National guidelines for management of cervical squamous intraepithelial lesion : A survey of European Federation for Colposcopy members

Acknowledgements: Austria: Olaf Reich: Belgium: Wiebrin Tjalma; Croatia: Drazan Butorac; Cyprus: Dinos Mavromoustakis; Estonia: Terje Raud, Liis Kriisa; Finland: Maija Jakobsson;bFrance: Xavier Carcopino; Georgia: Tamar Alibegashvili; Germany: Jens Quaas Volkmar Kuppers, Greece: Georgios Michail; Hungary: Robert Koiss; Iceland: Kristjan Oddsson; Ireland: Grainne Flannelly; Israel: Efraim Siegler; Italy: Andrea Ciavattini; Kosovo: Mazllom Smajli; Latvia: Kristine Pcolkina; Lithuania: Kristina Jariene; Macedonia: Goran Dimitrov; Moldova: Uliana Tabuica; Norway: Amelie Tropé; Poland: Robert Jach; Portugal: Amélia Pedro; Romania: Mihaela Grigore Russia: Vera Prilepskaya; Serbia: Vesna Kesic; Slovenia: Spela Smrkolj ; Spain: Marta del Pino; Sweden: Björn Strander; Switzerland: André Kind, Brigitte Frey Tirri; The Netherlands: A.M.L.D. van Haaften-de Jong; Turkey: Murat Gultekin; U.K.: Pierre Martin-Hirsch; Ukraine: Nataliya VolodkoPeer reviewedPostprin

Fostering Prevention of Cervical Cancer by a Correct Diagnosis of Precursors: A Structured Case-Based Colposcopy Course in Finland, Norway and UK

Simple Summary Cervical cancer prevention is presently undergoing a thorough reformation due to introduction of human papillomavirus (HPV)-testing and vaccines in primary prevention. The screening program, however, is more than a single test or preventive intervention-the possible lesion has to be found, located and treated. Colposcopy plays a major role in this management. Literature dealing with training and learning, especially with colposcopy, is extremely scarce. The aim of the European Federation of Colposcopy, EFC, is to improve the education and training in colposcopy, e.g., by organizing colposcopy courses. The aim of our prospective interventional study was to pilot this intensive participant activating EFC Basic Colposcopy Course on the short- and long-term learning of colposcopy-related knowledge, image recognition and the diagnostic confidence. High-quality colposcopy is essential in cervical cancer prevention. We performed a multicentre prospective interventional pilot-study, evaluating the effect of a six-hour case-based colposcopy course on short- and long-term learning of colposcopy-related knowledge, diagnostic accuracy levels and confidence. We recruited 213 colposcopists participating in three European Federation of Colposcopy (EFC) basic colposcopy courses (Finland, Norway, UK). The study consisted of three tests with identical content performed before, after and 2 months after the course, including ten colposcopic images, ten patient cases and scales for marking confidence in the answers. Outcome measures where mean scores in correct case-management, diagnosis (including high-grade lesion recognition), transformation-zone recognition and confidence in answers. Results were compared between the three tests and stratified according to experience. Mean test scores improved after the course for all participants. The increase was highest for beginners. Confidence in answers improved and the number of colposcopists showing high confidence with low scores decreased. A structured case-based course improves skills and confidence especially for inexperienced colposcopists; however, trainers should be aware of the risk of overconfidence. To complement theoretical training, further hands-on training including high-quality feedback is recommended. Conclusions drawn from long-term learning are limited due to the low participation in the follow-up test.Peer reviewe

Oscillations of starless cores

If the split, asymmetric molecular spectral line profiles that are seen in many starless cores are interpreted as indicative of global collapse or expansion of the core then one possible implication is that most starless cores have short lifetimes on the order of the collapse or sound crossing time scale. An alternative interpretation of the line profiles as indicative of perturbations on an underlying equilibrium structure leads to the opposite implication, that many cores have long lifetimes. While evidence suggests that some cores are collapsing on a free-fall time scale, we show that observations of some other starless cores can be reproduced by a model of non-radial oscillations about the equilibrium configuration of a pressure-bounded, thermally-supported sphere (Bonnor-Ebert sphere). We model the oscillations as linear perturbations following a standard analysis developed for stellar pulsations and compare the column densities and molecular spectral line profiles predicted from a particular model to observations of the Bok globule B68.Comment: submitted to the Astrophysical Journa

Phase II Trial of Cediranib in Combination With Cisplatin and Pemetrexed in Chemotherapy-Naïve Patients With Unresectable Malignant Pleural Mesothelioma (SWOG S0905).

