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Obstructive sleep apnea syndrome (OSAS) is the most common sleep disorder in humans. Although OSAS is clearly related to arterial hypertension, coronary artery disease, and heart failure, it remains unknown through which pathomechanisms OSAS influences cardiovascular health. Recent research has pinpointed long non-coding RNAs (lncRNA) as important molecular mediators of various cardiovascular pathologies. In this study, we have identified the lncRNA MRPL20-AS1 to be affected by OSAS in patients as well as by hypoxia in vitro.A transcriptomic analysis was performed on peripheral blood from four patients with severe OSAS taken after one night of polygraphic assessment. We found that three lncRNAs were significantly dysregulated, of which MRPL20-AS1 was the most significant. In a larger cohort of 22 OSAS patients, MRPL20-AS1 was inversely correlated with the apnea-hypopnea index (AHI). This indicates that OSAS patients with higher AHI levels and therefore more severe OSAS had lower levels of MRPL20-AS1 in the blood. The results were recapitulated in vitro by subjecting endothelial cells to hypoxia. In these experiments, hypoxia led to a significant downregulation of MRPL20-AS1 in endothelial cells.MRPL20-AS1 may serve as a useful tool to identify patients suffering from severe OSAS and further research should be done to evaluate the therapeutic potential of MRPL20-AS1 as a target to counteract the cardiovascular effects of OSAS.

We develop a general theory of random walks on hypergraphs which includes, as special cases, the different models that are found in literature. In particular, we introduce and analyze general random walk Laplacians for hypergraphs, and we compare them to hypergraph normalized Laplacians that are not necessarily related to random walks, but which are motivated by biological and chemical networks. We show that, although these two classes of Laplacians coincide in the case of graphs, they appear to have important conceptual differences in the general case. We study the spectral properties of both classes, as well as their applications to Coupled Hypergraph Maps: discrete-time dynamical systems that generalize the well-known Coupled Map Lattices on graphs. Our results also show why for some hypergraph Laplacian variants one expects more classical results from (weighted) graphs to generalize directly, while these results must fail for other hypergraph Laplacians.

Mixing characteristics of the non-Newtonian fluid in a stirred vessel with a side-entry novel propeller was investigated by using computational fluid dynamics (CFD). The SST model (SST), standard k-ω (SKO), Reynold stress model (RSM), standard k-e (SKE), Realizable k-e (KER), RNG k-e (RNG) were evaluated for nine generalized Reynolds numbers operating at different flow conditions. In order to determine the estimated trait generalized Reynolds number at the end of the laminar regime, both the laminar and turbulent model simulations were conducted. Those results were validated with the published literature experimental results and different simulated results. By comparing the simulated and experimental literature results, the SST and RSM models are found to be more accurate than the other four turbulence models in predicting the torque. The power consumption and power numbers curves calculated from the SST and RSM models are highly consistent with the experimental results. To verify the effect of the applied turbulence models on predictive accuracy, both the velocity field, streamlines distributions, and the velocity profiles are evaluated. The RSM model was found to be more realizable for capturing mixing behavior in lower concentration solutions and with lower rotation speeds. However, this model has some drawbacks for modeling stirred vessels, such as a large number of modeled revolutions and mesh statistical required to obtain good quantities. In contrasts with the RSM model, the SST model is more reliable to predict velocity profiles and flow patterns in higher concentration solutions, especially in the near wall region.

This special issue analyses and reflects on socio-technical futures as core elements in innovation processes and their governance. The special issue assembles twelve contributions that draw on several lines of research mobilizing concepts developed in science and technology studies, such as socio-technical imaginaries and the sociology of expectations, and technology assessment. The papers examine how socio-technical futures are constituted, change and unfold over time, shaped by different practices and in different contexts. Furthermore, they study how different socio-technical futures circulate amongst policy actors and others involved in the governance of innovations, how they shape the governance of innovations and the actual technologies and systems, and how forms of deliberative and reflective future-making can be integrated into policy and innovation processes.

