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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.)

The Cold Classical Kuiper Belt, a class of small bodies in undisturbed orbits beyond Neptune, is composed of primitive objects preserving information about Solar System formation. In January 2019, the New Horizons spacecraft flew past one of these objects, the 36-kilometer-long contact binary (486958) Arrokoth (provisional designation 2014 MU 69 ). Images from the flyby show that Arrokoth has no detectable rings, and no satellites (larger than 180 meters in diameter) within a radius of 8000 kilometers. Arrokoth has a lightly cratered, smooth surface with complex geological features, unlike those on previously visited Solar System bodies. The density of impact craters indicates the surface dates from the formation of the Solar System. The two lobes of the contact binary have closely aligned poles and equators, constraining their accretion mechanism., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

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.

Objective: To determine the predictive and prognostic roles of three blood-based biomarkers: circulating tumour DNA (ctDNA), circulating tumour cells (CTC) and carcinoembryonic antigen (CEA), in patients with advanced epidermal growth factor receptor-mutated (EGFR+) lung cancer., Materials and Methods: We recruited 28 patients with 103 serial blood samples. We performed mutational analyses for EGFR mutations using droplet digital PCR (ddPCR) on ctDNA. We evaluated the accuracy of EGFR mutation detection in ctDNA compared with tissue biopsy. We also quantified CTCs, ctDNA and CEA in serially collected blood samples, and evaluated the baseline and changes in these blood-based biomarkers with clinical outcomes., Results: EGFR mutation detection in plasma was highly concordant as compared with tissue biopsy. Detectable baseline ctDNA was associated with higher disease burden (p < 0.01). Early disappearance of ctDNA at 4 weeks was associated with radiological response at 12 weeks of treatment (p = 0.01) and improved progression free survival (PFS) (HR 5.47, 95%CI 1.32-22.72, p = 0.02) and overall survival (OS) (HR 5.46, 95%CI 1.28-23.22, p = 0.02). A decrease in CTC count at 4 weeks was associated with improved PFS (HR 3.81, 95%CI 1.13-12.79, p = 0.03) but not OS. 85% of patients with radiological progression had a ctDNA rise compared with 22% of patients with stable disease (p=0.01). ctDNA rise was seen on average 170 days prior to radiological progression. There is a significant association between the rise of CEA level with radiological progression (p=0.001)., Conclusion: Early change in ctDNA, CTC and CEA levels may be long-term predictors of treatment benefit and failure prior to availability of radiological response data., (Copyright © 2019 Elsevier B.V. All rights reserved.)

We present the case for the presence of complex organic molecules, such as amino acids and nucleobases, formed by abiotic processes on the surface and in near-subsurface regions of Pluto. Pluto's surface is tinted with a range of non-ice substances with colors ranging from light yellow to red to dark brown; the colors match those of laboratory organic residues called tholins. Tholins are broadly characterized as complex, macromolecular organic solids consisting of a network of aromatic structures connected by aliphatic bridging units ( e.g., Imanaka et al., 2004; Materese et al., 2014, 2015). The synthesis of tholins in planetary atmospheres and in surface ices has been explored in numerous laboratory experiments, and both gas- and solid-phase varieties are found on Pluto. A third variety of tholins, exposed at a site of tectonic surface fracturing called Virgil Fossae, appears to have come from a reservoir in the subsurface. Eruptions of tholin-laden liquid H 2 O from a subsurface aqueous repository appear to have covered portions of Virgil Fossae and its surroundings with a uniquely colored deposit (D.P. Cruikshank, personal communication) that is geographically correlated with an exposure of H 2 O ice that includes spectroscopically detected NH 3 (C.M. Dalle Ore, personal communication). The subsurface organic material could have been derived from presolar or solar nebula processes, or might have formed in situ . Photolysis and radiolysis of a mixture of ices relevant to Pluto's surface composition (N 2 , CH 4 , CO) have produced strongly colored, complex organics with a significant aromatic content having a high degree of nitrogen substitution similar to the aromatic heterocycles pyrimidine and purine (Materese et al., 2014, 2015; Cruikshank et al., 2016). Experiments with pyrimidines and purines frozen in H 2 O-NH 3 ice resulted in the formation of numerous nucleobases, including the biologically relevant guanine, cytosine, adenine, uracil, and thymine (Materese et al., 2017). The red material associated with the H 2 O ice may contain nucleobases resulting from energetic processing on Pluto's surface or in the interior. Some other Kuiper Belt objects also exhibit red colors similar to those found on Pluto and may therefore carry similar inventories of complex organic materials. The widespread and ubiquitous nature of similarly complex organic materials observed in a variety of astronomical settings drives the need for additional laboratory and modeling efforts to explain the origin and evolution of organic molecules. Pluto observations reveal complex organics on a small body that remains close to its place of origin in the outermost regions of the Solar System.

