The University of Michigan Dioxin Exposure Study: Methods for an Environmental Exposure Study of Polychlorinated Dioxins, Furans, and Biphenyls

Background: The University of Michigan Dioxin Exposure Study (UMDES) was undertaken in response to concerns that the discharge of dioxin-like compounds from the Dow Chemical Company facilities in Midland, Michigan, resulted in contamination of soils in the Tittabawassee River floodplain and areas of the city of Midland, leading to an increase in residents’ body burdens of polychlorinated dibenzodioxins and polychlorinated dibenzofurans. Objectives: The UMDES is a hypothesis-driven study designed to answer important questions about human exposure to dioxins in the environment of Midland, where the Dow Chemical Company has operated for \u3e 100 years, and in neighboring Saginaw, Michigan. In addition, the UMDES includes a referent population from an area of Michigan in which there are no unusual sources of dioxin exposure and from which inferences regarding the general Michigan population can be derived. A central goal of the study is to determine which factors explain variation in serum dioxin levels and to quantify how much variation each factor explains. Conclusions: In this article we describe the study design and methods for a large population-based study of dioxin contamination and its relationship to blood dioxin levels. The study collected questionnaire, blood, dust, and soil samples on 731 people. This study provides a foundation for understanding the exposure pathways by which dioxins in soils, sediments, fish and game, and homegrown produce lead to increased body burdens of these compounds

Pharmacokinetics and Exposure–Response Analyses of Daratumumab in Combination Therapy Regimens for Patients with Multiple Myeloma

Introduction: Daratumumab, a human IgG monoclonal antibody targeting CD38, has demonstrated activity as monotherapy and in combination with standard-of-care regimens in multiple myeloma. Population pharmacokinetic analyses were conducted to determine the pharmacokinetics of intravenous daratumumab in combination therapy versus monotherapy, evaluate the effect of patient- and disease-related covariates on drug disposition, and examine the relationships between daratumumab exposure and efficacy/safety outcomes. Methods: Four clinical studies of daratumumab in combination with lenalidomide/dexamethasone (POLLUX and GEN503); bortezomib/dexamethasone (CASTOR); pomalidomide/dexamethasone, bortezomib/thalidomide/dexamethasone, and bortezomib/melphalan/prednisone (EQUULEUS) were included in the analysis. Using various dosing schedules, the majority of patients (684/694) received daratumumab at a dose of 16 mg/kg. In GEN503, daratumumab was administered at a dose of 2 mg/kg (n = 3), 4 mg/kg (n = 3), 8 mg/kg (n = 4), and 16 mg/kg (n = 34). A total of 650 patients in EQUULEUS (n = 128), POLLUX (n = 282), and CASTOR (n = 240) received daratumumab 16 mg/kg. The exposure–efficacy and exposure–safety relationships examined progression-free survival (PFS) and selected adverse events (infusion-related reactions; thrombocytopenia, anemia, neutropenia, lymphopenia, and infections), respectively. Results: Pharmacokinetic profiles of daratumumab were similar between monotherapy and combination therapy. Covariate analysis identified no clinically important effects on daratumumab exposure, and no dose adjustments were recommended on the basis of these factors. Maximal clinical benefit on PFS was achieved for the majority of patients (approximately 75%) at the 16 mg/kg dose. No apparent relationship was observed between daratumumab exposure and selected adverse events. Conclusion: These data support the recommended 16 mg/kg dose of daratumumab and the respective dosing schedules in the POLLUX and CASTOR pivotal studies. Funding: Janssen Research & Development

Quantum dynamics of a single, mobile spin impurity

Quantum magnetism describes the properties of many materials such as transition metal oxides and cuprate superconductors. One of its elementary processes is the propagation of spin excitations. Here we study the quantum dynamics of a deterministically created spin-impurity atom, as it propagates in a one-dimensional lattice system. We probe the full spatial probability distribution of the impurity at different times using single-site-resolved imaging of bosonic atoms in an optical lattice. In the Mott-insulating regime, a post-selection of the data allows to reduce the effect of temperature, giving access to a space- and time-resolved measurement of the quantum-coherent propagation of a magnetic excitation in the Heisenberg model. Extending the study to the bath's superfluid regime, we determine quantitatively how the bath strongly affects the motion of the impurity. The experimental data shows a remarkable agreement with theoretical predictions allowing us to determine the effect of temperature on the coherence and velocity of impurity motion. Our results pave the way for a new approach to study quantum magnetism, mobile impurities in quantum fluids, and polarons in lattice systems

Relationships between convective asymmetry, imbalance and intensity in numerically simulated tropical cyclones