Context The oncological efficacy of routine lymphadenectomy (lymph node dissection [LND]) at the time of radical nephroureterectomy (RNU) remains controversial. Objective To systematically review the available literature assessing the impact of LND in upper tract urothelial carcinoma (UTUC) patients. Evidence acquisition Embase, Medline, and Cochrane databases were searched for all studies comparing outcomes of patients undergoing RNU without LND versus any form of LND. We identified nine retrospective studies eligible for inclusion in this systematic review. We took cancer-specific survival (CSS) as the primary end point, and performed a narrative review and risk of bias assessment. Evidence synthesis Six studies compared outcomes of no LND versus LND. Three studies compared complete LND versus incomplete LND versus no LND. The incidence of pN+ in patients with high-stage (≥pT2) tumours ranged from 14.3% to 40%. Pre- and postoperative characteristics differed among the study groups, potentially biasing the results, as demonstrated by the risk of bias assessment, potentially favouring the LND group. Oncological outcomes such as cancer-specific, overall, recurrence-free, and metastasis-free survival were reviewed, demonstrating a survival benefit with LND in high-stage disease of the renal pelvis. Conclusions Template-based and complete LND improves CSS in patients with high-stage (≥pT2) UTUC and reduces the risk of local recurrence. The impact of LND in ureteral tumours remains uncertain. Patient summary Studies comparing radical nephroureterectomy with or without the removal of nodes (lymph node dissection [LND]) were analysed. LND improves survival in patients with high-stage disease of the renal pelvis, if it is performed according to an anatomical template-based approach.

Many different procedures to design mixers have been investigated in research literature. The methods are either typically based on empiricism or already available mixers are scaled to adjust them to different but similar operating conditions, as considered in the original design process. For the most part the power characteristics of such a design of mixer has been proven through empirical methods, or is estimated within the mentioned scale-up methodology. The estimation of the power consumption has been shown as especially prone to error. The practice of estimation is associated with uncertainties, due to the determination of the power consumption in a late step of the design technique, or just simply has a low reliability. In this paper, a method will be derived in order to predict the full power characteristic without performing any experimental investigations within the design process. A new blade element momentum theory based design method will be taken and enhanced to calculate the power consumption by actually inverting the entire design procedure.

A side-entry propeller was designed and introduced in this study. The mixing performance of shear thinning fluids in a cylindrical stirred vessel equipped with this propeller was experimentally investigated via an ultrasonic Doppler anemometer (UDA, experimental results were consistent with theoretical findings. The power number and Reynolds number of this propeller were evaluated by using Chhabra, Metzner and Reed equations. Results showed that the power number versus the Reynolds number curves were highly comparable with Metzner and Reed equations. The velocity jet vectors flow field of 320, 380, and 440 rpm were described in detail. These findings demonstrated that the circulation loops, cavern size, and shape were highly influenced by shear thinning parameters and operating conditions. The average of the velocity profiles from five sample lines in front of the propeller was utilized to analyze the effect of rheological properties and operating conditions on the propeller. The axial, radial and tangential 2D velocity profiles located at one sample line (200 mm) in front of the propeller at the design rotation speed were evaluated.

The common design methods for mixers agitating non-Newtonian fluid flow are not suitable for developing a completely new geometrical shape. These design methods were originally intended only to scale an existing mixer with several correlation methods. For this, the dimensionless power characteristics of the mixer is first determined for agitating Newtonian fluid flow. Subsequently, for the desired operating conditions, the apparent viscosity of the non-Newtonian fluid is derived using the mentioned correlation principles. After setting the desired geometrical parameters, it is possible to calculate the apparent Reynolds number. By comparing the apparent Reynolds number with the dimensionless power characteristics, the estimated power consumption and, therefore, the engine to drive the mixer can be determined. This procedure comes with the assumption of a valid correlation between Newtonian and non-Newtonian fluid flow, which is not physical. Furthermore, the question of how to develop the geometric shape of a mixer for a considered operation point is still open. In this paper, a new method is introduced to develop the shape of a propeller mixer for arbitrary operating conditions in pseudo-plastic fluids by analytical methods. The method is based on the consequently implemented blade element momentum theory.

