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Frulloni, Luca/0000-0001-7417-2655; Hart, Phil/0000-0003-4346-6196; Capurso, Gabriele/0000-0002-0019-8753; de-Madaria, Enrique/0000-0002-2412-9541; Lohr, Matthias/0000-0002-7647-198X; Frokjaer, Jens Brondum/0000-0001-8722-0070 WOS:000542363500001 PubMed: 32552502 The overall objective of these guidelines is to provide evidence-based recommendations for the diagnosis and management of immunoglobulin G4 (IgG4)-related digestive disease in adults and children. IgG4-related digestive disease can be diagnosed only with a comprehensive work-up that includes histology, organ morphology at imaging, serology, search for other organ involvement, and response to glucocorticoid treatment. Indications for treatment are symptomatic patients with obstructive jaundice, abdominal pain, posterior pancreatic pain, and involvement of extra-pancreatic digestive organs, including IgG4-related cholangitis. Treatment with glucocorticoids should be weight-based and initiated at a dose of 0.6-0.8 mg/kg body weight/day orally (typical starting dose 30-40 mg/day prednisone equivalent) for 1 month to induce remission and then be tapered within two additional months. Response to initial treatment should be assessed at week 2-4 with clinical, biochemical and morphological markers. Maintenance treatment with glucocorticoids should be considered in multi-organ disease or history of relapse. If there is no change in disease activity and burden within 3 months, the diagnosis should be reconsidered. If the disease relapsed during the 3 months of treatment, immunosuppressive drugs should be added. National Societies Committee of the United European Gastroenterology (UEG) We gratefully acknowledge the support from the National Societies Committee of the United European Gastroenterology (UEG) for the conduct of these guidelines independent from other sources. No other funding was received.

The overall objective of these guidelines is to provide evidence-based recommendations for the diagnosis and management of immunoglobulin G4 (IgG4)-related digestive disease in adults and children. IgG4-related digestive disease can be diagnosed only with a comprehensive work-up that includes histology, organ morphology at imaging, serology, search for other organ involvement, and response to glucocorticoid treatment. Indications for treatment are symptomatic patients with obstructive jaundice, abdominal pain, posterior pancreatic pain, and involvement of extra-pancreatic digestive organs, including IgG4-related cholangitis. Treatment with glucocorticoids should be weight-based and initiated at a dose of 0.6-0.8 mg/kg body weight/day orally (typical starting dose 30-40 mg/day prednisone equivalent) for 1 month to induce remission and then be tapered within two additional months. Response to initial treatment should be assessed at week 2-4 with clinical, biochemical and morphological markers. Maintenance treatment with glucocorticoids should be considered in multi-organ disease or history of relapse. If there is no change in disease activity and burden within 3 months, the diagnosis should be reconsidered. If the disease relapsed during the 3 months of treatment, immunosuppressive drugs should be added.

In order to address the growing need for more accurate space-weather predictions, a new model named EUHFORIA (EUropean Heliospheric FORecasting Information Asset) was recently developed. We present the first results of the performance assessment for the solar-wind modeling with EUHFORIA and identify possible limitations of its present setup. Using the basic EUHFORIA 1.0.4 model setup with the default input parameters, we modeled background solar wind (no coronal mass ejections) and compared the obtained results with Advanced Composition Explorer (ACE) in-situ measurements. For the purposes of statistical study we developed a technique of combining daily EUHFORIA runs into continuous time series. The combined time series were derived for the years 2008 (low solar activity) and 2012 (high solar activity), from which in-situ speed and density profiles were extracted. We find for the low-activity phase a better match between model results and observations compared to the high-activity time interval considered. The quality of the modeled solarwind parameters is found to be rather variable. Therefore, to better understand the results obtained we also qualitatively inspected characteristics of coronal holes, i.e. the sources of the studied fast streams. We discuss how different characteristics of the coronal holes and input parameters to EUHFORIA influence the modeled fast solar wind, and suggest possibilities for the improvement of the model. ispartof: Solar Physics vol:294 issue:12 ispartof: location:Netherlands status: published

In order to address the growing need for more accurate space weather predictions, a new model named EUHFORIA (EUropean Heliospheric FORecasting Information Asset) was recently developed (Pomoell and Poedts, 2018). We present first results of the performance assessment for the solar wind modeling with EUHFORIA and identify possible limitations of its present setup. Using the basic EUHFORIA 1.0.4. model setup with the default input parameters, we modeled background solar wind (no coronal mass ejections) and compared the obtained results with ACE, in situ measurements. For the need of statistical study we developed a technique of combining daily EUHFORIA runs into continuous time series. The combined time series were derived for the years 2008 (low solar activity) and 2012 (high solar activity) from which in situ speed and density profiles were extracted. We find for the low activity phase a better match between model results and observations compared to the considered high activity time interval. The quality of the modeled solar wind parameters is found to be rather variable. Therefore, to better understand the obtained results we also qualitatively inspected characteristics of coronal holes, sources of the studied fast streams. We discuss how different characteristics of the coronal holes and input parameters to EUHFORIA influence the modeled fast solar wind, and suggest possibilities for the improvements of the model., submitted to Solar Physics

