569 research outputs found

    Near Earth space plasma monitoring under COST 296

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    This review paper presents the main achievements of the near Earth space plasma monitoring under COST 296 Action. The outputs of the COST 296 community making data, historical and real-time, standardized and available to the ionospheric community for their research, applications and modeling purposes are presented. The contribution of COST 296 with the added value of the validated data made possible a trusted ionospheric monitoring for research and modeling purposes, and it served for testing and improving the algorithms producing real-time data and providing data users measurement uncertainties. These value added data also served for calibration and validation of space-borne sensors. New techniques and parameters have been developed for monitoring the near Earth space plasma, as time dependent 2D maps of vertical total electron content (vTEC), other key ionospheric parameters and activity indices for distinguishing disturbed ionospheric conditions, as well as a technique for improving the discrepancies of different mapping services. The dissemination of the above products has been developed by COST 296 participants throughout the websites making them available on-line for real-time applications

    Observations of quiet-time moderate midlatitude L-band scintillation in association with plasma bubbles

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    Observations of moderate night time amplitude scintillation on the GPS L1C/A signal were recorded at the midlatitude station of Nicosia, corresponding geographic latitude and longitude of 35.18˚N and 33.38˚E respectively, on a geomagnetically quiet day. The variations of slant total electron content (STEC) and amplitude scintillation index (S4) on the night of June 12, 2014, indicate the presence of electron density depletions accompanying scintillation occurrence. The estimated apparent horizontal drift velocity and propagation direction of the plasma depletions are consistent with those observed for the equatorial plasma bubbles, thus suggesting that the moderate amplitude L-band scintillation observed over Nicosia may be associated with the extension of such plasma bubbles. The L-band scintillation occurrence was concurrent with the observations of range spread F on the ionograms recorded by the digisonde at Nicosia. The height–time–intensity plot generated using the ionogram data also showed features which can be attributed to off-angle reflections from electron density depletions, thus corroborating the STEC observations. This observation suggests that the midlatitude ionosphere is more active even during geomagnetically quiet days than previously thought and that further studies are necessary. This is particularly relevant for the GNSS user community and related applications

    Vedolizumab for the Treatment of Adults with Moderate-to-Severe Active Ulcerative Colitis: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

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    As part of its single technology appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer of vedolizumab (Takeda UK) to submit evidence of the clinical effectiveness and cost effectiveness of vedolizumab for the treatment of patients with moderate-to-severe active ulcerative colitis (UC). The Evidence Review Group (ERG) produced a critical review of the evidence for the clinical effectiveness and cost effectiveness of the technology, based upon the company's submission to NICE. The evidence was derived mainly from GEMINI 1, a Phase 3, multicentre, randomised, double-blinded, placebo-controlled study of the induction and maintenance of clinical response and remission by vedolizumab (MLN0002) in patients with moderate-to-severe active UC with an inadequate response to, loss of response to or intolerance of conventional therapy or anti-tumour necrosis factor (TNF)-α. The clinical evidence showed that vedolizumab performed significantly better than placebo in both the induction and maintenance phases. In the post hoc subgroup analyses in patients with or without prior anti-TNF-α therapy, vedolizumab performed better then placebo (p value not reported). In addition, a greater improvement in health-related quality of life was observed in patients treated with vedolizumab, and the frequency and types of adverse events were similar in the vedolizumab and placebo groups, but the evidence was limited to short-term follow-up. There were a number of limitations and uncertainties in the clinical evidence base, which warrants caution in its interpretation-in particular, the post hoc subgroup analyses and high dropout rates in the maintenance phase of GEMINI 1. The company also presented a network meta-analysis of vedolizumab versus other biologic therapies indicated for moderate-to-severe UC. However, the ERG considered that the results presented may have underestimated the uncertainty in treatment effects, since fixed-effects models were used, despite clear evidence of heterogeneity among the trials included in the network. Results from the company's economic evaluation (which included price reductions to reflect the proposed patient access scheme for vedolizumab) suggested that vedolizumab is the most effective option compared with surgery and conventional therapy in the following three populations: (1) a mixed intention-to-treat population, including patients who have previously received anti-TNF-α therapy and those who are anti-TNF-α naïve; (2) patients who are anti-TNF-α naïve only; and (3) patients who have previously failed anti-TNF-α therapy only. The ERG concluded that the results of the company's economic evaluation could not be considered robust, because of errors in model implementation, omission of relevant comparators, deviations from the NICE reference case and questionable model assumptions. The ERG amended the company's model and demonstrated that vedolizumab is expected to be dominated by surgery in all three populations

    HER2 and ESR1 mRNA expression levels and response to neoadjuvant trastuzumab plus chemotherapy in patients with primary breast cancer

