dataesr/scientific-paragraphs-categorization huggingface dataset:
Materials and Methods In this paper, we review and discuss the RCTs, CRs, and GLs concerning the CHIVA Cure available as of June 2023 on Medline and Cochrane Central databases. Indeed, only five RCTs including the CHIVA Cure are available,  [3] [4] [5] [6] [7]  with overall 419 limbs allocated to the CHIVA arm. Of these, three RCTs,  [3] [4] [5]  with overall 293 limbs allocated to the CHIVA arm, have compared the CHIVA Cure with stripping and were included in the previous Cochrane Review,  8  and other two RCTs,  6, 7  with overall 126 limbs allocated to the CHIVA arm, one.
Anti-Interleukin-17 Agents Secukinumab, the only anti-IL-17 agent studied in the treatment of uveitis, is a fully human monoclonal antibody  [147]. It has been tested subcutaneously against placebo in three RCTs. The SHIELD study included 118 patients with non-anterior BD uveitis, the INSURE study analyzed 31 patients with non-anterior non-BD uveitis, and the ENDURE study analyzed 125 patients with quiescent non-anterior non-BD uveitis. In the SHIELD study, as in the other two studies, the primary endpoint of a reduction in the rate of uveitis recurrence was not met. The secondary efficacy data from SHIELD and INSURE may suggest a potential beneficial effect of secukinumab in reducing the use of concomitant immunosuppressants  [148]. Nevertheless, a prospective study suggested the efficacy of intravenous secukinumab in the treatment of active chronic non-infectious uveitis requiring systemic immunosuppression in 16 patients, including one with BD uveitis  [149].
Clinical Lymphopenia During the randomised CLARITY study and its extension (96 weeks overall), administration of CladT 3. 5 mg/kg resulted in reports of Common Terminology Criteria for Adverse Events (CTCAE) lymphopenia of Grade 1 (800-1000 mm -3 ) in 26. 3% of patients, Grade 2 lymphopenia (500-800 mm -3 ) in 37. 7%, Grade 3 lymphopenia (200-500 mm -3 ) in 24. 9% and Grade 4 lymphopenia (\ 200 mm -3 ) in 0. 7%  [5]. All 3 cases of Grade 4 lymphopenia occurred in patients redosed with CladT while still demonstrating Grade 3 lymphopenia. The ALC remained within the normal range for 10%  [5]. Severe lymphopenia was of limited duration for most patients, consistent with the data on cell counts described above; data submitted for the approval of CladT in the USA showed that the median time to recover from Grade 3 lymphopenia was 28 weeks  [41].
Further study is required to understand this phenomenon and to evaluate to what extent it contributes to cases of lymphopenia attributed to CladT. Other realworld experience from a number of different countries demonstrated comparable or lower rates of lymphopenia than those seen following randomised treatment  [45] [46] [47] [48] [49] [50] [51] [52]. A 6-month analysis of Phase IV data concerning people with MS who received CladT demonstrated an incidence of lymphopenia of 8. 3%, with an incidence approximately threefold higher in patients who had received prior DMT therapy (10. 1%) vs. DMT-naı ¨ve patients (3. 6%)  [31]. Grade 3 lymphopenia occurred in in 24. 4% and Grade 4 lymphopenia in 0. 7% during 2 years of treatment in the MAGNIFY-MS study  [29]. Pre-treatment ALC was a predictor of lymphopenia during treatment with CladT in another real-world analysis  [53].
Summary of Clinical Relevance Overall, the severity of the lymphopenia following treatment with CladT is modest in severity and of limited duration for most patients, with limited potential to promote infection unless severe. Notably, the current European Summary of Product Characteristics allows a delay in the second treatment course of up to 6 months to allow recovery of lymphocytes, or for other medical reasons, based on experience in CLARITY  [23]. This guidance also states that ALC must be normal before initiation of treatment and [ 800/ mm 3 (0. 8 9 10 9 /l) before administration of the second course. database in Sweden in which 8/208 patients developed infections or infestations on CladT  [59]. Two of 138 patients in a real-world study in Portugal experienced herpes zoster as a SAE  [60].
Liver Injury The Phase III studies with CladT did not reveal any signal for serious hepatic AE. However, reports of rare but potentially serious liver toxicity have arisen from post-approval AE reporting  [81, 82]. Initially, a single case was noted, where a patient developed elevations of liver transaminases of up to 33 9 the upper limit of normal approximately 1 month following the conclusion of the first treatment course of CladT  [81]. Liver transaminases returned to within the normal range over approximately 2 months. Examination of the CladT clinical trials database revealed five further cases (0. 3% of patients) of CladT-related liver SAEs that were serious or led to treatment discontinuation  [41]. In all but one case these arose 2-4 weeks after the end of the first treatment course (all survived).
