektiven Fall-Kontroll-Kohortenstudie wurden Daten von NG mit maternaler 3GCRB-Besiedelung im Vergleich zu einer Kontrollgruppe mit unauffälligem Screening analysiert., Ergebnisse: In einer Kohorte von 3144 NG fanden sich 184 NG von 3GCRB-besiedelten Müttern. Bei 37 (20%) wurde im Verlauf eine Besiedelung mit 3GCRB nachgewiesen. In der Gruppe der 3GCRB-exponierten NG kam es seltener zu einer LOS (6,5 vs. 14,1%, p=0,03). Zwischen dem 4. Lebenstag und der Entlassung hatten 3GCRB-exponierte NG eine niedrigere AUR (Mittelwert 0,009 vs. 0,025, p=0,006) als die Kontrollgruppe. Die Behandlungstage mit Meropenem (Start in den ersten 3 Lebenstagen), war in der Kontrollgruppe signifikant geringer als in der 3GCRB-exponierten Gruppe (Mittelwert 0,13 vs. 0,43 Tage; p=0,002). In beiden Gruppen trat keine invasive Infektion mit 3GCRB auf., Schlussfolgerung: Neugeborene, deren Mütter 3GCRB besiedelt sind, haben kein erhöhtes a priori Risiko für eine invasive Infektion mit 3GCRB Erregern und profitieren wahrscheinlich von erweiterten Kohortierungs- und Isolationsmaßnahmen., Competing Interests: C. Dame is member of the Neonatology Group of the Commission for Hospital Hygiene, Infection Prevention and Control (KRINKO) of the Federal Robert-Koch Institute (RKI), Berlin, Germany. All other authors report no conflict of interest relevant to this article., (© Georg Thieme Verlag KG Stuttgart · New York.)

Metabolism during pregnancy is a dynamic and precisely programmed process, the failure of which can bring devastating consequences to the mother and fetus. To define a high-resolution temporal profile of metabolites during healthy pregnancy, we analyzed the untargeted metabolome of 784 weekly blood samples from 30 pregnant women. Broad changes and a highly choreographed profile were revealed: 4,995 metabolic features (of 9,651 total), 460 annotated compounds (of 687 total), and 34 human metabolic pathways (of 48 total) were significantly changed during pregnancy. Using linear models, we built a metabolic clock with five metabolites that time gestational age in high accordance with ultrasound (R = 0.92). Furthermore, two to three metabolites can identify when labor occurs (time to delivery within two, four, and eight weeks, AUROC ≥ 0.85). Our study represents a weekly characterization of the human pregnancy metabolome, providing a high-resolution landscape for understanding pregnancy with potential clinical utilities., Competing Interests: Declaration of Interests M.S. is a co-founder and member of the scientific advisory boards of the following: Personalis, SensOmics, Filtricine, Qbio, January, Mirvie, and Oralome. He is a member of the scientific advisory board of Jungla. M.M. is a co-founder of Mirvie. L.L., M.S., and M.M. are inventors on the patent application PCT/US2019/052515 related to this work., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Outbreaks of communicable diseases in hospitals need to be quickly detected in order to enable immediate control. The increasing digitalization of hospital data processing offers potential solutions for automated outbreak detection systems (AODS). Our goal was to assess a newly developed AODS., Methods: Our AODS was based on the diagnostic results of routine clinical microbiological examinations. The system prospectively counted detections per bacterial pathogen over time for the years 2016 and 2017. The baseline data covers data from 2013-2015. The comparative analysis was based on six different mathematical algorithms (normal/Poisson and score prediction intervals, the early aberration reporting system, negative binomial CUSUMs, and the Farrington algorithm). The clusters automatically detected were then compared with the results of our manual outbreak detection system., Results: During the analysis period, 14 different hospital outbreaks were detected as a result of conventional manual outbreak detection. Based on the pathogens' overall incidence, outbreaks were divided into two categories: outbreaks with rarely detected pathogens (sporadic) and outbreaks with often detected pathogens (endemic). For outbreaks with sporadic pathogens, the detection rate of our AODS ranged from 83% to 100%. Every algorithm detected 6 of 7 outbreaks with a sporadic pathogen. The AODS identified outbreaks with an endemic pathogen were at a detection rate of 33% to 100%. For endemic pathogens, the results varied based on the epidemiological characteristics of each outbreak and pathogen., Conclusion: AODS for hospitals based on routine microbiological data is feasible and can provide relevant benefits for infection control teams. It offers in-time automated notification of suspected pathogen clusters especially for sporadically occurring pathogens. However, outbreaks of endemically detected pathogens need further individual pathogen-specific and setting-specific adjustments., Competing Interests: The authors have declared that no competing interests exist.