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    Introduction: Recent data suggest that benefit from trastuzumab and chemotherapy might be related to expression of HER2 and estrogen receptor (ESR1). Therefore, we investigated HER2 and ESR1 mRNA levels in core biopsies of HER2-positive breast carcinomas from patients treated within the neoadjuvant GeparQuattro trial. Methods: HER2 levels were centrally analyzed by immunohistochemistry (IHC), silver in-situ hybridization (SISH) and qRT-PCR in 217 pretherapeutic formalin-fixed, paraffin-embedded (FFPE) core biopsies. All tumors had been HER2-positive by local pathology and had been treated with neoadjuvant trastuzumab/ chemotherapy in GeparQuattro. Results: Only 73% of the tumors (158 of 217) were centrally HER2-positive (cHER2-positive) by IHC/SISH, with cHER2-positive tumors showing a significantly higher pCR rate (46.8% vs. 20.3%, p<0.0005). HER2 status by qRT-PCR showed a concordance of 88.5% with the central IHC/SISH status, with a low pCR rate in those tumors that were HER2-negative by mRNA analysis (21.1% vs. 49.6%, p<0.0005). The level of HER2 mRNA expression was linked to response rate in ESR1-positive tumors, but not in ESR1-negative tumors. HER2 mRNA expression was significantly associated with pCR in the HER2-positive/ESR1-positive tumors (p=0.004), but not in HER2-positive/ESR1-negative tumors. Conclusions: Only patients with cHER2-positive tumors - irrespective of the method used - have an increased pCR rate with trastuzumab plus chemotherapy. In patients with cHER2-negative tumors the pCR rate is comparable to the pCR rate in the non-trastuzumab treated HER-negative population. Response to trastuzumab is correlated to HER2 mRNA levels only in ESR1-positive tumors. This study adds further evidence to the different biology of both subsets within the HER2-positive group

    The Future of International Investment Regulation: Towards a World Investment Organisation?

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    With growth in foreign investment and in the number of companies investing in foreign countries, the application of general principles of public international law has not been deemed adequate to regulate foreign investment and there is, as yet, no comprehensive international treaty on the regulation of foreign investment. Consequently, states have resorted to bilateral investment treaties (BITs), regional trade and international investment agreements (IIAs) and free trade agreements (FTAs) to supplement and complement the regime of protection for foreign investors. In the absence of an international investment court, states hosting foreign investment or investor states have opted for investor-state dispute settlement mechanism (ISDS). This mechanism has brought about its own challenges to the international law of foreign investment due to inconsistency in the application and interpretation of the key principles of international investment law by such arbitration tribunals, and further, there is no appellate mechanism to bring about some cohesion and consistency in jurisprudence. Therefore, there are various proposals mooted by scholars to address these challenges and they range from tweaks to BITs and IIAs, the creation of an appellate mechanism and the negotiation of a multilateral treaty to proposals for reform of ISDS only. After assessing the merits and demerits of such proposals, this study goes further, arguing for the creation of a World Investment Organisation (WIO) with a standing mechanism for settlement of investment disputes in order to ensure legal certainty, predictability and the promotion of the flow of foreign investment in a sustainable and responsible manner

    Trends in axillary lymph node dissection for early-stage breast cancer in Europe: Impact of evidence on practice

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    Background: Data from recently published trials have provided practice-changing recommendations for the surgical approach to the axilla in breast cancer. Patients with T1-2 lesions, treated with breast conservation, who have not received neoadjuvant chemotherapy and have 1\u20132 positive sentinel nodes (Z0011-criteria) may avoid axillary lymph node dissection (ALND). We aim to describe the dissemination of this practice in Europe over an extended period of time. Methods: Our source of data was the eusomaDB, a central data warehouse of prospectively collected information of the European Society of Breast Cancer Specialists (EUSOMA). We identified cases fulfilling Z0011-criteria from 2005 to 2016 from 34 European breast centers and report trends in ALND. Data derived from Germany, Italy, Belgium, Switzerland, Austria, and Netherlands. Results: 6671 patients fulfilled Z0011-criteria. Rates of ALND showed a statistically significant decrease from 2010 (89%) to 2011 (73%), reaching 46% in 2016 (p < 0.001). After multivariable analysis, factors associated with higher probability of ALND were earlier year of surgery, younger age, increasing tumor size and grade, and being operated in Italy (p < 0.001). The minimum and maximal rates of ALND in the most recent two-year period (2015\u20132016) were 0% and 83% in two centers located in different countries (p < 0.001). Conclusion: Our study demonstrates, a decrease in rates of ALND that started after year 2010 through the end of the study period. Wide differences were observed among centers and countries indicating the need to spread unified clinical guidelines in Europe to allow for homogeneous evidence-based practice patterns
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