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Current market developments, such as intensifying volatility and rising demand for individualized products, require highly flexible and adaptable production systems. Reconfigurable production systems enable manufacturing companies to meet these market developments due to the ability of short-term scalability of capacities and order-specific adjustments of production resources for preserving high delivery performance and utilization rate. The vast complexity of such systems raises the demand for decision support systems. Therefore, this paper presents an innovative approach combining optimization and material flow simulation for developing and selecting optimized reconfiguration scenarios. A prototypical application is presented to demonstrate the feasibility of the approach.

The amount of data generated in production systems increases continuously due to the integration of cyber-physical systems and additional sensors. This data contains potentially useful knowledge that can be used to improve production processes and product quality. Machine learning algorithms offer the potential of improvements for quality assurance. However, companies often do not have the necessary know-how to extract this knowledge. This publication therefore presents a service-based system for optical quality assurance using machine learning algorithms. The intelligent cloud service is tested and validated by an industrial use case for transparent injection molded parts.

Interleukin-34 (IL-34) is a ligand for the CSF-1R and has also two additional receptors, PTPRZ1 and syndecan-1. IL-34 plays a role in innate immunity, inflammation, and cancer. However, the role of IL-34 in breast cancer is still ill-defined. We analyzed IL-34 mRNA expression in breast cancer cell lines and breast cancer patients and applied established computational approaches (CIBERSORT, ESTIMATE, TIMER, TCIA), to analyze gene expression data from The Cancer Genome Atlas (TCGA). Expression of IL-34 was associated with a favorable prognosis in luminal and HER2 but not basal breast cancer patients. Gene expression of CSF-1 and CSF-1R was strongly associated with myeloid cell infiltration, while we found no or only weak correlations between IL-34, PTPRZ1, syndecan-1 and myeloid cells. In vitro experiments showed that tyrosine phosphorylation of CSF-1R, ERK, and FAK and cell migration are differentially regulated by IL-34 and CSF-1 in breast cancer cell lines. Collectively, our data suggest that correlation of IL-34 gene expression with survival is dependent on the molecular breast cancer subtype. Furthermore, IL-34 is not associated with myeloid cell infiltration and directly regulates breast cancer cell migration and signaling.

Genetic variants in CYP19A1, the gene encoding aromatase, have been reported to be associated with circulating estrogen concentrations, a key risk factor for breast cancer. The mechanism underlying this association is still unclear; it has been suggested that some of these variants may alter the expression and/or activity of aromatase. Here we analyzed the expression of intra-tumoral CYP19A1 messenger RNA (mRNA) and the genotypes of rs10046, a well-characterized single nucleotide polymorphism in CYP19A1, in 138 breast cancer patients and 15 breast cancer cell lines. The genotype TT was detected in 36 patients and six cell lines, genotype CT in 55 patients and five cell lines, and genotype CC in 28 patients and four cell lines. We found no evidence for a significant association of CYP19A1 levels with rs10046 genotypes, although expression tended to be higher in tumors and cell lines with the homozygous risk genotype TT. We also found no evidence for a significant association of rs10046 genotypes with breast cancer prognosis. In contrast, high CYP19A1 expression was highly significantly associated with a poor overall, disease-free, and metastasis-free survival in estrogen receptor-positive but not negative breast cancer patients. Moreover, CYP19A1 mRNA was significantly elevated in postmenopausal patients and in patients older than 50 years, and a trend towards a positive correlation with ER status and ESR1 mRNA expression was observed. These findings highlight the key role of aromatase in estrogen receptor-positive breast cancer biology. Electronic supplementary material The online version of this article (10.1007/s12672-017-0317-2) contains supplementary material, which is available to authorized users.

Zunehmende Anforderungen an die Anlagenzuverlässigkeit und -verfügbarkeit führen zu einer immer höheren Bedeutung von Predictive Maintenance Tools. Herkömmliche Fertigungsressourcen sind jedoch nicht mit einer ausreichenden Anzahl von Sensoren ausgestattet, um den Maschinenzustand zu überwachen und notwendige Instandhaltungsleistungen vorherzusagen. Dieser Beitrag stellt ein Vorgehen zur Integration zusätzlicher Sensoren in bestehende Fertigungsressourcen für Predictive-Maintenance-Werkzeuge vor. Increasing requirements for machine reliability and availability lead to an increased importance of predictive maintenance tools. How-ever, conventional manufacturing resources are not equipped with a sufficient number of sensors to monitor the machine condition and predict necessary maintenance measures. This paper presents a procedure for integrating additional sensors into existing manufacturing resources for predictive maintenance tools.

We summarize the current understanding of the physiology of the renal handling of potassium (K+), and present an integrative view of the renal response to K+ depletion caused by dietary K+ restriction. This renal response involves contributions from different nephron segments, and aims to diminish the rate of excretion of K+ as a result of: decreasing the rate of electrogenic (and increasing the rate of electroneutral) reabsorption of sodium in the aldosterone-sensitive distal nephron (ASDN), decreasing the abundance of renal outer medullary K+ channels in the luminal membrane of principal cells in the ASDN, decreasing the flow rate in the ASDN, and increasing the reabsorption of K+ in the cortical and medullary collecting ducts. The implications of this physiology for the association between K+ depletion and hypertension, and K+ depletion and formation of calcium kidney stones are discussed.