Background: Bloodstream infections (BSIs) are the most frequent nosocomial infections in neonatal intensive care units (NICUs), especially in very low birth weight (VLBW) infants (birth weight ≤ 1500g). An epidemiologic surveillance system may contribute to the prevention of infection by continuous monitoring of its frequency and associated risk factors. The aim of this article was to describe the implementation of the NeoKissEs surveillance system for BSIs in VLBW newborns in a group of Spanish NICUs., Methods: We assessed the clinical cohort consisting of all VLBW newborns aged less than 28 days admitted to the participating units. In the pilot phase, 2NICUs translated and adapted materials from the original German NEO-KISS system. During implementation, 210 health care professionals attended one of 8 educational workshops. A web-based system was created that allows entering data regarding patients and BSI episodes, data monitoring, benchmarking and providing feedback to the units. At each NICU, one neonatologist was responsible for the implementation of the system and reporting the difficulties perceived throughout the process., Results: Out of the 50 units that agreed to participate, 45 successfully started using the surveillance platform during the implementation phase, recording 1108 episodes of catheter-associated BSI (CABSI) in 3638 newborns, and finding an overall rate of CABSI of 18.4 (95% CI, 17.8-19.1) per 1000 catheter days., Conclusions: The NeoKissEs surveillance system constitutes a helpful source of information for the purpose of benchmarking the performance of neonatal units, assessing factors associated with BSI in VLBW infants and measuring the impact of future preventive interventions in NICUs., (Copyright © 2018 Asociación Española de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.)

Type 2 diabetes mellitus (T2D) is a growing health problem, but little is known about its early disease stages, its effects on biological processes or the transition to clinical T2D. To understand the earliest stages of T2D better, we obtained samples from 106 healthy individuals and individuals with prediabetes over approximately four years and performed deep profiling of transcriptomes, metabolomes, cytokines, and proteomes, as well as changes in the microbiome. This rich longitudinal data set revealed many insights: first, healthy profiles are distinct among individuals while displaying diverse patterns of intra- and/or inter-personal variability. Second, extensive host and microbial changes occur during respiratory viral infections and immunization, and immunization triggers potentially protective responses that are distinct from responses to respiratory viral infections. Moreover, during respiratory viral infections, insulin-resistant participants respond differently than insulin-sensitive participants. Third, global co-association analyses among the thousands of profiled molecules reveal specific host-microbe interactions that differ between insulin-resistant and insulin-sensitive individuals. Last, we identified early personal molecular signatures in one individual that preceded the onset of T2D, including the inflammation markers interleukin-1 receptor agonist (IL-1RA) and high-sensitivity C-reactive protein (CRP) paired with xenobiotic-induced immune signalling. Our study reveals insights into pathways and responses that differ between glucose-dysregulated and healthy individuals during health and disease and provides an open-access data resource to enable further research into healthy, prediabetic and T2D states.