The Kuiper Belt is a distant region of the outer Solar System. On 1 January 2019, the New Horizons spacecraft flew close to (486958) 2014 MU 69 , a cold classical Kuiper Belt object approximately 30 kilometers in diameter. Such objects have never been substantially heated by the Sun and are therefore well preserved since their formation. We describe initial results from these encounter observations. MU 69 is a bilobed contact binary with a flattened shape, discrete geological units, and noticeable albedo heterogeneity. However, there is little surface color or compositional heterogeneity. No evidence for satellites, rings or other dust structures, a gas coma, or solar wind interactions was detected. MU 69 's origin appears consistent with pebble cloud collapse followed by a low-velocity merger of its two lobes., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

The flyby of Pluto and Charon by the New Horizons spacecraft provided high-resolution images of cratered surfaces embedded in the Kuiper belt, an extensive region of bodies orbiting beyond Neptune. Impact craters on Pluto and Charon were formed by collisions with other Kuiper belt objects (KBOs) with diameters from ~40 kilometers to ~300 meters, smaller than most KBOs observed directly by telescopes. We find a relative paucity of small craters ≲13 kilometers in diameter, which cannot be explained solely by geological resurfacing. This implies a deficit of small KBOs (≲1 to 2 kilometers in diameter). Some surfaces on Pluto and Charon are likely ≳4 billion years old, thus their crater records provide information on the size-frequency distribution of KBOs in the early Solar System., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

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).

Objective: Patient reported outcomes (PROs) are important in oncology research; however, missing data can pose a threat to the validity of results. Psycho-oncology researchers should be aware of the statistical options for handling missing data robustly. One rarely used set of methods, which includes extensions for handling missing data, is generalized estimating equations (GEEs). Our objective was to demonstrate use of GEEs to analyze PROs with missing data in randomized trials with assessments at fixed time points., Methods: We introduce GEEs and show, with a worked example, how to use GEEs that account for missing data: inverse probability weighted GEEs and multiple imputation with GEE. We use data from an RCT evaluating a web-based brain training for cancer survivors reporting cognitive symptoms after chemotherapy treatment. The primary outcome for this demonstration is the binary outcome of cognitive impairment. Several methods are used, and results are compared., Results: We demonstrate that estimates can vary depending on the choice of analytical approach, with odds ratios for no cognitive impairment ranging from 2.04 to 5.74. While most of these estimates were statistically significant (P < 0.05), a few were not., Conclusions: Researchers using PROs should use statistical methods that handle missing data in a way as to result in unbiased estimates. GEE extensions are analytic options for handling dropouts in longitudinal RCTs, particularly if the outcome is not continuous., (Copyright © 2018 John Wiley & Sons, Ltd.)

Purpose: Cognitive symptoms are common in cancer patients, with up to 70% reporting cognitive symptoms following chemotherapy. These symptoms can have a major impact on how an individual functions in all aspects of their lives. This review evaluates self-reported cognitive function and its associations with neuropsychological tests and patient-reported outcomes in adult cancer patients who received chemotherapy treatment for a solid cancer., Methods: A search of multiple databases (Medline, Ovid at Nursing, PsycINFO, Allied and Complementary Medicine) from 1936 to 2017 was conducted, identifying 1563 unique articles, of which 101 met inclusion criteria., Results: Of the 101 included studies, 48 (47%) were cross-sectional and 38 (38%) longitudinal in design, with 12 (12%) randomised controlled trials. A minority (26%) incorporated a healthy control arm in the study design, whilst the majority (79%) were in women with breast cancer. There was diversity in the assessment of self-reported cognitive symptoms. A total of 43 of 44 studies that sought an association between self-reported cognitive function and patient-reported outcomes found a moderate to strong association. Overall, 31 studies showed a lack of association between self-reported cognitive symptoms and neuropsychological results, whilst 14 studies reported a significant association between the two, but the association was often restricted to limited cognitive domains., Conclusion: The review found widespread heterogeneity in the assessment of self-reported cognitive symptoms and consistently absent or weak association with neuropsychological test scores., Implications for Cancer Survivors: This research highlights the need for a standardised approach to measurement of self-reported cognitive symptoms in cancer patients.