Malignancies Analysis of patient populations treated within controlled clinical trials of CladT and their extensions revealed rates of malignancy of 0. 27 events/100 patient-years with CladT compared with 0. 13 events/100 patient-years for placebo  [41]. These data drove an apparently higher managed before CladT is given. As elevated rates of infection on CladT treatment appear to be related to lymphopenia, delaying administration of the second course of CladT until ALC has recovered to [ 800/mm 3 is important, as this is likely to reduce the risk of lymphopenia and viral reactivation or opportunistic infections. Vaccination (other than with live or attenuated live vaccines) is safe for people with MS receiving CladT and, in principle, a vaccine can be given any time during treatment with CladT; however, for prophylaxis against viral infection, etc.
other DMTs: excess risk = 0. 20 events (95% CI -0. 08 to 0. 39)/100 patient-years (p = 0. 46)  [90]. In addition, the integrated analysis showed that the longer-term (5 years onwards) rate of malignancy on CladT was not higher than that on placebo (0. 17 vs. 0. 29 events/100 patient-years  [24]. The integrated analysis of CladT trials also showed that the predicted rate of malignancy in the population that received CladT did not differ significantly from that from a matched population from the Global Cancer Observatory (GLOBOCAN) database (Fig. 4 )  [24]. These data confirmed the results of earlier integrated analyses  [91, 92]. There has been no suggestion of clustering of specific cancer types or haematological cancers in CladT-treated populations to date  [24, 42]. Post-approval AE reporting to date provided a rate for malignancy of 0.
Pregnancy Many diagnoses of MS occur during or before young adulthood; for example, one real-world study from Germany found that 65% of women receiving CladT for MS were aged \ 40 years  [95]. Pregnancy is a contraindication for CladT: women receiving the drug are required to avoid pregnancy until 6 months after the last dose and male patients should ensure pregnancy does not occur in their partner during this time period  [23]. Should a pregnancy occur during treatment, further treatment with CladT should be withheld until after delivery. Some pregnancies have occurred during or soon after treatment with CladT. An analysis of 70 pregnancies in patients exposed to oral or parenteral CladT for MS (n = 49) or placebo (n = 21) in CladT trials or from registry data found comparable rates of live births (39% vs.
The rate of spontaneous termination was 2/16 (13%) vs. 3/11 (27%) for the CladT-and placebo-exposed cohorts, respectively, and there were no congenital malformations in either group. Similar data were presented from an analysis of the trials database and the German Multiple Sclerosis and Pregnancy Registry  [97]. An ongoing cohort study of 39 pregnancies in women who received cladribine \ 6 months before, or after, their last period before pregnancy has described 27 live births so far that included a single major congenital malformation  [98]. There are no reports to date of adverse pregnancy outcomes from pregnancies fathered by male partners who received CladT during the at-risk period  [96, 97].
There appears to be no increased risk of malignancy with CladT vs. untreated, non-RMS populations or vs. other DMTs used in the management of RMS. Finally, the emergence of drug-induced liver disease as a new and potentially serious (if uncommon) SAE associated with CladT emphasises the importance of withholding CLadT treatment from people with pre-existing liver disease and maintaining vigilance for the emergence of liver disease during treatment (further information on the aetiology of this AE is required). The CLARION registry will continue to collect real-world efficacy and safety data on the use of CladT in the management of RMS  [54].
The immune reconstitution approach may support planning a pregnancy for some patients: a responder to IRT may expect a prolonged period free of either DMT or significant MS disease activity, providing a window of opportunity to complete a pregnancy from 6 months following the last dose of CladT (Fig. 1 ). Women with MS should be encouraged to breastfeed because of the proven benefits for mother and child  [99]. Women should not breastfeed for 1 week following the last CladT dose  [23, 99]. The serum half-life of cladribine is short (about 6-20 h  [105] ), and the drug is cleared from the system rapidly, although CladT may persist in cells for longer. The 6-month washout period for CladT before a pregnancy may occur is arbitrary and reflects a suitably cautious approach. Registry data will be instrumental in future for delineating the true duration of post-CladT washout to effectively protect pregnancies.
