dataesr/scientific-paragraphs-categorization huggingface dataset:
25 mg/kg; age $ 12 years, 4. 5 mg/kg, capsule or oral suspension divided into two equal doses daily); both 50% RP2D and 100% RP2D of dabrafenib were evaluated in combination with trametinib. Treatment was administered until unacceptable toxicity, progressive disease or lack of clinical benefit, or a patient/ physician decision to discontinue. At study completion for all patients (December 29, 2020), those who were deriving clinical benefit per investigator opinion were eligible to continue in a rollover study (ClinicalTrials. gov identifier: NCT03975829) for long-term follow-up.
Patient Selection Eligible patients had relapsed/refractory malignancies (exhausting any potentially curative treatments including surgery, radiation, chemotherapy, or combination thereof), had a Karnofsky/Lansky performance status of $ 50%, and were age $ 1 month (parts A and B) or $ 12 months (parts C and D) to , 18 years. Part A enrolled patients with solid tumors (ie, BRAF V600 mutation was not required), and part B included expansion cohorts for neuroblastoma, BRAFfusion LGG, neurofibromatosis type 1 (NF-1)-associated plexiform neurofibroma (PN), and BRAF V600-mutant tumors. In parts C and D, patients were required to have BRAF V600-mutant disease; disease-specific expansion cohorts in part D included LGG and Langerhans cell histiocytosis (Fig  1 ). Specific eligibility criteria for each part are given in detail in the Data Supplement (online only).
Assessments Adverse events (AEs), defined by the National Cancer Institute Common Terminology Criteria for Adverse Events v4. 03, were assessed at each visit; additional safety assessments are described in the Data Supplement. For trametinib with or without dabrafenib dose finding (parts A and C), dose-limiting toxicities (DLTs) were defined as potentially related to study treatment per the investigator, occurred during the first 28 days of treatment, and met specific criteria outlined in the Data Supplement. PK samples were obtained on days 15 and 22 (part A); day 15 (part B); or days 1, 15, and 22 (parts C and D). Dose escalation and RP2D determination were based on DLTs and PK criteria outlined in the Data Supplement. For the BRAF V600-mutant LGG cohort, radiographic disease assessments were performed at baseline, every 8 weeks 3 3, and then every 12 weeks and evaluated by independent radiology review and investigators using Response Assessment in Neuro-Oncology (RANO) criteria  23, 24  ; RANO 2017 criteria use T2 FLAIR magnetic resonance imaging sequences, were considered more relevant for pediatric LGG, and are presented here.
Study Overview Between January 15, 2015, and December 29, 2020, 139 patients were enrolled ( In part A (trametinib monotherapy), 8 of 48 DLT-evaluable patients (17%) experienced a total of 10 DLTs (Data Supplement) at the doses of 0. 025 (n 5 3) and 0. 04 (n 5 7) mg/kg once daily, including mucosal inflammation (n 5 3) and hyponatremia (n 5 2) in. 1 patient. Most (7 of 10) were grade 3; there were one grade 2 DLT (intolerable mucosal inflammation) at 0. 025 mg/kg once daily and two grade 4 DLTs (hyponatremia and hypotension) at 0. 04 mg/kg once daily. Although the dose of 0. 04 mg/kg once daily was not well tolerated, it was estimated on the basis of PK data that approximately 23% of patients age , 6 years would not achieve target trametinib exposure at the dose of 0. 025 mg/kg once daily.
Efficacy appeared to be greater with dabrafenib 1 trametinib, with response rates of 25% with combination therapy and 15% with trametinib monotherapy. Although few progression events were reported before study completion, median PFS with combination therapy was also longer than with trametinib monotherapy, at 36. 9 and 16. 4 months, respectively. Based in part on these results, dabrafenib 1 trametinib received tumor-agnostic approval from the US Food and Drug Administration for the treatment of patients age $ 6 years with unresectable/ metastatic BRAF V600E-mutant solid tumors who have progressed after prior treatment and have no satisfactory alternative. 20, 21 Moreover, recently presented results from a phase II randomized trial comparing dabrafenib 1 trametinib with standard-of-care chemotherapy in previously untreated BRAF V600-mutant pediatric LGG (ClinicalTrials.
