Search

Melanie L Bell,1,2 Lysbeth Floden,1,3 Brooke A Rabe,1 Stacie Hudgens,3 Haryana M Dhillon,2,4 Victoria J Bray,5 Janette L Vardy61Department of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ 85724, USA; 2Psycho-Oncology Co-operative Research Group, School of Psychology, University of Sydney, Sydney, NSW, Australia; 3Clinical Outcomes Solutions, Tucson, AZ 85718, USA; 4Centre for Medical Psychology & Evidence-Based Decision-Making, School of Psychology, University of Sydney, Sydney, NSW, Australia; 5Department of Medical Oncology, Liverpool Hospital and University of Sydney, Sydney, NSW, Australia; 6Concord Cancer Centre and Sydney Medical School, University of Sydney, Sydney, NSW, AustraliaAbstract: Patient-reported outcomes, such as quality of life, functioning, and symptoms, are used widely in therapeutic and behavioral trials and are increasingly used in drug development to represent the patient voice. Missing patient reported data is common and can undermine the validity of results reporting by reducing power, biasing estimates, and ultimately reducing confidence in the results. In this paper, we review statistically principled approaches for handling missing patient-reported outcome data and introduce the idea of estimands in the context of behavioral trials. Specifically, we outline a plan that considers missing data at each stage of research: design, data collection, analysis, and reporting. The design stage includes processes to prevent missing data, define the estimand, and specify primary and sensitivity analyses. The analytic strategy considering missing data depends on the estimand. Reviewed approaches include maximum likelihood-based models, multiple imputation, generalized estimating equations, and responder analysis. We outline sensitivity analyses to assess the robustness of the primary analysis results when data are missing. We also describe ad-hoc methods, including approaches to avoid. Last, we demonstrate methods using data from a behavioral intervention, where the primary outcome was self-reported cognition.Keywords: estimands, sensitivity analysis, missing data, imputation, patient-reported outcomes

Tidal interactions between planets or stars and the bodies that orbit them dissipate energy in their interiors. The dissipated energy heats the interior and a fraction of that energy will be released as seismic energy. Here we formalize a model to describe the tidally-driven seismic activity on planetary bodies based on tidal dissipation. To constrain the parameters of our model we use the seismic activity of the Moon, driven by tidal dissipation from the Earth-Moon interactions. We then apply this model to predict the amount of seismic energy release and largest seismic events on other moons in our Solar System and exoplanetary bodies. We find that many moons in the Solar System should be more seismically active than the Earth's Moon and many exoplanets should exhibit more seismic activity than the Earth. Finally, we examine how temporal-spatial variations in tidal dissipation manifest as variations in the locations and timing of seismic events on these bodies.

Tidal interactions between planets or stars and the bodies that orbit them dissipate energy in their interiors. The dissipated energy heats the interior and a fraction of that energy will be released as seismic energy. Here we formalize a model to describe the tidally-driven seismic activity on planetary bodies based on tidal dissipation. To constrain the parameters of our model we use the seismic activity of the Moon, driven by tidal dissipation from the Earth-Moon interactions. We then apply this model to predict the amount of seismic energy release and largest seismic events on other moons in our Solar System and exoplanetary bodies. We find that many moons in the Solar System should be more seismically active than the Earth's Moon and many exoplanets should exhibit more seismic activity than the Earth. Finally, we examine how temporal-spatial variations in tidal dissipation manifest as variations in the locations and timing of seismic events on these bodies.

Evidence of marine target impacts, binary impact craters, or impact clusters are rare on Earth. Seismic reflection data from the Guinea Plateau, West Africa, reveal a ≥8.5-km-wide structure buried below ~300 to 400 m of Paleogene sediment with characteristics consistent with a complex impact crater. These include an elevated rim above a terraced crater floor, a pronounced central uplift, and extensive subsurface deformation. Numerical simulations of crater formation indicate a marine target (~800-m water depth) impact of a ≥400-m asteroid, resulting in a train of large tsunami waves and the potential release of substantial quantities of greenhouse gases from shallow buried black shale deposits. Our stratigraphic framework suggests that the crater formed at or near the Cretaceous-Paleogene boundary (~66 million years ago), approximately the same age as the Chicxulub impact crater. We hypothesize that this formed as part of a closely timed impact cluster or by breakup of a common parent asteroid.

The New Horizons spacecraft returned images and compositional data showing that terrains on Pluto span a variety of ages, ranging from relatively ancient, heavily cratered areas to very young surfaces with few-to-no impact craters. One of the regions with very few impact craters is dominated by enormous rises with hummocky flanks. Similar features do not exist anywhere else in the imaged solar system. Here we analyze the geomorphology and composition of the features and conclude this region was resurfaced by cryovolcanic processes, of a type and scale so far unique to Pluto. Creation of this terrain requires multiple eruption sites and a large volume of material (>10 4 km 3 ) to form what we propose are multiple, several-km-high domes, some of which merge to form more complex planforms. The existence of these massive features suggests Pluto's interior structure and evolution allows for either enhanced retention of heat or more heat overall than was anticipated before New Horizons, which permitted mobilization of water-ice-rich materials late in Pluto's history., (© 2022. The Author(s).)

