dataesr/scientific-paragraphs-categorization huggingface dataset:
Velocity field reference frame Using the corrected position time-series of the selected stations, we compute the velocities in the ITRF2014  (Altamimi et al. 2016). There are 14 reference stations distributed around the GURN network in France, Germany, Netherlands, Sweden, Poland, Austria, Switzerland, Italy and Spain (see   The vertical velocity field has been obtained after removing the mean value from the velocities of the GURN network presented in Fig. 3 (-0. 29 mm yr -1 ). A correction by a mean value of vertical velocities is adequate for applying a uniform correction because the GURN network is not affected by long-wavelength phenomenon depending on latitude. The GURN network is also unaffected by the glacial isostatic adjustment (GIA) as shown by the ICE 6 G model  (Peltier et al. 2015) , which is computed from GNSS data and refined by GRACE data.
0. However, even if a very slow tectonic loading remains a possible explanation for the origin of the seismicity in the URG region, the analysis of the seismicity in light of the notion of a seismic cycle remains complex, due to the potential recurrence time being too long and the historical catalogue being too short. More investigation into palaoseismological data appear necessary to enlarge the fault slip database over the whole region in order to estimate the balance between tectonic strain accumulation and release by large earthquakes. The southern part of the URG is the only area with consistent observable deformation; the most intense seismicity of the region therefore suggests the possible role of the buildup and release of tectonic stresses on the fault reactivation associated with the Rhine Graben, the Jura front and the Alpine Arc.
A C K N O W L E D G E M E N T S This study has been finalized during the PhD of Eric HENRION co-funded by the companies Électricité de Strasbourg ( ÉS) and Storengy. The authors are thankful to Sophie Lambotte for the access to an updated instrumental seismicity database. We are indebted to late Jean Vogt and Julien Frechet for the access to the historical seismicity data. The GURN data are provided by several scientific institutions managing networks: SAPOS from Germany, private (ORPHEON) and public (RENAG-RESIF, RGP) networks from France, and Swisstopo from Switzerland. The geodetic data can be used on request by agreement of all partners. We are thankful to Maximilien Lehujeur for his code to correct the offsets in the GNSS position time-series. We would like to thank the editor and peer reviewers for their valuable comments and suggestions that helped in the improvement of earlier versions of the manuscript.
The drivers of recent decarbonization are examined in Le  Quéré et al. (2019). In contrast, there is no clear trend in CO 2 emissions from land-use change over the last decade (Fig. 6 , Table  6 ), though the data are very uncertain, with partly diverging trends over the last decade (Sect. 3. 1. 1). Larger emissions are expected increasingly over time for DGVM-based estimates as they include the loss of additional sink capacity, while the bookkeeping estimates do not. The LUH2-GCB2020 data set also features large dynamics in land use in particular in the tropics in recent years, causing higher emissions in DGVMs, BLUE, and the OSCAR best-guess, which includes simulations based on LUH2-GCB2020, than in HandN2017. Earth Syst. Sci. Data, 12, 3269-3340, 2020  https://doi. org/10. 5194/essd-12-3269-2020 This assumption does not hold on the regional level, where pre-industrial fluxes can be significantly different from zero.
FXR is a nuclear receptor activated by bile acids that is highly expressed in the enterohepatic system. In addition to suppressing bile acid synthesis, FXR activation protects against lipid accumulation in the liver by decreasing hepatic lipogenesis, favoring fatty acid oxidation as well as decreasing inflammation by repressing nuclear factor kappa B (NF-kB) signaling  [136]. Obeticholic acid (OCA) is a semi-synthetic steroidal FXR agonist. Phase 2 (FLINT) and phase 3 (REGENERATE) trial data indicate that OCA treatment improves fibrosis without worsening NASH (Clinical-Trials. gov identifier: NCT02548351). However, complete NASH resolution was not achieved. Unfortunately, these benefits are associated with an increase in LDL-C by approximately 20 mg/dL  [137, 138] , increasing the CVD risk score category from low or medium to high risk in 7.
Several other synthetic FXR agonists with potential selective modulator actions are currently being evaluated in phase 2 clinical trials enrolling patients with NASH. One such compound, cilofexor (ClinicalTrials. gov identifier: NCT02854605), an intestinally targeted, non-steroidal FXR agonist, decreases hepatic steatosis (assessed by MRI) without increasing LDL-C  [142]. Further studies should address whether these novel FXR agonists also impact CVD risk. Agonism of the FXR pathways has the potential to treat fibrotic NASH but the current class of compounds likely needs refinement to improve the metabolic and CV risk profile. Indeed, FXR activation favors reverse cholesterol transport, reduces VLDL secretion, and decreases lipoprotein (Lp) (a) levels but also increases plasma LDL-C by decreasing bile acid synthesis (which leads to decreased LDLR expression) and increasing CETP expression  [136].