Background: In 2011 and again in 2016, the European Centre for Disease Prevention and Control (ECDC) asked all European countries to carry out nationwide studies on the prevalence of nosocomial infection (NI) and antibiotic use (AU). Data on NI and AU constitute an essential basis for the development of measures to prevent infection and lessen antibiotic resistance., Methods: The German prevalence study of 2016 was carried out according to the ECDC protocol. Alongside a sample of 49 acute-care hospitals requested by the ECDC that was representative in terms of size (number of beds), further hospitals were invited to participate as well. Analyses were made of the overall group (218 hospitals, 64 412 patients), the representative group (49 hospitals), and the core group (46 hospitals). The core group consisted of the hospitals that had participated in the study of 2011., Results: The prevalence of patients with NI was 4.6% in the overall group in 2016; it had been 5.1% in 2011 (p <0.01). In the representative group, the prevalence was 3.6% (compared to 5.1% in 2011, p <0.01). In the core group, the prevalence of NI was the same in 2016 as it had been in 2011. The prevalence of patients with ABU in the overall group remained the same, but a fall was seen in the representative group (21.5% versus 23.3%; p <0.01) and a rise in the core group (27.3% versus 26.2%; p = 0.02). The staff-patient ratio among the infection prevention and control professionals improved in all three groups., Conclusion: A decrease in NI and AU prevalence was seen in the representative group, while mixed results were seen in the other analyzed groups. Further efforts to reduce NI and ABA are clearly necessary.

Background: Basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (CSCC) share exposure to UV light as the dominant risk factor, and these tumors therefore harbor high mutation burdens. In other malignancies, high mutation burden has been associated with clinical benefit from therapy with antibodies directed against the Programmed Death 1 (PD-1) immune checkpoint receptor. Highly mutated tumors are more likely to express immunogenic tumor neoantigens that attract effector T cells, which can be unleashed by blockade of the PD-1 immune checkpoint., Case Presentations: This report describes a patient with metastatic BCC and a patient with metastatic CSCC who were treated with REGN2810, a fully human anti-PD-1 monoclonal antibody, in an ongoing phase 1 trial (NCT02383212). The CSCC patient has experienced an ongoing complete response (16+ months), and the BCC patient has experienced an ongoing partial response (12+ months)., Conclusions: These case reports suggest that UV-associated skin cancers, beyond melanoma, are sensitive to PD-1 blockade., Trial Registration: Clinicaltrials.gov NCT02383212. Registered 2 February 2015.

OBJECTIVE To improve the patient safety of very-low-birthweight infants in neonatal departments in Germany. DESIGN Multicenter cohort study with a baseline (24 months), an intervention (12 months), and a postinterventional follow-up period (12 months) and time series analysis. STUDY POPULATION Very-low-birthweight patients from 32 neonatal departments in Germany. METHODS Neonatal departments showing a standardized infection ratio of bloodstream infection 10% higher than the expected number (standardized infection ratio ≥1.1) were invited to participate in the study. To reduce the occurrence of primary bloodstream infections, evidence-based bundles to improve catheter maintenance routines, insertion practice, and hand-hygiene compliance were implemented in the participating infirmaries. RESULTS Thirty-four departments participated in the study and 32 reported data. In total, 6,222 very-low-birthweight infants with 231,868 patient-days and 1,405 cases of bloodstream infections were analyzed. In the baseline period the pooled mean bloodstream infection rate was 6.63 (95% CI, 6.17-7.12) per 1,000 patient-days. The bloodstream infection rate decreased in the intervention period to 5.68 (relative risk, 0.86 [95% CI, 0.76-0.97]) and in the 1-year follow-up period to 5.31 per 1,000 patient-days (relative risk, 0.80 [95% CI, 0.70-0.92]). The multivariable time series analysis of monthly aggregated data showed a significant change in the slope for the frequency of bloodstream infections from the start to the end of the intervention (change in slope incidence rate ratio, 0.97; P=.001). CONCLUSION The implementation of an intervention bundle is feasible and can reduce bloodstream infections in neonatal departments. Infect Control Hosp Epidemiol 2016;37:798-804.