Background: Approximately half of all patients with advanced EGFR-mutant NSCLC will develop acquired resistance to first or second-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs) with a T790M mutation. In the AURA3 trial, patients with a T790M mutation had a response rate of 71% to osimertinib, a third-generation EGFR-TKI. The response to osimertinib may vary according to plasma T790M mutation frequency. Our aim was to determine the effect of plasma T790M mutation load on treatment response to osimertinib in an Australian multi-institutional cohort., Methods: We performed a retrospective study on patients treated with osimertinib in the second-line setting and beyond between 2016-2018 from ten centres in Australia, who had T790M mutations detected in tumour or plasma. The primary objective was to investigate if there was a difference in disease control rate (DCR) between patients with high vs. low T790M relative allelic frequency (RAF) as detected in plasma, using a 0.3 RAF cut-off, as determined by ddPCR or BEAMing PCR. Secondary objective was to determine the survival outcomes according to high versus low plasma T790M RAF. Additional analyses were performed to investigate the survival outcome for patients with plasma versus tissue T790M positivity., Results: A total of 139 patients were included in this study. Patients with higher RAF demonstrated higher DCR (74% vs. 36%, P=0.02), however there was no statistically significant difference in survival outcomes in the two groups. Exploratory analysis showed that patients with tissue T790M+ had improved DCR compared with those with plasma T790M+ (89% vs. 68%, P=0.01) and longer progression free survival (median 15.4 vs. 9.7 months; HR 0.51, 95% CI: 0.34 to 0.77, P=0.003) and overall survival (median not reached, HR 0.51, 95% CI: 0.30 to 0.86, P=0.02). Patients who were tissue T790M+ demonstrated superior survival compared to plasma T790M+ after correcting for confounding variables in a multivariate model., Conclusions: DCR was superior in patients with higher plasma T790M mutation load versus lower plasma T790M mutational load, without significant survival benefit. Plasma T790M RAF is a potential predictive biomarker which should be investigated and validated in larger prospective studies., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tlcr-20-1125). Dr. Ding reports grants from Astrazeneca, during the conduct of the study; personal fees from Roche, personal fees from Astrazeneca, outside the submitted work; Dr. Lee reports grants and personal fees from Astrazeneca, personal fees from Boehringer Ingelheim, personal fees from Norvatis, personal fees from Pfizer, personal fees from Roche, outside the submitted work; Dr. Itchins reports personal fees from Astrazeneca, personal fees from Roche, personal fees from MSD, personal fees from Pfizer, personal fees from Takeda, personal fees from Novartis, outside the submitted work; Dr. Clarke reports personal fees from Astrazeneca, outside the submitted work; Dr. Blinman reports personal fees from Astrazeneca, personal fees from Boehringer Ingelheim, outside the submitted work; Dr. Kao reports personal fees from Astrazeneca, personal fees from Boehringer Ingelheim, personal fees from Pfizer, personal fees from MSD, personal fees from BMS, personal fees from Takeda, personal fees from Roche, outside the submitted work; Dr. John reports personal fees from Roche, personal fees from BMS, personal fees from Merck, personal fees from Ignyta, personal fees from Astrazeneca, personal fees from Takeda, personal fees from MSD, personal fees from Specialised therapeutics, personal fees from Pfizer, outside the submitted work; Dr. Leal reports grants and personal fees from Roche, grants and personal fees from BMS, grants and personal fees from Astrazeneca, grants and personal fees from MSD, grants and personal fees from Pfizer, grants and personal fees from Boehringher Ingelheim, personal fees from Sanofi, personal fees from Elly-Lilly, personal fees from Tecnofarma, outside the submitted work. The other authors have no conflicts of interest to declare., (2021 Translational Lung Cancer Research. All rights reserved.)