4. 2. 1. 2. Fibroblast growth factor 19 analogs. The non-tumorigenic fibroblast growth factor (FGF) 19 analog NGM282 is also under evaluation for NASH treatment (ClinicalTrials. gov identifier: NCT02443116). FGF19, a hormone produced by the distal intestine and FXR target gene, participates in a feedback loop to reduce bile acid synthesis. FGF19 also exerts metabolic actions that may be beneficial against NAFLD such as lowering liver TG and reducing plasma TG levels  [143]. Interestingly, circulating FGF19 is decreased in NASH patients, providing further therapeutic rationale  [144]. In two 12-week trials, NGM282 improved all of the histological parameters of NASH and fibrosis and reduced ALT and AST  [145, 146]. However, as with OCA, NGM282 treatment increased plasma LDL-C  [145]  mostly as large, buoyant LDL particles  [147].
Plasma TG levels decreased  [145]  as a result of fewer large VLDL particles  [147]. The net effect of these changes on CVD risk remains unclear. Preclinical studies of ApoE-deficient mice demonstrated a clear atheroprotective action of NGM282  [148]. In humans, FGF19 levels correlated negatively with CAD (defined by coronary angiography) independent of BMI, hypertension, dyslipidemia, and diabetes  [149]. As with OCA, increased plasma LDL-C was blunted by statin treatment  [146, 147] , suggesting that the action mechanism of NGM282 is similar to OCA. Larger phase 3 trials are ongoing. 4. 2. 1. 3. Future directions for treatments targeting the bile acid pathways. Volixibat (an intestinal ASBT inhibitor that prevents reabsorption of bile acids) decreased plasma total cholesterol and LDL-C but did not improve NASH in an interim analysis from a phase 2 trial (ClinicalTrials.
gov identifier: NCT02787304)  [150]. Bile acid sequestrants, such as colesevelam and cholestyramine, improve glucose metabolism in T2D and lower CV risk (WHO trial) without improving liver histology (ClinicalTrials. gov identifier: NCT01066364)  [151]. Therefore, intra-vascular cholesterol and lipid metabolism appear to be regulated in a dissociated manner from liver histological NAFLD.
Fibrates (for example, fenofibrate, gemfibrozil, and pemafibrate, among others) mainly target PPARa and thereby improve atherogenic dyslipidemia observed in obesity, T2D, and NAFLD. Pre-statin era and post hoc analysis of the FIELD and ACCORD studies indicated a reduction in CV risk, especially in high TG/ low HDL-C subpopulations  [153]. Several small studies have found poor efficacy for older fibrates (fenofibrate, gemfibrozil, and clofibrate) on histological improvements for NASH despite correction of dyslipidemia  [154]. Pemafibrate, a new PPARa agonist, is currently being evaluated for CV risk in the PROMINENT trial (ClinicalTrials. gov identifier: NCT03071692). Studies of NASH assessed by non-invasive methods (MRI for steatosis, FIB4, NFS, and enhanced liver fibrosis [ELF] tests) are underway.
These different effects of rosiglitazone and pioglitazone may be due to the fact that pioglitazone also activates PPARa  [170, 171]. Thus, whereas selective PPARg activators may reduce steatosis by lowering adiposeliver free fatty acid flux as a result of enhanced insulin sensitivity, pioglitazone's additional beneficial effects on inflammation and fibrosis may be a result of its modest activation of PPARa. Seladelpar is a PPARd agonist analyzed in a phase 2 clinical trial (ClinicalTrials. gov identifier: NCT03551522). Importantly, the trial was prematurely stopped after interim analysis due to the presence of abnormal hepatic inflammation during interim analysis, reportedly unrelated to seladelpar treatment, despite improvements in liver function biomarkers. Another trial in patients with mixed dyslipidemia showed that seladelpar decreased plasma LDL-C and TG and increased HDL-C levels.
