@phdthesis{Witz2013,
  author    = {Witz, Eva-Katharina},
  title     = {Verbesserung des linksventrikul{\"a}ren Remodelings durch Inhibition des Transkriptionsfaktors Nuclear Factor kappa B (NF-κB) in Makrophagen und Granulozyten},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-103828},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2013},
  abstract  = {Nach einem Myokardinfarkt werden ventrikul{\"a}res Remodeling und myokardiale Funktion unter anderem durch die ablaufenden Reaktionen des angeborenen Immunsystems beeinflusst. Von zentraler Bedeutung f{\"u}r die Regulation dieser Immunreaktion ist der Transkriptionsfaktor Nuclear Factor kappa B. Tiere, bei denen NF-κB durch das Fehlen seiner Untereinheit p50 global inaktiv ist, wei- sen einen Schutz vor linksventrikul{\"a}rem Remodeling auf. Bisher ist jedoch un- klar, welche Zellen f{\"u}r diesen protektiven Effekt verantwortlich sind. Vorange- gangene Studien konnten zeigen, dass die Protektion nicht auf die fehlende NF- κB Aktivierung in Kardiomyozyten zur{\"u}ckzuf{\"u}hren ist. Aus Isch{\"a}mie- Reperfusions-Experimenten an NF-κB-defizienten Tieren ergaben sich Hinwei- se, dass v.a. die Hemmung von NF-κB in Entz{\"u}ndungszellen die protektiven Effekte vermittelt. Durch Kreuzung von LysMCre- mit lox-IKKβ-Tieren erzeugten wir Tiere, denen makrophagenspezifisch IκB-Kinase β (IKKβ) fehlt. IKK deaktiviert den Inhibitor von NF-κB und ist somit essentiell f{\"u}r eine NF-κB-Aktivierung. Als Modell der Herzinsuffizienz diente der chronische Myokardinfarkt. Die Nachbeobachtung erfolgte {\"u}ber 56 Tage. Die Knockout-Tiere (KO) hatten im Vergleich zu den Wildtyp-Tiere (WT) eine signifikant bessere {\"U}berlebensrate (KO vs. WT, 100\% vs. 49\%, p < 0,01). Pr{\"a}operativ sowie postoperativ an den Tagen 1, 21 und 56 wurden transthora- kale Echokardiographien durchgef{\"u}hrt. Bei gleicher Infarktgr{\"o}ße zeigten die KO-Tiere eine deutlich geringere linksventrikul{\"a}re Dilatation. Es konnte moleku- larbiologisch keine Reduktion der humoralen Entz{\"u}ndungsreaktion nachgewie- sen werden, ebenso blieb das Entz{\"u}ndungszellinfiltrat immunhistochemisch unver{\"a}ndert. Auch bez{\"u}glich Apoptoserate und Neovaskularisation zeigte sich kein Unterschied zwischen den Gruppen. Allerdings zeigten die LysM-IKKβ-KO-Tiere 56 Tage nach Myokardinfarkt einen deutlich erh{\"o}hten septalen Kollagen- gehalt als Hinweis auf ein ver{\"a}ndertes extrazellul{\"a}res Remodeling. Aus diesen Ergebnissen kann geschlossen werden, dass die protektiven Effek- te der globalen NF-κB-Hemmung durch die fehlende NF-κB-Aktivierung in Ma- krophagen und Granulozyten, nicht aber in Kardiomyozyten vermittelt wurden. Die durch die makrophagenspezifische NF-κB-Hemmung vermittelten Ver{\"a}nde- rungen im Remodeling der extrazellul{\"a}ren Matrix f{\"u}hren zu einer Verbesserung der {\"U}berlebensrate, besseren funktionellen Ergebnissen und einem insgesamt verminderten linksventrikul{\"a}ren Remodeling nach Myokardinfarkt.},
  subject      = {Remodeling},
  language  = {de}
}
@article{ChopraLangSalzmannetal.2013,
  author    = {Chopra, Martin and Lang, Isabell and Salzmann, Steffen and Pachel, Christina and Kraus, Sabrina and B{\"a}uerlein, Carina A. and Brede, Christian and Jord{\´a}n Garrote, Ana-Laura and Mattenheimer, Katharina and Ritz, Miriam and Schwinn, Stefanie and Graf, Carolin and Sch{\"a}fer, Viktoria and Frantz, Stefan and Einsele, Hermann and Wajant, Harald and Beilhack, Andreas},
  title     = {Tumor Necrosis Factor Induces Tumor Promoting and Anti-Tumoral Effects on Pancreatic Cancer via TNFR1},
  series = {PLoS ONE},
  journal   = {PLoS ONE},
  doi       = {10.1371/journal.pone.0075737},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-97246},
  year      = {2013},