Background:Peritoneal dialysis (PD)-associated peritonitis carries significant morbidity, mortality, and is a leading cause of PD technique failure. This study aimed to assess the scope and variability of PD-associated peritonitis reported in randomized trials and observational studies.Methods:Cochrane Controlled Register of Trials, MEDLINE, and Embase were searched from 2007 to June 2018 for randomized trials and observational studies in adult and pediatric patients on PD that reported PD-associated peritonitis as a primary outcome or as a part of composite primary outcome. We assessed the peritonitis definitions used, characteristics of peritonitis, and outcome reporting and analysis.Results:Seventy-seven studies were included, three were randomized trials. Thirty-eight (49%) of the included studies were registry-based observational studies. Twenty-nine percent ( n = 22) of the studies did not specify how PD-associated peritonitis was defined. Among those providing a definition of peritonitis, three components were reported: effluent cell count ( n = 42, 54%), clinical features consistent with peritonitis (e.g. abdominal pain and/or cloudy dialysis effluent) ( n = 35, 45%), and positive effluent culture ( n = 19, 25%). Of those components, 1 was required to make the diagnosis in 6 studies (8%), 2 out of 2 were required in 22 studies (29%), 2 out of 3 in 11 studies (14%), and 3 out of 3 in 4 studies (5%). Peritonitis characteristics and outcomes reported across studies included culture-negative peritonitis ( n = 47, 61%), refractory peritonitis ( n = 42, 55%), repeat peritonitis ( n = 9, 12%), relapsing peritonitis ( n = 5, 7%), concomitant exit site ( n = 16, 21%), and tunnel infections ( n = 8, 10%). Peritonitis-related hospitalization was reported in 38% of the studies ( n = 29), and peritonitis-related mortality was variably defined and reported in 55% of the studies ( n = 42). Peritonitis rate was most frequently reported as episodes per patient year ( n = 40, 52%).Conclusion:Large variability exists in the definitions, methods of reporting, and analysis of PD-associated peritonitis across trials and observational studies. Standardizing definitions for reporting of peritonitis and associated outcomes will better enable assessment of the comparative effect of interventions on peritonitis. This will facilitate continuous quality improvement measures through reliable benchmarking of this patient-important outcome across centers and countries.

Worldwide, only 10% of the approximately 1.7 million patients on dialysis are treated with home-based peritoneal dialysis (PD); the majority receive facility-based hemodialysis (HD), although most patients prefer PD when educated about their options ([1][1]). There is substantial geographic

Background SAPHO syndrome has to be considered as a rare subtype of seronegative spondyloarthritis (SpA) showing typical manifestations with palmoplantar pustolosis and osteitis with hyperostosis; the clinical response of conventional or biological disease modifying drugs (DMARDs) in SAPHO syndrome are often disappointing. Whereas in SpA peripheral arthritis and inflammatory back pain represent the leading symptoms, the SAPHO patients often complain painful osteitis with hyperostosis in the sternal region as well as the palmoplantar pustulosis accompanied by synovitis preferentially in large joints including sacroiliitis. Recently, the detection of higher numbers of CD4+IL17+ lymphocytes in the peripheral blood of SAPHO patients has arisen the hypothesis that Th4/17 helper cells with their secretion of interleukin 17 (IL17) could be involved in the development of inflammation in SAPHO syndrome (1) Objectives Here we present an observational study of 12 SAPHO patients which were treated with the IL 17 blocking agent secukinumab. In addition, the fraction of CD4/17+ lymphocytes in peripheral blood specimen has been monitored on treatment. Methods Between January 2015 and February 2017 clinical activity of disease were measured in 37 SAPHO patients with a disease duration of 11 years (median). The disease activity were evaluated by the osteitis score and skin score (ranging from 0 to 6, assessed by physician), the HAQ score (ranging from 0 to 3, assessed by patient), and MRI of the osteitis lesion (activity score 0-3, analogously to 3 domains of OMERACT RAMRIS scoring synovitis, bone marrow edema, and erosions; assessed by radiologist). In this period of time 12 of them showed disease activity due to osteitis and/or skin disease, at which time the treatment of secukinumab at dosage of 300mg as monotherapy has been started, re-evaluated after at least 12 weeks (ranging from 12 to 18 weeks). For monitoring blood specimens were derived to assess the CD4+/IL17+ lymphocyte subpopulation using immunofluorescence technique commercial antibodies for CD4, IL17 (Boehringer Ingelheim, Germany). To analyse the differences between the disease activity scores prior to secukinumab treatment and after treatment we applied the nonparametric analysis according to Wilcoxon test. The p-value Results Secukinumab improved osteitis and palmoplantar pustolosis (osteitis score 3.8 to 2.4; p=0.007; PPP 3.4 to 2.4; p=0.071), the HAQ score was reduced from 1.25 to 1.0 (p=0.018), the MRI score from 2.08 to 1.58 (p=0.034). The reduction of at least two clinical activity parameters (osteitis, HAQ and/or MRI) after secukinumab treatment could be documented in all SAPHO patients who showed CD4+IL17+ lymphocytes in higher frequency of 0.4% of leukocytes of peripheral blood. Conclusion Secukinumab seems to control osteitis and PPP in SAPHO syndrome resulting in reduced burden of disease. High Th17 lymphocytes numbers seems to be associated with higher probability of clinical response to secukinumab. Reference: [1] Firinu D, Barca MP, Lorrai MM, Perra S, Cabras S, Muggianu E, Di Martino ML, Manconi PE, Del Giacco SR. TH17 cells are increased in the peripheral blood of patients with SAPHO syndrome. Autoimmunity. 2014Sep;47(6):389-94 Disclosure of Interests None declared

Kurzfassung Die Komplexität heutiger industrieller Produktionsprozesse zieht viele unbekannte gegenseitige Abhängigkeiten und Wechselwirkungen zwischen den Komponenten nach sich. Die Beherrschung dieser Komplexität obliegt oftmals einzelnen Experten. Demgegenüber führt der Einsatz von Sensorik insgesamt zu einem hohen Aufkommen von Daten. Hieraus ergibt sich ein hohes, bislang ungenutztes Potenzial. Das Forschungsprojekt OpenServ4P entwickelt hierzu eine internetbasierte Plattform, von der aus verschiedene Werkzeuge „as a service“ abgerufen werden können.

Diabetic ketoacidosis (DKA), a common cause of severe metabolic acidosis, remains a life-threatening condition due to complications of both the disease and its treatment. This Acid-Base and Electrolyte Teaching Case discusses DKA management, emphasizing complications of treatment. Because cerebral edema is the most common cause of mortality and morbidity, especially in children with DKA, we emphasize its pathophysiology and implications for therapy. The risk for cerebral edema may be minimized by avoiding a bolus of insulin, excessive saline resuscitation, and a decrease in effective plasma osmolality early in treatment. A goal of fluid therapy is to lower muscle venous Pco 2 to ensure effective removal of hydrogen ions by bicarbonate buffer in muscle and diminish the binding of hydrogen ions to intracellular proteins in vital organs (such as the brain). In patients with DKA and a relatively low plasma potassium level, insulin administration may cause hypokalemia and cardiac arrhythmias. It is suggested in these cases to temporarily delay insulin administration and first administer potassium chloride intravenously to bring the plasma potassium level close to 4mmol/L. Sodium bicarbonate administration in adult patients should be individualized. We suggest it be considered in a subset of patients with moderately severe acidemia (pH