Objective: To determine the effect of dual-strain probiotics on the development of necrotizing enterocolitis (NEC), mortality and nosocomial bloodstream infections (BSI) in preterm infants in German neonatal intensive care units (NICUs)., Design: A multi-center interrupted time series analysis., Setting: 44 German NICUs with routine use of dual-strain probiotics on neonatal ward level., Patients: Preterm infants documented by NEO-KISS, the German surveillance system for nosocomial infections in preterm infants with birth weights below 1,500 g, between 2004 and 2014., Intervention: Routine use of dual-strain probiotics containing Lactobacillus acidophilus and Bifidobacterium spp. (Infloran) on the neonatal ward level., Main Outcome Measures: Incidences of NEC, overall mortality, mortality following NEC and nosocomial BSI., Results: Data from 10,890 preterm infants in 44 neonatal wards was included in this study. Incidences of NEC and BSI were 2.5% (n = 274) and 15.0%, (n = 1631), respectively. Mortality rate was 6.1% (n = 665). The use of dual-strain probiotics significantly reduced the risk of NEC (HR = 0.48; 95% CI = 0.38-0.62), overall mortality (HR = 0.60, 95% CI = 0.44-0.83), mortality after NEC (HR = 0.51, 95% CI = 0.26-0.999) and nosocomial BSI (HR = 0.89, 95% CI = 0.81-0.98). These effects were even more pronounced in the subgroup analysis of preterm infants with birth weights below 1,000 g., Conclusion: In order to reduce NEC and mortality in preterm infants, it is advisable to add routine prophylaxis with dual-strain probiotics to clinical practice in neonatal wards.

Background and Objectives: Nosocomial infections in NICUs tend to cluster, sometimes as devastating outbreaks, but pathogen-specific transmission probabilities are unknown. We aimed to quantify the pathogen-specific risk of a blood stream infection (BSI) in preterm infants after an index case with that pathogen in the same department., Methods: Data of 44 818 infants below 1500 g birth weight of the German NICU surveillance system (2000-2011) were used to calculate the probability of a BSI in the presence or absence of another infant in the same unit with a same-pathogen BSI., Results: The relative risk was similar for the more common pathogens, Enterococcus spp (4.3; 95% confidence interval: 2.7-6.9; n = 243), Enterobacter spp (7.9, 5.4-11.4; n = 246), Escherichia coli (7.9; 5.1-12.1; n = 210), Candida albicans (8.7; 5.0-15.4; n = 138), Staphylococcus aureus (9.5; 7.6-12.1; n = 407) and Klebsiella spp (13.1; 9.0-19.1; n = 190) but markedly elevated for Serratia spp (77.5; 41.1-146.1; n = 58) and Pseudomonas aeruginosa (64.5; 25.7-162.1; n = 38). Rates of BSI per 100 exposed infants ranged between 2.21 (Enterococcus) and 8.15 (Serratia). The same pattern emerged after adjustments were made for patients' characteristics or when the analysis was restricted to positive blood cultures during the preceding 30 days., Conclusions: Although BSIs with P aeruginosa or Serratia spp in preterm infants are rare, they are associated with a markedly elevated risk of secondary same-pathogen BSI and should prompt intensified active surveillance and infection control measures., (Copyright © 2016 by the American Academy of Pediatrics.)

Background: Carbapenemase-producing Enterobacteriaceae (CPE) have become a major problem for healthcare systems worldwide. While the first reports from European hospitals described the introduction of CPE from endemic countries, there is now a growing number of reports describing outbreaks of CPE in European hospitals. Here we report an outbreak of Carbapenem-resistant K. pneumoniae in a German University hospital which was in part associated to duodenoscopy., Findings: Between December 6, 2012 and January 10, 2013, carbapenem-resistant K. pneumoniae (CRKP) was cultured from 12 patients staying on 4 different wards. The amplification of carbapenemase genes by multiplex PCR showed presence of the bla OXA-48 gene. Molecular typing confirmed the identity of all 12 isolates. Reviewing the medical records of CRKP cases revealed that there was a spatial relationship between 6 of the cases which were located on the same wards. The remaining 6 cases were all related to endoscopic retrograde cholangiopancreatography (ERCP) which was performed with the same duodenoscope. The outbreak ended after the endoscope was sent to the manufacturer for maintenance., Conclusions: Though the outbreak strain was also disseminated to patients who did not undergo ERCP and environmental sources or medical personnel also contributed to the outbreak, the gut of colonized patients is the main source for CPE. Therefore, accurate and stringent reprocessing of endoscopic instruments is extremely important, which is especially true for more complex instruments like the duodenoscope (TJF Q180V series) involved in the outbreak described here.