gov identifier: NCT02684058) further support BRAF 1 MEK inhibitor targeted therapy as an emerging standard of care in BRAF V600-mutant pediatric LGG. 31  Indirect comparison of trametinib monotherapy and combination therapy within our trial suggests that  BRAF 1 MEK inhibitor combination may offer improved efficacy and safety over MEK inhibitor monotherapy in BRAF V600-mutant pediatric LGG. However, the relative benefit of combination therapy vs BRAF inhibitor monotherapy in these patients is less clear. 32 7] [18]  Such direct evidence is not available for adults with BRAF V600-mutant gliomas although cross-trial comparison of BRAF inhibitor monotherapy with combination therapy favors the latter. 22, 33 However, in pediatric phase I/II studies of dabrafenib (n 5 32) or vemurafenib (n 5 19) monotherapy, response rates comparable with those observed with combination therapy in the present study were achieved in BRAF V600-mutant LGG.
6, 15 This is consistent with a retrospective analysis of pediatric patients with BRAF V600-mutant LGG treated with BRAF inhibitors or chemotherapy in which the objective response rates were reported to be 42% versus 10%, respectively. 14 These results illustrate the number of potentially confounding factors inherent in cross-trial comparison, including the heterogeneity of patients with LGG and different versions of RANO response criteria applied. As emergence of resistance may be a key differentiator, additional PFS analyses from the ongoing rollover study (ClinicalTrials. gov identifier: NCT03975829) may further elucidate the relative merits of BRAF inhibitor monotherapy vs combination therapy in this patient population and provide insight into the optimal treatment duration for targeted therapy in this setting.
However, lack of head-to-head comparison and small trial sizes are limitations. The present trial included several cohorts with non-BRAF V600-mutant diagnoses, including BRAF-fusion LGG and NF-1-associated PN. Evidence suggests that these malignancies have management considerations distinct from those for BRAF V600-mutant disease and benefit from MEK inhibition only  34, 35  ; as such, they will be reported separately in the future. Phase II data have been reported for the MEK inhibitor selumetinib in a molecularly mixed pediatric LGG population, with a response rate of 36% in the cohort of patients with BRAF aberrations (n 5 25), the majority of which were KIAA1549:BRAF fusions. 36 Thus, the present trial adds to a growing body of evidence supporting the utility of molecularly targeted therapy in pediatric malignancies and the importance of conducting molecular profiling in this population.
This phase I/II, multicenter, open-label study (An Open-Label, Dose-Escalation, Phase I/II Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of the MEK Inhibitor Trametinib in Children and Adolescents Subjects With Cancer or Plexiform Neurofibromas and Trametinib in Combination With Dabrafenib in Children and Adolescents With Cancers Harboring V600 Mutations; ClinicalTrials. gov identifier: NCT02124772) had four parts (Fig 1): trametinib monotherapy dose escalation (followed by age-specific extension; part A) and diseasespecific expansion (part B), and dabrafenib 1 trametinib dose escalation (followed by age-specific extension; part C) and disease-specific expansion (part D).
Two patients with BRAF V600-mutant HGG were enrolled in part C and are included in this predominantly LGG cohort as a diagnosis of HGG did not define any other disease-specific cohort in the trial. b Includes four patients in the trametinib monotherapy group and six in the dabrafenib 1 trametinib combination therapy group who just had biopsies. c One patient was pending approval for rollover study at the data cutoff date.
ACKNOWLEDGMENT The authors thank the patients who participated in the trial and their families. The authors also thank the physicians, nurses, research coordinators, and other staff at each site who assisted with the study. We also thank  Karen Wright ,  Kenneth Cohen , and  Lindsay Kilburn  for enrollment of patients onto the trial and  Neha Pakhle  ( Novartis Pharmaceuticals Corporation ) for statistical analysis, guidance, and critical review of the report. Editorial assistance was provided by  Amy Ghiretti, PhD ;  Allison Lytle, PhD ; and  Laura Hilditch, PhD  ( Articulate Science LLC ), and was funded by  Novartis Pharmaceuticals Corporation.
a Two patients with BRAF V600-mutant HGG were enrolled in part C and are included in this predominantly LGG cohort as a diagnosis of HGG did not define any other disease-specific cohort in the trial. b Includes four patients in the trametinib monotherapy group and six in the dabrafenib 1 trametinib combination therapy group who just had biopsies. c One patient was pending approval for rollover study at the data cutoff date.