Context While medical curricula were traditionally almost entirely comprised of bioscientific knowledge, widely accepted competency frameworks now make clear that physicians must be competent in far more than biomedical knowledge and technical skills. For example, of the influential CanMEDS roles, six are conceptually based in the social sciences and humanities (SSH). Educators frequently express uncertainty about what to teach in this area. This study concretely identifies the knowledge beyond bioscience needed to support the training of physicians competent in the six non-Medical Expert CanMEDS roles. Methods We interviewed 58 non-clinician university faculty members with doctorates in over 20 SSH disciplines. We abstracted our transcripts (meaning condensation, direct quotations) resulting in approximately 300 pages of data which we coded using top-down (by CanMEDS role) and bottom-up (thematically) approaches and analysed within a critical constructivist framework. Participants and clinicians with SSH PhDs member-checked and refined our results. Results Twelve interrelated themes were evident in the data. An understanding of epistemology, including the constructed nature of social knowledge, was seen as the foundational theme without which the others could not be taught or understood. Our findings highlighted three anchoring themes (Justice, Power, Culture), all of which link to eight more specific themes concerning future physicians’ relationships to the world and the self. All 12 themes were cross-cutting, in that each related to all six non-Medical Expert CanMEDS roles. The data also provided many concrete examples of potential curricular content. Conclusions There is a definable body of SSH knowledge that forms the academic underpinning for important physician competencies and is outside the experience of most medical educators. Curricular change incorporating such content is necessary if we are to strengthen the non-Medical Expert physician competencies. Our findings, particularly our cross-cutting themes, also provide a pedagogically useful mechanism for holistically teaching the underpinnings of physician competence. We are now implementing our findings into medical curricula.

SNP309T&gt, G (rs2279744) and SNP285G&gt, C (rs117039649) in the MDM2 promoter are thought to have opposite effects on the binding of transcription factor SP1 (specificity protein 1), and consequently on MDM2 expression, p53 levels, cancer risk, age at onset, and prognosis. Here, we genotyped SNP309 and SNP285 in 406 Austrian breast cancer patients and 254 female controls. The SNP309GG genotype was associated with an increased breast cancer risk in p53 negative (OR, 1.82, 95% CI, 1.09&ndash, 3.03, p = 0.02), but not p53 positive or unselected patients. In contrast, the SNP309TT genotype was associated with an earlier age at onset (TT, 57.0 &plusmn, 12.9, TG, 58.6 &plusmn, 13.9, GG, 59.7 &plusmn, 15.0 years, p = 0.048). 31% of SNP309TT, 26% of TG, and 13% of GG tumors were p53 positive (p = 0.034), indicating a lower selective pressure to mutate TP53 in the presence of the G-allele. Moreover, SNP309TT patients exhibited a shortened metastasis-free survival in multivariable analysis. Censoring carriers of the SNP285C-allele hardly altered the strength of these associations of SNP309, thus challenging the proposed antagonistic function of SNP285C towards SNP309G. The minor SNP285C-allele tended to be non-significantly associated with an increased breast cancer risk and a poor disease-free and metastasis-free survival, which may be bystander effects of its complete linkage disequilibrium with SNP309G. We conclude that the SNP309G-allele attenuates the p53-response and leads to a higher breast cancer risk, but also to a later onset of breast cancer and a trend towards a good prognosis.

Rising production costs and efficiency requirements are challenges for manufacturing companies. One possibility to cope with these challenges is to improve maintenance efficiency and effectiveness by integrating predictive maintenance tools into cyber-physical production systems. However, the integration of these tool information into production and maintenance planning systems in order to determine necessary maintenance tasks is one of the main challenges for manufacturing companies. Therefore, this paper presents an innovative system for an effective integrated production and maintenance planning in complex cyber-physical production systems using multi-criteria decision-making. A prototypical application is presented to demonstrate the feasibility of the approach.

With the stagnation of processor core performance, further reductions in the time-to-solution for geophysical fluid problems are becoming increasingly difficult with standard time integrators. Parallel-in-time exposes and exploits additional parallelism in the time dimension which is inherently sequential in traditional methods. The rational approximation of exponential integrators (REXI) method allows taking arbitrarily long time steps based on a sum over a number of decoupled complex PDEs that can be solved independently massively parallel. Hence REXI is assumed to be well suited for modern massively parallel super computers which are currently trending. To date the study and development of the REXI approach has been limited to linearized problems on the periodic 2D plane. This work extends the REXI time stepping method to the linear shallow-water equations (SWE) on the rotating sphere, thus moving the method one step closer to solving fully nonlinear fluid problems of geophysical interest on the sphere. The rotating sphere poses particular challenges for finding an efficient solver due to the zonal dependence of the Coriolis term. Here we present an efficient REXI solver based on spherical harmonics, showing the results of: a geostrophic balance test, a comparison with alternative time stepping methods, an analysis of dispersion relations, indicating superior properties of REXI, and finally a performance comparison on Cheyenne supercomputer. Our results indicate that REXI is not only able to take larger time steps, but that REXI can also be used to gain higher accuracy and significantly reduced time-to-solution compared to currently existing time stepping methods.

Background The optimal treatment for managing anemia in peritoneal dialysis (PD) patients and best clinical practices are not completely understood. We sought to characterize international variations in anemia measures and management among PD patients. Methods The Peritoneal Dialysis Outcomes and Practice Patterns Study (PDOPPS) enrolled adult PD patients from 6 countries from 2014 to 2017. Hemoglobin (Hb), ferritin levels, and transferrin saturation (TSAT), as well as erythropoiesis stimulating agents (ESAs) and iron use were compared cross-sectionally at study enrollment in Australia and New Zealand (A/NZ), Canada, Japan, the United Kingdom (UK), and the United States (US). Results Among 3,603 PD patients from 193 facilities, mean Hb ranged from 11.0 – 11.3 g/dL across countries. The majority of patients (range 53% – 59%) had Hb 10 – 11.9 g/dL, with 4% – 12% patients ≥ 13 g/dL and 16% – 23% < 10 g/dL. Use of ESAs was higher in Japan (94% of patients) than elsewhere (66% – 79% of patients). In the US, 63% of patients had a ferritin level > 500 ng/mL, compared with 5% – 38% in other countries. In the US and Japan, 87% – 89% of PD patients had TSAT ≥ 20%, compared with 73% – 76% in other countries. Intravenous (IV) iron use within 4 months of enrollment was higher in the US (55% of patients) than elsewhere (6% – 17% patients). Conclusions In this largest international observational study of anemia and anemia management in patients receiving PD, comparable Hb levels across countries were observed but with notable differences in ESA and iron use. Peritoneal dialysis patients in the US have higher ferritin levels and higher IV iron use than other countries.