Context The European Association of Urology (EAU) panel on Non–muscle-invasive Bladder Cancer (NMIBC) released an updated version of the guidelines on Non–muscle-invasive Bladder Cancer. Objective To present the 2016 EAU guidelines on NMIBC. Evidence acquisition A broad and comprehensive scoping exercise covering all areas of the NMIBC guidelines published between April 1, 2014, and May 31, 2015, was performed. Databases covered by the search included Medline, Embase, and the Cochrane Libraries. Previous guidelines were updated, and levels of evidence and grades of recommendation were assigned. Evidence synthesis Tumours staged as TaT1 or carcinoma in situ (CIS) are grouped as NMIBC. Diagnosis depends on cystoscopy and histologic evaluation of the tissue obtained by transurethral resection of the bladder (TURB) in papillary tumours or by multiple bladder biopsies in CIS. In papillary lesions, a complete TURB is essential for the patient's prognosis. If the initial resection is incomplete, there is no muscle in the specimen, or a high-grade or T1 tumour is detected, a second TURB should be performed within 2–6 wk. The risks of both recurrence and progression may be estimated for individual patients using the European Organisation for Research and Treatment of Cancer (EORTC) scoring system and risk tables. The stratification of patients into low-, intermediate-, and high-risk groups is pivotal to recommending adjuvant treatment. For patients with a low-risk tumour and intermediate-risk patients at a lower risk of recurrence, one immediate instillation of chemotherapy is recommended. Patients with an intermediate-risk tumour should receive 1 yr of full-dose bacillus Calmette-Guerin (BCG) intravesical immunotherapy or instillations of chemotherapy for a maximum of 1 yr. In patients with high-risk tumours, full-dose intravesical BCG for 1–3 yr is indicated. In patients at highest risk of tumour progression, immediate radical cystectomy (RC) should be considered. RC is recommended in BCG-refractory tumours. The long version of the guidelines is available at the EAU Web site (www.uroweb.org/guidelines). Conclusions These abridged EAU guidelines present updated information on the diagnosis and treatment of NMIBC for incorporation into clinical practice. Patient summary The European Association of Urology has released updated guidelines on Non–muscle-invasive Bladder Cancer (NMIBC). Stratification of patients into low-, intermediate-, and high-risk groups is essential for decisions about adjuvant intravesical instillations. Risk tables can be used to estimate risks of recurrence and progression. Radical cystectomy should be considered only in case of failure of instillations or in NMIBC with the highest risk of progression.

Endocrine disruption (ED) can trigger far-reaching effects on environmental populations, justifying a refusal of market approval for chemicals with ED properties. For the hazard assessment of ED effects on the thyroid system, regulatory decisions mostly rely on amphibian studies. Here, we used transcriptomics and proteomics for identifying molecular signatures of interference with thyroid hormone signaling preceding physiological effects in zebrafish embryos. For this, we analyzed the thyroid hormone 3,3',5-triiodothyronine (T3) and the thyroid peroxidase inhibitor 6-propyl-2-thiouracil (6-PTU) as model substances for increased and repressed thyroid hormone signaling in a modified zebrafish embryo toxicity test. We identified consistent gene expression fingerprints for both modes-of-action (MoA) at sublethal test concentrations. T3 and 6-PTU both significantly target the expression of genes involved in muscle contraction and functioning in an opposing fashion, allowing for a mechanistic refinement of key event relationships in thyroid-related adverse outcome pathways in fish. Furthermore, our fingerprints identify biomarker candidates for thyroid disruption hazard screening approaches. Perspectively, our findings will promote the AOP-based development of in vitro assays for thyroidal ED assessment, which in the long term will contribute to a reduction of regulatory animal tests.

Context There is uncertainty regarding the oncologic effectiveness of kidney-sparing surgery (KSS) compared with radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC). Objective To systematically review the current literature comparing oncologic outcomes of KSS versus RNU for UTUC. Evidence acquisition A computerised bibliographic search of the Medline, Embase, and Cochrane databases was performed for all studies reporting comparative oncologic outcomes of KSS versus RNU. Approaches considered for KSS were segmental ureterectomy (SU) and ureteroscopic (URS) or percutaneous (PC) management. Using the methodology recommended by the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines, we identified 22 nonrandomised comparative retrospective studies published between 1999 and 2015 that were eligible for inclusion in this systematic review. A narrative review and risk-of-bias (RoB) assessment were performed using cancer-specific survival (CSS) as the primary end point. Evidence synthesis Seven studies compared KSS overall ( n =547) versus RNU ( n =1376). Information on the comparison of SU ( n =586) versus RNU ( n =3692), URS ( n =162) versus RNU ( n =367), and PC ( n =66) versus RNU ( n =114) was available in 10, 5, and 2 studies, respectively. No significant difference was found between SU and RNU in terms of CSS or any other oncologic outcomes. Only patients with low-grade and noninvasive tumours experienced similar CSS after URS or PC when compared with RNU, despite an increased risk of local recurrence following endoscopic management of UTUC. The RoB assessment revealed, however, that the analyses were subject to a selection bias favouring KSS. Conclusions Our systematic review suggests similar survival after KSS versus RNU only for low-grade and noninvasive UTUC when using URS or PC. However, selected patients with high-grade and invasive UTUC could safely benefit from SU when feasible. These results should be interpreted with caution due to the risk of selection bias. Patient summary We reviewed the studies that compared kidney-sparing surgery versus radical nephroureterectomy for upper tract urothelial carcinoma. We found similar oncologic outcomes for favourable tumours when using ureteroscopic or percutaneous management, whereas indications for segmental ureterectomy could be extended to selected cases of aggressive tumours.