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.)

Purpose Cognitive impairment is reported frequently by cancer survivors. There are no proven treatments. We evaluated a cognitive rehabilitation program (Insight) and compared it with standard care in cancer survivors self-reporting cognitive symptoms. Patients and Methods We recruited adult cancer survivors with a primary malignancy (excluding central nervous system malignancies) who had completed three or more cycles of adjuvant chemotherapy in the previous 6 to 60 months and reported persistent cognitive symptoms. All participants received a 30-minute telephone consultation and were then randomly assigned to the 15-week, home-based intervention or to standard care. Primary outcome was self-reported cognitive function (Functional Assessment of Cancer Therapy Cognitive Function [FACT-COG] perceived cognitive impairment [PCI] subscale): difference between groups after intervention (T2) and 6 months later (T3). Results A total of 242 participants were randomly assigned: median age, 53 years; 95% female. The primary outcome of difference in FACT-COG PCI was significant, with less PCI in the intervention group at T2 ( P < .001). This difference was sustained at T3 ( P < .001). At T2, there was a significant difference in all FACT-COG subscales, favoring the intervention. Neuropsychological results were not significantly different between the groups at T2 or T3. There were significantly lower levels of anxiety/depression and fatigue in the intervention group at T2. There were significant improvements in stress in the intervention group at both time points. There was no significant difference in quality of life between the groups at T2, but the intervention group had better quality of life at T3. Conclusion The intervention, Insight, led to improvements in cognitive symptoms compared with standard care. To our knowledge, this is the first large randomized controlled trial showing an improvement in self-reported cognitive function in cancer survivors, indicating that this intervention is a feasible treatment.

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.

NASA's New Horizons spacecraft has revealed the complex geology of Pluto and Charon. Pluto's encounter hemisphere shows ongoing surface geological activity centered on a vast basin containing a thick layer of volatile ices that appears to be involved in convection and advection, with a crater retention age no greater than ~10 million years. Surrounding terrains show active glacial flow, apparent transport and rotation of large buoyant water-ice crustal blocks, and pitting, the latter likely caused by sublimation erosion and/or collapse. More enigmatic features include tall mounds with central depressions that are conceivably cryovolcanic and ridges with complex bladed textures. Pluto also has ancient cratered terrains up to ~4 billion years old that are extensionally faulted and extensively mantled and perhaps eroded by glacial or other processes. Charon does not appear to be currently active, but experienced major extensional tectonism and resurfacing (probably cryovolcanic) nearly 4 billion years ago. Impact crater populations on Pluto and Charon are not consistent with the steepest impactor size-frequency distributions proposed for the Kuiper belt., (Copyright © 2016, American Association for the Advancement of Science.)

The New Horizons mission has provided resolved measurements of Pluto's moons Styx, Nix, Kerberos, and Hydra. All four are small, with equivalent spherical diameters of ~40 kilometers for Nix and Hydra and ~10 kilometers for Styx and Kerberos. They are also highly elongated, with maximum to minimum axis ratios of ~2. All four moons have high albedos (~50 to 90%) suggestive of a water-ice surface composition. Crater densities on Nix and Hydra imply surface ages of at least 4 billion years. The small moons rotate much faster than synchronous, with rotational poles clustered nearly orthogonal to the common pole directions of Pluto and Charon. These results reinforce the hypothesis that the small moons formed in the aftermath of a collision that produced the Pluto-Charon binary., (Copyright © 2016, American Association for the Advancement of Science.)

The Pluto system was recently explored by NASA's New Horizons spacecraft, making closest approach on 14 July 2015. Pluto's surface displays diverse landforms, terrain ages, albedos, colors, and composition gradients. Evidence is found for a water-ice crust, geologically young surface units, surface ice convection, wind streaks, volatile transport, and glacial flow. Pluto's atmosphere is highly extended, with trace hydrocarbons, a global haze layer, and a surface pressure near 10 microbars. Pluto's diverse surface geology and long-term activity raise fundamental questions about how small planets remain active many billions of years after formation. Pluto's large moon Charon displays tectonics and evidence for a heterogeneous crustal composition; its north pole displays puzzling dark terrain. Small satellites Hydra and Nix have higher albedos than expected., (Copyright © 2015, American Association for the Advancement of Science.)