PurposeAntiangiogenic agents combined with chemotherapy have efficacy in the treatment of unresectable malignant pleural mesothelioma (MPM). Cediranib (AstraZeneca, Cheshire, United Kingdom), a vascular endothelial growth factor receptor and platelet-derived growth factor receptor inhibitor, demonstrated therapeutic potential in a prior phase I trial. We evaluated a phase II trial for efficacy.Patients and methodsSWOG S0905 (ClinicalTrials.gov identifier: NCT01064648) randomly assigned cediranib or placebo with platinum-pemetrexed for six cycles followed by maintenance cediranib or placebo in unresectable chemotherapy-naïve patients with MPM of any histologic subtype. Primary end point was Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 progression-free survival (PFS). Secondary end points included overall survival, PFS by modified RECIST v1.1, response (modified RECIST and RECIST v1.1), disease control, and safety/toxicity. The trial was designed to detect a difference in RECIST v1.1 PFS at the one-sided 0.1 level using a stratified log-rank test.ResultsNinety-two eligible patients were enrolled (75% epithelioid and 25% biphasic or sarcomatoid). The cediranib arm had more grade 3 and 4 diarrhea, dehydration, hypertension, and weight loss. Cediranib improved PFS by RECIST v1.1 (hazard ratio, 0.71; 80% CI, 0.54 to 0.95; P = .062; 7.2 months v 5.6 months) and increased modified RECIST v1.1 response (50% v 20%; P = .006). By modified RECIST v1.1, cediranib numerically increased PFS (hazard ratio, 0.77; 80% CI, 0.59 to 1.02; P = .12; median, 6.9 months v 5.6 months). No significant difference in overall survival was observed.ConclusionThe addition of cediranib to platinum-pemetrexed improved PFS by RECIST v1.1 and response rate by modified RECIST in patients with unresectable MPM. Whereas adding antiangiogenics to chemotherapy has been a successful strategy for some patients, the cediranib toxicity profile and small incremental survival benefit precludes additional development in MPM

Changes in biodiversity and trade-offs among ecosystem services, stakeholders, and components of well-being: the contribution of the International Long-Term Ecological Research network (ILTER) to Programme on Ecosystem Change and Society (PECS)

The International Long-Term Ecological Research (ILTER) network comprises > 600 scientific groups conducting site-based research within 40 countries. Its mission includes improving the understanding of global ecosystems and informs solutions to current and future environmental problems at the global scales. The ILTER network covers a wide range of social-ecological conditions and is aligned with the Programme on Ecosystem Change and Society (PECS) goals and approach. Our aim is to examine and develop the conceptual basis for proposed collaboration between ILTER and PECS. We describe how a coordinated effort of several contrasting LTER site-based research groups contributes to the understanding of how policies and technologies drive either toward or away from the sustainable delivery of ecosystem services. This effort is based on three tenets: transdisciplinary research; cross-scale interactions and subsequent dynamics; and an ecological stewardship orientation. The overarching goal is to design management practices taking into account trade-offs between using and conserving ecosystems toward more sustainable solutions. To that end, we propose a conceptual approach linking ecosystem integrity, ecosystem services, and stakeholder well-being, and as a way to analyze trade-offs among ecosystem services inherent in diverse management options. We also outline our methodological approach that includes: (i) monitoring and synthesis activities following spatial and temporal trends and changes on each site and by documenting cross-scale interactions; (ii) developing analytical tools for integration; (iii) promoting trans-site comparison; and (iv) developing conceptual tools to design adequate policies and management interventions to deal with trade-offs. Finally, we highlight the heterogeneity in the social-ecological setting encountered in a subset of 15 ILTER sites. These study cases are diverse enough to provide a broad cross-section of contrasting ecosystems with different policy and management drivers of ecosystem conversion; distinct trends of biodiversity change; different stakeholders’ preferences for ecosystem services; and diverse components of well-being issues

Cetuximab Plus Carboplatin and Paclitaxel With or Without Bevacizumab Versus Carboplatin and Paclitaxel With or Without Bevacizumab in Advanced NSCLC (SWOG S0819): A Randomised, Phase 3 Study

