The orbits of the quadruple star system 88 Tau A from PHASES differential astrometry and radial velocity

We have used high precision differential astrometry from the Palomar High-precision Astrometric Search for Exoplanet Systems (PHASES) project and radial velocity measurements covering a time-span of 20 years to determine the orbital parameters of the 88 Tau A system. 88 Tau is a complex hierarchical multiple system comprising a total of six stars; we have studied the brightest 4, consisting of two short-period pairs orbiting each other with an 18-year period. We present the first orbital solution for one of the short-period pairs, and determine the masses of the components and distance to the system to the level of a few percent. In addition, our astrometric measurements allow us to make the first determination of the mutual inclinations of the orbits. We find that the sub-systems are not coplanar.Comment: Corrected Author Ordering; 12 Pages, Accepted for publication in Ap

Potential Role of Platelet-Derived Growth Factor Receptor Inhibition Using Imatinib in Combination with Docetaxel in the Treatment of Recurrent Non-small Cell Lung Cancer

Introduction:Platelet-derived growth factor receptor (PDGFR) is expressed in lung cancer and is involved in angiogenesis. Preclinical models demonstrated that imatinib (Im) regulates angiogenesis through PDGFR inhibition and enhances efficacy of chemotherapy. Hypothesis: We hypothesized that Im plus docetaxel (D) would have a synergistic effect detectable by an increase in response rate in patients with recurrent non-small cell lung cancer (NSCLC).Methods:A phase II trial to evaluate Im in combination with D in patients with recurrent NSCLC was conducted. The primary end point was response rate, using a Simon two-stage design. Eligible patients had measurable disease and no more than two chemotherapy regimens. D was given at 30 mg/m2/wk intravenously ×3 every 4 weeks and oral Im at 600 mg daily for four cycles. Patients required two cycles to be evaluable for response. Nonprogressors after four cycles continued with Im maintenance until progression or for a total of 12 months.Results:Twenty-three patients were enrolled in the first stage. Toxicity was mainly nonhematologic. We observed one partial response (5.5%), four stable disease (22.2%), and 13 progressed (72.2%). Median time to progression was 1.9 months, and median overall survival was 6.1 months. Two patients who went on Im maintenance had time to progression of 7.78 months and 15.8 months.Conclusion:Im in combination with D did not achieve its primary objective of improving response rate in patients with recurrent NSCLC. An increased understanding of the complex PDGFR pathway in lung cancer and alternative strategies to inhibit it are needed

Adaptive capacity beyond the household: a systematic review of empirical social-ecological research

The concept of adaptive capacity has received significant attention within social-ecological and environmental change research. Within both the resilience and vulnerability literatures specifically, adaptive capacity has emerged as a fundamental concept for assessing the ability of social-ecological systems to adapt to environmental change. Although methods and indicators used to evaluate adaptive capacity are broad, the focus of existing scholarship has predominately been at the individual- and household- levels. However, the capacities necessary for humans to adapt to global environmental change are often a function of individual and societal characteristics, as well as cumulative and emergent capacities across communities and jurisdictions. In this paper, we apply a systematic literature review and co-citation analysis to investigate empirical research on adaptive capacity that focus on societal levels beyond the household. Our review demonstrates that assessments of adaptive capacity at higher societal levels are increasing in frequency, yet vary widely in approach, framing, and results; analyses focus on adaptive capacity at many different levels (e.g. community, municipality, global region), geographic locations, and cover multiple types of disturbances and their impacts across sectors. We also found that there are considerable challenges with regard to the ‘fit’ between data collected and analytical methods used in adequately capturing the cross-scale and cross-level determinants of adaptive capacity. Current approaches to assessing adaptive capacity at societal levels beyond the household tend to simply aggregate individual- or household-level data, which we argue oversimplifies and ignores the inherent interactions within and across societal levels of decision-making that shape the capacity of humans to adapt to environmental change across multiple scales. In order for future adaptive capacity research to be more practice-oriented and effectively guide policy, there is a need to develop indicators and assessments that are matched with the levels of potential policy applications

The success of the Montreal Protocol in mitigating interactive effects of stratospheric ozone depletion and climate change on the environment

The Montreal Protocol and its Amendments have been highly effective in protecting the stratospheric ozone layer, preventing global increases in solar ultraviolet-B radiation (UV-B; 280-315 nm) at Earth's surface, and reducing global warming. While ongoing and projected changes in UV-B radiation and climate still pose a threat to human health, food security, air and water quality, terrestrial and aquatic ecosystems, and construction materials and fabrics, the Montreal Protocol continues to play a critical role in protecting Earth's inhabitants and ecosystems by addressing many of the United Nations Sustainable Development Goals.Non peer reviewe

Tumour stage, treatment, and survival of women with high-grade serous tubo-ovarian cancer in UKCTOCS: an exploratory analysis of a randomised controlled trial