Background: We evaluated the mortality due to nosocomial bloodstream infection (BSI) and necrotizing enterocolitis (NEC) in very low birth weight (VLBW) infants in 229 neonatal departments participating in the German national neonatal infection surveillance system between 2000 and 2011., Methods: For each infection type, we conducted a retrospective cohort study and a case-control study. In the cohort studies, the mortality risk due to BSI and/or NEC was estimated by calculating adjusted hazard ratios (AHRs) with 95% confidence intervals (CIs) using Cox proportional hazard regression with time the dependent variable infection. In the matched case-control studies, the attributable mortality was calculated., Results: A total of 43,116 VLBW infants, of which 6911 patients had at least 1 BSI and 1271 patients had at least 1 NEC, were analyzed. Overall mortality was 6.6%. Patients with at least 1 BSI had a mortality of 5.6%, and patients with at least 1 NEC had a mortality of 19.2%. The cohort studies revealed that BSI (AHR=1.83; 95% CI: 1.61-2.08) and NEC (AHR=6.35; 95% CI: 5.47-7.37) are independently associated with increased mortality. In the case-control study for BSI, 5187 (75.1%) patients with BSI were matched. Attributable mortality was 1.4% (95% CI: 0.7-2.2). In the case-control study for NEC, 1092 (85.9%) patients with NEC were matched. Attributable mortality was 14.7% (95% CI: 12.2-17.1)., Conclusions: Nosocomial BSI and NEC increased mortality in VLBW infants. BSI, however, was associated with a relatively small attributable mortality of 1.4%, whereas NEC had a high attributable mortality of 14.7%.

Objectives: This study aimed to determine the prevalence of and risk factors for colonization with extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-E) and methicillin-resistant Staphylococcus aureus (MRSA) in very low birth weight (VLBW; <1500 g) infants and their mothers., Methods: This investigation was conducted in the perinatal centre at the Charité Berlin between May 2012 and June 2013. VLBW infants and their mothers were screened for colonization with ESBL-E and MRSA. Demographic and clinical data were obtained from the German nationwide surveillance system for nosocomial infections in VLBW infants (NEO-KISS) and used to perform univariate and multivariate analyses., Results: Of 209 VLBW infants, 12 (5.7%) were colonized with ESBL-E. Eighteen of 209 (8.6%) ESBL-E-tested neonates were related to an ESBL-E-positive mother. Univariate analysis, strain typing and multivariate analysis (OR 7.4, 95% CI 2.1-26.7, P = 0.002) identified an ESBL-E-positive mother and maternal-neonatal transmission as a main source of colonization. The prevalence of MRSA was 2.3% (5 of 221) among VLBW infants. One of the 221 (0.5%) MRSA-tested neonates was related to an MRSA-positive mother. No risk factors for transmission of MRSA could be detected in this study., Conclusions: Our study demonstrated that maternal-neonatal transmission of ESBL-E from mother to child is an important risk factor for colonization of VLBW infants. As a consequence, routine ESBL-E screening of neonates and mothers should be considered as a means of reducing neonatal morbidity and mortality., (© The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: In 2011, seventeen years after the first national study on the prevalence of nosocomial infections and antibiotic use in German hospitals, a second national prevalence study was carried out according to the specifications of the European Centre for Disease Prevention and Control (ECDC)., Methods: The ECDC protocol, containing uniform surveillance definitions and ascertainment methods, was implemented. The only infections counted were those that were active or under treatment with antibiotics on the day of the study. In addition to the representative sample required by the ECDC, which consisted of 46 hospitals, further hospitals participated on a voluntary basis., Results: Data on 41 539 patients in 132 hospitals were analyzed. The prevalence of infections that had arisen during the current hospital stay was 3.8% in the overall group and 3.4% in the representative sample of 9626 patients in 46 hospitals. The prevalence of all nosocomial infections, including those acquired before the current hospital stay and still present upon admission, was 5.1% in both the overall group and the representative sample. The prevalence of antibiotic use on the day of the study was 25.5% and 23.3% in the two groups, respectively., Conclusion: The prevalence of nosocomial infection has not changed since 1994, but the prevalence of antibiotic use has increased. In interpreting these findings, one should bear in mind that confounders may have influenced them in different directions: The mean length of hospital stay is now shorter than in 1994, but the mean age of hospitalized patients is higher.

