Reduced-basis Output Bound Methods for Parametrised Partial Differential Equations

An efficient and reliable method for the prediction of outputs of interest of partial differential equations with affine parameter dependence is presented. To achieve efficiency we employ the reduced-basis method: a weighted residual Galerkin-type method, where the solution is projected onto low-dimensional spaces with certain problem-specific approximation properties. Reliability is obtained by a posteriori error estimation methods - relaxations of the standard error-residual equation that provide inexpensive but sharp and rigorous bounds for the error in outputs of interest. Special affine parameter dependence of the differential operator is exploited to develop a two-stage off-line/on-line blackbox computational procedure. In the on-line stage, for every new parameter value, we calculate the output of interest and an associated error bound. The computational complexity of the on-line stage of the procedure scales only with the dimension of the reduced-basis space and the parametric complexity of the partial differential operator; the method is thus ideally suited for the repeated and rapid evaluations required in the context of parameter estimation, design, optimization, and real-time control. The theory and corroborating numerical results are presented for: symmetric coercive problems (e.g. problems in conduction heat transfer), parabolic problems (e.g. unsteady heat transfer), noncoercive problems (e.g. the reduced-wave, or Helmholtz, equation), the Stokes problem (e.g flow of highly viscous fluids), and certain nonlinear equations (e.g. eigenvalue problems)

Fungal and Bacterial Loads: Noninvasive Inflammatory Bowel Disease Biomarkers for the Clinical Setting

Malaltia inflamatòria intestinal; Càrrega microbiana; PrediccióEnfermedad inflamatoria intestinal; Carga microbiana; PredicciónInflammatory bowel disease; Microbial load; PredictionMicrobiome sequence data have been used to characterize Crohn's disease (CD) and ulcerative colitis (UC). Based on these data, we have previously identified microbiomarkers at the genus level to predict CD and CD relapse. However, microbial load was underexplored as a potential biomarker in inflammatory bowel disease (IBD). Here, we sought to study the use of fungal and bacterial loads as biomarkers to detect both CD and UC and CD and UC relapse. We analyzed the fecal fungal and bacterial loads of 294 stool samples obtained from 206 participants using real-time PCR amplification of the ITS2 region and the 16S rRNA gene, respectively. We combined the microbial data with demographic and standard laboratory data to diagnose ileal or ileocolonic CD and UC and predict disease relapse using the random forest algorithm. Fungal and bacterial loads were significantly different between healthy relatives of IBD patients and nonrelated healthy controls, between CD and UC patients in endoscopic remission, and between UC patients in relapse and non-UC individuals. Microbial load data combined with demographic and standard laboratory data improved the performance of the random forest models by 18%, reaching an average area under the receiver operating characteristic curve (AUC) of 0.842 (95% confidence interval [CI], 0.65 to 0.98), for IBD diagnosis and enhanced CD and UC discrimination and CD and UC relapse prediction. Our findings show that fecal fungal and bacterial loads could provide physicians with a noninvasive tool to discriminate disease subtypes or to predict disease flare in the clinical setting. IMPORTANCE Next-generation sequence data analysis has allowed a better understanding of the pathophysiology of IBD, relating microbiome composition and functions to the disease. Microbiome composition profiling may provide efficient diagnosis and prognosis tools in IBD. However, the bacterial and fungal loads of the fecal microbiota are underexplored as potential biomarkers of IBD. Ulcerative colitis (UC) patients have higher fecal fungal and bacterial loads than patients with ileal or ileocolonic CD. CD patients who relapsed harbor more-unstable fungal and bacterial loads than those of relapsed UC patients. Fecal fungal and bacterial load data improved prediction performance by 18% for IBD diagnosis based solely on clinical data and enhanced CD and UC discrimination and prediction of CD and UC relapse. Combined with existing laboratory biomarkers such as fecal calprotectin and C-reactive protein (CRP), microbial loads may improve the diagnostic accuracy of IBD and of ileal CD and UC disease activity and prediction of UC and ileal CD clinical relapse.This work was funded by Instituto de Salud Carlos III, grant PI17/00614, cofinanced by the European Regional Development Fund (ERDF) and by the PERIS (SLT002/16). F. Casellas has received research funding from AbbVie, Ferring, MSD, Shire, and Zambon and speaker fees from AbbVie, Chiesi, Ferring, Gebro, MSD, Shire, Takeda, and Zambon. S. Vermeire has received grant support from AbbVie, MSD, Pfizer, J&J, and Takeda; received speaker fees from AbbVie, MSD, Takeda, Ferring, Dr. Falk Pharma, Hospira, Pfizer Inc., and Tillots; and served as a consultant for AbbVie, MSD, Takeda, Ferring, Genentech/Roche, Robarts clinical trials, Gilead, Celgene, Prometheus, Avaxia, Prodigest, Shire, Pfizer Inc, Galapagos, Mundipharma, Hospira, Celgene, Second Genome, and Janssen. C. Manichanh has received financial support for research from Danone