The MAPLE-MS Registry is following outcomes of pregnancies exposed to CladT and publication of data is awaited. Open Access. This article is licensed under a Creative Commons Attribution-NonCommercial 4. 0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
ACKNOWLEDGEMENTS Funding. Merck Serono, Lyon, France , an affiliate of  Merck KGaA, Darmstadt, Germany  (CrossRef Funder ID: https://doi. org/ 10. 13039/100009945 ) funded editorial support (see below) and the journal's  Rapid Service Fee. No other funding was received. Disclosures. Pierre Clavelou  has received honoraria, and contributions to meeting from  Almirall ,  Biogen ,  Janssen ,  Merck ,  Novartis ,  Roche ,  Sanofi-Genzyme  and  Teva. Giovanni Castelnovo  received fees for consulting and speaking from  Biogen ,  Abbvie ,  Merck ,  Novartis ,  Roche ,  Sanofi Genzyme ,  Merz  and  Celgene BMS. Jerome De Se  `ze has received fees for consultancy, advisory board and clinical trials from  UCB ,  Novartis ,  Biogen ,  Merck ,  Teva ,  Genzyme/ Sanofi ,  Roche ,  Alexion ,  BMS/Celegene ,  Janssen  and  Horizon Therapeutics.
BÉNARD ET AL. Given that the total budget of the magmatic CO 2 diffuse degassing can be equivalent or higher to the emissions during eruptive events  (Caliro et al. , 2005; Chiodini et al. , 2000; Werner et al. , 2019)  it represents the long term CO 2 contribution to the soils and then to the atmosphere in volcanic settings. Therefore, at volcanoes all over the world, these fluxes are monitored to track deep transfers of magma, providing years-long large datasets of CO 2 concentrations and/or fluxes in diverse soils settings. In all monitoring sites, it has been evidenced that variations of air temperature, atmospheric pressure, wind, rainfall, humidity and water level induce substantial modifications of soil CO 2 concentrations and fluxes  (Boudoire et al. , 2017a; Camarda et al. , 2019; Carapezza et al.
Then, stations BLEN and GITN were installed in 2015 and 2018, respectively. All stations are located on the western flank of the volcano within 14 km or less of each other, at high elevations (>1,000 m), with normal annual temperatures from 6. 4 to 20. 8°C. The sites are characterized by substantial normal annual rainfall, from 2020 to 5190 mm. The stations are installed on thin soils (<0. 5-1 m thick) formed on basaltic lavas which are highly permeable (∼10 -2 to 10 -4 m 2 ,  Bourhane et al. , 2015; Folio, 2001; Join et al. , 2005). As a result, water can infiltrate deeply and quickly, and aquifers are unconfined. At PNRN station, located at 700 m from the borehole. Forage Bras Creux with available water level data (online data repository: https://donnees. eaureunion. fr/), the vadose zone is ∼110 m thick.
Stations used to measure soil CO 2 concentrations and environmental parameters (P, T, RH, wind speed and direction) are described in detail in  Boudoire et al. (2017a)  and summarized here. Data are acquired on hourly basis and transmitted in real time at the Observatoire Volcanologique du Piton de la Fournaise (OVPF/IPGP). The stations were designed by the Istituto Nazionale di Geofisica e Vulcanologia (INGV) Sezione di Palermo  (Gurrieri et al. , 2008). For the measurement of soil CO 2 concentration, a 50 cm long probe is inserted into the soil and connected by a Teflon pipe to a Gascard NG dual-wavelength nondispersive infrared gas analyzer (CO 2 gas measurement range 0%-10%). The molar fraction of CO 2 is measured in a soil-air gas mixture pumped at 0. 8 L/min and are automatically corrected for air temperature and atmospheric pressure effects on gas molecular density  (Gurrieri and Valenza (1988) ).
27%). The highest concentrations in our data set are recorded in Mayotte. At UDMN, average daily soil CO 2 concentration was 2. 34% ± 0. 88% (full range from 1. 10% to 4. 88%). Spurious data (<10 days) related to technical malfunction was removed from the datasets. There are larger data gaps (months) when the equipment failed to acquire data. Air temperature and atmospheric pressure are measured hourly by meteorological stations located at a height of 2 m at each site. Temperature is measured by Mela® sensors PK-ME with a precision of ±0. 2 K. Pressure is measured by STS® sensors ATM. ECO with a precision of ±0. 375 psi. Soil CO 2 concentrations, air temperature and atmospheric pressure data are available on the IPGP online data repository at https://dataverse. ipgp. fr/privateurl. xhtml?token=c93d13c3-e998-428d-877a-1ab70773e5ad (a permanent DOI will be generated if the article is accepted).