  abstract  = {Multiple activities are ascribed to the cytokine tumor necrosis factor (TNF) in health and disease. In particular, TNF was shown to affect carcinogenesis in multiple ways. This cytokine acts via the activation of two cell surface receptors, TNFR1, which is associated with inflammation, and TNFR2, which was shown to cause anti-inflammatory signaling. We assessed the effects of TNF and its two receptors on the progression of pancreatic cancer by in vivo bioluminescence imaging in a syngeneic orthotopic tumor mouse model with Panc02 cells. Mice deficient for TNFR1 were unable to spontaneously reject Panc02 tumors and furthermore displayed enhanced tumor progression. In contrast, a fraction of wild type (37.5\%), TNF deficient (12.5\%), and TNFR2 deficient mice (22.2\%) were able to fully reject the tumor within two weeks. Pancreatic tumors in TNFR1 deficient mice displayed increased vascular density, enhanced infiltration of CD4+ T cells and CD4+ forkhead box P3 (FoxP3)+ regulatory T cells (Treg) but reduced numbers of CD8+ T cells. These alterations were further accompanied by transcriptional upregulation of IL4. Thus, TNF and TNFR1 are required in pancreatic ductal carcinoma to ensure optimal CD8+ T cell-mediated immunosurveillance and tumor rejection. Exogenous systemic administration of human TNF, however, which only interacts with murine TNFR1, accelerated tumor progression. This suggests that TNFR1 has basically the capability in the Panc02 model to trigger pro-and anti-tumoral effects but the spatiotemporal availability of TNF seems to determine finally the overall outcome.},
  language  = {en}
}
@article{DoerhoeferLammertKraneetal.2013,
  author    = {D{\"o}rh{\"o}fer, Lena and Lammert, Alexander and Krane, Vera and Gorski, Mathias and Banas, Bernhard and Wanner, Christoph and Kr{\"a}mer, Bernhard K. and Heid, Iris M. and B{\"o}ger, Carsten A.},
  title     = {Study design of DIACORE (DIAbetes COhoRtE) - a cohort study of patients with diabetes mellitus type 2},
  series = {BMC Medical Genetics},
  volume    = {14},
  journal   = {BMC Medical Genetics},
  number    = {25},
  issn      = {1471-2350},
  doi       = {10.1186/1471-2350-14-25},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-122040},
  year      = {2013},
  abstract  = {Background: Diabetes mellitus type 2 (DM2) is highly associated with increased risk for chronic kidney disease (CKD), end stage renal disease (ESRD) and cardiovascular morbidity. Epidemiological and genetic studies generate hypotheses for innovative strategies in DM2 management by unravelling novel mechanisms of diabetes complications, which is essential for future intervention trials. We have thus initiated the DIAbetes COhoRtE study (DIACORE). Methods: DIACORE is a prospective cohort study aiming to recruit 6000 patients of self-reported Caucasian ethnicity with prevalent DM2 for at least 10 years of follow-up. Study visits are performed in University-based recruiting clinics in Germany using standard operating procedures. All prevalent DM2 patients in outpatient clinics surrounding the recruiting centers are invited to participate. At baseline and at each 2-year follow-up examination, patients are subjected to a core phenotyping protocol. This includes a standardized online questionnaire and physical examination to determine incident micro-and macrovascular DM2 complications, malignancy and hospitalization, with a primary focus on renal events. Confirmatory outcome information is requested from patient records. Blood samples are obtained for a centrally analyzed standard laboratory panel and for biobanking of aliquots of serum, plasma, urine, mRNA and DNA for future scientific use. A subset of the cohort is subjected to extended phenotyping, e. g. sleep apnea screening, skin autofluorescence measurement, non-mydriatic retinal photography and non-invasive determination of arterial stiffness. Discussion: DIACORE will enable the prospective evaluation of factors involved in DM2 complication pathogenesis using high-throughput technologies in biosamples and genetic epidemiological studies.},