This paper argues that uncertainty is a general feature of projects, occurring in technological, organizational, and social contexts. In situations of uncertainty, rational plan-oriented action is only practicable and successful to a limited degree. Based upon empirical research of project work, forms of experience-based action to deal with uncertainty will be presented. This kind of work action has only marginally been investigated by scientific research and has been widely disregarded in practice. This is essentially due to the fact that plan-oriented rational action is a deeply rooted guiding principle for professional work and management in Western cultures and societies. For this reason, this paper first outlines from a sociological perspective that dealing with uncertainty in projects has to be seen in a comprehensive societal context. Thus, a new way to deal with uncertainty requires fundamental re-orientations concerning the understanding and investigation of work and organization. Empirical findings in this field are presented and discussed, and the concept of a dual uncertainty in project work is exposed.

This work deals with the accuracy of non-Newtonian Lattice Boltzmann simulations. Previous work for Newtonian fluids indicate that, depending on the numerical value of the dimensionless collision frequency ?, additional artificial viscosity is introduced, which negatively influences the accuracy. Since the non-Newtonian fluid behavior is incorporated through appropriate modeling of the dimensionless collision frequency, a ? dependent error E ? is introduced and its influence on the overall error is investigated. Here, simulations with the SRT and the MRT model are carried out for power-law fluids in order to numerically investigate the accuracy of non-Newtonian Lattice Boltzmann simulations. A goal of this accuracy analysis is to derive a recommendation for an optimal choice of the time step size and the simulation Mach number, respectively. For the non-Newtonian case, an error estimate for E ? in the form of a functional is derived on the basis of a series expansion of the Lattice Boltzmann equation. This functional can be solved analytically for the case of the Hagen-Poiseuille channel flow of non-Newtonian fluids. With the help of the error functional, the prediction of the global error minimum of the velocity field is excellent in regions where the E ? error is the dominant source of error. With an optimal simulation Mach number, the simulation is about one order of magnitude more accurate. Additionally, for both collision models a detailed study of the convergence behavior of the method in the non-Newtonian case is conducted. The results show that the simulation Mach number has a major impact on the convergence rate and second order accuracy is not preserved for every choice of the simulation Mach number.

In this work, we consider the limited fitness for practical use of the Lattice Boltzmann Method for non-Newtonian fluid flows. Several authors have shown that the LBM is capable of correctly simulating those fluids. However, due to stability reasons the modeled viscosity range has to be truncated. The resulting viscosity boundaries are chosen arbitrarily, because the correct simulation Mach number for the physical problem is unknown a priori. This easily leads to corrupt simulation results. A viscosity adaption method (VAM) is derived which drastically improves the applicability of LBM for non-Newtonian fluid flows by adaption of the modeled viscosity range to the actual physical problem. This is done through tuning of the global Mach number to the solution-dependent shear rate. We demonstrate that the VAM can be used to accelerate LBM simulations and improve their accuracy, for both steady state and transient cases.

In this study we describe the use of a rope-in-a-bait sampling method (“pSWAB”: pathogen sampling wild animals with baits) for non-invasive saliva sampling aimed at the detection of foot-and-mouth disease (FMD) viral genome in wild boar. The pSWABs are produced in the form of a standardized product by embedding a 10 cm long cotton rope in a cereal-based bait matrix. To assess the general suitability of this novel sampling technique an animal experiment was conducted to detect FMD viral genome in saliva of infected wild boar. Two juvenile animals were inoculated in the bulb of the heel with a recent wild boar FMD virus isolate and kept together with three noninoculated wild boar of the same age. Over a period of 29 days, the animals were sampled by using five pSWABs per day in addition to the collection of blood and conventional saliva swabs taken every three to four days. Viral RNA in pSWABs was identified already 24 h after infection during the incubation period and until 23 dpi. Comparison of the results of pSWAB sampling with those of conventional saliva swabs or serum samples showed satisfactory sensitivity. These experimental data demonstrate the suitability of non-invasive sampling of wild boar by using pSWABs as a sensitive, cheap and feasible sample collection technique independent of hunting activities. In addition, the use of non-invasive sampling in an appropriate surveillance strategy is discussed.