Evidence-based guidelines on the management of pancreatic cystic neoplasms (PCN) are lacking. This guideline is a joint initiative of the European Study Group on Cystic Tumours of the Pancreas, United European Gastroenterology, European Pancreatic Club, European-African Hepato-Pancreato-Biliary Association, European Digestive Surgery, and the European Society of Gastrointestinal Endoscopy. It replaces the 2013 European consensus statement guidelines on PCN. European and non-European experts performed systematic reviews and used GRADE methodology to answer relevant clinical questions on nine topics (biomarkers, radiology, endoscopy, intraductal papillary mucinous neoplasm (IPMN), mucinous cystic neoplasm (MCN), serous cystic neoplasm, rare cysts, (neo)adjuvant treatment, and pathology). Recommendations include conservative management, relative and absolute indications for surgery. A conservative approach is recommended for asymptomatic MCN and IPMN measuring < 40 mm without an enhancing nodule. Relative indications for surgery in IPMN include a main pancreatic duct (MPD) diameter between 5 and 9.9 mm or a cyst diameter >= 40 mm. Absolute indications for surgery in IPMN, due to the high-risk of malignant transformation, include jaundice, an enhancing mural nodule > 5 mm, and MPD diameter > 10 mm. Lifelong follow-up of IPMN is recommended in patients who are fit for surgery. The European evidence-based guidelines on PCN aim to improve the diagnosis and management of PCN.

OBJECTIVE: Desmoplasia and hypovascularity are thought to impede drug delivery in pancreatic ductal adenocarcinoma (PDAC). However, stromal depletion approaches have failed to show clinical responses in patients. Here, we aimed to revisit the role of the tumour microenvironment as a physical barrier for gemcitabine delivery. DESIGN: Gemcitabine metabolites were analysed in LSL-KrasG12D/+ ; LSL-Trp53R172H/+ ; Pdx-1-Cre (KPC) murine tumours and matched liver metastases, primary tumour cell lines, cancer-associated fibroblasts (CAFs) and pancreatic stellate cells (PSCs) by liquid chromatography-mass spectrometry/mass spectrometry. Functional and preclinical experiments, as well as expression analysis of stromal markers and gemcitabine metabolism pathways were performed in murine and human specimen to investigate the preclinical implications and the mechanism of gemcitabine accumulation. RESULTS: Gemcitabine accumulation was significantly enhanced in fibroblast-rich tumours compared with liver metastases and normal liver. In vitro, significantly increased concentrations of activated 2',2'-difluorodeoxycytidine-5'-triphosphate (dFdCTP) and greatly reduced amounts of the inactive gemcitabine metabolite 2',2'-difluorodeoxyuridine were detected in PSCs and CAFs. Mechanistically, key metabolic enzymes involved in gemcitabine inactivation such as hydrolytic cytosolic 5'-nucleotidases (Nt5c1A, Nt5c3) were expressed at low levels in CAFs in vitro and in vivo, and recombinant expression of Nt5c1A resulted in decreased intracellular dFdCTP concentrations in vitro. Moreover, gemcitabine treatment in KPC mice reduced the number of liver metastases by >50%. CONCLUSIONS: Our findings suggest that fibroblast drug scavenging may contribute to the clinical failure of gemcitabine in desmoplastic PDAC. Metabolic targeting of CAFs may thus be a promising strategy to enhance the antiproliferative effects of gemcitabine.

Background: Large-scale international collaboration is essential to decipher relevant information in the context of omics-scale interrogations in cancer research. This is even more important for rare and fatal diseases like pancreas cancer (PC). Methods: The COST Action BM1204 is a unique platform to facilitate the collaboration of a broad range of European and international PC multidisciplinary research groups in order to: (1) integrate knowledge and experience in a multidisciplinary way ‘from cell to society', (2) promote the application of uniform study tools and protocols, (3) foster their optimal use by early-stage researchers, (4) enhance the mobility and training of researchers, and (5) disseminate the results produced to the broader society. Results: This Action will develop novel interdisciplinary tools for collaborative research to improve our understanding of PC and its prevention, diagnosis and treatment. It also aims to answer questions related to the etiology, early detection, evidence-based and personalized treatment, and health management for PC. Furthermore, the Action will contribute to new insights into PC personalized medicine and beyond as well as to the understanding of complex and rare diseases taking PC as a best practice example. The Action aims at attracting young scholars across a range of disciplines in collaboration with more experienced researchers and enhancing active European participation in the international scenario of PC research. Conclusion: The ultimate aim is to foster PC research in Europe and to coordinate this effort with other international initiatives to reduce disease mortality.