Dual and pan-PPAR agonists. Different dual-and triple-PPAR agonists that leverage the complementary actions of each PPAR isoform are also being evaluated for NASH. Elafibranor is a dual-PPARa/d agonist that in a phase 2b study demonstrated improvements in histological ballooning and lobular inflammation without worsening of fibrosis, benefits that were most apparent in patients with more severe NASH at baseline (ClinicalTrials. gov identifier: NCT01694849)  [173]. Improvements in insulin sensitivity and decreased systemic inflammation markers (measured by CRP, fibrinogen, and haptoglobin) were also observed in elafibranor-treated patients. Decreases in plasma TG and LDL-C were observed with concomitant increases in HDL-C, even among patients treated with statins. However, recently reported interim phase 3 results did not show statistically significant differences in resolving NASH between elafibranor and placebo.
Longterm evaluation of CVD risk reduction by elafibranor in NASH patients has not yet been demonstrated. Saroglitazar is a dual-PPARa/g agonist currently in phase 3 clinical trials in the US and Europe (ClinicalTrials. gov identifier: NCT03061721) already approved for treating NASH in India. Lanifibranor is a triple-PPARa/g/d agonist that was recently reported to reach primary and secondary endpoints by significantly decreasing the Steatosis Activity Fibrosis Score (SAF), inducing NASH resolution and lowering fibrosis in the NATIVE phase 2b trial (ClinicalTrials. gov identifier: NCT03008070). Preclinical results indicated that saroglitazar decreases plasma TG levels, reduces hepatic steatosis, ballooning, and inflammation in the choline-deficient, L-amino aciddefined, high-fat diet NASH mouse model, and protects against carbon tetrachloride (CCl 4 )-induced fibrosis  [174] , whereas lanifibranor treatment decreases CCl 4 -induced hepatic fibrosis, plasma glucose, and TG levels in db/db mice  [175].
4. 2. 2. 3. FGF21 analog. FGF21, a hepatokine and PPARa target gene, displays many favorable metabolic actions, including enhancing fatty acid oxidation, reducing lipogenesis, and improving dyslipidemia and insulin sensitivity  [176]. Accordingly, a recombinant analog of human FGF21, pegbelfermin (ClinicalTrials. gov identifier: NCT02413372), reduced hepatic fat (assessed by MRI) and plasma transaminases and improved dyslipidemia (reduced plasma TG and LDL-C and increased HDL-C) in a phase 2 study of biopsy-diagnosed NASH patients (no post-treatment biopsy was performed)  [177]. In ApoE-deficient mice, FGF21 protects against atherosclerosis progression acting on several pathways by reducing plasma cholesterol levels and cholesterol biosynthesis in the liver and reducing apoptosis in the aortic roots  [178, 179]   [181].
Other treatments in clinical trials The glucagon-like peptide-1 (GLP1) analog liraglutide used for T2D treatment showed promise for NASH treatment with improvements in body weight and glycemic control in 9 biopsy-proven NASH patients (ClinicalTrials. gov identifier: NCT01237119)  [182] , prompting confirmation in larger studies with histological endpoints. Interestingly, the GLP1 receptor (GLP1-R) agonists liraglutide  [183]  and semaglutide  [184]  both reduce CVD risk in T2D patients. Considering the lack of GLP1-R expression in hepatocytes, it is unclear how GLP1 analogs improve NAFLD (either through non-parenchymal actions on the liver or by enhancing systemic insulin sensitivity and weight loss). In Western diet-fed ApoE or LDLR-deficient mice, both liraglutide and semaglutide decrease atherosclerosis through anti-inflammatory effects independent of cholesterol lowering and weight loss  [185].
Moreover, GLP1 may prevent macrophage foam cell formation  [186]. In high-fat dietfed ApoE*3-Leiden CETP-transgenic mice, GLP1-R agonist treatment decreased hepatic steatosis and plasma TG by respectively decreasing DNL and VLDL production  [187]. Several drugs in development target the increase in DNL observed in NASH patients  [32]. Recent phase 2 studies with the ACC1/ACC2 inhibitor firsocostat showed reduced hepatic steatosis but increased plasma VLDL particles and TG levels (ClinicalTrials. gov identifier: NCT02856555)  [188]. Thus, despite improving hepatic steatosis, firsocostat may increase CVD risk by increasing the amount of atherogenic particles. In conclusion, several therapeutic strategies for NAFLD with evidence or potential for CVD protection are emerging. However, a detailed assessment of CV outcomes (MACE and subclinical atherosclerosis) is lacking, and in several short-term studies, changes in plasma lipid profiles were unreported.