Several classical swine fever (CSF) epidemics in wild boar and domestic pigs in Europe during the last decades have been caused by CSF virus (CSFV) strains of genotype 2.3. This genotype is known to be virulent leading to high morbidity and mortality. We experimentally infected two eight months old wild boar with 10(5,5) TCID50 of CSFV genotype 2.3 and kept the animals together with five noninoculated wild boar of the same age. Our original purpose was to evaluate a non-invasive sampling method based on saliva collection using "rope-in-a-bait" sampling baits. While expecting high morbidity, high level of virus shedding and some mortality, we actually observed a subclinical course of infection with an unexpected low contagiosity. The two inoculated animals infected only three contact animals while two contact animals remained uninfected. These findings substantially add to our epidemiological understanding of CSFV circulation in wild boar populations. CSFV infected animals older than six months and in good condition may not shed sufficient virus to transmit infection to all seronegative in-contact animals. The contagiosity in relation to the animal's age is discussed. This supports the hypothesis of silent perpetuation of CSFV in wild boar populations for several months if the wild boar density is sufficiently high. The feasibility of the "rope-in-a-bait" sampling method could be proven during the short viraemic phase of infected animals during the second week of infection.

This study conducts an experimental investigation of the effects of the mixing performance of a novel propeller fixed at three positions (0°, −10°, and 30°) was combined with the inference of the generalized Reynolds number and rheology properties. These were investigated using an ultrasonic Doppler anemometer (UDA) technique. All the experiments have been performed at three rheology concentration solutions (Rheo1, Rheo2, and Rheo3) and three rotation speeds (320 rpm, 380 rpm, and 440 rpm), which means nine generalized Reynolds numbers (Reg11, Reg12, Reg13, Reg21, Reg22, Reg23, Reg31, Reg32, Reg33), are selected for investigation. Torque features are first to demonstrate the characteristics of power consumption of the stirred system, and phase-averaged vorticity distributions provide the information of the vortex evolutions during the interaction between the jet vortex rings and the propeller. With the help of quantitative UDA data, instantaneous streamlines and velocity jet development are evaluated simultaneously to link the fluid dynamic characteristics in the vicinity of the propeller and the several cross-sections within the stirred vessel fields. The results showed that the inverse theoretical calculation for the propeller torque was highly comparable with the experimental measurements. It is found that the vorticity effect on the mixing quality is mainly reflected in the vortex ring in front of the propeller, whereas the impact of the Reynolds number on the fluid dynamic behavior for −10° and 30° are more significant than that of a 0°. Specifically, the vortex ring shed from the propeller hub is beneficial in suppressing the flow separation as well as the development of the secondary vortex ring.

Objective Ticagrelor is a direct and reversible competitive antagonist of the P2Y12 receptor and inhibits platelet activation. From 2013 to 2016, 1027 ticagrelor-affiliated deaths were reported from 59 countries to the Food and Drug Administration and the trend is on the rise [1] . In order to highlight ticagrelor-related risk of hemorrhage, we report herein a documented lethal intoxication and a disproportionality analysis using World Heath Organization (WHO) VigiBase®. Case history A 47-year-old man died from a severe cerebral hemorrhage secondary to a fall and cranial trauma 4 days after an assumed massive ticagrelor intake. Iterative platelet transfusions did not improve his condition. Methods Ticagrelor and its active metabolite AR-C124910XX plasma levels were determined by LC-MS/MS during patient hospitalization, using an Sciex API 3200 QTRAP mass spectrometer in negative electro-spray ionization mode [2] . Pharmacokinetics parameters were calculated using PK Solver® 2.0. We performed a disproportionality analysis using VigiBase®, the WHO pharmacovigilance database. Up to December 2018, more than 18 million Individual Case Safety Reports (ICSRs) have been collected from 131 countries. We extracted all the ICSRs with the MedDRA (version 21.1) preferred terms “cerebral hemorrhage” associated with antiplatelet agents, recorded from December 9, 1970 to December 16, 2018. Results LC-MS/MS toxicological analyses revealed high plasma concentrations of ticagrelor (3343 μg/L) and AR-C124910XX (656 μg/L) 10 h after the intake and remained quantifiable until patient death. Ticagrelor and AR-C124910XX elimination half-lives were 12.5 h and 32.8 h, respectively (normally 7.3 and 8.6 h). The ingested dose was therefore extrapolated to 1677 mg, which was a massive overdose (recommended dosage: 90 mg bid). In addition, the relationship between the use of ticagrelor and the occurrence of cerebral hemorrhage was assessed by calculating the reporting odds ratio (ROR) associated with its 95% confidence interval (CI) in a case-non-case model compared to other drugs. ROR value was significant (95% CI: lower boundary > 1 and ≥ 3 cases): ticagrelor (n = 229, ROR = 8,01, 95% CI: 7,03–9,13), confirming that ticagrelor treatment is associated with intracerebral hemorrhage. Conclusion Further studies are needed to better understand ticagrelor pharmacokinetics in cases of massive intoxication. These findings emphasized the need for a specific antidote to manage such complications resulting from ticagrelor overdose, but also the contribution of LC-MS/MS analysis to confirm a ticagrelor intoxication.

