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PURPOSE: The CAPTIVATE study investigated first-line ibrutinib plus venetoclax for chronic lymphocytic leukemia in 2 cohorts: minimal residual disease (MRD)-guided randomized discontinuation (MRD cohort) and Fixed Duration (FD cohort). We report outcomes of fixed-duration ibrutinib plus venetoclax in patients with high-risk genomic features [del(17p), TP53 mutation, and/or unmutated immunoglobulin heavy chain (IGHV)] in CAPTIVATE. PATIENTS AND METHODS: Patients received three cycles of ibrutinib 420 mg/day then 12 cycles of ibrutinib plus venetoclax (5-week ramp-up to 400 mg/day). FD cohort patients (n = 159) received no further treatment. Forty-three MRD cohort patients with confirmed undetectable MRD (uMRD) after 12 cycles of ibrutinib plus venetoclax received randomized placebo treatment. RESULTS: Of 195 patients with known status of genomic risk features at baseline, 129 (66%) had ≥1 high-risk feature. Overall response rates were >95% regardless of high-risk features. In patients with and without high-risk features, respectively, complete response (CR) rates were 61% and 53%; best uMRD rates: 88% and 70% (peripheral blood) and 72% and 61% (bone marrow); 36-month progression-free survival (PFS) rates: 88% and 92%. In subsets with del(17p)/TP53 mutation (n = 29) and unmutated IGHV without del(17p)/TP53 mutation (n = 100), respectively, CR rates were 52% and 64%; uMRD rates: 83% and 90% (peripheral blood) and 45% and 80% (bone marrow); 36-month PFS rates: 81% and 90%. Thirty-six-month overall survival (OS) rates were >95% regardless of high-risk features. CONCLUSIONS: Deep, durable responses and sustained PFS seen with fixed-duration ibrutinib plus venetoclax are maintained in patients with high-risk genomic features, with similar PFS and OS to those without high-risk features. See related commentary by Rogers, p. 2561.

Xiaoxiao Lu,1 Bruno Emond,2 Laura Morrison,2 Frederic Kinkead,2 Patrick Lefebvre,2 Marie-Hélène Lafeuille,2 Wasiulla Khan,1 Linda H Wu,1 Zaina P Qureshi,1 Ryan Jacobs3 1Real World Value and Evidence, Oncology, Janssen Scientific Affairs, LLC, Horsham, PA, USA; 2Health Economics and Outcomes Research, Analysis Group, Inc, Montréal, Québec, Canada; 3Hematology and Medical Oncology, Atrium Health Levine Cancer Institute, Charlotte, NC, USACorrespondence: Bruno Emond, Analysis Group, Inc, 1190 avenue des Canadiens-de-Montréal, Tour Deloitte, Suite 1500, Montréal, Quebec, H3B 0G7, Canada, Tel +1-514-394-4455, Fax +1-514-394-4461, Email Bruno.Emond@analysisgroup.comPurpose: Increased dosing frequency adversely affects treatment adherence and outcomes in chronic diseases; however, such data related to treatment adherence is lacking in chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). This study compared adherence between patients treated with ibrutinib (once-daily) versus acalabrutinib (twice-daily) as first-line (1L) therapy for CLL/SLL.Patients and Methods: Specialty pharmacy electronic medical records were used to identify adults with CLL/SLL initiating 1L ibrutinib or acalabrutinib between 01/01/2018 and 11/30/2020. Adherence was measured by the proportion of days covered (PDC) and medication possession ratio (MPR) and was compared between cohorts using odds ratios (ORs) obtained from logistic regression models adjusted for baseline characteristics.Results: Between 01/01/2018 and 11/30/2020, 1374 and 140 patients initiated ibrutinib and acalabrutinib, respectively. Based on PDC/MPR ≥ 80%, patients treated with once-daily ibrutinib were more likely to be adherent than those treated with twice-daily acalabrutinib (OR ranges: PDC: 1.04– 1.76; MPR: 1.03– 1.58). At 6 months, patients on ibrutinib had a 58– 76% higher likelihood of staying adherent compared to patients on acalabrutinib (PDC: 75.9% for ibrutinib vs 63.6% for acalabrutinib, OR

