This study evaluated the safety, antitumor activity, pharmacokinetics, and pharmacodynamics of inotuzumab ozogamicin (InO) for CD22-positive relapsed/refractory acute lymphoblastic leukemia. In phase 1, patients received InO 1.2 (n = 3), 1.6 (n = 12), or 1.8 (n = 9) mg/m per cycle on days 1, 8, and 15 over a 28-day cycle (≤6 cycles). The recommended phase 2 dose (RP2D) was confirmed (expansion cohort; n = 13); safety and activity of InO were assessed in patients receiving the RP2D in phase 2 (n = 35) and in all treated patients (n = 72). The RP2D was 1.8 mg/m per cycle (0.8 mg/m on day 1; 0.5 mg/m on days 8 and 15), with reduction to 1.6 mg/m per cycle after complete remission (CR) or CR with incomplete marrow recovery (CRi). Treatment-related toxicities were primarily cytopenias. Four patients experienced treatment-related venoocclusive disease/sinusoidal obstruction syndrome (VOD/SOS; 1 fatal). Two VOD/SOS events occurred during treatment without intervening transplant; of 24 patients proceeding to poststudy transplant, 2 experienced VOD/SOS after transplant. Forty-nine (68%) patients had CR/CRi, with 41 (84%) achieving minimal residual disease (MRD) negativity. Median progression-free survival was 3.9 (95% confidence interval, 2.9-5.4) months; median overall survival was 7.4 (5.7-9.2) months for all treated patients, with median 23.7 (range, 6.8-29.8) months of follow-up for all treated patients alive at data cutoff. Achievement of MRD negativity was associated with higher InO exposure. InO was well tolerated and demonstrated high single-agent activity and MRD-negativity rates. This trial was registered at www.clinicaltrials.gov as #NCT01363297.

Triangle enumeration is a fundamental graph operation. Despite the lack of provably efficient (linear, or slightly superlinear) worst-case algorithms for this problem, practitioners run simple, efficient heuristics to find all triangles in graphs with millions of vertices. How are these heuristics exploiting the structure of these special graphs to provide major speedups in running time?We study one of the most prevalent algorithms used by practitioners. A trivial algorithm enumerates all paths of length 2, and checks if each such path is incident to a triangle. A good heuristic is to enumerate only those paths of length 2 where the middle vertex has the lowest degree. It is easily implemented and is empirically known to give remarkable speedups over the trivial algorithm.We study the behavior of this algorithm over graphs with heavy-tailed degree distributions, a defining feature of realworld graphs. The erased configuration model (ECM) efficiently generates a graph with asymptotically (almost) any desired degree sequence. We show that the expected running time of this algorithm over the distribution of graphs created by the ECM is controlled by the 4/3 -norm of the degree sequence. As a corollary of our main theorem, we prove expected linear-time performance for degree sequences following a power law with exponent α ≥ 7/3, and non-trivial speedup whenever α ∈ (2, 3).

In a cluster-randomized study, we investigate the impact of an argument-based approach to teaching science in elementary school on science learning and critical thinking skills. Forty-eight schools participated in the study, with data on 9,963 students across the 2 years of the intervention. Annual standardized tests assessing science content knowledge were used to evaluate the effect of the intervention on science using a hierarchical linear model. To assess critical thinking abilities, scores for the Cornell Critical Thinking instrument were assessed for the 2,353 students in fifth grade using a multilevel model. While no statistically significant gains were found for science content, there was statistically significant evidence that the intervention was associated with an improvement in critical thinking scores (p < .05, ES = 0.167). In particular, the strongest gains were for students in the following groups: individual education plan, free and reduced price lunch, and English language learners. K E Y W O R D Sargument-based instruction, elementary science education, improvements in critical thinking, multilevel modeling, randomized controlled trial, science learning

Listing all triangles is a fundamental graph operation. Triangles can have important interpretations in real-world graphs, especially social and other interaction networks. Despite the lack of provably efficient (linear, or slightly super-linear) worst-case algorithms for this problem, practitioners run simple, efficient heuristics to find all triangles in graphs with millions of vertices. How are these heuristics exploiting the structure of these special graphs to provide major speedups in running time?We study one of the most prevalent algorithms used by practitioners. A trivial algorithm enumerates all paths of length 2, and checks if each such path is incident to a triangle. A good heuristic is to enumerate only those paths of length 2 where the middle vertex has the lowest degree. It is easily implemented and is empirically known to give remarkable speedups over the trivial algorithm.We study the behavior of this algorithm over graphs with heavy-tailed degree distributions, a defining feature of real-world graphs. The erased configuration model (ECM) efficiently generates a graph with asymptotically (almost) any desired degree sequence. We show that the expected running time of this algorithm over the distribution of graphs created by the ECM is controlled by the 4/3 -norm of the degree sequence. Norms of the degree sequence are a measure of the heaviness of the tail, and it is precisely this feature that allows non-trivial speedups of simple triangle enumeration algorithms. As a corollary of our main theorem, we prove expected linear-time performance for degree sequences following a power law with exponent α ≥ 7/3, and non-trivial speedup whenever α ∈ (2, 3). *

Gemtuzumab ozogamicin (Mylotarg; Pfizer, New York, NY) was the first antibody–drug conjugate to be approved for CD33‐positive acute myeloid leukemia (AML). However, it was voluntarily withdrawn from the US market due to lack of clinical benefit in the confirmatory phase III trial. In 2012, several investigator cooperative studies using a different dosing regimen showed efficacy, but pharmacokinetic (PK) data were not collected in these trials. Through simulation of expected concentrations for new dosing regimens, PK/pharmacodynamic modeling was able to support the safety and efficacy of these regimens. Significant exposure–response relationships were found for the attainment of complete remission with and without platelet recovery, attainment of blast‐free status, the time course of myelosuppression, several grade ≥ 3 hepatic adverse events, and veno‐occlusive disease. Gemtuzumab ozogamicin received full approval by the US Food and Drug Administration (FDA) in September 2017 for newly diagnosed and relapsed AML in adult patients and relapsed AML in pediatric patients aged 2–17 years.