The unique properties of MOFs (MOF = metal–organic framework) such as their adjustable pore size, high intrinsic surface area and organic functionalizations make them a suitable class of materials for chromatographic separations. Micro particles of [Cu2(bdc)2(dabco)] (bdc2− = terephthalate, DABCO = 1,4-diazabicyclo[2.2.2]octane) were prepared by a cyclic deposition method based on the technique of the so called “controlled SBU approach” and anchored via SAMs (SAM = self-assembled monolayer) in a short GC capillary column to generate a wall-bonded cross linked stationary phase. It could be demonstrated, that the fabricated column exhibits a high separation power for the light hydrocarbons C1–C7. Chromatographic parameters, including resolution factors and selectivity as well as thermodynamic data characterizing the interaction between the stationary phase and the analytes, were determined from the temperature-dependent measurements of the retentions times of these analytes. In addition, isothermal measurements were used for the calculation of diffusion constants in [Cu2(bdc)2(dabco)].

Context The first European Association of Urology (EAU) guidelines on bladder cancer were published in 2002 [1]. Since then, the guidelines have been continuously updated. Objective To present the 2013 EAU guidelines on non–muscle-invasive bladder cancer (NMIBC). Evidence acquisition Literature published between 2010 and 2012 on the diagnosis and treatment of NMIBC was systematically reviewed. Previous guidelines were updated, and the levels of evidence and grades of recommendation were assigned. Evidence synthesis Tumours staged as Ta, T1, or carcinoma in situ (CIS) are grouped as NMIBC. Diagnosis depends on cystoscopy and histologic evaluation of the tissue obtained by transurethral resection (TUR) in papillary tumours or by multiple bladder biopsies in CIS. In papillary lesions, a complete TUR is essential for the patient's prognosis. Where the initial resection is incomplete, where there is no muscle in the specimen, or where a high-grade or T1 tumour is detected, a second TUR should be performed within 2–6 wk. The risks of both recurrence and progression may be estimated for individual patients using the EORTC scoring system and risk tables. The stratification of patients into low-, intermediate-, and high-risk groups is pivotal to recommending adjuvant treatment. For patients with a low-risk tumour, one immediate instillation of chemotherapy is recommended. Patients with an intermediate-risk tumour should receive one immediate instillation of chemotherapy followed by 1 yr of full-dose bacillus Calmette-Guerin (BCG) intravesical immunotherapy or by further instillations of chemotherapy for a maximum of 1 yr. In patients with high-risk tumours, full-dose intravesical BCG for 1–3 yr is indicated. In patients at highest risk of tumour progression, immediate radical cystectomy should be considered. Cystectomy is recommended in BCG-refractory tumours. The long version of the guidelines is available from the EAU Web site: http://www.uroweb.org/guidelines/. Conclusions These abridged EAU guidelines present updated information on the diagnosis and treatment of NMIBC for incorporation into clinical practice. Patient summary The EAU Panel on Non-muscle Invasive Bladder Cancer released an updated version of their guidelines. Current clinical studies support patient selection into different risk groups; low, intermediate and high risk. These risk groups indicate the likelihood of the development of a new (recurrent) cancer after initial treatment (endoscopic resection) or progression to more aggressive (muscle-invasive) bladder cancer and are most important for the decision to provide chemo- or immunotherapy (bladder installations). Surgical removal of the bladder (radical cystectomy) should only be considered in patients who have failed chemo- or immunotherapy, or who are in the highest risk group for progression.