Pharmacokinetic (Pk) Activity of Cabazitaxel (Cbz) in Patients (Pts) with Renal Impairment (Ri)

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Mushrooms Red Book of Ukraine in Culture. 1. Patterns of Growth Hericium coralloides

На території НПП «Гуцульщина» виявлено лише три локалітети Hericium coralloides – гриба, занесеного до Червоної книги України. У результаті проведених досліджень виділено в чисту культуру аборигенний штам К01. Як для виділення, так і для підтримки та забезпечення життєздатності гриба в культурі картопельно-глюкозний агар виявився оптимальним серед апробованих середовищ. Індивідуальні особливості росту H. coralloides К01 вказують на вузькі трофічні можливості цього штаму при поверхневому культивуванні, оскільки з п’яти апробованих середовищ придатними для росту виявилися лише два. Цей штам гриба вважаємо перспективним для використання як інокулянта відповідних субстратів у природному середовищі, оскільки для нього характерні високі показники радіального росту, короткий період log-фази та утворення в чистій культурі стадії телеоморфи. The national park «Hutsulshchyna» found only three localities of Hericium coralloides − mushroom Red Book of Ukraine. The result of the research was to obtain in a pure culture of the native strain K01. As for the release, and to support and ensure the viability of the fungus in culture potato - glucose agar was the best among the tested environments. Individual features of the growth of H. coralloides K01 indicate the narrow trophic features of this strain at cultivation because from five tested media suitable for growth were only two. This strain K01 H. coralloides may be considered promising for use as an inoculant respective substrates in the environment , because it is characterized by high rates of radial growth , a short period of log- phase and ability to form stage teleomorfy in pure culture.Роботу виконано у НПП «Гуцульщина», ННЦ «Інститут біології» КНУ ім. Т. Шевченк

A phase I pharmacokinetic and safety study of cabazitaxel in adult cancer patients with normal and impaired renal function

$\textbf{PURPOSE}$ Limited data are available on cabazitaxel pharmacokinetics in patients with renal impairment. This open-label, multicenter study assessed cabazitaxel in patients with advanced solid tumors and normal or impaired renal function. $\textbf{METHODS}$ Cohorts A (normal renal function: creatinine clearance [CrCL] >80 mL/min/1.73 m$^{2}$), B (moderate renal impairment: CrCL 30 to <50 mL/min/1.73 m$^{2}$) and C (severe impairment: CrCL <30 mL/min/1.73 m(2)) received cabazitaxel 25 mg/m$^{2}$ (A, B) or 20 mg/m(2) (C, could be escalated to 25 mg/m$^{2}$), once every 3 weeks. Pharmacokinetic parameters and cabazitaxel unbound fraction (F$_{U}$) were assessed using linear regression and mixed models. Geometric mean (GM) and GM ratios (GMRs) were determined using mean CrCL intervals (moderate and severe renal impairment: 40 and 15 mL/min/1.73 m$^{2}$) versus a control (90 mL/min/1.73 m$^{2}$). $\textbf{RESULTS}$ Overall, 25 patients received cabazitaxel (median cycles: 3 [range 1-20]; Cohort A: 5 [2-13]; Cohort B: 3 [1-15]; and Cohort C: 5 [1-20]), of which 24 were eligible for pharmacokinetic analysis (eight in each cohort). For moderate and severe renal impairment versus normal renal function, GMR estimates were: clearance normalized to body surface area (CL/BSA) 0.95 (90% CI 0.80-1.13) and 0.89 (0.61-1.32); area under the curve normalized to dose (AUC/dose) 1.06 (0.88-1.27) and 1.14 (0.76-1.71); and F U 0.99 (0.94-1.04) and 0.97 (0.87-1.09), respectively. Estimated slopes of linear regression of log parameters versus log CrCL (renal impairment) were: CL/BSA 0.06 (-0.15 to 0.28); AUC/dose -0.07 (-0.30 to 0.16); and F U 0.02 (-0.05 to 0.08). Cabazitaxel safety profile was consistent with previous reports. $\textbf{CONCLUSIONS}$ Renal impairment had no clinically meaningful effect on cabazitaxel pharmacokinetics.This study was supported by Sanofi. Javier Garcia-Corbacho acknowledges clinical fellowship support from SEOM. Experimental Cancer Medicine Centre (ECMC) and NIHR Biomedical Research Centre (BRC) funding is also acknowledged for the Cambridge Cancer Centre