Second, the authors use data on the Dow Jones Global Sukuk and S&P Green Bond Index. Unlike their study, we opt for a disaggregated analysis using a large sample of both sukuk and green bond indices from different regions to explore the potential differences in the reactions of the different markets which could be more useful for investors in formulating their investment strategies at both a regional and international levels. More formally, this study investigates the asymmetric dynamic linkages and spillover effects between these two types of financial assets. In addition, we examine the impact of global risk factors on connectedness and risk transmission between sukuk and green bonds. Using a sample of 15 sukuk markets from different regions of the world (i. e. , GCC, Asia, Europe and Africa) and four continental green bond indices, we evaluate the dynamic connection and transmission of information among and between these two markets as well as the way these could be affected by global factors.
Data and preliminary analysis In order to examine the dynamic connectedness and spillover effects between sukuk and green bond markets, authors constructed Sukuk indices based on a daily dataset obtained from Bloomberg Professional Service for fifteen countries. The sample includes data for the GCC countries, namely Bahrain, Kuwait, Oman, Qatar and Saudi Arabia, United Arab Emirates; Turkey from West Asia; Hong Kong, Indonesia, Malaysia, and Singapore from Southeast Asia; Pakistanis from South Asia; Nigerians from Africa; and Europe, Ireland and the United Kingdom. The reason for choosing this period is to study the impact of global shocks on the integration of the Sukuk market. Using a large sample of countries also allows researchers to study the effects of proliferation within and between regions.
To study the impact of global risks on Sukuk, we also use a volatility index developed by the Chicago Board Options Exchange (CBOE). The CBOE volatility index estimates the expected market volatility over 30 days. We use volatility indices of three main assets, namely oil (CBOE Crude Oil ETF Volatility Index, OVX), gold (CBOE Gold Volatility Index, GVZ) and stocks (CBOE SPDR ETF Volatility Index, VIX). Thomson Reuters Eikon, DataStream, and Bloomberg Databases were used as data sources, with an indicative timeframe from January 1, 2016, to April 1, 2022. The start date is based on data available in the Sukuk market. The daily return is calculated as the first difference between the natural logarithms of each index multiplied by , where p represents the closing 100 (𝑟 = 𝑙𝑛(𝑃𝑡/𝑃𝑡 -1) × 100) price.
We hypothesize that incorporation of a test like the ExoVita test into surveillance and/or diagnostic programs for PDAC high-risk patients will be a costeffective way to address an unmet need in the community setting by elevating patients with a high probability of cancer to more intensive management programs, as well as stage-shift patients to early-stage diagnoses. Further investigations on this topic are underway including a prospective, multi-center, observational registry study -ExoLuminate to evaluate patients at high-risk for PDAC (NCT0562552) (21) as well as health economic and cost-effectiveness utility studies. In conclusion, this case report highlights how a novel diagnostic test based on the detection of exosomes biomarkers allowed early diagnosis of PDAC and improved patient outcome.
There were twenty-four questions in total. Where participants were asked to compare telehealth services with service delivery prior to the Covid-19 pandemic a Likert scale with the following categories was utilised (1) much worse (2) somewhat worse (3) about the same (4) somewhat better and (5) much better. The force response option in Qualtrics was used to ensure that participants did not overlook or miss any of the questions that were vital to the analysis. There was no missing data. Data were collected between April-June 2021. During this time there were significant restrictions on nonessential social contact imposed by the UK government.
Limitations While the questionnaire was developed from key published literature and met the aims of this study, pilot testing only occurred with four members of the IAPT team. Further testing of the validity of the questionnaire is recommended for further research. There are inherent limitations in self-reported questionnaires, particularly related to social desirability bias. There is a risk that participants in this study felt compelled to answer positively, however, the results indicate that participants perceived benefits and barriers. Data in this study were collected over a three-month period (April-June 2021) which provides an understanding of how practitioners felt after one year of working with telehealth approaches rather than more immediate responses. Staff may have adjusted to delivering IAPT services via telehealth which could explain the high levels of satisfaction reported in this survey.