This article examines the relationships between convective asymmetry (CA), imbalance and intensity in tropical cyclones (TCs) that emerge from random winds on the periodic f-plane in a cloud-system-resolving numerical model. The model is configured with warm-rain microphysics and includes a basic parameterisation of long-wave radiation. Within the simulation set, the sea-surface temperature ranges from 26 to 32°C, and the Coriolis parameter f ranges from 10−5 to 10−4 s−1. The number of TCs that develop in a simulation increases rapidly with f and ranges from 1 to 18. Taken together, the simulations provide a diverse spectrum of vortices that can be used for a meaningful statistical study.Consistent with earlier studies, mature TCs with minimal asymmetry are found to have maximum wind speeds greater than the classic theoretical value derived by Emanuel under the assumptions of gradient-wind and hydrostatic balance. In a statistical sense, it is found that the degree of superintensity with respect to balance theory reliably decays with an increasing level of inner-core CA. It is verified that a more recent version of axisymmetric steady-state theory, revised to incorporate imbalance, provides a good approximation for the maximum (azimuthally averaged) azimuthal wind speed V max when CA is relatively weak. More notably, this theory for axisymmetric vortices maintains less than 10% error as CA becomes comparable in magnitude to the symmetric component of inner-core convection. Above a large but finite threshold of CA, axisymmetric steady-state theory generally over-predicts V max. The underachievement of TCs in this parameter regime is shown to coincide with substantial violation of the theoretical assumption of slantwise convective neutrality in the main updraft of the basic state. Of further interest, a reliable curve-fit is obtained for the anticorrelation between a simple measure of CA and V max normalised to an estimate of its balanced potential intensity that is based solely on environmental conditions and air–sea interaction parameters. Sensitivity of results to the surface-flux parameterisation of the numerical model is briefly discussed

Continuous Treatment with Lenalidomide Plus Low-Dose Dexamethasone (Ld) Versus Ld Induction Followed By Autologous Stem Cell Transplant (ASCT) in Patients with Newly Diagnosed Multiple Myeloma (NDMM): A Pooled Analysis of Two Randomized Clinical Trials

Abstract Background: High-dose chemotherapy followed by ASCT remains the standard of care for patients aged ≤75 years with NDMM. The ability of novel agents, such as lenalidomide and bortezomib, to produce treatment response rates comparable to those seen with ASCT has raised questions about the necessity for upfront ASCT in transplant-eligible NDMM patients. This analysis aimed to compare the efficacy and safety of continuous Ld versus Ld+ASCT in patients with NDMM. Methods: Data were pooled from two randomized clinical trials (NCT01731886 and NCT00807599) that compared Ld alone versus Ld+ASCT in NDMM patients aged ≤75 years. Patients received four 28-day cycles of Ld (lenalidomide 25mg daily on days 1-21; dexamethasone 40mg on days 1, 8, 15, and 22) followed by stem-cell mobilization and collection, and either a) Arm A: continuous Ld (an additional 4 cycles +/- lenalidomide maintenance in NCT01731886, or continuous lenalidomide at the last tolerated dose until disease progression plus dexamethasone 20mg for 1 year following treatment initiation in NCT00807599); or b) Arm B: ASCT conditioned with high-dose melphalan, and followed by lenalidomide maintenance therapy. In both trials, patients were withdrawn if they developed progressive disease (PD) at any time, or had stable disease (SD) after cycle 4 of Ld induction. We evaluated overall response rate (ORR; defined as a partial response or better), progression-free survival (PFS), overall survival (OS), and adverse event (AE) incidence rates, focusing on those randomized patients who responded to 4 cycles of Ld induction. Results: Sixty patients were enrolled into NCT01731886, and 63 into NCT00807599. The analysis included a total of 85 patients who had been randomized and achieved a response to 4 cycles of Ld induction: 41 in Arm A, and 44 in Arm B. Mean ages in Arm A versus Arm B were 61.8 versus 61.7 years; median (range) follow-up times were 3.97 (0.27-6.19) versus 3.71 (0.16-5.66) years. Baseline cytogenetic risk profiles were similar overall, although Arm A contained a higher percentage of intermediate-risk patients (17.1% versus 11.4%). More than half of all patients included in the analysis had International Staging System stage 1 disease: 63.4% of patients in Arm A, and 47.7% of those in Arm B. Median PFS was similar with the two treatment approaches: 4.3 versus 4.4 years (Figure 1; p = 0.9107). OS also did not differ significantly between the two arms (Figure 2). As expected, both treatment regimens were well tolerated. Clinically significant grade 3 and 4 AEs occurring outside of the transplant period included the following: anemia (17.1% Arm A versus 15.9% Arm B); neutropenia (36.6% versus 38.6%); thrombocytopenia (17.1% versus 18.4%); infectious complications (14.6% versus 27.3%); thromboembolic events (7.3% versus 6.8%); and secondary malignancies (7.3% versus 4.5%). Conclusions: The findings of this pooled analysis suggest that, in transplant-eligible patients responsive to Ld induction, continuous Ld results in similar PFS and OS to Ld+ASCT. Larger phase III trials addressing this question are awaited. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Lentzsch: Celgene: Consultancy; BMS: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Axiom: Honoraria. Landau:Janssen: Consultancy; Spectrum Pharmaceuticals: Honoraria; Prothena: Consultancy, Honoraria; Janssen: Consultancy; Onyx: Honoraria, Research Funding; Takeda: Research Funding. Lesokhin:Efranat: Consultancy; Genentech: Research Funding; Aduro: Consultancy; Janssen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding. Kewalramani:Celgene: Consultancy; Abbvie: Consultancy; Getchell v Doon East Community Hospital, Alfred Wakeman et al.: Consultancy. Comenzo:Karyopharm: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Prothena: Research Funding; Takeda Millennium: Research Funding; Takeda Millennium: Membership on an entity's Board of Directors or advisory committees. Landgren:Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Medscape: Honoraria; Onyx: Honoraria; International Myeloma Foundation: Research Funding; Onyx: Research Funding; BMJ Publishing: Consultancy; BMJ Publishing: Honoraria; Medscape: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy; Onyx: Consultancy. Hassoun:Novartis: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Takeda: Research Funding