PurposeThe phase II CAPTIVATE study investigated first-line treatment with ibrutinib plus venetoclax for chronic lymphocytic leukemia in two cohorts: minimal residual disease (MRD)-guided randomized treatment discontinuation (MRD cohort) and fixed duration (FD cohort). We report tumor debulking and tumor lysis syndrome (TLS) risk category reduction with three cycles of single-agent ibrutinib lead-in before initiation of venetoclax using pooled data from the MRD and FD cohorts.Patients and methodsIn both cohorts, patients initially received three cycles of ibrutinib 420 mg/day then 12 cycles of ibrutinib plus venetoclax (5-week ramp-up to 400 mg/day).ResultsIn the total population (N = 323), the following decreases from baseline to after ibrutinib lead-in were observed: percentage of patients with a lymph node diameter ≥5 cm decreased from 31% to 4%, with absolute lymphocyte count ≥25 × 109/L from 76% to 65%, with high tumor burden category for TLS risk from 23% to 2%, and with an indication for hospitalization (high TLS risk, or medium TLS risk and creatinine clearance <80 mL/minute) from 43% to 18%. Laboratory TLS per Howard criteria occurred in one patient; no clinical TLS was observed.ConclusionsThree cycles of ibrutinib lead-in before venetoclax initiation provides effective tumor debulking, decreases the TLS risk category and reduces the need for hospitalization for intensive monitoring for TLS.

PurposeCAPTIVATE (NCT02910583), a randomized phase II study, evaluates minimal residual disease (MRD)-guided treatment discontinuation following completion of first-line ibrutinib plus venetoclax treatment in patients with chronic lymphocytic leukemia (CLL).MethodsPreviously untreated CLL patients age < 70 years received three cycles of ibrutinib and then 12 cycles of combined ibrutinib plus venetoclax. Patients in the MRD cohort who met the stringent random assignment criteria for confirmed undetectable MRD (Confirmed uMRD) were randomly assigned 1:1 to double-blind placebo or ibrutinib; patients without Confirmed uMRD (uMRD Not Confirmed) were randomly assigned 1:1 to open-label ibrutinib or ibrutinib plus venetoclax. Primary end point was 1-year disease-free survival (DFS) rate with placebo versus ibrutinib in the Confirmed uMRD population. Secondary end points included response rates, uMRD, and safety.ResultsOne hundred sixty-four patients initiated three cycles of ibrutinib lead-in. After 12 cycles of ibrutinib plus venetoclax, best uMRD response rates were 75% (peripheral blood) and 68% (bone marrow). Patients with Confirmed uMRD were randomly assigned to receive placebo (n = 43) or ibrutinib (n = 43); patients with uMRD Not Confirmed were randomly assigned to ibrutinib (n = 31) or ibrutinib plus venetoclax (n = 32). Median follow-up was 31.3 months. One-year DFS rate was not significantly different between placebo (95%) and ibrutinib (100%; arm difference: 4.7% [95% CI, -1.6 to 10.9]; P = .15) in the Confirmed uMRD population. After ibrutinib lead-in tumor debulking, 36 of 40 patients (90%) with high tumor lysis syndrome risk at baseline shifted to medium or low tumor lysis syndrome risk categories. Adverse events were most frequent during the first 6 months of ibrutinib plus venetoclax and generally decreased over time.ConclusionThe 1-year DFS rate of 95% in placebo-randomly assigned patients with Confirmed uMRD suggests the potential for fixed-duration t

In this work, we perform semantic segmentation of multiple defect types in electron microscopy images of irradiated FeCrAl alloys using a deep learning Mask Regional Convolutional Neural Network (Mask R-CNN) model. We conduct an in-depth analysis of key model performance statistics, with a focus on quantities such as predicted distributions of defect shapes, defect sizes, and defect areal densities relevant to informing modeling and understanding of irradiated Fe-based materials properties. To better understand the performance and present limitations of the model, we provide examples of useful evaluation tests which include a suite of random splits, and dataset size-dependent and domain-targeted cross validation tests. Overall, we find that the current model is a fast, effective tool for automatically characterizing and quantifying multiple defect types in microscopy images, with a level of accuracy on par with human domain expert labelers. More specifically, the model can achieve average defect identification F1 scores as high as 0.8, and, based on random cross validation, have low overall average (+/- standard deviation) defect size and density percentage errors of 7.3 (+/- 3.8)% and 12.7 (+/- 5.3)%, respectively. Further, our model predicts the expected material hardening to within 10-20 MPa (about 10% of total hardening), which is about the same error level as experiments. Our targeted evaluation tests also suggest the best path toward improving future models is not expanding existing databases with more labeled images but instead data additions that target weak points of the model domain, such as images from different microscopes, imaging conditions, irradiation environments, and alloy types. Finally, we discuss the first phase of an effort to provide an easy-to-use, open-source object detection tool to the broader community for identifying defects in new images.