FUNDING SOURCES This study was supported by the French National Research Agency (ANR-10-LABX-46 and ANR-16-RHUS-0006). B. S. is a recipient of an ERC Advanced Grant (694717). A. D. was supported by a doctoral fellowship from the University of Lille as well as support from the Association Française pour l'Étude du Foie (AFEF) and Fondation pour la Recherche Médicale.
Thyroid hormone receptor b agonists Thyroid hormones (TH) regulate several pathways of hepatic lipid metabolism mainly through TH receptor b (TR-b), the major isoform in the liver. In NAFLD, TR-b activation induces fatty acid uptake and oxidation and enhances mitochondrial biogenesis and activity. TR-b agonism also favors LDLR-mediated endocytosis and reverse cholesterol transport [180]. At least two TR-b selective agonists are under investigation for NASH, resmetirom (ClinicalTrials. gov identifier: NCT02912260) and VK2809 (ClinicalTrials. gov identifier: NCT04173065), employing distinct pharmacological mechanisms for liver selectivity. Resmetirom treatment decreased liver fat content (assessed by MRI) and NAS on biopsy in patients with biopsy-proven NASH with fibrosis (stages 1e3).
4. 2. 3. 23 Thyroid hormone receptor b agonists Thyroid hormones (TH) regulate several pathways of hepatic lipid metabolism mainly through TH receptor b (TR-b), the major isoform in the liver. In NAFLD, TR-b activation induces fatty acid uptake and oxidation and enhances mitochondrial biogenesis and activity. TR-b agonism also favors LDLR-mediated endocytosis and reverse cholesterol transport [180]. At least two TR-b selective agonists are under investigation for NASH, resmetirom (ClinicalTrials. gov identifier: NCT02912260) and VK2809 (ClinicalTrials. gov identifier: NCT04173065), employing distinct pharmacological mechanisms for liver selectivity. Resmetirom treatment decreased liver fat content (assessed by MRI) and NAS on biopsy in patients with biopsy-proven NASH with fibrosis (stages 1e3).
Analyses were performed in R software version 3. 3. 2 (R Core Team 2016). Data were tested for normality with Q-Q plots of the residuals. All analyses were carried out using linear mixed models using the package 'lme4'  [52]. The respondents' profiles, the scenarios, and the ESs were analyzed as fixed variables, while the individual respondents were analyzed as random variables. Models were constructed from the experimental variables listed above, adding interaction(s) when the Chi-square test (<0. 05) using the 'anova' function showed that the interaction significantly affected the model. Multiple comparisons were carried out with the function 'glht' of the 'multcomp' package to depict differences of appreciation between scenarios  [53]. The effects of the mixed linear models were tested by means of an F test (<0.
Acknowledgments: We wish to thank all participants in the focus groups and the questionnaire, without whom the presented work could not have taken place. We thank the  Parc Naturel des Plaines de l'Escaut  for their support in reaching participants for the focus group and for providing the material and technical support for the organization of the meeting. We thank the  Fond National de la Recherche Scientifique (FNRS)  for the financial support of this research.
Rheological measurements Rheological evaluations were performed using a rheometer AR-2000 (TA Instrument, Great Britain, Ltd) fitted with a 40 mm cone-plate geometry (54 microns gap) equipped with a Peltier heating system for accurate control. After loading, the samples were held for 15 min before measurements and then covered with a thin layer of hexadecane  (Benaoun et al. , 2017). The TA Instrument Rheology Advantage software (V5. 7. 0) was used to collect and analyze the rheological data. All rheological measurements in all tested conditions were performed in duplicate and the values of effectively overlapping traces were reported.
Introduction: Nonalcoholic steatohepatitis (NASH) is a sub-classification of nonalcoholic fatty liver disease (NAFLD) characterized by increased risk of progressive liver fibrosis. Cenicriviroc (CVC) is a novel, orally administered, potent chemokine 2 and 5 receptor antagonist currently in development for the treatment of liver fibrosis in adults with NASH. Methods and analysis: Efficacy and safety of CVC will be comprehensively evaluated in a global, Phase 3, multicenter, randomized, double-blind, placebo-controlled study (AURORA, NCT03028740) of subjects with NASH and Stage F2 or F3 fibrosis. Approximately 2000 adults (Part 1, 1200 subjects; Part 2, 800 additional subjects) aged 18-75 years with histological evidence of NASH with Stage F2 or F3 fibrosis (NASH Clinical Research Network classification system) will be randomized 2:1 to CVC 150 mg or placebo orally once daily.