Background: Very low birthweight (VLBW) newborns on neonatal intensive care units (NICU) are at increased risk for developing central venous catheter-associated bloodstream infections (CVC BSI). In addition to the established intrinsic risk factors of VLBW newborns, it is still not clear which process and structure parameters within NICUs influence the prevalence of CVC BSI., Methods: The study population consisted of VLBW newborns from NICUs that participated in the German nosocomial infection surveillance system for preterm infants (NEO-KISS) from January 2008 to June 2009. Structure and process parameters of NICUs were obtained by a questionnaire-based enquiry. Patient based date and the occurrence of BSI derived from the NEO-KISS database. The association between the requested parameters and the occurrance of CVC BSI and laboratory-confirmed BSI was analyzed by generalized estimating equations., Results: We analyzed data on 5,586 VLBW infants from 108 NICUs and found 954 BSI cases in 847 infants. Of all BSI cases, 414 (43%) were CVC-associated. The pooled incidence density of CVC BSI was 8.3 per 1,000 CVC days. The pooled CVC utilization ratio was 24.3 CVC-days per 100 patient days. A low realized staffing rate lead to an increased risk of CVC BSI (OR 1.47; p=0.008) and also of laboratory-confirmed CVC BSI (OR 1.78; p=0.028)., Conclusions: Our findings show that low levels of realized staffing are associated with increased rates of CVC BSI on NICUs. Further studies are necessary to determine a threshold that should not be undercut.

Background: Methicillin-resistant Staphylococcus aureus (MRSA) may cause prolonged outbreaks of infections in neonatal intensive care units (NICUs). While the specific factors favouring MRSA spread on neonatal wards are not well understood, colonized infants, their relatives, or health-care workers may all be sources for MRSA transmission. Whole-genome sequencing may provide a new tool for elucidating transmission pathways of MRSA at a local scale., Methods and Findings: We applied whole-genome sequencing to trace MRSA spread in a NICU and performed a case-control study to identify risk factors for MRSA transmission. MRSA genomes had accumulated sequence variation sufficiently fast to reflect epidemiological linkage among individual patients, between infants and their mothers, and between infants and staff members, such that the relevance of individual nurses' nasal MRSA colonization for prolonged transmission could be evaluated. In addition to confirming previously reported risk factors, we identified an increased risk of transmission from infants with as yet unknown MRSA colonisation, in contrast to known MRSA-positive infants., Conclusions: The integration of epidemiological (temporal, spatial) and genomic data enabled the phylogenetic testing of several hypotheses on specific MRSA transmission routes within a neonatal intensive-care unit. The pronounced risk of transmission emanating from undetected MRSA carriers suggested that increasing the frequency or speed of microbiological diagnostics could help to reduce transmission of MRSA.