Background: In UKCTOCS, there was a decrease in the diagnosis of advanced stage tubo-ovarian cancer but no reduction in deaths in the multimodal screening group compared with the no screening group. Therefore, we did exploratory analyses of patients with high-grade serous ovarian cancer to understand the reason for the discrepancy.// Methods: UKCTOCS was a 13-centre randomised controlled trial of screening postmenopausal women from the general population, aged 50–74 years, with intact ovaries. The trial management system randomly allocated (2:1:1) eligible participants (recruited from April 17, 2001, to Sept 29, 2005) in blocks of 32 using computer generated random numbers to no screening or annual screening (multimodal screening or ultrasound screening) until Dec 31, 2011. Follow-up was through national registries until June 30, 2020. An outcome review committee, masked to randomisation group, adjudicated on ovarian cancer diagnosis, histotype, stage, and cause of death. In this study, analyses were intention-to-screen comparisons of women with high-grade serous cancer at censorship (Dec 31, 2014) in multimodal screening versus no screening, using descriptive statistics for stage and treatment endpoints, and the Versatile test for survival from randomisation. This trial is registered with the ISRCTN Registry, 22488978, and ClinicalTrials.gov, NCT00058032.// Findings: 202 562 eligible women were recruited (50 625 multimodal screening; 50 623 ultrasound screening; 101 314 no screening). 259 (0·5%) of 50 625 participants in the multimodal screening group and 520 (0·5%) of 101 314 in the no screening group were diagnosed with high-grade serous cancer. In the multimodal screening group compared with the no screening group, fewer were diagnosed with advanced stage disease (195 [75%] of 259 vs 446 [86%] of 520; p=0·0003), more had primary surgery (158 [61%] vs 219 [42%]; p<0·0001), more had zero residual disease following debulking surgery (119 [46%] vs 157 [30%]; p<0·0001), and more received treatment including both surgery and chemotherapy (192 [74%] vs 331 [64%]; p=0·0032). There was no difference in the first-line combination chemotherapy rate (142 [55%] vs 293 [56%]; p=0·69). Median follow-up from randomisation of 779 women with high-grade serous cancer in the multimodal and no screening groups was 9·51 years (IQR 6·04–13·00). At censorship (June 30, 2020), survival from randomisation was longer in women with high-grade serous cancer in the multimodal screening group than in the no screening group with absolute difference in survival of 6·9% (95% CI 0·4–13·0; p=0·042) at 18 years (21% [95% CI 15·6–26·2] vs 14% [95% CI 10·5–17·4]).// Interpretation: To our knowledge, this is the first evidence that screening can detect high-grade serous cancer earlier and lead to improved short-term treatment outcomes compared with no screening. The potential survival benefit for women with high-grade serous cancer was small, most likely due to only modest gains in early detection and treatment improvement, and tumour biology. The cumulative results of the trial suggest that surrogate endpoints for disease-specific mortality should not currently be used in screening trials for ovarian cancer

Tumour stage, treatment, and survival of women with high-grade serous tubo-ovarian cancer in UKCTOCS: an exploratory analysis of a randomised controlled trial

Background: In UKCTOCS, there was a decrease in the diagnosis of advanced stage tubo-ovarian cancer but no reduction in deaths in the multimodal screening group compared with the no screening group. Therefore, we did exploratory analyses of patients with high-grade serous ovarian cancer to understand the reason for the discrepancy. Methods: UKCTOCS was a 13-centre randomised controlled trial of screening postmenopausal women from the general population, aged 50–74 years, with intact ovaries. The trial management system randomly allocated (2:1:1) eligible participants (recruited from April 17, 2001, to Sept 29, 2005) in blocks of 32 using computer generated random numbers to no screening or annual screening (multimodal screening or ultrasound screening) until Dec 31, 2011. Follow-up was through national registries until June 30, 2020. An outcome review committee, masked to randomisation group, adjudicated on ovarian cancer diagnosis, histotype, stage, and cause of death. In this study, analyses were intention-to-screen comparisons of women with high-grade serous cancer at censorship (Dec 31, 2014) in multimodal screening versus no screening, using descriptive statistics for stage and treatment endpoints, and the Versatile test for survival from randomisation. This trial is registered with the ISRCTN Registry, 22488978, and ClinicalTrials.gov, NCT00058032. Findings: 202 562 eligible women were recruited (50 625 multimodal screening; 50 623 ultrasound screening; 101 314 no screening). 259 (0·5%) of 50 625 participants in the multimodal screening group and 520 (0·5%) of 101 314 in the no screening group were diagnosed with high-grade serous cancer. In the multimodal screening group compared with the no screening group, fewer were diagnosed with advanced stage disease (195 [75%] of 259 vs 446 [86%] of 520; p=0·0003), more had primary surgery (158 [61%] vs 219 [42%]; p<0·0001), more had zero residual disease following debulking surgery (119 [46%] vs 157 [30%]; p<0·0001), and more received treatment including both surgery and chemotherapy (192 [74%] vs 331 [64%]; p=0·0032). There was no difference in the first-line combination chemotherapy rate (142 [55%] vs 293 [56%]; p=0·69). Median follow-up from randomisation of 779 women with high-grade serous cancer in the multimodal and no screening groups was 9·51 years (IQR 6·04–13·00). At censorship (June 30, 2020), survival from randomisation was longer in women with high-grade serous cancer in the multimodal screening group than in the no screening group with absolute difference in survival of 6·9% (95% CI 0·4–13·0; p=0·042) at 18 years (21% [95% CI 15·6–26·2] vs 14% [95% CI 10·5–17·4]). Interpretation: To our knowledge, this is the first evidence that screening can detect high-grade serous cancer earlier and lead to improved short-term treatment outcomes compared with no screening. The potential survival benefit for women with high-grade serous cancer was small, most likely due to only modest gains in early detection and treatment improvement, and tumour biology. The cumulative results of the trial suggest that surrogate endpoints for disease-specific mortality should not currently be used in screening trials for ovarian cancer. Funding: National Institute for Health Research, Medical Research Council, Cancer Research UK, The Eve Appeal