As with all areas of medicine, high-quality clinical research is essential to improving the care of trauma patients. This research is crucial in developing evidence-based treatments that decrease cost, decrease morbidity, and improve mortality. Trauma continues to extract a significant toll on society and is the single largest cause of years of life lost in the United States. The need to conduct high-quality clinical research in trauma is not disputed. However, significant challenges and barriers unique to the field of trauma make performing this research more difficult. It is critical to be aware of these challenges and barriers to performing clinical research involving trauma patients so these challenges can be accounted for and solutions implemented to minimize their impact on research. This review will focus on the barriers and challenges that are encountered while performing clinical research in trauma.

Home dialysis therapy, including home hemodialysis and peritoneal dialysis, is underused as a modality for the treatment of chronic kidney failure. The National Kidney Foundation–Kidney Disease Outcomes Quality Initiative sponsored a home dialysis conference in late 2017 that was designed to identify the barriers to starting and maintaining patients on home dialysis therapy. Clinical, operational, policy, and societal barriers were identified that need to be overcome to ensure that dialysis patients have the freedom to choose their treatment modality. Education of patients and patient partners, as well as health care providers, about home dialysis therapy, if offered at all, is often provided in a cursory manner. Lack of exposure to home dialysis therapies perpetuates a lack of familiarity and thus a hesitancy to refer patients to home dialysis therapies. Patient and care partner support, both psychosocial and financial, is also critical to minimize the risk for burnout leading to dropout from a home dialysis modality. Thus, the facilitation of home dialysis therapy will require a systematic change in chronic kidney disease education and the approach to dialysis therapy initiation, the creation of additional incentives for performing home dialysis, and breakthroughs to simplify the performance of home dialysis modalities. The home dialysis work group plans to develop strategies to overcome these barriers to home dialysis therapy, which will be presented at a follow-up home dialysis conference.

© 2018 Elsevier Inc. Efficient time integration schemes are necessary to capture the complex processes involved in atmospheric flows over long periods of time. In this work, we propose a high-order, implicit–explicit numerical scheme that combines Multi-Level Spectral Deferred Corrections (MLSDC) and the Spherical Harmonics (SH) transform to solve the wave-propagation problems arising from the shallow-water equations on the rotating sphere. The iterative temporal integration is based on a sequence of corrections distributed on coupled space–time levels to perform a significant portion of the calculations on a coarse representation of the problem and hence to reduce the time-to-solution while preserving accuracy. In our scheme, referred to as MLSDC-SH, the spatial discretization plays a key role in the efficiency of MLSDC, since the SH basis allows for consistent transfer functions between space–time levels that preserve important physical properties of the solution. We study the performance of the MLSDC-SH scheme with shallow-water test cases commonly used in numerical atmospheric modeling. We use this suite of test cases, which gradually adds more complexity to the nonlinear system of governing partial differential equations, to perform a detailed analysis of the accuracy of MLSDC-SH upon refinement in time. We illustrate the stability properties of MLSDC-SH and show that the proposed scheme achieves up to eighth-order convergence in time. Finally, we study the conditions in which MLSDC-SH achieves its theoretical speedup, and we show that it can significantly reduce the computational cost compared to single-level Spectral Deferred Corrections (SDC).

Background: Aberrant DNA methylation is more prominent in proximal compared with distal colorectal cancers. Although a number of methylation markers were identified for colon cancer, yet few are available for rectal cancer. Methods: DNA methylation differences were assessed by a targeted DNA microarray for 360 marker candidates between 22 fresh frozen rectal tumour samples and 8 controls and validated by microfluidic high-throughput and methylation-sensitive qPCR in fresh frozen and formalin-fixed paraffin-embedded (FFPE) samples, respectively. The CpG island methylator phenotype (CIMP) was assessed by MethyLight in FFPE material from 78 patients with pT2 and pT3 rectal adenocarcinoma. Results: We identified and confirmed two novel three-gene signatures in fresh frozen samples that can distinguish tumours from adjacent tissue as well as from blood with a high sensitivity and specificity of up to 1 and an AUC of 1. In addition, methylation of individual CIMP markers was associated with specific clinical parameters such as tumour stage, therapy or patients' age. Methylation of CDKN2A was a negative prognostic factor for overall survival of patients. Conclusions: The newly defined methylation markers will be suitable for early disease detection and monitoring of rectal cancer.

