Estimation of treatment policy estimands for continuous outcomes using off treatment sequential multiple imputation

The estimands framework outlined in ICH E9 (R1) describes the components needed to precisely define the effects to be estimated in clinical trials, which includes how post-baseline "intercurrent" events (IEs) are to be handled. In late-stage clinical trials, it is common to handle intercurrent events like "treatment discontinuation" using the treatment policy strategy and target the treatment effect on all outcomes regardless of treatment discontinuation. For continuous repeated measures, this type of effect is often estimated using all observed data before and after discontinuation using either a mixed model for repeated measures (MMRM) or multiple imputation (MI) to handle any missing data. In basic form, both of these estimation methods ignore treatment discontinuation in the analysis and therefore may be biased if there are differences in patient outcomes after treatment discontinuation compared to patients still assigned to treatment, and missing data being more common for patients who have discontinued treatment. We therefore propose and evaluate a set of MI models that can accommodate differences between outcomes before and after treatment discontinuation. The models are evaluated in the context of planning a phase 3 trial for a respiratory disease. We show that analyses ignoring treatment discontinuation can introduce substantial bias and can sometimes underestimate variability. We also show that some of the MI models proposed can successfully correct the bias but inevitably lead to increases in variance. We conclude that some of the proposed MI models are preferable to the traditional analysis ignoring treatment discontinuation, but the precise choice of MI model will likely depend on the trial design, disease of interest and amount of observed and missing data following treatment discontinuation

Supernova-Remnant Origin of Cosmic Rays?

It is thought that Galactic cosmic ray (CR) nuclei are gradually accelerated to high energies (up to ~300 TeV/nucleon, where 1TeV=10^12eV) in the expanding shock-waves connected with the remnants of powerful supernova explosions. However, this conjecture has eluded direct observational confirmation^1,2 since it was first proposed in 1953 (ref. 3). Enomoto et al.^4 claim to have finally found definitive evidence that corroborates this model, proposing that the very-high-energy, TeV-range, gamma-rays from the supernova remnant (SNR) RX J1713.7-3946 are due to the interactions of energetic nuclei in this region. Here we argue that their claim is not supported by the existing multiwavelength spectrum of this source. The search for the origin(s) of Galactic cosmic ray nuclei may be closing in on the long-suspected supernova-remnant sources, but it is not yet over.Comment: 4 pages, 1 Figur

Value of Inpatient Diagnostic CCTV-EEG Monitoring in the Elderly

Purpose: To examine the outcome of inpatient diagnostic closed circuit TV-EEG (CCTV-EEG) monitoring in a consecutive series of elderly patients admitted to an adult epilepsy-monitoring unit (EMU) over a continuous 6-year period. Methods: Retrospective review of all admissions to a university hospital adult EMU. Those older than 60 years were identified. Patients who were monitored for status epilepticus were excluded. Data on duration of events, frequency of events, physical examination, medications, preadmission EEG, brain imaging, length of stay, and interictal and ictal EEG were obtained. Results: Of the 18 patients admitted for monitoring only, mean age was 69.5 years (range, 60–90 years). Mean length of stay was 4.3 days (range, 2–9 days). Five patients had complex partial seizures recorded. Three patients, all treated with antiepileptic drugs (AEDs), had no spells recorded, and no additional diagnostic information was gained from the admission. The other 10 patients, eight of whom had been treated with AEDs, were symptomatic during their admission, leading to a variety of neurologic but not epileptic, psychiatric, or other medical disorders, and allowing tapering of AEDs. Conclusions: In elderly patients with suspected epilepsy, CCTV-EEG is a very useful diagnostic tool. In this series of 18, 10 patients were diagnosed with potentially treatable medical illnesses not responsive to AEDs.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65172/1/j.1528-1157.1999.tb00825.x.pd

A Common Network of Functional Areas for Attention and Eye Movements

AbstractFunctional magnetic resonance imaging (fMRI) and surface-based representations of brain activity were used to compare the functional anatomy of two tasks, one involving covert shifts of attention to peripheral visual stimuli, the other involving both attentional and saccadic shifts to the same stimuli. Overlapping regional networks in parietal, frontal, and temporal lobes were active in both tasks. This anatomical overlap is consistent with the hypothesis that attentional and oculomotor processes are tightly integrated at the neural level