Funding The author(s) declare financial support was received for the research, authorship, and/or publication of this article. BB is a recipient of a fellowship from the  Rennes University , the  Reǵion Bretagne , and the  Ligue Nationale contre le Cancer. This work is supported by the  Ligue Nationale contre le Cancer (Equipe Labelliseé) , and the  Institut National du cancer  ( INCA AAP PNP-19-009  and  TRANSCAN-3 BIALYMP program ).
Each Γ is assumed to correspond to a single A → γγ leg of the presumed H → AA → 4γ decay. We construct signal (S) 2D-m Γ templates for each signal mass hypothesis m A = 0. 1-1. 2 GeV, in 0. 1 GeV steps, using simulation. This defines our signal model at each m A hypothesis. The relative m Γ resolution varies from approximately 100% to 20% for m A = 0. 1-1. 2 GeV  [23]. Background (B) 2D-m Γ templates are constructed for the SM processes contributing to our selected sample, derived from data and simulation. The sum of these background templates defines our background model, representing the SM-only hypothesis. A scan over different signal m A hypotheses is performed. At each point, maximum likelihood estimation (MLE)  [42]  is used to extract the best fit between the observed 2D-m Γ spectrum and the signal-plus-background model, µS + B, for some signal strength parameter µ.
Events reconstructed with two photonlike objects are used, where each photonlike object is assumed to be a merged A → γγ candidate. A method is developed to measure the invariant mass of merged diphoton candidates to discriminate a potential signal from the standard model background. This is the first search of its kind at CMS and made possible by a novel end-to-end reconstruction technique of merged diphotons. No excess of events above the estimated background is found. An upper limit on the branching fraction B(H → AA → 4γ) of (0. 9-3. 3)×10 -3 is set at 95% C. L. for masses of A in the range 0. 1-1. 2 GeV, assuming prompt A decays. These are the current best constraints on H → AA → 4γ in this m A range. Tabulated results for this analysis are provided in the HEPData record  [25].
Acknowledgments We congratulate our colleagues in the  CERN accelerator departments  for the excellent performance of the LHC and thank the technical and administrative staffs at  CERN  and at other  CMS institutes  for their contributions to the success of the CMS effort. In addition, we gratefully acknowledge the computing centers and personnel of the  Worldwide LHC Computing Grid  and other centers for delivering so effectively the computing infrastructure essential to our analyses. Finally, we acknowledge the enduring support for the construction and operation of the  LHC , the CMS detector, and the supporting computing infrastructure provided.
METHOD 03: SOCIETAL CONTEXTUALIZATION WITHIN PUBLIC POLICIES Public policies play a crucial role in the leverage of contemporary urban and architectural interventions and they offer the possibility of comparing research through a common framework of information. This research aims to consider middle-class mass housing as an effect of public policies that predated its maximum spread and, therefore, understand the middle-class mass housing role in the long term. The country representatives were asked to construct a national synthesis about the main urban policies that have had influences in developing middle-class mass housing as an urban phenomenon in the 20th century. The information was collected through general data such as the name of the law, the acronyms, the author/body, the date, the title and subtitle, and the main objectives and measures.
ACKNOWLEDGMENTS This article is based upon work from the  COST-Action   CA18137 MCMH -EU supported by  COST (European Cooperation in Science and Technology). This paper is based on the data collection of the WG 1 (Case Studies) and WG 3 (Policies) and the analyses executed in the three Short Term Scientific Missions (STSM) of  Luisa Smeragliuolo Perrotta  at  OWL, University of Applied Sciences (TH OWL ) in  Detmold , and of  Ahmed El-Amine Benbernou  and  Kritika Singhal  at the  University of Salerno. Olga Harea  worked on the compilation and evaluation of the research posters and activities, also supported by  Müge Akkar Ercan.
We use a horizontal model grid spacing of 200 m. Hyper-parameter values (Table  S1 ) are chosen to be realistic and representative of the study glacier, and real observational uncertainties. Some trial and error is nevertheless required to determine values that yield plausible results. In what follows, we perform four inversions on each dataset: one each for a deformation-dominated ('quiescent') glacier flow regime, a slip-dominated ('surge') flow regime, a single time interval that includes both quiescent and surge regimes ('full-epoch inversion') and multiple time intervals that include but partition quiescent and surge regimes ('multi-epoch inversion'). The first three of these use the original model in Eqn (6), while the multiepoch inversion uses Eqn (7).