Purpose: For patients with rheumatoid arthritis (RA) who do not respond or lose response to anti-tumor necrosis factor (TNF) biologics, switching to a different anti-TNF can be an effective means to manage symptoms and disease progression. This study examined the utilization and effectiveness of intravenous golimumab within a real-world population of patients with RA switching directly from infliximab, a potent anti-TNF., Methods: Patient charts (n = 113) were collected from five US-based rheumatology practices. Patient demographics, treatment characteristics, infliximab and intravenous golimumab utilization data, and Clinical Disease Activity Index (CDAI), Patient Global Assessment (PtGA), Physician Global Assessment (PhGA), and Routine Assessment of Patient Index Data (RAPID3) scores were extracted from charts. The effectiveness of intravenous golimumab was assessed by comparing disease activity status pre- and post-initiation of intravenous golimumab therapy., Findings: Significant decreases in patient disease activity were observed following treatment with intravenous golimumab. Mean CDAI and PhGA scores significantly decreased, and a significantly increased proportion of the population exhibited low disease activity or remission in the post intravenous golimumab period (p < 0.05). Limited changes were observed through the RAPID3 and PtGA., Conclusions: Findings from this study indicate that intravenous golimumab is effective in managing RA in a population of patients switching directly from infliximab (mean last dose 7.4 mg/kg).

Patient reported outcomes (PROs) are becoming increasingly important in cancer studies, particularly with the emphasis on patient centered outcome research. However, multiple PROs, using different scales, with different directions of favorability are often used within a trial, making interpretation difficult. To enhance interpretability, we propose the use of a standardized effect size graph, which shows all PROs from a study on the same figure, on the same scale. Plotting standardized effects with their 95% confidence intervals (CIs) on a single graph clearly showing the null value conveys a comprehensive picture of trial results. We demonstrate how to create such a graph using data from a randomized controlled trial that measured 12 PROs at two time points. The 24 effect sizes and CIs are shown on one graph and clearly indicate that the intervention is effective and sustained., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

A unique feature of Pluto's large satellite Charon is its dark red northern polar cap. Similar colours on Pluto's surface have been attributed to tholin-like organic macromolecules produced by energetic radiation processing of hydrocarbons. The polar location on Charon implicates the temperature extremes that result from Charon's high obliquity and long seasons in the production of this material. The escape of Pluto's atmosphere provides a potential feedstock for a complex chemistry. Gas from Pluto that is transiently cold-trapped and processed at Charon's winter pole was proposed as an explanation for the dark coloration on the basis of an image of Charon's northern hemisphere, but not modelled quantitatively. Here we report images of the southern hemisphere illuminated by Pluto-shine and also images taken during the approach phase that show the northern polar cap over a range of longitudes. We model the surface thermal environment on Charon and the supply and temporary cold-trapping of material escaping from Pluto, as well as the photolytic processing of this material into more complex and less volatile molecules while cold-trapped. The model results are consistent with the proposed mechanism for producing the observed colour pattern on Charon.

There is increasing evidence for the use of circulating tumor cells (CTCs) as a "liquid biopsy" for early detection of lung cancer recurrence, prognosticating disease and monitoring treatment response. Further, CTC molecular analysis and interrogation of single cells hold significant potential in providing insights into tumor biology and the metastatic process. Ongoing research will likely see the translation of CTCs as a prognostic and predictive biomarker in both small cell, and non-small cell, lung cancer to routine clinical practice., (Crown Copyright © 2014. Published by Elsevier Ireland Ltd. All rights reserved.)

Byssinosis is an occupational respiratory disease contracted by cotton mill workers who inhale cotton mill dust. The acute byssinotic reaction is characterized by a drop in the 1-sec forced expiratory volume (FEV1.0) on Monday following a weekend's absence from work. This physiological reaction is the result of the contraction of bronchial smooth muscle, which causes narrowing of small airways. An isolated tissue bath technique was used to assay smooth muscle contractions induced by cotton dust extract (CDE) and cotton bract extract (CBE). CBE-induced contractions of rat stomach smooth muscle were blocked (82%) by 100 ng/ml methysergide (blocks 5-hydroxytryptamine (5HT) 100%); CDE was not significantly blocked by methysergide (13%). CDE-induced contractions were blocked (100%) by 25 micrograms/ml indomethacin and 100 micrograms/ml salicylic acid (blocks prostaglandin F2 alpha (PGF2 alpha) 100%). The portion of CBE contracting ability not blocked by methysergide was blocked totally by indomethacin. Blocking agents ineffective against CDE or CBE include atropine (acetylcholine blocker), pyrilamine maleate and diphenhydramine (histamine blockers), imidazole and 7-(1-imidazolyl)heptanoic acid (7IHA) (thromboxane blockers), and carboxypeptidase B2 (kinin blocker). The data suggest that cotton bract contains 5HT, which is responsible for a majority of the CBE-induced contraction and a minority of the CDE-induced contraction. The data also suggest that cotton dust and bract contain a substance which causes the release of PGF2 alpha which in turn causes the contraction of smooth muscle. This substance is responsible for a majority of the CDE-induced and a minority of the CBE-induced contractions. Radioimmunoassay (RIA) confirmed PGF2 alpha release from rat fundal smooth muscle when exposed to CDE and CBE. Increased synthesis and release of arachidonic acid metabolites might be a major mechanism in the bronchoconstriction observed in the acute byssinotic reaction.