T0 monitoringplan voor effectmeting van VIBEG maatregelen in natura 2000 gebied Noordzeekustzone

In december 2011 is door vertegenwoordigers van de visserijsector, de natuurorganisaties en het ministerie (momenteel: Economische Zaken) het ‘VIBEG-akkoord’ gesloten. In dit akkoord wordt een ruimtelijke zonering van visserij-activiteit gegeven en is een tijdschema aangegeven voor wanneer welke maatregelen in werking treden. Voor het evalueren van de effecten van de maatregelen is monitoring nodig. Dit monitoringplan beschrijft de nulmeting voor de benodigde monitoring. Het vormt een onderdeel van de T0 bemonstering van het benthische ecosysteem in de Noordzeekustzone en Vlakte van de Raan in het kader van de Vogel- en Habitatrichtlijn. Het doel van specifiek dit onderdeel is het opstellen van een plan voor het verzamelen van een dataset waarmee later (in T1 en T2) de effecten van de ruimtelijke zonering van visserij in de Noordzeekustzone op het benthische ecosysteem in beeld kunnen worden gebracht

Outcomes in Patients With Metastatic Renal Cell Carcinoma Who Develop Everolimus-Related Hyperglycemia and Hypercholesterolemia: Combined Subgroup Analyses of the RECORD-1 and REACT Trials

In this study we examined the outcome of metastatic renal cell cancer patients with everolimus treatment-related hyperglycemia and hypercholesterolemia. All patients were treated in 2 large, international prospective trials, RECORD-1 (REnal Cell cancer treatment with Oral RAD001 given Daily) and REACT (RAD001 Expanded Access Clinical Trial in RCC). Patients who experienced these events might have experienced an improved response to everolimus. Background Hyperglycemia and hypercholesterolemia are class effects of mammalian target of rapamycin inhibitors. The purpose of this study was to characterize safety and efficacy of patients with metastatic renal cell carcinoma (mRCC) treated with everolimus in RECORD-1 (REnal Cell cancer treatment with Oral RAD001 given Daily) and REACT (RAD001 Expanded Access Clinical Trial in RCC) who developed these events. Patients and Methods Adults with vascular endothelial growth factor–refractory mRCC received everolimus 10 mg/d in the randomized RECORD-1 (n = 277) and open-label REACT (n = 1367) studies. Outcomes included safety, treatment duration, overall response, and progression-free survival for patients who developed hypercholesterolemia or hyperglycemia. Results In RECORD-1, 12% (33 of 277) and 20% (55 of 277) of patients developed any grade hyperglycemia or hypercholesterolemia, respectively, with only 6% (78 of 1367) and 1% (14 of 1367) of the same events, respectively, in REACT. Median everolimus treatment duration was similar for patients with hyperglycemia or hypercholesterolemia (RECORD-1, 6.2 and 6.2 months, respectively; REACT, 4.4 and 4.5 months, respectively), but longer than the overall populations (RECORD-1, 4.6 months; REACT, 3.2 months). In RECORD-1/REACT, 82%/68% of patients with hyperglycemia and 75%/71% of patients with hypercholesterolemia achieved partial response or stable disease. The incidence of clinically notable Grade 3 or 4 adverse events, other than anemia and lymphopenia, appeared to be similar across trials and subgroups. Although there was a trend for improved progression-free survival with development of hyperglycemia or hypercholesterolemia, the association was not statistically significant. Conclusion Hyperglycemia and hypercholesterolemia were observed in low numbers of patients, and although these events might be associated with improved response to everolimus, the differences were not significant. These findings should be validated with prospective biomarker studies

Pembrolizumab for recurrent head and neck squamous cell carcinoma (HNSCC): Post hoc analyses of treatment options from the phase III KEYNOTE-040 trial

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Managing cancer patients during the COVID-19 pandemic: an ESMO multidisciplinary expert consensus.

We established an international consortium to review and discuss relevant clinical evidence in order to develop expert consensus statements related to cancer management during the severe acute respiratory syndrome coronavirus 2-related disease (COVID-19) pandemic. The steering committee prepared 10 working packages addressing significant clinical questions from diagnosis to surgery. During a virtual consensus meeting of 62 global experts and one patient advocate, led by the European Society for Medical Oncology, statements were discussed, amended and voted upon. When consensus could not be reached, the panel revised statements until a consensus was reached. Overall, the expert panel agreed on 28 consensus statements that can be used to overcome many of the clinical and technical areas of uncertainty ranging from diagnosis to therapeutic planning and treatment during the COVID-19 pandemic