  language  = {en}
}
@article{FrantzKlaiberBabaetal.2013,
  author    = {Frantz, Stefan and Klaiber, Michael and Baba, Hideo A. and Oberwinkler, Heinz and V{\"o}lker, Katharina and Gaßner, Birgit and Bayer, Barbara and Abeßer, Marco and Schuh, Kai and Feil, Robert and Hofmann, Franz and Kuhn, Michaela},
  title     = {Stress-dependent dilated cardiomyopathy in mice with cardiomyocyte-restricted inactivation of cyclic GMP-dependent protein kinase I},
  series = {European Heart Journal},
  volume    = {34},
  journal   = {European Heart Journal},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-134693},
  pages     = {1233-1244},
  year      = {2013},
  abstract  = {Aims: Cardiac hypertrophy is a common and often lethal complication of arterial hypertension. Elevation of myocyte cyclic GMP levels by local actions of endogenous atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP) or by pharmacological inhibition of phosphodiesterase-5 was shown to counter-regulate pathological hypertrophy. It was suggested that cGMP-dependent protein kinase I (cGKI) mediates this protective effect, although the role in vivo is under debate. Here, we investigated whether cGKI modulates myocyte growth and/or function in the intact organism. Methods and results: To circumvent the systemic phenotype associated with germline ablation of cGKI, we inactivated the murine cGKI gene selectively in cardiomyocytes by Cre/loxP-mediated recombination. Mice with cardiomyocyte-restricted cGKI deletion exhibited unaltered cardiac morphology and function under resting conditions. Also, cardiac hypertrophic and contractile responses to β-adrenoreceptor stimulation by isoprenaline (at 40 mg/kg/day during 1 week) were unaltered. However, angiotensin II (Ang II, at 1000 ng/kg/min for 2 weeks) or transverse aortic constriction (for 3 weeks) provoked dilated cardiomyopathy with marked deterioration of cardiac function. This was accompanied by diminished expression of the \([Ca^{2+}]_i\)-regulating proteins SERCA2a and phospholamban (PLB) and a reduction in PLB phosphorylation at Ser16, the specific target site for cGKI, resulting in altered myocyte \(Ca^{2+}_i\) homeostasis. In isolated adult myocytes, CNP, but not ANP, stimulated PLB phosphorylation, \(Ca^{2+}_i\)-handling, and contractility via cGKI. Conclusion: These results indicate that the loss of cGKI in cardiac myocytes compromises the hypertrophic program to pathological stimulation, rendering the heart more susceptible to dysfunction. In particular, cGKI mediates stimulatory effects of CNP on myocyte \(Ca^{2+}_i\) handling and contractility.},
  language  = {en}
}
@article{SbieraRonchiLeichetal.2013,
  author    = {Sbiera, Silviu and Ronchi, Cristina L. and Leich, Ellen and Henzel, Katharina and Rosenwald, Andreas and Allolio, Bruno and Fassnacht, Martin},
  title     = {Single Nucleotide Polymorphism Array Profiling of Adrenocortical Tumors - Evidence for an Adenoma Carcinoma Sequence?},
  series = {PLoS ONE},
  journal   = {PLoS ONE},
  doi       = {10.1371/journal.pone.0073959},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-97218},
  year      = {2013},
  abstract  = {Adrenocortical tumors consist of benign adenomas and highly malignant carcinomas with a still incompletely understood pathogenesis. A total of 46 adrenocortical tumors (24 adenomas and 22 carcinomas) were investigated aiming to identify novel genes involved in adrenocortical tumorigenesis. High-resolution single nucleotide polymorphism arrays (Affymetrix) were used to detect copy number alterations (CNAs) and copy neutral losses of heterozygosity (cnLOH). Genomic clustering showed good separation between adenomas and carcinomas, with best partition including only chromosome 5, which was highly amplified in 17/22 malignant tumors. The malignant tumors had more relevant genomic aberrations than benign