Structure AURORA (NCT03028740) is a global, Phase 3, multicenter, randomized, double-blind, placebo-controlled study, which will be conducted in two parts (Fig. 1 ). In Part 1, approximately 1200 subjects with histological evidence of NASH and Stage F2 or F3 fibrosis will be randomized 2:1 to CVC 150 mg orally or placebo once daily to evaluate a surrogate histology endpoint at Year 1. There will be approximately 2000 subjects in Part 2, including approximately 1200 subjects from Part 1 and 800 newly randomized subjects, also with histological evidence of NASH and Stage F3 fibrosis. A target of at least 60% of subjects with Stage F3 fibrosis will be enrolled in the study overall. Part 2 will assess clinical outcomes and will end when adjudicated events have been accrued in approximately 367 individual subjects across both parts of the study.
Study drug administration Subjects will take one 150 mg tablet of study drug (double-blinded CVC or placebo) daily with food. Subjects, investigators, and all site personnel will be blinded to CVC and placebo individual treatment assignment until Part 2 is complete and the database has been locked. Blinding will be accomplished by the sponsor providing the study drug, and packaging for active and placebo products will be identical apart from a unique bottle identification number on the label. Data will be unblinded at the end of Part 1 to allow for data analysis, although individual subject treatment assignments will not be provided to sites or subjects until the analysis of Part 2 is completed. Emergency unblinding may take place where immediate knowledge of the treatment received (CVC versus placebo) is necessary for the management of the subject and may be requested via the interactive response system.
Patient-reported outcomes Three patient-reported outcomes measures will assess change in health outcomes from baseline: the Chronic Liver Disease Questionnaire -Nonalcoholic Fatty Liver Disease (CLDQ-NAFLD-NASH)  [43] , Work Productivity and Activity Impairment in NASH (WPAI-NASH)  [44] , and 36-Item Short Form Health Survey (SF-36) version 2 (health-related quality of life index)  [45, 46]. Data will be collected at baseline, Months 6 and 12 for Part 1; at baseline and Month 12 for newly randomized subjects in Part 2; and annually thereafter for all study subjects.
Safety assessments Adverse events (AEs) will be assessed at each study visit and classified as shown in Table  2. AEs of special interest include elevations in biochemistry associated with liver injury. Various laboratory tests will be performed periodically throughout the study, and confirmation of compliance with eligibility criteria regarding concomitant medications and alcohol consumption will be obtained at each study visit. Population pharmacokinetics of CVC will also be assessed: pre-dose and 1 h post-dosing plasma samples will be collected at Months 3 and 12 of Part 1; at Month 6, plasma samples will be collected pre-dose and 2-6 h post dosing. An independent data and safety monitoring board will review the safety data from the study. An independent adjudication committee will review all events which may potentially contribute to the Part 2 primary endpoint; only events confirmed by the adjudication committee will be included in this analysis.
Missing data For the Part 1 primary efficacy analysis, any available liver biopsy obtained after receipt of at least 6 months of assigned study drug but before 15 months of follow up may be used for the Month 12 biopsy. For subjects with multiple liver biopsies, the evaluable biopsy closest to the Month 12 visit will be used. Subjects without an evaluable liver biopsy at both screening and Month 12 will be included as non-responders. Sensitivity analyses will account for both "missing at random" and "missing not at random" scenarios. For the Part 2 primary efficacy analysis, any available liver biopsy after baseline may be used. If a subject has any biopsy that meets the primary endpoint definition (determined by the adjudication committee), this will be included as an event. Subjects without evaluable biopsies at screening and post baseline will be included as non-events, unless they meet criteria for a primary endpoint component unrelated to the biopsy.
While there are currently no approved treatments for NASH, obeticholic acid, resmetirom, and elafibranor are also undergoing clinical investigations in Phase 3 trials in the setting of non-cirrhotic NASH, with similar development timelines (NCT02548351 [REGENERATE]; NCT03900429 [MAESTRO-NASH]; NCT02704403 [RESOLVE-IT], respectively). However, to date, comprehensive study designs have only been published for REGENERATE  [54]. In conclusion, the AURORA Phase 3 study has been carefully designed based on the clinically meaningful results of the well-powered Phase 2b CENTAUR study to ensure a comprehensive assessment of the efficacy and safety of CVC treatment compared to placebo in adult subjects with NASH and Stage F2 or F3 liver fibrosis. This assessment is consistent with the recently recommended baseline assessments of patients in NASH trials for harmonizing clinical trial data across trials  [3].