Showing papers by "Michael D. Smith published in 2016"

When Is Osteonecrosis Not Osteonecrosis?: Adjudication of Reported Serious Adverse Joint Events in the Tanezumab Clinical Development Program

Abstract: Objective Tanezumab, a monoclonal antibody against nerve growth factor, has demonstrated efficacy in clinical trials of chronic pain in osteoarthritis (OA) and chronic low back pain. Unexpected adverse events (AEs) described as osteonecrosis (ON) occurred during tanezumab development, leading the US Food and Drug Administration to impose a partial clinical hold for all indications except cancer pain. A blinded Adjudication Committee (AC) including orthopedic surgeons, rheumatologists, and an orthopedic pathologist reviewed and adjudicated joint-related AEs in the tanezumab clinical program. Methods The AC adjudicated all reported cases of ON as well as cases of total joint replacements (TJRs) not reported as ON for which radiographs obtained within 9 months of the surgery were available. The AC prespecified categories for joint safety events including primary ON, worsening OA (rapid progression of OA [RPOA], normal progression of OA, insufficient information to distinguish between rapid and normal progression of OA), other, or insufficient information to distinguish between primary ON and worsening OA or another diagnosis. Results The AC reviewed events in 249 of 386 patients with an investigator-reported AE of ON and/or a TJR. Two events were adjudicated as primary ON, 200 events were adjudicated as worsening OA (68 of which were classified as RPOA), 29 events had another diagnosis, 11 had insufficient information to distinguish primary ON from worsening OA, and 7 did not have committee member consensus. Conclusion Despite initial reports, tanezumab treatment was not associated with an increase in ON but was associated with an increase in RPOA. Higher doses of tanezumab, tanezumab administered with nonsteroidal antiinflammatory drugs, and preexisting subchondral insufficiency fractures were risk factors for RPOA in this cohort.

End‐member identification and spectral mixture analysis of CRISM hyperspectral data: A case study on southwest Melas Chasma, Mars

Abstract: We present spectral unmixing results over the southwest Melas Chasma region, where a variety of hydrated minerals were identified. We use the DISORT radiative transfer model to simultaneously model Mars atmospheric gases, aerosols, and surface scattering and retrieve the single scattering albedos (SSAs) modeled by the Hapke bidirectional scattering function from CRISM data. We employ a spectral unmixing algorithm to quantitatively analyze the mineral abundances by modeling the atmospherically corrected CRISM SSAs using a non-negative least squares (NNLS) linear deconvolution algorithm. To build the spectral library used for spectral unmixing, we use the factor analysis and target transformation (FATT) technique to recover spectral end-members within the CRISM scenes. We investigate several distinct geologic units, including an interbedded poly- and monohydrated sulfate unit (interbedded unit 1) and an interbedded phyllosilicate-sulfate unit (interbedded unit 2). Our spectral unmixing results indicate that, polyhydrated sulfates in the interbedded unit 1 have a much lower abundance (~10%) than that of the surrounding unit (~20%) and thus may have been partially dehydrated into kieserite to form the interbedded strata, supporting a two-staged precipitation-dehydration formation hypothesis. In the interbedded unit 2 phyllosilicates have an abundance of ~40% and are interbedded with ~20% sulfates. The results, in combination with thermodynamic calculations performed previously, suggest that the interbedded phyllosilicates and sulfates likely formed through coupled basalt weathering and evaporation. The methodology developed in this study provides a powerful tool to derive the mineral abundances, aiming to better constrain the formation processes of minerals and past aqueous environment on Mars.

A Randomized, Double-Blind, Double-Dummy, Placebo-Controlled, Intranasal Drug Liking Study on a Novel Abuse-Deterrent Formulation of Morphine—Morphine ARER

Abstract: Objective. Misuse and abuse of prescription opioids remains a major healthcare concern despite considerable efforts to increase public awareness. Abuse-deterrent formulations of prescription opioids are designed to reduce intentional misuse, abuse, and prescription opioid–related death. A novel extended-release (ER) formulation of morphine (Morphine ARER; MorphaBond™) resists physical manipulation and retains the drug’s ER characteristics, even if attempts are made to manipulate the formulation. Design. This randomized, double-blind, double-dummy, placebo-controlled, four-way crossover study investigated the abuse potential and safety of crushed intranasal and intact oral Morphine ARER compared with commercially available crushed intranasal ER morphine sulfate (ER morphine). Outcome Measures. Endpoints included maximum mean drug liking (Emax) as measured by subjects on a bipolar 100 mm visual analog scale (primary), a subject’s desire to take the drug again, good effects of the drug, and drug high. Results. Twenty-five subjects completed the treatment phase. There was a 40% reduction in Emax for crushed intranasal Morphine ARER compared with crushed intranasal ER morphine ( P < .0001). There was no significant difference when comparing the Emax for crushed intranasal vs intact Morphine ARER. When comparing crushed intranasal Morphine ARER with ER morphine, subjects reported lower mean scores for good effects of the drug, drug high, and overall drug liking, as well as a lower desire to use Morphine ARER again. Other than adverse events associated with intranasal administration of a drug, all adverse events were typical of those reported for opioid-containing drugs. Conclusions. Overall, these data suggest that Morphine ARER has a lower abuse potential via the intranasal route of administration when compared with ER morphine.

Human Abuse Potential of an Abuse-Deterrent (AD), Extended-Release (ER) Morphine Product Candidate (Morphine-ADER Injection-Molded Tablets) versus Extended-Release Morphine Administered Orally in Nondependent Recreational Opioid Users.