Dislocation interactions during low-temperature plasticity of olivine and their impact on the evolution of lithospheric strength

The strength of the lithosphere is typically modelled based on constitutive equations for steady-state flow. However, strain hardening may cause significant evolution of strength in the colder load-bearing portion of the lithosphere. Recent rheological data from low-temperature deformation experiments on olivine suggest that strain hardening occurs due to the presence of temperature-independent back stresses generated by long-range elastic interactions among dislocations. These interpretations provided the basis for a flow law that incorporates hardening by the development of back stress. Here, we test this dislocation-interaction hypothesis by examining the microstructures of olivine samples deformed plastically at room temperature either in a deformation-DIA apparatus at differential stresses of ≤4.3GPa or in a nanoindenter at applied contact stresses of ≥10.2GPa. High-angular resolution electron backscatter diffraction maps reveal the presence of geometrically necessary dislocations with densities commonly above 1014m−2 and intragranular heterogeneities in residual stress on the order of 1 GPa in both sets of samples. Scanning transmission electron micrographs reveal straight dislocations aligned in slip bands and interacting with dislocations of other types that act as obstacles. The resulting accumulations of dislocations in their slip planes, and associated stress heterogeneities, are consistent with strain hardening resulting from long-range back-stresses acting among dislocations and thereby support the form of the flow law for low-temperature plasticity. Based on these observations, we predict that back stresses among dislocations will impart significant mechanical anisotropy to deformed lithosphere by enhancing or reducing the effective stress. Therefore, strain history, with associated microstructural and micromechanical evolution, is an important consideration for models of lithospheric strength. The microstructural observations also provide new criteria for identifying the operation of back-stress induced strain hardening in natural samples and therefore provide a means to test the applicability of the flow law for low-temperature plasticity.This research was supported by Natural Environment Research Council grants NE/M000966/1 to LNH, AJW, and DW and 1710DG008/JC4 to LNH and AJW; European Plate Observing System Transnational Access grant EPOS-TNA-MSL 2018-022 to LNH; Advanced Photon Source General User Proposal 55176 to LNH, DLG, and WBD; and National Science Foundation Awards EAR-1361319 to WBD, EAR-1625032 to JMW, and EAR-1806791 to KMK

Benthic Biofilm Controls on Fine Particle Dynamics in Streams

Este artículo contiene 15 páginas, 7 figuras, 3 tablas.Benthic (streambed) biofilms metabolize a substantial fraction of particulate organic matter and nutrient inputs to streams. These microbial communities comprise a significant proportion of overall biomass in headwater streams, and they present a primary control on the transformation and export of labile organic carbon. Biofilm growth has been linked to enhanced fine particle deposition and retention, a feedback that confers a distinct advantage for the acquisition and utilization of energy sources. We quantified the influence of biofilm structure on fine particle deposition and resuspension in experimental stream mesocosms. Biofilms were grown in identical 3 m recirculating flumes over periods of 18–47 days to obtain a range of biofilm characteristics. Fluorescent, 8 mm particles were introduced to each flume, and their concentrations in the water column were monitored over a 30 min period. We measured particle concentrations using a flow cytometer and mesoscale (10 mm to 1 cm) biofilm structure using optical coherence tomography. Particle deposition-resuspension dynamics were determined by fitting results to a stochastic mobile-immobile model, which showed that retention timescales for particles within the biofilm-covered streambeds followed a power-law residence time distribution. Particle retention times increased with biofilm areal coverage, biofilm roughness, and mean biofilm height. Our findings suggest that biofilm structural parameters are key predictors of particle retention in streams and rivers.This study was funded by a Marie Curie Intra- European Fellowship to WRH (FP7- PEOPLE-2011-IEF-302297) and an Austrian Science Fund grant to T.J.B. (START Y420-B17). K.R.R. was supported by a CUAHSI Pathfinder fellowship and U.S. NSF Graduate Research Fellowship. J.D.D. was supported by a Fulbright-Spain fellowship. The modeling effort was supported by U.S. NSF grants EAR- 1215898 and EAR-1344280 to AIP. Supporting data are provided at doi:10.6084/m9.figshare.4252193.Peer reviewe

Is the Supernova Remnant RX J1713.7-3946 a Hadronic Cosmic Ray Accelerator ?