// Jino Park 1 , Michaela Schlederer 2,12 , Martin Schreiber 3 , Ryan Ice 4,5 , Olaf Merkel 6 , Martin Bilban 7 , Sebastian Hofbauer 3 , Soojin Kim 1 , Joseph Addison 4,5 , Jie Zou 8 , Chunyan Ji 8 , Silvia T. Bunting 9 , Zhengqi Wang 9 , Menachem Shoham 10 , Gang Huang 11 , Zsuzsanna Bago-Horvath 12 , Laura F. Gibson 4 , Yon Rojanasakul 4,13 , Scot Remick 4 , Alexey Ivanov 4,5 , Elena Pugacheva 4,5 , Kevin D. Bunting 9 , Richard Moriggl 2,14 , Lukas Kenner 2,12,15,* and William Tse 1,* 1 James Graham Brown Cancer Center, Division of Blood and Bone Marrow Transplantation, Department of Medicine, University of Louisville School of Medicine, Louisville, KY, USA 2 Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria 3 Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria 4 Mary Babb Randolph Cancer Center, West Virginia University Health Science Center, Morgantown, WV, USA 5 Department of Biochemistry, West Virginia University School of Medicine, Morgantown, WV, USA 6 National Center for Tumor Diseases, German Cancer Research Center, Heidelberg, Germany 7 Department of Laboratory Medicine, Medical University of Vienna and Core Facility Genomics, Core Facilities, Medical University of Vienna, Vienna, Austria 8 Department of Hematology, Qilu Hospital, Shandong University School of Medicine, Jinan, Shandong, PR China 9 Aflac Cancer and Blood Disorders Center of Children’s Healthcare of Atlanta and Emory University School of Medicine, Atlanta, GA, USA 10 Case Western University School of Medicine, Cleveland, OH, USA 11 Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA 12 Clinical Institute for Pathology, Medical University Vienna, Austria 13 Department of Pharmaceutical Science, West Virginia University School of Medicine, Morgantown, WV, USA 14 Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Medical University of Vienna, Vienna, Austria 15 Unit of Pathology of Laboratory Animals (UPLA), University of Veterinary Medicine, Vienna, Austria * These authors have contributed equally to this work Correspondence to: Lukas Kenner, email: // William Tse, email: // Keywords : AF1q, TCF7, CD44, Wnt, metastasis Received : March 02, 2015 Accepted : April 21, 2015 Published : June 07, 2015 Abstract AF1q is an MLL fusion partner that was identified from acute myeloid leukemia (AML) patients with t (1; 11) (q21; q23) chromosomal abnormality. The function of AF1q is not yet fully known, however, elevated AF1q expression is associated with poor clinical outcomes in various malignancies. Here, we show that AF1q specifically binds to T-cell-factor-7 (TCF7) in the Wnt signaling pathway and results in transcriptional activation of CD44 as well as multiple downstream targets of the TCF7/LEF1. In addition, enhanced AF1q expression promotes breast cancer cell proliferation, migration, mammosphere formation, and chemo-resistance. In xenograft models, enforced AF1q expression in breast cancer cells also promotes liver metastasis and lung colonization. In a cohort of 63 breast cancer patients, higher percentages of AF1q-positive cancer cells in primary sites were associated with significantly poorer overall survival (OS), disease-free survival (DFS), and brain metastasis-free survival (b-MFS). Using paired primary/metastatic samples from the same patients, we demonstrate that AF1q-positive breast cancer cells become dynamically dominant in the metastatic sites compared to the primary sites. Our findings indicate that breast cancer cells with a hyperactive AF1q/TCF7/CD44 regulatory axis in the primary sites may represent “metastatic founder cells” which have invasive properties.

This work focuses on the Parareal parallel-in-time method and its application to the viscous Burgers equation. A crucial component of Parareal is the coarse time stepping scheme, which strongly impacts the convergence of the parallel-in-time method. Three choices of coarse time stepping schemes are investigated in this work: explicit Runge–Kutta, implicit–explicit Runge–Kutta, and implicit Runge–Kutta with semi-Lagrangian advection. Manufactured solutions are used to conduct studies, which provide insight into the viability of each considered time stepping method for the coarse time step of Parareal. One of our main findings is the advantageous convergence behavior of the semi-Lagrangian scheme for advective flows.

Background Though the Expanded Disability Status Scale (EDSS) is commonly used to assess disability level in relapsing-remitting multiple sclerosis (RRMS), the criteria defining disability progression are used for patients with a wide range of baseline levels of disability in relatively short-term trials. As a result, not all EDSS changes carry the same weight in terms of future disability, and treatment benefits such as decreased risk of reaching particular disability milestones may not be reliably captured. The objectives of this analysis are to assess the probability of confirmed disability worsening to specific EDSS milestones (i.e., EDSS scores ≥3.0, ≥4.0, or ≥6.0) at 288 weeks in the Tysabri Observational Program (TOP) and to examine the impact of relapses occurring during natalizumab therapy in TOP patients who had received natalizumab for ≥24 months. Methods TOP is an ongoing, open-label, observational, prospective study of patients with RRMS in clinical practice. Enrolled patients were naive to natalizumab at treatment initiation or had received ≤3 doses at the time of enrollment. Intravenous natalizumab (300 mg) infusions were given every 4 weeks, and the EDSS was assessed at baseline and every 24 weeks during treatment. Results Of the 4161 patients enrolled in TOP with follow-up of at least 24 months, 3253 patients with available baseline EDSS scores had continued natalizumab treatment and 908 had discontinued (5.4% due to a reported lack of efficacy and 16.4% for other reasons) at the 24-month time point. Those who discontinued due to lack of efficacy had higher baseline EDSS scores (median 4.5 vs. 3.5), higher on-treatment relapse rates (0.82 vs. 0.23), and higher cumulative probabilities of EDSS worsening (16% vs. 9%) at 24 months than those completing therapy. Among 24-month completers, after approximately 5.5 years of natalizumab treatment, the cumulative probabilities of confirmed EDSS worsening by 1.0 and 2.0 points were 18.5% and 7.9%, respectively (24-week confirmation), and 13.5% and 5.3%, respectively (48-week confirmation). The risks of 24- and 48-week confirmed EDSS worsening were significantly higher in patients with on-treatment relapses than in those without relapses. An analysis of time to specific EDSS milestones showed that the probabilities of 48-week confirmed transition from EDSS scores of 0.0–2.0 to ≥3.0, 2.0–3.0 to ≥4.0, and 4.0–5.0 to ≥6.0 at week 288 in TOP were 11.1%, 11.8%, and 9.5%, respectively, with lower probabilities observed among patients without on-treatment relapses (8.1%, 8.4%, and 5.7%, respectively). Conclusions In TOP patients with a median (range) baseline EDSS score of 3.5 (0.0–9.5) who completed 24 months of natalizumab treatment, the rate of 48-week confirmed disability worsening events was below 15%; after approximately 5.5 years of natalizumab treatment, 86.5% and 94.7% of patients did not have EDSS score increases of ≥1.0 or ≥2.0 points, respectively. The presence of relapses was associated with higher rates of overall disability worsening. These results were confirmed by assessing transition to EDSS milestones. Lower rates of overall 48-week confirmed EDSS worsening and of transitioning from EDSS score 4.0–5.0 to ≥6.0 in the absence of relapses suggest that relapses remain a significant driver of disability worsening and that on-treatment relapses in natalizumab-treated patients are of prognostic importance.

Continuously rising production costs and efficiency requirements present challenges for manufacturing companies. One way of overcoming these challenges is to improve maintenance efficiency and effectiveness by developing and integrating predictive maintenance tools, and using this information for the targeted planning of maintenance measures. However, the integration of sensors into previously-installed manufacturing resources for predicting the necessary maintenance tasks is one of the main challenges facing manufacturing companies. Therefore, this paper presents an innovative methodology for predictive maintenance tools as intelligent cloud services and the industrial application of this methodology for an integrated production and maintenance planning.