01 is the prescribed amplitude-to-wavelength ratio, H = 100 m is the characteristic ice thickness and k = [5, 6, …, 15]. We choose the value of R such that perturbations are significant in amplitude but do not change the overall shape of the bed (see Supplementary material). The value of H is based on the mean ice thickness of the reference geometry. The minimum value of k corresponds to a perturbation wavelength of k H = 500 m, and is chosen to be slightly larger than the Nyquist wavelength of 400 m determined from the 200 m horizontal grid spacing of the inverse model. Finally, a composite bed B synth is also defined by adding the sum of all perturbations for k = [5, 6, …, 15] to B F2019 : B synth = B F2019 + 15 k=5 A k sin 2p k H. ( 10 ) To produce self-consistent synthetic datasets that represent both deformation-and slip-dominated glacier flow regimes, we first compute steady-state surface profiles (with no sliding) for each bed that resemble the real glacier in its pre-surge state.
Data Surface-elevation change rates were calculated from DEMs for 13 September 2007, 30 September 2016 and 1 October 2018. The 2007 and 2018 DEMs are derived from SPOT5 and SPOT7 data and were used in a previous study  (Young and others, 2021) , while the 2016 DEM is derived from Advanced Spaceborne Thermal Emission and Reflection Radiometer (ASTER) stereoimages using the Ames Stereo Pipeline  (Shean and others, 2016; Brun and others, 2017). The processing of the DEMs follows the workflow presented in  Berthier and Brun (2019) : briefly, all DEMs are coregistered to the global TanDEM-X DEM  (Rizzoli and others, 2017)  on stable terrain, masking out glaciers using the Randolph Glacier Inventory (RGI) v6. 0  (Pfeffer and others, 2014). We associate elevation change rates from 2007 to 2016 with quiescence, and those from 2016 to 2018 with the surge (Fig.
A combination of these two datasets are needed, because ITS_LIVE velocities are unreliable during the surge, while the dataset from  Samsonov and others (2021a)  begins only in 2016. A self-consistent velocity dataset spanning both quiescence and surging is currently under development  (personal communication from L. Copland, 2022). The mean surface mass-balance profile for 2007-18 is identical to that used to initialize the synthetic simulations  (Young and others, 2021) , but without the applied offset (see Supplementary material). Ground-based ice-thickness measurements were made in several locations after the surge in July 2019 and July 2021 (Fig. 1 ) using an impulse radar system  (Mingo and Flowers, 2010)  and resistively loaded dipole antennas of 10 MHz centre frequency. Bed elevations were derived by subtracting the ice-thickness measurements from the October 2018 (post-surge) surface DEM.
One exception is the case from no slip to slip, where elevation perturbations decrease slightly in 3-D, but increase in 2-D  (Sergienko, 2012). While our use of 2-D flowband models leads to overestimation of the information content in high-slip regimes, and thus an optimistic assessment of the power of exploiting these regimes in inferences of bed topography, observations indeed demonstrate measurable amplification of 3-D surface perturbations following glacier surges (e. g. Sharp, 2021)  suggesting our approach has merit. The tidy and intuitive results of the synthetic tests benefit from internally consistent noise-free data (see Supplementary material for simulations with added noise) with shorter-wavelength spectral content compared to the corresponding real data (spectra not shown). Despite the lower magnitudes of the synthetic surge velocities and elevation changes rates, the information content of the synthetic datasets may still be higher.
The synthetic data also benefit from an unambiguous transition between quiescent and surge-like flow regimes that is abrupt in time and occurs uniformly along the flowline. The extent to which this situation mimics reality varies (e. g. Frappé and Clarke, 2007). The real data further suffer from some internal inconsistency, particularly between surge velocities and elevation change rates near the terminus, making satisfaction of the continuity equation impossible (Supplementary material). Such situations are not unique to this study, but can lead, for example, to unphysical posteriors such as negative surface velocities. We would anticipate improvement with internally consistent datasets, as well as with more precise temporal isolation of the high-slip regime which, in our case, was limited by the number of surface DEMs.