Preclinical evaluation of (S)-[18F]GE387, a novel 18-kDa translocator protein (TSPO) PET radioligand with low binding sensitivity to human polymorphism rs6971.

Funder: Herchel Smith Fellowship programmePURPOSE: Positron emission tomography (PET) studies with radioligands for 18-kDa translocator protein (TSPO) have been instrumental in increasing our understanding of the complex role neuroinflammation plays in disorders affecting the brain. However, (R)-[11C]PK11195, the first and most widely used TSPO radioligand has limitations, while the next-generation TSPO radioligands have suffered from high interindividual variability in binding due to a genetic polymorphism in the TSPO gene (rs6971). Herein, we present the biological evaluation of the two enantiomers of [18F]GE387, which we have previously shown to have low sensitivity to this polymorphism. METHODS: Dynamic PET scans were conducted in male Wistar rats and female rhesus macaques to investigate the in vivo behaviour of (S)-[18F]GE387 and (R)-[18F]GE387. The specific binding of (S)-[18F]GE387 to TSPO was investigated by pre-treatment with (R)-PK11195. (S)-[18F]GE387 was further evaluated in a rat model of lipopolysaccharide (LPS)-induced neuroinflammation. Sensitivity to polymorphism of (S)-GE387 was evaluated in genotyped human brain tissue. RESULTS: (S)-[18F]GE387 and (R)-[18F]GE387 entered the brain in both rats and rhesus macaques. (R)-PK11195 blocked the uptake of (S)-[18F]GE387 in healthy olfactory bulb and peripheral tissues constitutively expressing TSPO. A 2.7-fold higher uptake of (S)-[18F]GE387 was found in the inflamed striatum of LPS-treated rodents. In genotyped human brain tissue, (S)-GE387 was shown to bind similarly in low affinity binders (LABs) and high affinity binders (HABs) with a LAB to HAB ratio of 1.8. CONCLUSION: We established that (S)-[18F]GE387 has favourable kinetics in healthy rats and non-human primates and that it can distinguish inflamed from normal brain regions in the LPS model of neuroinflammation. Crucially, we have reconfirmed its low sensitivity to the TSPO polymorphism on genotyped human brain tissue. Based on these factors, we conclude that (S)-[18F]GE387 warrants further evaluation with studies on human subjects to assess its suitability as a TSPO PET radioligand for assessing neuroinflammation

The cost-effectiveness of screening for ovarian cancer: results from the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)

Background: To assess the within trial cost-effectiveness of an NHS ovarian cancer screening (OCS) programme using data from UKCTOCS and extrapolate results based on average life expectancy. Methods: Within trial economic evaluation of no screening (C) versus either (1) an annual OCS programme using transvaginal ultrasound (USS) or (2) an annual ovarian cancer multimodal screening programme with serum CA125 interpreted using a risk algorithm (ROCA) and transvaginal ultrasound as a second line test (MMS), plus comparison of lifetime extrapolation of the no screening arm and the MMS programme using both a predictive and a Markov model. Results: Using a CA125-ROCA cost of £20, the within trial results show USS to be strictly dominated by MMS, with the MMS versus C comparison returning an Incremental Cost-Effectiveness ratio (ICER) of £91,452 per life year gained (LYG). If the CA125-ROCA unit cost is reduced to £15 the ICER becomes £77,818 per LYG. Predictive extrapolation over the expected lifetime of the UKCTOCS women returns an ICER of £30,033 per LYG, while Markov modelling produces an ICER of £46,922 per QALY. Conclusions: Analysis suggests that, after accounting for the lead-time required to establish full mortality benefits, a national OCS programme based on the MMS strategy quickly approaches the current NICE thresholds for cost-effectiveness when extrapolated out to lifetime as compared to the within trial ICER estimates. Whether MMS could be recommended on economic grounds would depend on the confirmation and size of the mortality benefit at the end of an ongoing follow-up of the UKCTOCS cohort