The importance of confidence for learning and performance makes learners' perceptions of readiness for the next level of training valuable indicators of curricular success. The "Readiness for Clerkship" (RfC) and "Readiness for Residency" (RfR) surveys have been shown to provide reliable ratings of the relative effectiveness of various aspects of training. This study examines the generalizability of those results.Surveys were administered at four medical schools approximately four months after the start of clerkship and eight months after the start of residency during 2013-2015. Collected data were anonymized. A total of 647 medical students and 483 residents participated.Reliabilities of G = 0.8 could be obtained with only 6 to 12 medical students and 8 to 15 residents. Within MD programs, no meaningful differences in item ratings were observed across cohorts. Residents in each school consistently rated themselves higher than clerks on the majority of Medical Expert and Communicator competencies common to both surveys. Similar strengths and weaknesses were identified across programs, but differences were observed on five clerkship items and one residency item.Across four MD programs, the RfC and RfR surveys provided reliable ratings of the relative effectiveness of aspects of training with small numbers of respondents. The capacity of these surveys to efficiently identify perceived strengths and weaknesses held by cohorts of learners may, thereby, facilitate program improvement.

The CYP19 gene encodes aromatase, an enzyme catalyzing the conversion of androgens to estrogens. Studies analyzing associations between single nucleotide polymorphisms in CYP19 and breast cancer risk have shown inconsistent results. The rs10046 polymorphism is located in the 3' untranslated region of the CYP19 gene, but the influence of this polymorphism on breast cancer risk is unclear. In this study, we investigated the impact of rs10046 SNP on breast cancer risk, age at onset and association with clinical characteristics in an Austrian population of 274 breast cancer patients and 253 controls. The results show that a significantly increased fraction of patients with the TT genotype of rs10046 develop breast cancer under the age of 50 (41.8% of TT patients, compared to 26.6% of C carriers; p = 0.018, Chi-square test). No rs10046 genotypes were significantly associated with increased breast cancer risk or patient characteristics other than age at onset. These results suggest that the rs10046 polymorphism in the CYP19 gene may have an effect on breast cancer susceptibility at an age under 50 in the investigated population.

Electronic health records (EHRs) were first developed in the 1960s as clinical information systems for document storage and retrieval. Adoption of EHRs has increased in the developed world and is increasing in developing countries. Studies have shown that quality of patient care is improved among health centers with EHRs. In this article, we review the structure and function of EHRs along with an examination of its potential application in CKD care and research. Well-designed patient registries using EHRs data allow for improved aggregation of patient data for quality improvement and to facilitate clinical research. Preliminary data from the United States and other countries have demonstrated that CKD care might improve with use of EHRs-based programs. We recently developed a CKD registry derived from EHRs data at our institution and complimented the registry with other patient details from the United States Renal Data System and the Social Security Death Index. This registry allows us to conduct a EHRs-based clinical trial that examines whether empowering patients with a personal health record or patient navigators improves CKD care, along with identifying participants for other clinical trials and conducting health services research. EHRs use have shown promising results in some settings, but not in others, perhaps attributed to the differences in EHRs adoption rates and varying functionality. Thus, future studies should explore the optimal methods of using EHRs to improve CKD care and research at the individual patient level, health system and population levels.

Objective Painful swelling of the anterior chest wall caused by osteitis and hyperostosis in the sternocostoclavicular region are characteristically observed in patients suffering from SAPHO syndrome. Autoimmune triggering of inflammation and bacterial infection is hypothesized to be involved in the pathogenesis. Promising treatment modalities include antirheumatic and antibiotic medications. Methods Ten patients with SAPHO syndrome and symptomatic osteitis in the sternocostoclavicular region were treated by a single instillation of glucocorticosteroids (20 mg triamcinolone) into the sternocostoclavicular joints. The disease activity was evaluated on the basis of a questionnaire asking for osteitis activity (quantified for complains on a scale of 0-6), by Health Assessment Questionnaire (HAQ) score, erythrocyte sedimentation rate, C-reactive protein, and magnet resonance imaging (MRI) scanning of the sternocostoclavicular region (osteitis scores quantified for inflammation on a scale of 0-2 by the radiologist) prior to injection and after 12 weeks. No changes of the preexisting antirheumatic therapy were allowed during the observation interval. Results All patients continued the study during the follow-up. The osteitis score changed from 4.2 (mean; standard error (SE) ±0.3) to 3.2 (±0.4), [ P = 0.062], the erythrocyte sedimentation rate from 19.0 (range from 12 to 30) to 19.9 (from 12 to 27), [ P = 0.430], and the MRI score from 1.6 (±0.2) to 1.5 (±0.2) [ P = 1.0]. One patient developed an increase of the clinical osteitis activity from 3 to 5 according the scoring system; only 2 patients showed a reduction of the MRI activity score from 2 to 1. Conclusions Intra-articular glucocorticosteroid instillation does not appear to reduce osteitis in the sternocostoclavicular region in patients with SAPHO syndrome.

Sodium polysterene sulfonate (Kayexalate ® ) is a crosslinked polymer to which reactive sulfonic groups are attached and preloaded with sodium (Na + ). When placed in a solution, its reactive sulfonate groups exchange their bound Na + for another cation in the solution. Sodium polysterene sulfonate (SPS) [Although ‘SPS’ is often used as an abbreviation for sodium polystyrene sulfonate, SPS ® is actually a brand name for sodium polystyrene sulfonate in sorbitol.] has long been used for the treatment of hyperkalemia, assuming that its reactive sulfonate groups exchange bound Na + for potassium (K + ) in the lumen of the gastrointestinal (GI) tract, causing loss of K +

Background: The effect of blood component ratios on the survival of patients with traumatic brain injury (TBI) has not been studied. Methods: A database of patients transfused in the first 24 hours after admission for injury from 22 Level I trauma centers over an 18-month period was queried to find patients who (1) met different definitions of massive transfusion (5 units red blood cell [RBC] in 6 hours vs. 10 units RBC in 24 hours), (2) received high or low ratios of platelets or plasma to RBC units (1:2 vs. /=1:2), and (3) had severe TBI (head abbreviated injury score /=3) (TBI+). Results: Of 2,312 total patients, 850 patients were transfused with /= 5 RBC units in 6 hours and 807 could be classified into TBi+ (n = 281) or TBI- (n = 526). Six hundred forty-three patients were transfused with /=10 RBC units in 24 hours with 622 classified into TBI+ (n = 220) and TBi- (n = 402). For both high-risk populations, a high ratio of platelets:RBCs (not plasma) was independently associated with improved 30-day survival for patients with TBI+ and a high ratio of plasma:RBCs (not platelets) was independently associated with improved 30-day survival in TBI- patients. Conclusions: High platelet ratio was associated with improved survival in TBI+ patients while a high plasma ratio was associated with improved survival in TBI- patients. Prospective studies of blood product ratios should include TBI in the analysis for determination of optimal use of ratios on outcome in injured patients.