Surveillance of nosocomial infections is meanwhile a cornerstone of infection prevention activities in hospitals. The objective of this article is to compare healthcare-associated infection rates in intensive care patients, neonatal intensive care patients and operated patients (ICU-KISS, OP-KISS, NEO-KISS) of the German nosocomial infection surveillance system (KISS) with the corresponding data of the US American National Healthcare Safety Network (NHSN) and the European Centre for Disease Prevention and Control (ECDC). In general, the methodological differences among the three surveillance systems are minor but there are some exceptions. Therefore, differences between countries have to be interpreted very carefully as they may be due to differences in diagnostics, patient mix, types of interventions, length of stay, selection of participating hospitals, post-discharge surveillance activities and interpretation of case definitions. Organizational aspects, such as mandatory participation with public disclosure on infection rates may also have an impact.

Background: The German national nosocomial infection surveillance system, KISS, has a component for very low birth weight (VLBW) infants (called NEO-KISS) which changed from a system with voluntary participation and confidential data feedback to a system with mandatory participation and confidential feedback., Methods: In order to compare voluntary and mandatory surveillance data, two groups were defined by the surveillance start date. Neonatal intensive care unit (NICU) parameters and infection rates of the NICUs in both groups were compared. In order to analyze the surveillance effect on primary bloodstream infection rates (BSI), all VLBW infants within the first three years of participation in both groups were considered. The adjusted effect measures for the year of participation were calculated., Results: An increase from 49 NICUs participating in 2005 to 152 in 2006 was observed after the introduction of mandatory participation. A total of 4280 VLBW infants was included in this analysis. Healthcare-associated incidence densities rates were similar in both groups. Using multivariate analysis with the endpoint primary BSI rate and comparing the first and third year of participation lead to an adjusted incidence rate ratio (IRR) of 0.78 (CI95 0.66-0.93) for old (voluntary) and 0.81 (CI95 0.68-0.97) for new (mandatory) participants., Conclusions: The step from a voluntary to a mandatory HCAI surveillance system alone may lead to substantial improvements on a countrywide scale.

Background: NEO-KISS is a national surveillance system generating reference data for nosocomial infections among very low birth weight infants (VLBW) and was established 2000 as a voluntary based system. Since 2006 exist an official decision that participation in NEO-KISS is a prerequisite for the care of VLBW at level III NICUs in Germany., Method: Comparing the reference data before and after the resolution and analysing the structure and the infection rates between the departments participating since 2006 (new-departments) and the neonatology departments participating voluntary before 2006 (old-departments)., Results: Since 2006 the number of participating departments increased clarion. The characteristic of the 110 new-departments differs from the 46 old-departments in many ways. The old-departments treated more VLBW per month, have more beds and are located at larger hospitals. The distribution of the treated VLBW shows a trend to lower birth-weights in the old-departments. However, the comparison of the reference data 2005, generated only from data from old-departments, shows no systematic changes to the reference data 2006 (including data from numerous new-departments). Also the comparison of the infection rates from for an identical time period separated for new and old-departments shows only minor differences., Conclusion: The inclusion of many new departments in NEO-KISS shows no influence to the reference data. And also the comparison of infection rates between new and old-departments shows no systematic discrepancy. It follows the unnecessary of separating the data from old-departments and new-departments and the appropriateness of the entire databank to generate the national reference data.

Mass spectrometry-based proteomics holds great promise as a discovery tool for biomarker candidates in the early detection of diseases. Recently much emphasis has been placed upon producing highly reliable data for quantitative profiling for which highly reproducible methodologies are indispensable. The main problems that affect experimental reproducibility stem from variations introduced by sample collection, preparation, and storage protocols and LC-MS settings and conditions. On the basis of a formally precise and quantitative definition of similarity between LC-MS experiments, we have developed Chaorder, a fully automatic software tool that can assess experimental reproducibility of sets of large scale LC-MS experiments. By visualizing the similarity relationships within a set of experiments, this tool can form the basis of systematic quality control and thus help assess the comparability of mass spectrometry data over time, across different laboratories, and between instruments. Applying Chaorder to data from multiple laboratories and a range of instruments, experimental protocols, and sample complexities revealed biases introduced by the sample processing steps, experimental protocols, and instrument choices. Moreover we show that reducing bias by correcting for just a few steps, for example randomizing the run order, does not provide much gain in statistical power for biomarker discovery.