tumors, such as a higher median number of recurrent CNA (2631 vs 94), CNAs >100 Kb (62.5 vs 7) and CN losses (72.5 vs 5.5), and a higher percentage of samples with cnLOH (91\% vs 29\%). Within the carcinoma cohort, a precise genetic pattern (i.e. large gains at chr 5, 7, 12, and 19, and losses at chr 1, 2, 13, 17, and 22) was associated with a better prognosis (overall survival: 72.2 vs 35.4 months, P=0.063). Interestingly, >70\% of gains frequent in beningn were also present in malignant tumors. Notch signaling was the most frequently involved pathway in both tumor entities. Finally, a CN gain at imprinted "IGF2" locus chr 11p15.5 appeared to be an early alteration in a multi-step tumor progression, followed by the loss of one or two alleles, associated with increased IGF2 expression, only in carcinomas. Our study serves as database for the identification of genes and pathways, such as Notch signaling, which could be involved in the pathogenesis of adrenocortical tumors. Using these data, we postulate an adenoma-carcinoma sequence for these tumors.},
  language  = {en}
}
@phdthesis{Lang2013,
  author    = {Lang, Katharina},
  title     = {Selektive Aldosteronsynthaseinhibitoren in der funktionellen Bildgebung zur Differenzialdiagnose des Prim{\"a}ren Hyperaldosteronismus - Entwicklung eines Testsystems und Evaluation geeigneter Substanzen},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-108693},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2013},
  abstract  = {5 - 13\% aller Hypertoniker leiden an einem Prim{\"a}ren Hyperaldosteronismus (PA), was diese Erkrankung zu der h{\"a}ufigsten Form sekund{\"a}rer Hypertonie macht. Die Subtypdifferenzierung dient der Unterscheidung zwischen unilateraler, operativ zu therapierender und bilateraler, medikament{\"o}s zu therapierender Form. Der diagnostische Goldstandard in der Subtypdifferenzierung, der selektive Nebennierenvenenkatheter, ist aufgrund seiner Limitationen immer wieder Gegenstand kontroverser Diskussionen. W{\"a}hrend CT- und MRT- Bildgebung einen fester Bestandteil der Stufendiagnostik des PA darstellen, hat die funktionelle Bildgebung, PET und SPECT, hierbei noch keinen festen Platz. In der bildgebenden Darstellung der Nebennieren allgemein gewinnen diese Verfahren, vor allem auf der Basis von Etomidat und seinen Derivaten, zunehmend an Bedeutung. Beipiele hierf{\"u}r sind 11C- Meto- bzw. 18F- FETO- PET und 123I- IMTO- SPECT. Relativ neu in der Entwicklung sind selektive Aldosteronsynthaseinhibitoren. Problematisch hierbei ist die 93\% Homologie in der Aminos{\"a}uresequenz von CYP11B1 und CYP11B2, der Aldosteronsynthase. Die dieser Arbeit zugrunde liegende Idee ist die Entwicklung eines funktionellen Bildgebungsverfahrens zur Differenzialdiagnose des PA auf der Basis fluorierter und iodierter Aldosteronsynthasenhibitoren. Mittels Realtime- PCR konnte gezeigt werden, dass die {\"U}berexpression von CYP11B2 in aldosteronproduzierenden Tumoren dieses Enzym zu einem geeigneten Ansatzpunkt f{\"u}r radioaktiv markierte Tracer macht. Zur Evaluation geeigneter Substanzen wurde daher eine, humanes CYP11B1 bzw. CYP11B2 stabil exprimierende Zelllinie auf Basis der murinen Y1- Nebennierenrindenkarzinom- Zellen, entwickelt. Dies gelang durch Klonierung der humanen Enzyme in den pcDNA3.1zeo(+)- Vektor und anschließende Transfektion mit Lipofectamine. Zur weiteren Substanztestung wurde jeweils der Klon mit hoher Expression der CYP11B Enzyme auf mRNA- und Proteinebene bei gleichzeitig h{\"o}chster Hormonkonzentration im Zellkultur{\"u}berstand ausgew{\"a}hlt. Inkubation dieser Zelllinien mit den CYP11B- Inhibitoren Etomidat und Metomidat erbrachte IC50- Werte im nanomolekularen Bereich. In dem Testsystem stellte sich das fluorierte Naphthenylpyridin- Derivat 5.1 als potentester und zugleich sehr selektiver Inhibitor von CYP11B2 heraus, der erst ab einer Zehnerpotenz {\"u}ber der ermittelten