© 2019 American Chemical Society. Electronic structure descriptors are computationally efficient quantities used to construct qualitative correlations for a variety of properties. In particular, the oxygen p-band center has been used to guide material discovery and fundamental understanding of an array of perovskite compounds for use in catalyzing the oxygen reduction and evolution reactions. However, an assessment of the effectiveness of the oxygen p-band center at predicting key measures of perovskite catalytic activity has not been made and would be highly beneficial to guide future predictions and codify best practices. Here, we have used density functional theory at the Perdew-Burke-Ernzerhof (PBE), PBEsol, PBE + U, strongly constrained and appropriately normed functional, and Heyd-Scuseria-Ernzerhof (HSE06) levels to assess the correlations of numerous measures of catalytic performance for a series of technologically relevant perovskite oxides, using the bulk oxygen p-band center as an electronic structure descriptor. We have analyzed correlations of the calculated oxygen p-band center for all considered functionals with the experimentally measured X-ray emission spectroscopy oxygen p-band center and multiple measures of catalytic activity, including high-temperature oxygen reduction surface exchange rates, aqueous oxygen evolution current densities, and binding energies of oxygen evolution intermediate species. Our results show that the best correlations for all measures of catalytic activity considered here are made with PBE-level calculations, with strong observed linear correlations with the bulk oxygen p-band center (R 2 = 0.81-0.87). This study shows that strong linear correlations between numerous important measures of catalytic activity and the oxygen p-band bulk descriptor can be obtained under a consistent computational framework, and these correlations can serve as a guide for future experiments and simulations for development of perovskite and rela

PurposeVenetoclax-based therapy is a standard-of-care option in first-line and relapsed/refractory chronic lymphocytic leukemia (CLL). Patient management following venetoclax discontinuation remains nonstandard and poorly understood.Experimental designTo address this, we conducted a large international study to identify a cohort of 326 patients who discontinued venetoclax and have been subsequently treated. Coprimary endpoints were overall response rate (ORR) and progression-free survival for the post-venetoclax treatments stratified by treatment type [Bruton's tyrosine kinase inhibitor (BTKi), PI3K inhibitor (PI3Ki), and cellular therapies].ResultsWe identified patients with CLL who discontinued venetoclax in the first-line (4%) and relapsed/refractory settings (96%). Patients received a median of three therapies prior to venetoclax; 40% were BTKi naïve (n = 130), and 81% were idelalisib naïve (n = 263). ORR to BTKi was 84% (n = 44) in BTKi-naïve patients versus 54% (n = 30) in BTKi-exposed patients. We demonstrate therapy selection following venetoclax requires prior novel agent exposure consideration and discontinuation reasons.ConclusionsFor BTKi-naïve patients, selection of covalently binding BTKis results in high ORR and durable remissions. For BTKi-exposed patients, covalent BTK inhibition is not effective in the setting of BTKi resistance. PI3Kis following venetoclax do not appear to result in durable remissions. We conclude that BTKi in naïve or previously responsive patients and cellular therapies following venetoclax may be the most effective strategies.See related commentary by Rogers, p. 3501.

Chaitra Ujjani, 1 Anthony Mato, 2 Brian T Hill, 3 John N Allan, 4 Frederick Lansigan, 5 Ryan Jacobs, 6 Alan Skarbnik, 7 Hande Tuncer, 8 John Pagel, 9 Danielle Brander, 10 Bruce Cheson, 11 Paul Barr, 12 Lindsey E Roeker, 2 Jeffrey Pu, 13 Nirav N Shah, 14 Andre Goy, 15 Stephen J Schuster, 16 Nicole Lamanna, 17 Alison Sehgal, 18 Constantine S Tam, 19 Mazyar Shadman 1 1Seattle Cancer Care Alliance, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; 2Division of Hematological Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; 3Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA; 4Division of Hematology and Medical Oncology, New York Presbyterian & Weill Cornell, New York, NY, USA; 5Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA; 6Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute, Charlotte, NC, USA; 7Novant Health Cancer Institute, Charlotte, NC 28204, USA; 8Lowell General Hospital, Tufts Medical Center, Boston, MA, USA; 9Center for Blood Disorders and Stem Cell Transplantation, Swedish Cancer Institute, Seattle, WA, USA; 10Division of Hematologic Malignancies and Cellular Therapy, Duke University, Durham, NC, USA; 11Lombardi Comprehensive Cancer Center, Georgetown University Hospital, Washington, DC, USA; 12Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA; 13Division of Hematology/Oncology, SUNY Upstate Medical University, Syracuse, NY, USA; 14Division of Hematology & Oncology, Medical College of Wisconsin, Milwaukee, WI, USA; 15John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ, USA; 16Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA; 17Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA; 18University of Pittsburgh Medical Center, Pittsburgh, PA, USA; 19Peter McCallum Cancer Centre, University of Melbourne, East