Resumen Contexto y objetivo Presentar la guia clinica de la Asociacion Europea de Urologia (EAU) de 2011 del carcinoma de vejiga no musculo-invasivo (CVNMI). Adquisicion de la evidencia Se ha realizado una revision sistematica de la literatura publicada entre 2004 y 2010 acerca del diagnostico y el tratamiento del CVNMI. Se actualizaron las guias clinicas previas, y se asigno un nivel de evidencia (NE) y un grado de recomendacion (GR). Sintesis de la evidencia Los tumores en estadio Ta, T1 o carcinoma in situ (CIS) se agrupan como CVNMI. El diagnostico depende de la cistoscopia y de la evaluacion histologica del tejido obtenido por reseccion transuretral (RTU) en los tumores papilares o por biopsias de vejiga multiples en el CIS. En las lesiones papilares, una completa RTU es esencial para el pronostico del paciente. Cuando la primera reseccion es incompleta o cuando se detecta un tumor de alto grado o T1, se debe realizar una segunda RTU a las 2-6 semanas. En los tumores papilares, el riesgo tanto de recurrencia como de progresion se puede calcular de manera individual mediante los sistemas de puntuacion y tablas de riesgo. La estratificacion de los pacientes en grupos de riesgo bajo, intermedio y alto (separando la recidiva y la progresion) es fundamental para recomendar un tratamiento adyuvante. Para los pacientes con bajo riesgo de recurrencia y progresion se recomienda una instilacion inmediata de quimioterapia. Los pacientes con riesgo intermedio o alto de recurrencia y riesgo intermedio de progresion deben recibir una instilacion inmediata de quimioterapia seguida de un minimo de un ano con inmunoterapia intravesical con bacilo de Calmette-Guerin (BCG) o mas instilaciones de quimioterapia. Los tumores papilares con alto riesgo de progresion y CIS deben recibir BCG intravesical durante un ano. Se puede ofrecer una cistectomia a los pacientes de mas alto riesgo, y por lo menos se recomienda a los pacientes en los que ha fallado la BCG. Conclusion La version reducida de esta guia clinica de la EAU presenta una informacion actualizada sobre el diagnostico y el tratamiento del CVNMI para la incorporacion a la practica clinica.

Bacillus Calmette-Guerin (BCG) is a proven and valuable adjunct to transurethral resection (TUR) for decreasing recurrence and progression of non–muscle-invasive bladder cancer (NMIBC). The European Association of Urology (EAU) and American Urological Association (AUA) have similar recommendations for induction and maintenance treatment in patients based on clinical and pathologic risk factors. To most effectively treat this disease, clinicians must be aware of the risk factors for treatment failure, strategies to deal with failures and BCG intolerance, and the appropriate threshold to proceed with radical cystectomy (RC). Combination, alternative, and multimodal intravesical treatments for patients with BCG failure have arisen in recent years, and the outcomes data are reviewed here.

Background Recurrence prophylaxis with intravesical gemcitabine (GEM) was effective and safe in patients with non-muscle-invasive bladder cancer (NMIBC); efficacy as single-shot instillation remains to be proved. Objective To compare the efficacy of a single GEM instillation versus placebo (PBO) immediately after transurethral resection (TUR) of tumour in patients with histologically confirmed NMIBC (pTa/pT1,G1–3). Design, setting, and participants This was a double-blind, randomised, PBO-controlled study in patients with clinical evidence of primary or recurrent NMIBC (Ta/T1,G1–3). Of 355 patients randomised at 24 urologic centres, 328 underwent TUR and received instillation (92.4%; GEM/PBO: 166/162). In case of nonmalignancy, carcinoma in situ (CIS), ≥pT2 disease, or intraoperative complications, patients were discontinued. Intervention We used a single, postoperative 30–40-min instillation of GEM (2000mg/100ml of saline) or PBO (100ml of saline) followed by continuous bladder irrigation for ≥20h. A second TUR (no instillation) and adjuvant bacillus Calmette-Guerin (BCG) instillations were allowed. Measurements Primary outcome was recurrence-free survival (RFS). Secondary outcomes included type of recurrence and adverse events. To detect a difference in RFS, 191 recurrences were required (80% power, log-rank-test, α=0.050). Results and limitations Two hundred forty-eight patients (69.9%, GEM, PBO: 124, 124) had histologically confirmed pTa/pT1 G1–3 Gx tumour and were eligible for efficacy (GEM: 76.6% male; median age: 65 yr; PBO: 83.1% male; median age: 67 yr). Treatment groups were balanced (pTa: 75.0%, 71.0%; G1–G2: 85.5%, 87.9%; recurrent tumour: 24.2%, 21.0%; BCG: 10.5%, 16.9%). After a median follow-up of 24 mo, there were only 94 recurrences and 11 deaths. The study was terminated early based on predefined decision criteria. RFS was high in both groups (12-mo RFS [95% confidence interval (CI)]: GEM: 77.7% [68.8–84.3]; PBO: 75.3% [66.3–82.3]). There was no significant group difference (hazard ratio [HR]: 0.946 [0.64–1.39], log-rank test, p =0.777). Conclusions In this study of NMIBC, the immediate single instillation of GEM 2000mg/100ml of saline after TUR was not superior to PBO in terms of RFS. Rigid continuous irrigation and improved TUR/cystoscopy techniques may have contributed to the high RFS in both groups.