Abstract: Objective . To compare the relative human abuse potential of intact and manipulated morphine abuse-deterrent, extended-release injection-molded tablets (morphine-ADER-IMT) with that of marketed morphine sulfate ER tablets Methods . This randomized, double-blind, triple-dummy, active- and placebo-controlled, 4-way crossover, single-center study included adult volunteers who were experienced, nondependent, recreational opioid users. Participants were randomized 1:1:1:1 to placebo, morphine-ADER-IMT (60 mg, intact), morphine-ADER-IMT (60 mg, manipulated), and morphine ER (60 mg, manipulated) and received 1 dose of each oral agent in crossover fashion, separated by ≥5 days. Pharmacodynamic and pharmacokinetic endpoints were assessed, including the primary endpoint of peak effect of Drug Liking (Emax) via Drug Liking Visual Analog Scale (VAS) score and the secondary endpoints of time to Emax (TEmax) and mean abuse quotient (AQ; a pharmacokinetic parameter associated with drug liking). Results . Thirty-eight participants completed the study. Median Drug Liking VAS Emax was significantly lower after treatment with manipulated morphine-ADER-IMT (67) compared with manipulated morphine ER (74; P = 0.007). TEmax was significantly shorter after treatment with manipulated morphine ER compared with intact ( P < 0.0001) or manipulated ( P = 0.004) morphine-ADER-IMT. Mean AQ was lower after treatment with intact (5.7) or manipulated (16.4) morphine-ADER-IMT compared with manipulated morphine ER (45.9). Conclusions . Manipulated morphine-ADER-IMT demonstrated significantly lower Drug Liking Emax compared with manipulated morphine ER when administered orally. Morphine-ADER-IMT would be an important new AD, ER morphine product with lower potential for unintentional misuse by chewing or intentional manipulation for oral abuse than currently available non-AD morphine ER products.

Fecal sludge management: diagnostics for service delivery in urban areas - tools and guidelines

Abstract: Addressing the need for fecal sludge management (FSM) from on-site sanitation systems is critical to improving sanitation in poor urban settlements. A preliminary review of the status of FSM in 12 cities, using secondary data, adopted certain diagnostic tools and proposed that others be developed further. This study has since been built on by further World Bank work using extensive primary data from five cities (Balikpapan, Dhaka, Hawassa, Lima and Santa Cruz). Using the field data, a series of diagnostic and decision-support tools have been developed to guide FSM intervention options in the context of the economic and political economy reality. This report describes diagnostic and decision-support tools to guide the improvement of FSM services. It also advises how to use them, with links to a number of other resources. Related documents include (i) a summary report on the tools, and experiences of using them in the context of five city case studies, and (ii) the data collection protocols and instruments and (iii) terms of reference.

Unique Spectroscopy and Imaging of Mars with the James Webb Space Telescope

Abstract: In this paper, we summarize the main capabilities of the James Webb Space Telescope (JWST) for performing observations of Mars. The distinctive vantage point of JWST at the Sun-Earth Lagrange point (L2) will allow sampling the full observable disk, permitting the study of short-term phenomena, diurnal processes (across the east-west axis), and latitudinal processes between the hemispheres (including seasonal effects) with excellent spatial resolutions (0.''07 at 2 micron). Spectroscopic observations will be achievable in the 0.7-5 micron spectral region with NIRSpec at a maximum resolving power of 2700 and with 8000 in the 1-1.25 micron range. Imaging will be attainable with the Near-Infrared Camera at 4.3 micrometers and with two narrow filters near 2 micron, while the nightside will be accessible with several filters in 0.5 to 2 micron. Such a powerful suite of instruments will be a major asset for the exploration and characterization of Mars. Some science cases include the mapping of the water D/H ratio, investigations of the Martian mesosphere via the characterization of the non-local thermodynamic equilibrium CO2 emission at 4.3 micron, studies of chemical transport via observations of the O2 nightglow at 1.27 micron, high-cadence mapping of the variability dust and water-ice clouds, and sensitive searches for trace species and hydrated features on the Martian surface. In-flight characterization of the instruments may allow for additional science opportunities.

Fecal sludge management tools : data collection instruments

Abstract: This document contains data collection instruments to support data collection, for which the resulting data will inform diagnostic and decision-making tools for Fecal Sludge Management (FSM) services. The diagnostic and decision-making tools shown are those developed in a World Bank global FSM study (2016) that are further described in (i) a Summary Report of the FSM study (ii) Tools and Guidelines for improving fecal sludge management (FSM) services.

Advances in the Management of the Potential Organ Donor After Neurologic Determination of Death

Abstract: Transplantation is often the only treatment for patients with end-stage organ failure, but the gap between organ availability and those awaiting a transplant remains a worldwide problem [1, 2]. A limited donor pool and low number of potentially transplantable organs retrieved from each donor are the main reasons for this everwidening gap. Two complementary strategies for resolving this issue are:

The Milky Way's halo in 6D: Gaia's Radial Velocity Spectrometer performance

Abstract: Gaia's Radial Velocity Spectrometer (RVS) has been operating in routine phase for over one year since initial commissioning. RVS continues to work well but the higher than expected levels of straylight reduce the limiting magnitude. The end-of-mission radial-velocity (RV) performance requirement for G2V stars was 15 km/s at V = 16.5 mag. Instead, 15 km/s precision is achieved at 15 < V < 16 mag, consistent with simulations that predict a loss of 1.4 mag. Simulations also suggest that changes to Gaia's onboard software could recover ~0.14 mag of this loss. Consequently Gaia's onboard software was upgraded in April 2015. The status of this new commissioning period is presented, as well as the latest scientific performance of the on-ground processing of RVS spectra. We illustrate the implications of the RVS limiting magnitude on Gaia's view of the Milky Way's halo in 6D using the Gaia Universe Model Snapshot (GUMS).