IC50 einen signifikanten antiproliferativen Effekt auf NCI- H295 Zellen aus{\"u}bte. Die stabil transfizierten Y1-CYP11B Zellen stellten sich als geeignetes Testsystem zur Evaluation von Potenz und Selektivit{\"a}t der Aldosteronsynthase- Inhibitoren heraus. Mit der Substanz 5.1 konnte bereits ein potenter und selektiver Inhibitor von CYP11B2 entwickelt werden. Der IC50- Wert f{\"u}r die Inhibition von CYP11B2 lag f{\"u}r diese Substanz aber noch etwa um den Faktor 100 h{\"o}her als f{\"u}r die Referenzsubstanz Etomidat, so dass die Entwicklung und Testung weiterer Inhibitoren folgen muss, bis eine geeignete Substanz f{\"u}r die funktionale Bildgebung zur Differenzialdiagnose des PA gefunden ist.},
  subject      = {Diagnostik / Bildgebendes Verfahren},
  language  = {de}
}
@article{BrandenburgKramannKoosetal.2013,
  author    = {Brandenburg, Vincent M. and Kramann, Rafael and Koos, Ralf and Krueger, Thilo and Schurgers, Leon and M{\"u}hlenbruch, Georg and H{\"u}bner, Sinah and Gladziwa, Ulrich and Drechler, Christiane and Ketteler, Markus},
  title     = {Relationship between sclerostin and cardiovascular calcification in hemodialysis patients: a cross-sectional study},
  series = {BMC Nephrology},
  volume    = {14},
  journal   = {BMC Nephrology},
  number    = {219},
  issn      = {1471-2369},
  doi       = {10.1186/1471-2369-14-219},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-122070},
  year      = {2013},
  abstract  = {Background: Sclerostin is a Wnt pathway antagonist regulating osteoblast activity and bone turnover. Here, we assessed the potential association of sclerostin with the development of coronary artery (CAC) and aortic valve calcifications (AVC) in haemodialysis (HD) patients. Methods: We conducted a cross-sectional multi-slice computed tomography (MS-CT) scanning study in 67 chronic HD patients (59.4 +/- 14.8 yrs) for measurement of CAC and AVC. We tested established biomarkers as well as serum sclerostin (ELISA) regarding their association to the presence of calcification. Fifty-four adults without relevant renal disease served as controls for serum sclerostin levels. Additionally, sclerostin expression in explanted aortic valves from 15 dialysis patients was analysed ex vivo by immunohistochemistry and mRNA quantification (Qt-RT-PCR). Results: CAC (Agatston score > 100) and any AVC were present in 65\% and in 40\% of the MS-CT patient group, respectively. Serum sclerostin levels (1.53 +/- 0.81 vs 0.76 +/- 0.31 ng/mL, p < 0.001) were significantly elevated in HD compared to controls and more so in HD patients with AVC versus those without AVC (1.78 +/- 0.84 vs 1.35 +/- 0.73 ng/mL, p = 0.02). Multivariable regression analysis for AVC revealed significant associations with higher serum sclerostin. Ex vivo analysis of uraemic calcified aortic valves (n = 10) revealed a strong sclerostin expression very close to calcified regions (no sclerostin staining in non-calcified valves). Correspondingly, we observed a highly significant upregulation of sclerostin mRNA in calcified valves compared to non-calcified control valves. Conclusion: We found a strong association of sclerostin with calcifying aortic heart valve disease in haemodialysis patients. Sclerostin is locally produced in aortic valve tissue adjacent to areas of calcification.},
  language  = {en}
}
@article{EiseleBlozikStoerketal.2013,
  author    = {Eisele, Marion and Blozik, Eva and St{\"o}rk, Stefan and Tr{\"a}der, Jens-Martin and Herrmann-Lingen, Christoph and Scherer, Martin},
  title     = {Recognition of depression and anxiety and their association with quality of life, hospitalization and mortality in primary care patients with heart failure - study protocol of a longitudinal observation study},
  series = {BMC Family Practice},
  volume    = {14},
  journal   = {BMC Family Practice},
  number    = {180},
  issn      = {1471-2296},