The Materials Genome Initiative (MGI) advanced a new paradigm for materials discovery and design, namely that the pace of new materials deployment could be accelerated through complementary efforts in theory, computation, and experiment. Along with numerous successes, new challenges are inviting researchers to refocus the efforts and approaches that were originally inspired by the MGI. In May 2017, the National Science Foundation sponsored the workshop “Advancing and Accelerating Materials Innovation Through the Synergistic Interaction among Computation, Experiment, and Theory: Opening New Frontiers” to review accomplishments that emerged from investments in science and infrastructure under the MGI, identify scientific opportunities in this new environment, examine how to effectively utilize new materials innovation infrastructure, and discuss challenges in achieving accelerated materials research through the seamless integration of experiment, computation, and theory. This article summarizes key findings from the workshop and provides perspectives that aim to guide the direction of future materials research and its translation into societal impacts.

The art of theatre has been classified and critiqued as being a mimetic art which is different from architecture. The mimetic arts, such as the performing arts, occur in performance spaces concealed in the physical architecture of a theater building. This fixed location of the theatre has led to the elements of the theatre to be hidden and contained within the box of the architecture. These elements could be referred to as the "troupes of theatre" in the tradition of a group of thespians being considered a troupe. The performing arts have been traditionally confined as temporary entertainment whose lasting value is situated by virtue of existing only while being on stage within the building. Architecture, on the other hand, holds tectonic value by being present as a real, physical addition to the built environment and the world, yet it also performs as a mimetic art. This creates disconnect and discrimination against theatre, as a mimetic art, which is evident through the neglect and concealment of these troupes of theatre within architecture. This is present in contemporary architecture by the location of the portions of theatre's performances spaces being hidden and concealed within. There is a disconnect between the physical theater and the physical architecture of the building that houses it. The question then arises, could these parts of the theatre, the troupes of theatre, participate in the design of the whole building? In this thesis, the troupes of theatre are celebrated and brought into the same light as the rest of the building that normally confines them to be revealed to the world. Those troupes of the theatre that typically are contained within the box of architecture, are expressed to influence the form of the building. This thesis project seeks to reveal these troupes of theatre that are typically hidden. The troupes that are usually concealed are revealed; the stage rigging, the repetition of the level changes of the seating within a proscenium thea

Increased naval patrols, infrastructure construction, and diplomatic visits characterize China’s expanding political, economic, and military presence in the Indo-Asia-Pacific region. This expansion creates challenges and opportunities for regional states and extra-regional powers that depend on the Indian Ocean’s sea-lanes. The alignment strategies undertaken by regional states in response to Chinese moves will critically influence how the region develops over the next 15 years. This project sought to identify the alignment strategies of smaller countries in the Indian Ocean Region (IOR) in the face of increasing Chinese presence in the region as well as the emerging Sino-Indian competition (the subject of a previous study by the same PIs). The aim was to inform the development of naval strategy and policy by providing USN leaders with insights that enable them to identify the most promising opportunities for building partnerships in the IOR. Focusing mainly on Sri Lanka and Indonesia, this project gathered a wide array of qualitative data through archival research and meetings with high-level officials and experts, mainly in India, Indonesia, and Sri Lanka. In general, we found that India remains strongly inclined to balance against China and aims to strengthen its partnerships with the United States and other countries to achieve this aim. However, smaller countries in the IOR are much less inclined to balance against China. They seek to enhance their ties with the United States and China, but wish to avoid taking sides in a Sino-American contest. This calls for a high degree of sensitivity, creativity, and patience in developing maritime security partnerships in the IOR.