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.)

Still's disease is characterized by arthritis, fever, rash, lymphoid hypertrophy, leukocytosis, and anemia, often in association with thrombocytosis. We describe a patient with Still's disease and thrombocytopenia secondary to disseminated intravascular coagulation (DIC). Fifteen definite cases of DIC complicating Still's disease have been reported in the English literature. Most developed this complication while receiving high doses of salicylates in association with hepatic dysfunction. In a few, the coagulopathy has been associated with gold therapy. Our patient is only the second reported to develop DIC in the absence of drug therapy and the fourth reported to die from this complication. The clinical features of these 16 patients are summarized and proposed mechanisms of pathogenesis are reviewed.

Two patients developed drug induced lupus secondary to sulfasalazine (SSZ). One patient was receiving SSZ for Crohn's disease and was subsequently treated with olsalazine, which lacks the sulfapyridine component of SSZ. Her inflammatory bowel disease (IBD) remained controlled and she did not develop a recurrence of lupus, suggesting that olsalazine is safe in patients with IBD and a history of SSZ induced lupus. The SSZ induced antibodies were predominantly IgG against the (H2A-H2B)-DNA complex. Since lupus induced by 7 other drugs was associated with a similar antibody response, our findings support the existence of a common pathway for autoantibody induction.

An 18-year-old woman with thrombotic thrombocytopenic purpura (TTP) had recurrent thrombocytopenia due to antiplatelet antibodies associated with systemic lupus erythematosus (SLE). The simultaneous occurrence of TTP and SLE is rare. We briefly summarize eight previously reported cases in which these two diseases have developed in the same patient within a 12-month period. The possibility of a common pathogenesis is discussed.

Background: There have been many case reports of substantial renal disease in association with anticoagulation, yet the intensity of anticoagulation has changed over the years. In 1986, the American College of Chest Physicians and the Heart, Lung, and Blood Institute recommended a decrease in anticoagulation intensity. In addition, a variety of new methods to investigate hematuria have evolved, including computed tomography and red blood cell morphologic analysis. Because of these developments, we initiated a prospective study to evaluate the relationship between anticoagulation, microscopic hematuria, and major genitourinary tract disease., Methods: To determine the incidence, prevalence, and cause of microscopic hematuria, patients receiving long-term anticoagulation therapy and controls not receiving such therapy were monitored with monthly urinalyses in a 2-year prospective study. Patients who developed hematuria were further studied for genitourinary tract disease. The incidence of hematuria was analyzed with regard to relative levels of anticoagulation., Results: The incidence of hematuria in the anticoagulated and control groups was 0.05 and 0.08 per 100 patient-months, respectively. The prevalence of hematuria was 3.2% in the anticoagulated group and 4.8% in the control group. Genitourinary tract disease was identified in 81% of patients with more than one episode of microscopic hematuria, and the cause of hematuria did not vary between groups. There was no correlation between the level of anticoagulation and the incidence of hematuria., Conclusions: Anticoagulation at currently recommended levels does not predispose patients to hematuria. Identifiable genitourinary tract disease is present in the majority of anticoagulated patients with microscopic hematuria.

Two cases of Wegener's granulomatosis presenting with prostatic involvement are described and compiled with the five previously detailed cases. Each of these patients presented with obstructive symptoms, proteinuria, leukocyturia, and hematuria. The urinary sediment normalized with treatment of the underlying granulomatous vasculitis. Wegener's granulomatosis is a rare cause of prostatic obstructive symptoms, but should be considered whenever the relatively unusual entity of granulomatous prostatitis is diagnosed. One patient was initially treated exclusively with trimethoprim-sulfamethoxazole (TMP-SMX). He responded, but noted recurrence during the 15th month of treatment. We also report on this patient's antineutrophil cytoplasmic antibody (ANCA) titers, which correlated with clinical assessment and predicted recurrence 2 months before elevation of the Westergren sedimentation rate (WSR) and clinical diagnosis.

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.