Validation and application of an ensemble Kalman filter in the Selat Pauh of Singapore

The effectiveness of an ensemble Kalman filter (EnKF) is assessed in the Selat Pauh of Singapore using observing system simulation experiment. Perfect model experiments are first considered. The perfect model experiments examine the EnKF in reducing the initial perturbations with no further errors than those in the initial conditions. Current velocity at 15 observational sites from the true ocean is assimilated every hour into the false ocean. While EnKF reduces the initial velocity error during the first few hours, it fails after one tidal cycle (approximately 12 h) due to the rapid convergence of the ensemble members. Successively, errors are introduced in the surface wind forcing. A random perturbation ε [epsilon] is applied independently to each ensemble member to maintain the ensemble spread. The assimilation results showed that the success of EnKF depends critically on the presence of ε [epsilon], yet it is not sensitive to the magnitude of ε [epsilon], at least in the range of weak to moderate perturbations. Although all experiments were made with EnKF only, the results could be applicable in general to all other ensemble-based data assimilation methods.United States. Office of Naval ResearchSingapore. National Research FoundationSingapore-MIT Alliance for Research and Technology CenterSingapore-MIT Alliance. Center for Environmental Sensing and Monitorin

Using sea-level data to constrain a finite-element primitive-equation ocean model with a local SEIK filter

Inspired by the pioneering work of Christian Le Provost on finiteelement ocean modeling a new ocean circulation model was developedover the last few years. It applies a surface triangulation and finiteelements for an accurate description of coasts and bathymetry and theirsteering effect on the ocean circulation. A novel feature is the meshdesign which allows a vertical structure in geopotential (z)coordinates without loss of flexibility and avoids pressure gradienterrors everywhere except for the lowest layer of abyssal ocean. Themodel is combined with sea level measurements and data assimilation,another major research topic of Christian Le Provost. We apply the SEIKfilter which was developed in Grenoble while Christian was teachingthere. The addition of a local analysis scheme improves the filterperformance first of all in its variance estimates but also in its meansolution

A phase Ib/II study of ivosidenib with venetoclax plus /- azacitidine in IDH1-mutated myeloid malignancies

Background: Isocitrate dehydrogenase-1 (IDH1+) mutations are present in 5-15% of myeloid malignancies, promoting leukemogenesis through production of the oncometabolite 2-hydroxyglutarate resulting in arrested myeloid differentiation. IDH1+ malignancies demonstrate increased reliance on the anti-apoptotic protein BCL-2, enhancing susceptibility to the BCL-2 inhibitor venetoclax (VEN). We report an interim safety and efficacy analysis of the IDH1 inhibitor ivosidenib (IVO; 500 mg PO daily D15-continuous) combined with VEN (D1-14) +/- azacitidine (AZA; 75mg/m2 D1-7 every 28 days). Methods: Eligible patients age ≥18 with IDH1+ MDS, newly diagnosed AML (ND: treatment naïve [TN] or secondary/treated secondary AML [sAML]), or relapsed/refractory (R/R) AML enrolled into three dose levels (DL): DL1 (IVO+VEN 400 mg), DL2 (IVO+VEN 800 mg), DL3 (IVO+VEN 400 mg+AZA). Primary objectives included safety and tolerability, and IWG defined overall response (ORR: CR+CRi+CRh+PR+MLFS). Prior receipt of IVO or VEN was exclusionary. Results: 25 evaluable patients (DL1: 6, DL2: 6, DL3: 13) enrolled with a median follow-up of 16.1 months. Median age was 67 (range: 44-84). 84% (N=21) of patients had AML (ND: N=13 [TN: 8, sAML: 5], R/R: N=8), while 16% (N=4) had MDS. ELN risk was intermediate and adverse in 16% (N=4) and 56% (N=14). Median IDH1 VAF at enrollment was 22.7% (range: 5.1%-47.8%). Two patients had received a prior IDH1 inhibitor. The ORR was 92% (DL1: 67%, DL2: 100%, DL3: 100%). Composite CR (CRc: CR+CRi+CRh) was 84% (DL1: 67%, DL2: 100%, DL3: 85%) including 92% (TN: 100%, sAML: 80%), 63%, and 100% of patients with ND-AML, R/R-AML, or MDS. Median number of cycles received was 4 (DL1: 8.5, DL2: 6, DL3: 4) with ongoing responses in 62% (DL1: 33%, DL2: 50%, DL3: 82%) at 1-year. 8 patients transitioned to SCT (DL1: 0, DL2: 2, DL3: 6), and 8 patients remain on study (DL1: 2, DL2: 1, DL3: 5). 1-year OS was 68% for the entire study population (DL1: 50%, DL2: 67%, DL3: 78%), 71% in ND-AML (TN: 86%, sAML: 60%), 50% in R/R-AML, and 100% in MDS. Measurable residual disease negative CRc by multiparameter flow cytometry was attained in 60% (ND-AML: 67%, R/R-AML: 60%, MDS: 33%) correlating with improved OS (median OS: NR vs. 8.5 months, p-value: 0.038). Common grade 3/4 adverse events included febrile neutropenia (28%) and pneumonia (24%). Tumor lysis and differentiation syndrome occurred in two and four patients; all cases resolved with medical management. Conclusions: IVO+VEN +/- AZA is an effective treatment regimen in patients with IDH1+myeloid malignancies. The combination therapy is associated with an acceptable and expected toxicity profile with notable efficacy and high rates of MRD-negative CRc in AML. Enrollment into the study continues. Clinical trial information: NCT03471260.</p