Thesis: M.B.A., Massachusetts Institute of Technology, Sloan School of Management, 2015. In conjunction with the Leaders for Global Operations Program at MIT., Thesis: S.M., Massachusetts Institute of Technology, Department of Mechanical Engineering, 2015. In conjunction with the Leaders for Global Operations Program at MIT., Cataloged from PDF version of thesis., Includes bibliographical references (page 69)., Inventory is the largest asset on Nike's balance sheet-$3.9 Billion on May 3 1 st, 2014-and a key indicator of supply chain health. With new markets, products, and channels being added to Nike's sales portfolio each year, the environment in which Nike's supply chain must operate is becoming increasingly complex. Nike has responded to this complexity by splintering their supply chain into smaller segments, tailoring each segment to specific market and consumer needs. As a result of these market developments and Nike's organizational response, the task of understanding and predicting inventory movements has become increasingly challenging for Nike's business planning teams. This project creates an analytical method by which Nike can combine historical supply chain performance with sales forecasts to accurately predict future changes to company inventory levels. To achieve this goal and facilitate simple and flexible inventory predictions, a model was developed around the key segmentation dimensions that define Nike's supply chain. Use of this model enables Nike's senior management team to accurately predict movements in inventory due to product mix changes in the baseline sales forecasts. Additionally, the model provides Nike with a mechanism to evaluate sensitivity to forecast errors and the inventory costs associated with key strategic decisions to grow or shrink segments of their business. Preliminary results from the model over the time period FY15 - FY18 show a 2% increase in baseline inventory by the end of FY18 due both to growth in Apparel relative to Footwear and to growth in Direct-to-Consumer relative to Wholesale. This upward pressure on inventory leaves Nike in a precarious spot with Wall Street analysts who associate inventory growth relative to sales with poor marketplace performance. By carefully segmenting inventory, applying segment specific forecasts, and analyzing aggregated results through the use of the model, Nike can more accurately predict and, by Ryan Jacobs., M.B.A., S.M.

Thesis: M.B.A., Massachusetts Institute of Technology, Sloan School of Management, 2015. In conjunction with the Leaders for Global Operations Program at MIT., Thesis: S.M., Massachusetts Institute of Technology, Department of Mechanical Engineering, 2015. In conjunction with the Leaders for Global Operations Program at MIT., Cataloged from PDF version of thesis., Includes bibliographical references (page 69)., Inventory is the largest asset on Nike's balance sheet-$3.9 Billion on May 3 1 st, 2014-and a key indicator of supply chain health. With new markets, products, and channels being added to Nike's sales portfolio each year, the environment in which Nike's supply chain must operate is becoming increasingly complex. Nike has responded to this complexity by splintering their supply chain into smaller segments, tailoring each segment to specific market and consumer needs. As a result of these market developments and Nike's organizational response, the task of understanding and predicting inventory movements has become increasingly challenging for Nike's business planning teams. This project creates an analytical method by which Nike can combine historical supply chain performance with sales forecasts to accurately predict future changes to company inventory levels. To achieve this goal and facilitate simple and flexible inventory predictions, a model was developed around the key segmentation dimensions that define Nike's supply chain. Use of this model enables Nike's senior management team to accurately predict movements in inventory due to product mix changes in the baseline sales forecasts. Additionally, the model provides Nike with a mechanism to evaluate sensitivity to forecast errors and the inventory costs associated with key strategic decisions to grow or shrink segments of their business. Preliminary results from the model over the time period FY15 - FY18 show a 2% increase in baseline inventory by the end of FY18 due both to growth in Apparel relative to Footwear and to growth in Direct-to-Consumer relative to Wholesale. This upward pressure on inventory leaves Nike in a precarious spot with Wall Street analysts who associate inventory growth relative to sales with poor marketplace performance. By carefully segmenting inventory, applying segment specific forecasts, and analyzing aggregated results through the use of the model, Nike can more accurately predict and, by Ryan Jacobs., M.B.A., S.M.

The sustainability of strategic stability in South Asia remains of the highest importance to U.S. national security policy. The South Asian Nuclear Learning project was accordingly conceived to examine the region’s nuclear experiences after the 1998 tests. The end of the first decade (1998-2008) represented a good starting point. Later, the project expanded to further analyze the nuclear learning curve in the next decade, when security environment and technological innovations undertook major shifts. The National Nuclear Security Administration sponsored this research, which involved selected scholars and experts from Pakistan, India and United States. Some of these contributors also helped shape their state’s nuclear decisions in the earlier period following the nuclear tests.

This collection of selected papers brings together findings from the Center on Contemporary Conflict’s (CCC) South Asian Nuclear Learning project. With support from the National Nuclear Security Administration, a group of regional scholars from India, Pakistan, and the United States convened in Bangkok, Thailand in 2012 to discuss the concept of nuclear learning and apply it to the regional context of South Asia. Participants presented research findings assessing regional perspectives on nuclear learning, doctrinal developments, command and control setups, deterrence strategies, and approaches towards arms control, and confidence-building measures.