In individuals with mammary carcinoma, the most relevant prognostic predictor of distant organ metastasis and clinical outcome is the status of axillary lymph node metastasis. Metastases form initially in axillary sentinel lymph nodes and progress via connecting lymphatic vessels into postsentinel lymph nodes. However, the mechanisms of consecutive lymph node colonization are unknown. Through the analysis of human mammary carcinomas and their matching axillary lymph nodes, we show here that intrametastatic lymphatic vessels and bulk tumor cell invasion into these vessels highly correlate with formation of postsentinel metastasis. In an in vitro model of tumor bulk invasion, human mammary carcinoma cells caused circular defects in lymphatic endothelial monolayers. These circular defects were highly reminiscent of defects of the lymphovascular walls at sites of tumor invasion in vivo and were primarily generated by the tumor-derived arachidonic acid metabolite 12S-HETE following 15-lipoxygenase-1 (ALOX15) catalysis. Accordingly, pharmacological inhibition and shRNA knockdown of ALOX15 each repressed formation of circular defects in vitro. Importantly, ALOX15 knockdown antagonized formation of lymph node metastasis in xenografted tumors. Furthermore, expression of lipoxygenase in human sentinel lymph node metastases correlated inversely with metastasis-free survival. These results provide evidence that lipoxygenase serves as a mediator of tumor cell invasion into lymphatic vessels and formation of lymph node metastasis in ductal mammary carcinomas.

Summary Background and objectives Chronic kidney disease (CKD) is increasing, and outcomes-related research from diverse health care settings is needed to target appropriate efforts and interventions. We developed an electronic health record (EHR)-based CKD registry at the Cleveland Clinic and validated comorbid conditions. Design, setting, participants, & measurements Patients who had at least one face-to-face outpatient encounter with a Cleveland Clinic health care provider and (1) had two estimated GFR values 90 days apart as of January 1, 2005 and/or (2) were patients with International Classification of Diseases-9 (ICD-9) diagnosis codes for kidney disease were included. Results Our registry includes 57,276 patients (53,399 patients met estimated GFR criteria and 3877 patients met ICD-9 diagnosis code criteria) as of March 2010. Mean age was 69.5 ± 13.4 years, with 55% women and 12% African Americans. Medicare is the primary insurer for more than one half of the study cohort. The κ statistics to assess the extent of agreement between the administrative dataset extracted from the EHR and actual EHR chart review showed substantial agreement (>0.80) for all conditions except for coronary artery disease and hypertension, which had moderate agreement ( Conclusions Development of an EHR-based CKD registry is feasible in a large health system, and the comorbid conditions included in the registry are reliable. In addition to conducting research studies, such a registry could help to improve the quality of care delivered to CKD patients and complement the ongoing nationwide efforts to develop a CKD surveillance project.

Background: 2009 influenza A has spread globally. Respiratory complications and renal failure have been the leading causes for hospitalization and critical illness. We describe the risk factors and complications of acute kidney injury (AKI) in patients with influenza A. Methods: Observational study of adult patients tested for influenza A. Outcome measures include AKI [AKI Network (AKIN) criteria] and mortality. Results: From August through December 2009, 17% (89/515) of hospitalized subjects were tested positive for influenza A. The incidence of AKI (AKINI–III) was 42% (37/89) in subjects with influenza A; the majority (65%, 24/37) of whom were critically ill. Risk factors for AKI included obesity, chronic kidney disease (CKD), and elevated creatine kinase. Positive influenza A status was associated with lower AKI (AKINI–III) risk compared to seronegative subjects (OR 0.5, CI 0.3–0.9). Mortality in patients with influenza A and AKI requiring dialysis was 50%. Conclusions: Obesity, CKD, and elevated creatine kinase are associated with AKI in patients with influenza A. Influenza A is not independently associated with higher incidence of AKI in hospitalized patients. AKI is an independent risk factor for mortality in patients with influenza A.

Ultrathin conductive carbon layers (UCCLs) were created by spin coating resists and subsequently converting them to conductive films by pyrolysis. Homogeneous layers as thin as 3 nm with nearly atomically smooth surfaces could be obtained. Layer characterization was carried out with the help of atomic force microscopy, profilometry, four-point probe measurements, Raman spectroscopy and ultraviolet–visible spectroscopy. The Raman spectra and high-resolution transmission electron microscopy image indicated that a glassy carbon like material was obtained after pyrolysis. The electrical properties of the UCCL could be controlled over a wide range by varying the pyrolysis temperature. Variation in transmittance with conductivity was investigated for applications as transparent conducting films. It was observed that the layers are continuous down to a thickness below 10 nm, with conductivities of 1.6 × 10 4 S/m, matching the best values observed for pyrolyzed carbon films. Further, the chemical stability of the films and their utilization as transparent electrochemical electrodes has been investigated using cyclic voltammetry and electrochemical impedance spectroscopy.

Metastasis is the major cause of carcinoma-induced death, but mechanisms involved are poorly understood. Metastasis crucially involves epithelial-to-mesenchymal transition (EMT), causing loss of epithelial polarity. Here we identify Annexin A1 (AnxA1), a protein with important functions in intracellular vesicle trafficking, as an efficient suppressor of EMT and metastasis in breast cancer. AnxA1 levels were strongly reduced in EMT of mammary epithelial cells, in metastatic murine and human cell lines and in metastatic mouse and human carcinomas. RNAi-mediated AnxA1 knockdown cooperated with oncogenic Ras to induce TGFβ-independent EMT and metastasis in non-metastatic cells. Strikingly, forced AnxA1 expression in metastatic mouse and human mammary carcinoma cells reversed EMT and abolished metastasis. AnxA1 knockdown stimulated multiple signalling pathways but only Tyk2/Stat3 and Erk1/2 signalling were essential for EMT.