  doi       = {10.1186/1471-2296-14-180},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-121881},
  year      = {2013},
  abstract  = {Background: International disease management guidelines recommend the regular assessment of depression and anxiety in heart failure patients. Currently there is little data on the effect of screening for depression and anxiety on the quality of life and the prognosis of heart failure (HF). We will investigate the association between the recognition of current depression/anxiety by the general practitioner (GP) and the quality of life and the patients' prognosis. Methods/Design: In this multicenter, prospective, observational study 3,950 patients with HF are recruited by general practices in Germany. The patients fill out questionnaires at baseline and 12-month follow-up. At baseline the GPs are interviewed regarding the somatic and psychological comorbidities of their patients. During the follow-up assessment, data on hospitalization and mortality are provided by the general practice. Based on baseline data, the patients are allocated into three observation groups: HF patients with depression and/or anxiety recognized by their GP (P+/+), those with depression and/or anxiety not recognized (P+/-) and patients without depression and/or anxiety (P-/-). We will perform multivariate regression models to investigate the influence of the recognition of depression and/or anxiety on quality of life at 12 month follow-up, as well as its influences on the prognosis (hospital admission, mortality). Discussion: We will display the frequency of GP-acknowledged depression and anxiety and the frequency of installed therapeutic strategies. We will also describe the frequency of depression and anxiety missed by the GP and the resulting treatment gap. Effects of correctly acknowledged and missed depression/anxiety on outcome, also in comparison to the outcome of subjects without depression/anxiety will be addressed. In case results suggest a treatment gap of depression/anxiety in patients with HF, the results of this study will provide methodological advice for the efficient planning of further interventional research.},
  language  = {en}
}
@article{deZeeuwAkizawaAgarwaletal.2013,
  author    = {de Zeeuw, Dick and Akizawa, Tadao and Agarwal, Rajiv and Audhya, Paul and Bakris, George L. and Chin, Melanie and Krauth, Melissa and Lambers Heerspink, Hiddo J. and Meyer, Colin J. and McMurray, John J. and Parving, Hans-Henrik and Pergola, Pablo E. and Remuzzi, Giuseppe and Toto, Robert D. and Vaziri, Nosratola D. and Wanner, Christoph and Warnock, David G. and Wittes, Janet and Chertow, Glenn M.},
  title     = {Rationale and Trial Design of Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes: The Occurrence of Renal Events (BEACON)},
  series = {American Journal of Nephrology},
  volume    = {37},
  journal   = {American Journal of Nephrology},
  number    = {3},
  issn      = {0250-8095},
  doi       = {10.1159/000346948},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196832},
  pages     = {212-222},
  year      = {2013},
  abstract  = {Background: Chronic kidney disease (CKD) associated with type 2 diabetes mellitus constitutes a global epidemic complicated by considerable renal and cardiovascular morbidity and mortality, despite the provision of inhibitors of the renin-angiotensin-aldosterone system (RAAS). Bardoxolone methyl, a synthetic triterpenoid that reduces oxidative stress and inflammation through Nrf2 activation and inhibition of NF-κB was previously shown to increase estimated glomerular filtration rate (eGFR) in patients with CKD associated with type 2 diabetes mellitus. To date, no antioxidant or anti-inflammatory therapy has proved successful at slowing the progression of CKD. Methods: Herein, we describe the design of Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes: the Occurrence of Renal Events (BEACON) trial, a