Background EGFR antibodies have shown promise in patients with advanced non-small-cell lung cancer (NSCLC), particularly with squamous cell histology. We hypothesised that EGFR copy number by fluorescence in-situ hybridisation (FISH) can identify patients most likely to benefit from these drugs combined with chemotherapy and we aimed to explore the activity of cetuximab with chemotherapy in patients with advanced NSCLC who are EGFR FISH-positive. Methods We did this open-label, phase 3 study (SWOG S0819) at 277 sites in the USA and Mexico. We randomly assigned (1:1) eligible patients with treatment-naive stage IV NSCLC to receive paclitaxel (200 mg/m 2; every 21 days) plus carboplatin (area under the curve of 6 by modified Calvert formula; every 21 days) or carboplatin plus paclitaxel and bevacizumab (15 mg/kg; every 21 days), either with cetuximab (250 mg/m 2 weekly after loading dose; cetuximab group) or without (control group), stratified by bevacizumab treatment, smoking status, and M-substage using a dynamic-balancing algorithm. Co-primary endpoints were progression-free survival in patients with EGFR FISH-positive cancer and overall survival in the entire study population. We analysed clinical outcomes with the intention-to-treat principle and analysis of safety outcomes included patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov (number NCT00946712). Findings Between Aug 13, 2009, and May 30, 2014, we randomly assigned 1313 patients to the control group (n=657; 277 with bevacizumab and 380 without bevacizumab in the intention-to-treat population) or the cetuximab group (n=656; 283 with bevacizumab and 373 without bevacizumab in the intention-to-treat population). EGFR FISH was assessable in 976 patients and 400 patients (41%) were EGFR FISH-positive. The median follow-up for patients last known to be alive was 35·2 months (IQR 22·9–39·9). After 194 progression-free survival events in the cetuximab group and 198 in the control group in the EGFR FISH-positive subpopulation, progression-free survival did not differ between treatment groups (hazard ratio [HR] 0·92, 95% CI 0·75–1·12; p=0·40; median 5·4 months [95% CI 4·5–5·7] vs 4·8 months [3·9–5·5]). After 570 deaths in the cetuximab group and 593 in the control group, overall survival did not differ between the treatment groups in the entire study population (HR 0·93, 95% CI 0·83–1·04; p=0·22; median 10·9 months [95% CI 9·5–12·0] vs 9·2 months [8·7–10·3]). In the prespecified analysis of EGFR FISH-positive subpopulation with squamous cell histology, overall survival was significantly longer in the cetuximab group than in the control group (HR 0·58, 95% CI 0·36–0·86; p=0·0071), although progression-free survival did not differ between treatment groups in this subgroup (0·68, 0·46–1·01; p=0·055). Overall survival and progression-free survival did not differ among patients who were EGFR FISH non-positive with squamous cell histology (HR 1·04, 95% CI 0·78–1·40; p=0·77; and 1·02, 0·77–1·36; p=0·88 respectively) or patients with non-squamous histology regardless of EGFR FISH status (for EGFR FISH-positive 0·88, 0·68–1·14; p=0·34; and 0·99, 0·78–1·27; p=0·96; respectively; and for EGFR FISH non-positive 1·00, 0·85–1·17; p=0·97; and 1·03, 0·88–1·20; p=0·69; respectively). The most common grade 3–4 adverse events were decreased neutrophil count (210 [37%] in the cetuximab group vs 158 [25%] in the control group), decreased leucocyte count (103 [16%] vs 74 [20%]), fatigue (81 [13%] vs 74 [20%]), and acne or rash (52 [8%] vs one [\u3c 1%]). 59 (9%) patients in the cetuximab group and 31 (5%) patients in the control group had severe adverse events. Deaths related to treatment occurred in 32 (6%) patients in the cetuximab group and 13 (2%) patients in the control group. Interpretation Although this study did not meet its primary endpoints, prespecified subgroup analyses of patients with EGFR FISH-positive squamous-cell carcinoma cancers are encouraging and support continued evaluation of anti-EGFR antibodies in this subpopulation

A Regulatory Network for Coordinated Flower Maturation

For self-pollinating plants to reproduce, male and female organ development must be coordinated as flowers mature. The Arabidopsis transcription factors AUXIN RESPONSE FACTOR 6 (ARF6) and ARF8 regulate this complex process by promoting petal expansion, stamen filament elongation, anther dehiscence, and gynoecium maturation, thereby ensuring that pollen released from the anthers is deposited on the stigma of a receptive gynoecium. ARF6 and ARF8 induce jasmonate production, which in turn triggers expression of MYB21 and MYB24, encoding R2R3 MYB transcription factors that promote petal and stamen growth. To understand the dynamics of this flower maturation regulatory network, we have characterized morphological, chemical, and global gene expression phenotypes of arf, myb, and jasmonate pathway mutant flowers. We found that MYB21 and MYB24 promoted not only petal and stamen development but also gynoecium growth. As well as regulating reproductive competence, both the ARF and MYB factors promoted nectary development or function and volatile sesquiterpene production, which may attract insect pollinators and/or repel pathogens. Mutants lacking jasmonate synthesis or response had decreased MYB21 expression and stamen and petal growth at the stage when flowers normally open, but had increased MYB21 expression in petals of older flowers, resulting in renewed and persistent petal expansion at later stages. Both auxin response and jasmonate synthesis promoted positive feedbacks that may ensure rapid petal and stamen growth as flowers open. MYB21 also fed back negatively on expression of jasmonate biosynthesis pathway genes to decrease flower jasmonate level, which correlated with termination of growth after flowers have opened. These dynamic feedbacks may promote timely, coordinated, and transient growth of flower organs

Nothing Lasts Forever: Environmental Discourses on the Collapse of Past Societies

The study of the collapse of past societies raises many questions for the theory and practice of archaeology. Interest in collapse extends as well into the natural sciences and environmental and sustainability policy. Despite a range of approaches to collapse, the predominant paradigm is environmental collapse, which I argue obscures recognition of the dynamic role of social processes that lie at the heart of human communities. These environmental discourses, together with confusion over terminology and the concepts of collapse, have created widespread aporia about collapse and resulted in the creation of mixed messages about complex historical and social processes