International audience; A comprehensive experimental investigation of helicopter blunt fuselage drag reduction using active flow control is being carried out within the Clean Sky project. The objective is to demonstrate the capability of several active technologies to decrease fuselage drag by alleviating the flow separation occurring in the backdoor area of some helicopters (with pronounced ramp for backdoor loading). The work is performed on a simplified blunt fuselage at model scale. Several active flow control actuators are considered for evaluation: steady blowing, unsteady blowing (or pulsed jets), and zero-net-massflux blowing (or synthetic jets). Laboratory tests of each individual actuator are first performed to assess their performance and properties. The fuselage model is then equipped with these actuators distributed in eight slots forming a U-shape on the fuselage backdoor. This paper addresses the promising results obtained during the wind tunnel campaign, since significant drag reductions are achieved for a wide range of fuselage angles of attack. Moreover, a flow control strategy depending on the fuselage attitude is proposed. The link between the best actuation scheme for this attitude and the corresponding flow topology of the backdoor separation is also discussed.

Current airframes being already highly optimized nowadays, further aerodynamic performance improvements may only be reached by the implementation of flow manipulation techniques. The sixth issue of Aerospace Lab Journal is aimed at providing the reader with a comprehensive overview of the current developments of these methods. The papers presented successively review main aspects of flow control, both from the point of view of technology and that of the applications. Technologies consist not only in fluidic and plasma actuator development, but also in the specific know-how relative to closed-loop algorithms, reduced order models and actuator effect on the flow. Additionally, the potential of flow control techniques is presented on civil aircraft (both for low speed and cruise conditions), helicopters and turbomachinery applications., Journal Aerospace Lab, Issue 6, June 2013; ISSN: 2107-6596

This paper concerns the recent and most representative work performed at Onera on the application of flow control technologies to high-lift systems of aircraft wings. Two different objectives are considered. First, keeping present architecture, flow control could either enhance the aerodynamic performance (mainly mean and stall lift coefficients) or simplify the mechanisms (flap gap or size). Secondly, a drastic geometry simplification, very attractive for aircraft manufacturers, like slot or even slat suppression, leads to a strong depletion of aerodynamic performance. In that case, the objective of flow control is to retrieve as much as possible the reference airfoil performance. Various flow control devices, from simple mechanical or fluidic vortex generators to pulsed blowing, are considered. Combined numerical and experimental studies are presented and the efficiency of the control is discussed., Journal Aerospace Lab, Issue 6, June 2013; ISSN: 2107-6596

Background Recently, the first randomized trials comparing minimally invasive distal pancreatectomy (MIDP) with open distal pancreatectomy (ODP) for non-malignant and malignant disease showed a 2-day reduction in time to functional recovery after MIDP. However, for pancreatic ductal adenocarcinoma (PDAC), concerns have been raised regarding the oncologic safety (i.e., radical resection, lymph node retrieval, and survival) of MIDP, as compared to ODP. Therefore, a randomized controlled trial comparing MIDP and ODP in PDAC regarding oncological safety is warranted. We hypothesize that the microscopically radical resection (R0) rate is non-inferior for MIDP, as compared to ODP. Methods/design DIPLOMA is an international randomized controlled, patient- and pathologist-blinded, non-inferiority trial performed in 38 pancreatic centers in Europe and the USA. A total of 258 patients with an indication for elective distal pancreatectomy with splenectomy because of proven or highly suspected PDAC of the pancreatic body or tail will be randomly allocated to MIDP (laparoscopic or robot-assisted) or ODP in a 1:1 ratio. The primary outcome is the microscopically radical resection margin (R0, distance tumor to pancreatic transection and posterior margin ≥ 1 mm), which is assessed using a standardized histopathology assessment protocol. The sample size is calculated with the following assumptions: 5% one-sided significance level (α), 80% power (1-β), expected R0 rate in the open group of 58%, expected R0 resection rate in the minimally invasive group of 67%, and a non-inferiority margin of 7%. Secondary outcomes include time to functional recovery, operative outcomes (e.g., blood loss, operative time, and conversion to open surgery), other histopathology findings (e.g., lymph node retrieval, perineural- and lymphovascular invasion), postoperative outcomes (e.g., clinically relevant complications, hospital stay, and administration of adjuvant treatment), time and site of disease recurrence, survival, quality of life, and costs. Follow-up will be performed at the outpatient clinic after 6, 12, 18, 24, and 36 months postoperatively. Discussion The DIPLOMA trial is designed to investigate the non-inferiority of MIDP versus ODP regarding the microscopically radical resection rate of PDAC in an international setting. Trial registration ISRCTN registry ISRCTN44897265. Prospectively registered on 16 April 2018.