multinational, multicenter, double-blind, randomized, placebo-controlled Phase 3 trial designed to determine whether long-term administration of bardoxolone methyl (on a background of standard therapy, including RAAS inhibitors) safely reduces renal and cardiac morbidity and mortality. Results: The primary composite endpoint is time-to-first occurrence of either end-stage renal disease or cardiovascular death. Secondary endpoints include the change in eGFR and time to occurrence of cardiovascular events. Conclusion: BEACON will be the first event-driven trial to evaluate the effect of an oral antioxidant and anti-inflammatory drug in advanced CKD.},
  language  = {en}
}
@article{EliasHeuschmannSchmittetal.2013,
  author    = {Elias, Johannes and Heuschmann, Peter U. and Schmitt, Corinna and Eckhardt, Frithjof and Boehm, Hartmut and Maier, Sebastian and Kolb-M{\"a}urer, Annette and Riedmiller, Hubertus and M{\"u}llges, Wolfgang and Weisser, Christoph and Wunder, Christian and Frosch, Matthias and Vogel, Ulrich},
  title     = {Prevalence dependent calibration of a predictive model for nasal carriage of methicillin-resistant Staphylococcus aureus},
  series = {BMC Infectious Diseases},
  journal   = {BMC Infectious Diseases},
  doi       = {10.1186/1471-2334-13-111},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-96091},
  year      = {2013},
  abstract  = {Background Published models predicting nasal colonization with Methicillin-resistant Staphylococcus aureus among hospital admissions predominantly focus on separation of carriers from non-carriers and are frequently evaluated using measures of discrimination. In contrast, accurate estimation of carriage probability, which may inform decisions regarding treatment and infection control, is rarely assessed. Furthermore, no published models adjust for MRSA prevalence. Methods Using logistic regression, a scoring system (values from 0 to 200) predicting nasal carriage of MRSA was created using a derivation cohort of 3091 individuals admitted to a European tertiary referral center between July 2007 and March 2008. The expected positive predictive value of a rapid diagnostic test (GeneOhm, Becton \& Dickinson Co.) was modeled using non-linear regression according to score. Models were validated on a second cohort from the same hospital consisting of 2043 patients admitted between August 2008 and January 2012. Our suggested correction score for prevalence was proportional to the log-transformed odds ratio between cohorts. Calibration before and after correction, i.e. accurate classification into arbitrary strata, was assessed with the Hosmer-Lemeshow-Test. Results Treating culture as reference, the rapid diagnostic test had positive predictive values of 64.8\% and 54.0\% in derivation and internal validation corhorts with prevalences of 2.3\% and 1.7\%, respectively. In addition to low prevalence, low positive predictive values were due to high proportion (> 66\%) of mecA-negative Staphylococcus aureus among false positive results. Age, nursing home residence, admission through the medical emergency department, and ICD-10-GM admission diagnoses starting with "A" or "J" were associated with MRSA carriage and were thus included in the scoring system, which showed good calibration in predicting probability of carriage and the rapid diagnostic test's expected positive predictive value. Calibration for both probability of carriage and expected positive predictive value in the internal validation cohort was improved by applying the correction score. Conclusions Given a set of patient parameters, the presented models accurately predict a) probability of nasal carriage of MRSA and b) a rapid diagnostic test's expected positive predictive value. While the former can inform decisions regarding empiric antibiotic treatment and infection control, the latter can influence choice of screening method.},
  language  = {en}
}