The non-thermal supernova remnant RX J1713.7-3946 (G347.3-0.5) has recently been shown to be a site of cosmic ray (CR) electron acceleration to TeV energies (Muraishi et al. 2000). Here we present evidence that this remnant is also accelerating CR nuclei. Such nuclei can interact with ambient interstellar gas to produce high energy gamma-rays via the decay of neutral pions. We associate the unidentified EGRET GeV gamma- ray source 3EG J1714-3857 with a massive (~3*10 5 Mo) and dense (~500 nucleons cm -3) molecular cloud interacting with RX J1713.7-3946. Direct evidence for such interaction is provided by observations of the lowest two rotational transitions of CO in the cloud; as in other clear cases of interaction, the CO(J=2-1)/CO(J=1-0) ratio is significantly enhanced. Since the cloud is of low radio and X-ray brightness, CR electrons cannot be responsible for the bulk of its GeV emission there. A picture thus emerges where both electrons and nuclei are being accelerated by the SNR: whereas the CR electrons dominate the local non-thermal radio, X-ray and TeV emission, the shock accelerated CR protons and ions (hadrons) are revealed through their interactions in the adjacent massive cloud. Such a scenario had been anticipated by Aharonian, Drury and Volk (1994).Comment: 15 pages, 2 low-resolution figures, submitted to ApJL Aug 10, 2001; this version includes referee's suggestion

South Pacific Paleogene Climate

International Ocean Discovery Program (IODP) Expedition 378 was designed to recover the first comprehensive set of Paleogene sedimentary sections from a transect of sites strategically positioned in the South Pacific to reconstruct key changes in oceanic and atmospheric circulation. These sites would have provided an unparalleled opportunity to add crucial new data and geographic coverage to existing reconstructions of Paleogene climate. In addition to the ~15 month postponement of Expedition 378 and subsequent port changes resulting in a reduction of the number of primary sites, testing and evaluation of the R/V JOIDES Resolution derrick in the weeks preceding the expedition determined that it would not support deployment of drill strings in excess of 2 km. Because of this determination, only 1 of the originally approved 7 primary sites was drilled. Expedition 378 recovered the first continuously cored, multiple-hole Paleogene sedimentary section from the southern Campbell Plateau at Site U1553. This high–southern latitude site builds on the legacy of Deep Sea Drilling Project (DSDP) Site 277, a single, partially spot cored hole, providing a unique opportunity to refine and augment existing reconstructions of the past ~66 My of climate history. This also includes the discovery of a new siliciclastic unit that had never been drilled before. As the world’s largest ocean, the Pacific Ocean is intricately linked to major changes in the global climate system. Previous drilling in the low-latitude Pacific Ocean during Ocean Drilling Program (ODP) Legs 138 and 199 and Integrated Ocean Drilling Program Expeditions 320 and 321 provided new insights into climate and carbon system dynamics, productivity changes across the zone of divergence, time-dependent calcium carbonate dissolution, bio- and magnetostratigraphy, the location of the Intertropical Convergence Zone, and evolutionary patterns for times of climatic change and upheaval. Expedition 378 in the South Pacific Ocean uniquely complements this work with a high-latitude perspective, especially because appropriate high-latitude records are unobtainable in the Northern Hemisphere of the Pacific Ocean. Site U1553 and the entire corpus of shore-based investigations will significantly contribute to the challenges of the “Climate and Ocean Change: Reading the Past, Informing the Future” theme of the IODP Science Plan (How does Earth’s climate system respond to elevated levels of atmospheric CO2? How resilient is the ocean to chemical perturbations?). Furthermore, Expedition 378 will provide material from the South Pacific Ocean in an area critical for high-latitude climate reconstructions spanning the Paleocene to late Oligocene