In spite of the importance of effcient supply chain cooperation, planning in production and transportation are still conducted separately today. This paper presents a model that simultaneously creates lot-based plans for both production and transportation. It is assumed that transports are organized as milk runs, i.e. one truck stops at several suppliers before heading to the buyer. The integration of production planning and inbound logistics tour planning into a dynamic model has not been studied before. After a brief review of literature on integrated planning models, requirements for a model that is able to solve the outlined problem are given. A mathematical model is formulated along with a heuristic which is necessary because the model combines production planning and vehicle routing which are both computationally intensive problems and thus not mathematically solvable in acceptable time. Results show that supply chain-wide costs can be reduced with the help of the presented algorithm. Some comments on the applicability in practice and the need for further research are given in an outlook.

Context The guidelines of the European Association of Urology (EAU), the First International Consultation on Bladder Tumors (FICBT), the National Comprehensive Cancer Network (NCCN), and the American Urological Association (AUA) all provide an excellent evidence-based background for the management of non-muscle invasive bladder cancer (NMIBC). Although there are areas of consensus among the four guidelines, their recommendations vary with respect to important issues surrounding NMIBC. Objective To provide community urologists with practical and unified guidance on the management of NMIBC through a comprehensive review of current influencing guidelines. Evidence acquisition A committee of internationally renowned leaders in bladder cancer management, known as the International Bladder Cancer Group (IBCG), was convened in October 2006 to review current literature surrounding the management of NMIBC as well as the current clinical practice guidelines of the EAU, the FICBT, the NCCN and the AUA. Following the inaugural meeting in October 2006, the IBCG met on three subsequent occasions (March 2007, September 2007, and March 2008) to critically analyze and compare the EAU, FICBT, NCCN, and AUA guidelines. Evidence synthesis The IBCG critically analyzed and summarized the EAU, FICBT, NCCN, and AUA guidelines and identified the key similarities and differences in their recommendations. Conclusions Established areas of consensus among the four guidelines include the importance of transurethral resection of the bladder tumour (TURBT) and an immediate, postoperative dose of chemotherapy (agent optional) in all patients with NMIBC, as well as the benefit of adjuvant bacillus Calmette-Guerin (BCG) therapy in high-risk disease. However, the four guideline recommendations vary with regard to the following important issues: (1) the definitions of low-, intermediate-, and high-risk disease, and (2) the appropriate management and follow-up of patients in each of these risk categories. Furthermore, there is currently no consensus on the definition and appropriate management strategies for primary intravesical treatment failures among the four guidelines.

Context and objective: To present the updated version of 2008 European Association of Urology (EAU) guidelines on non-muscle-invasive bladder cancer. Evidence acquisition: A systematic review of the recent literature on the diagnosis and treatment of non-muscle-invasive bladder cancer was performed. The guidelines were updated and the level of evidence and grade of recommendation were assigned. Evidence synthesis: The diagnosis of bladder cancer depends on cystoscopy and histologic evaluation of the resected tissue. A complete and correct transurethral resection (TUR) is essential for the prognosis of the patient. When the initial resection is incomplete or when a high-grade or T1 tumour is detected, a second TUR within 2–6 wk should be performed. The short- and long-term risks of both recurrence and progression may be estimated for individual patients using the scoring system and risk tables. The stratification of patients to low, intermediate, and high-risk groups—separately for recurrence and progression—represents the cornerstone for indication of adjuvant treatment. In patients at low risk of tumour recurrence and progression, one immediate instillation of chemotherapy is strongly recommended. In those at an intermediate or high risk of recurrence and an intermediate risk of progression, one immediate instillation of chemotherapy should be followed by further instillations of chemotherapy or a minimum of 1 yr of bacillus Calmette-Guerin (BCG). In patients at high risk of tumour progression, after an immediate instillation of chemotherapy, intravesical BCG for at least 1 yr is indicated. Immediate cystectomy may be offered to the highest risk patients and in patients with BCG failure. The long version of the guidelines is available on www.uroweb.org. Conclusions: These EAU guidelines present the updated information about the diagnosis and treatment of non-muscle-invasive bladder cancer and offer the recent findings for the routine clinical application.