Due to the shortage of organs, living donor acceptance criteria are becoming less stringent. An accurate determination of the glomerular filtration rate (GFR) is critical in the evaluation of living kidney donors and a value exceeding 80 ml/min per 1.73 m 2 is usually considered suitable. To improve strategies for kidney donor screening, an understanding of factors that affect GFR is needed. Here we studied the relationships between donor GFR measured by 125 I-iothalamate clearances (mGFR) and age, gender, race, and decade of care in living kidney donors evaluated at the Cleveland Clinic from 1972 to 2005. We report the normal reference ranges for 1057 prospective donors (56% female, 11% African American). Females had slightly higher mGFR than males after adjustment for body surface area, but there were no differences due to race. The lower limit of normal for donors (5th percentile) was less than 80 ml/min per 1.73 m 2 for females over age 45 and for males over age 40. We found a significant doubling in the rate of GFR decline in donors over age 45 as compared to younger donors. The age of the donors and body mass index increased over time, but their mGFR, adjusted for body surface area, significantly declined by 1.49±0.61 ml/min per 1.73 m 2 per decade of testing. Our study shows that age and gender are important factors determining normal GFR in living kidney donors.

One of the most common complications after total hip arthroplasty is instability. This study reviewed the recent literature concerning the indications, contraindications, and results of recent studies using both constrained liners and large femoral heads to treat instability after total hip arthroplasty. We also report on the results of a series of 41 patients (52 hips) considered being at high risk for dislocation who were treated with large-diameter metal-on-metal bearings and who were compared with a matched group of hips treated with standard-size metal-on-polyethylene bearings. The large-diameter femoral head group had no dislocations at a minimum follow-up of 24 months, whereas the standard-size group had 2 dislocations. We support the use of large femoral heads to treat instability in a wide variety of patients because of the increased stability, decreased wear of modern metal-on-metal designs, increased range of motion, and variety of revision options.

In den vergangenen 25 Jahren hat sich die Leistungsdichte in Werkzeugmaschinen insgesamt mehr als vervierfacht, die Bearbeitungsgeschwindigkeiten haben sich sogar verzehnfacht. Die Komplexitat von derlei Anforderungen verlangt von einem Lagerhersteller wie der Schaeffler Gruppe ein Hochstmas an Systemverstandnis und Entwicklungs-Know-how.

Over the past 25 years, the performance density in machine tools has more than quadrupled and there has even been a tenfold increase in machining speeds. The number of axes is steadily increasing, since more and more machining steps are to be carried out in one chucking. This affects both the machine structure and the individual components. The complexity of demands requires maximum understanding of the underlying system as well as development expertise from a bearing manufacturer such as the Schaeffler Group.

The molecular mechanisms that regulate DC differentiation and subset distribution are largely unknown. In this study we report the identification of the C(2)H(2) zinc finger transcription factors (TF) CTCF as a regulator of DC differentiation. CTCF was expressed in human and murine DC and its expression was downregulated during the differentiation of human monocyte-derived DC. Enforced expression of CTCF during the differentiation of murine BM-derived DC (BMDC) caused increased apoptosis and reduced proliferation leading to a dramatically reduced number of CTCF transduced DC. The CTCF expressing BMDC that developed had a more immature phenotype than control cells, and showed defects in maturation upon TLR stimulation. Furthermore, in vivo expression of CTCF led to an increase in the percentage of plasmacytoid DC (pDC) within the DC lineage. Our data provide new insight into molecular mechanisms regulating DC differentiation and subset development and identify CTCF as a factor involved in the regulation of these important processes.

Insulin-like growth factor (IGF) signaling is a key regulator of breast development and breast cancer. We have analyzed the expression of the IGF signaling cascade in 17 human breast cancer and 4 mammary epithelial cell lines. Five cell lines expressed high levels of IGF1 receptor, insulin (INS)/IGF receptor substrate 1, IGF-binding proteins 2 and 4, as well as the estrogen receptor (ESR), indicating a co-activation of IGF and ESR signaling. Next, we stably overexpressed IGF1 and IGF2 in MCF7 breast cancer cells, which did not affect their epithelial characteristics and the expression and localization of the epithelial marker genes E-cadherin and beta-catenin. Conversely, IGF1 and IGF2 overexpression potently increased cellular proliferation rates and the efficiency of tumor formation in mouse xenograft experiments, whereas the resistance to chemotherapeutic drugs such as taxol was unaltered. Expression profiling of overexpressing cells with whole-genome oligonucleotide microarrays revealed that 21 genes were upregulated >2-fold by both IGF1 and IGF2, 9 by IGF1, and 9 by IGF2. Half of the genes found to be upregulated are involved in transport and biosynthesis of amino acids, including several amino acid transport proteins, argininosuccinate and asparagine synthetases, and methionyl-tRNA synthetase. Upregulation of these genes constitutes a novel mechanism apparently contributing to the stimulatory effects of IGF signaling on the global protein synthesis rate. We conclude that the induction of cell proliferation and tumor formation by long-term IGF stimulation may primarily be due to anabolic effects, in particular increased amino acid production and uptake.

Like other RECQ helicases, WRN/RECQL2 plays a crucial role in DNA replication and the maintenance of genome stability. Inactivating mutations in RECQL2 lead to Werner syndrome, a rare autosomal disease associated with premature aging and an increased susceptibility to multiple cancer types. We analyzed the association of two coding single-nucleotide polymorphisms in WRN, Cys1367Arg (rs1346044), and Arg834Cys (rs3087425), with the risk, age at onset, and clinical subclasses of breast cancer in a hospital-based case-control study of an Austrian population of 272 breast cancer patients and 254 controls. Here we report that the rare homozygous CC genotype of rs1346044 was associated with an approximately two-fold elevated breast cancer risk. Moreover, patients with the CC genotype exhibited a significantly increased risk of developing breast cancer under the age of 55 in both recessive and log-additive genetic models. CC patients developed breast cancer at a mean age of 55.2 ± 13.3 years and TT patients at 60.2 ± 14.7 years. Consistently, the risk of breast cancer was increased in pre-menopausal patients in the recessive model. These findings suggest that the CC genotype of WRN rs1346044 may contribute to an increased risk and a premature onset of breast cancer.