For Piton de la Fournaise, water table level daily time series were obtained from the Office de l'eau online data repository (https://donnees. eaureunion. fr/). We selected the borehole Forage Petite Plaine (Figure  1 , BSS ID: 12292X0041/F) for comparison with soil CO 2 concentrations for the stations PCRN and BLEN. This unexploited borehole is the closest to these soil CO 2 stations with water table level data available for the study period. The borehole is located 7 km away from PCRN and 4 km away from BLEN. This borehole appears to be connected to the Plaine des Cafres aquifer system  (Aunay et al. , 2012). For comparison with the soil CO 2 station PNRN, we selected the unexploited borehole Forage Bras Creux (BSS ID: 12276X0071/FORAGE) located only 700 m away. For GITN, there is no available water table level data so this parameter was not considered.
We found ourselves limited by the available knowledge about the site's precise hydrogeological characteristics (thickness of the vadose zone, permeability), and thus unable to verify our hypotheses numerically by modeling the soil CO 2 transfers. Future research should address these limitations by using geophysical data to estimate the thickness of the vadose zone and the permeability profiles. Additionally, the consequences of this diffuse degassing on the soil and on the biosphere should be studied, for example, from the evolution of the isotopic composition of soil CO 2. The postdoctoral fellowship of B. Bénard is part of the Hatari Project INTERREG V Indian Ocean N° Synergie RE0023208, cofunded by the European Union, Région La Réunion, and Préfecture de La Réunion. The data used in this paper were acquired by soil CO 2 monitoring stations as part of the permanent instrumental network of Observatoire Volcanologique du Piton de la Fournaise-Institut de Physique du Globe de Paris (OVPF-IPGP).
The operation and equipment are funded by Institut National des Sciences de l'Univers-Centre National de la Recherche Scientifique (INSU-CNRS), Ministère français de l'Enseignement supérieur, de la Recherche et de l'Innovation (MESRI), Préfecture de La Réunion, and Région La Réunion. Since June 2019, monitoring of Mayotte eruption was funded by Ministère de l'Enseignement Supérieur, de la Recherche et de l'Innovation (MESRI), Ministère de la Transition Ecologique (MTE) and Ministère des Outremers (MOM) with the support of Ministère de l'Intérieur (MI) and Ministère des Armées (MINARM) through the REVOSIMA (Réseau de surveillance volcanologique et sismologique de Mayotte). Data from Mayotte used in this paper have been acquired, processed and modeled in the framework of the REVOSIMA.
3d /e; Suppl. Fig. 12 )  18, 24. However, all the OdhA cryo-EM datasets, including those corresponding to complexes with CoASH, succinyl-CoA and SP, show an acetyl-CoA molecule bound to E1o allosteric site which could be positioned unambiguously (Fig. 3d /e; Suppl. Fig. 13 ). The presence of a bound acetyl-CoA activator, most likely acquired following heterologous overexpression of the enzyme in E. coli, may therefore explain the observed OdhA activated conformation through a mechanism that involves the stabilization of the loop 809-836 in its extended form (Suppl. Fig. 13 ), promoting, in turn, the activated conformation  18. This hypothesis is supported by previous observations showing that acetyl-CoA binding to MsKGD contributed to stabilize the activated conformation  18  , as well as by steady-state kinetic and spectroscopy studies that concluded that acetyl-CoA acts as a mixed V and K type allosteric activator on mycobacterial KGD  27.
A salt bridge in between Asp777 (helix aE) and Arg153 from the E2o domain is observed instead (Suppl. Fig. 18 ). Intrigued by these differences that suggest interdomain mobility, we performed 3D variability analysis 31 on all our EM datasets. The results indicate indeed a twisting movement of the longitudinal axis of the E1o domain, which deviates from its average position on the three-fold axis of the hexamer, as well as tilting of the E1o domain on the hexamer plane (Suppl. Movie 3), reinforcing the hypothesis that interdomain flexibility is a major contributor to protein dynamics, which, by remodelling the contact network, may contribute to enzyme regulation. The homohexameric OdhA architecture also provides a further example of conservation of structural motifs at the domain interfaces.
Crystals of the OdhAD97-CoASH complex were obtained from a 26 mg/ml OdhAD97 solution, supplemented with 5 mM CoASH and crystallized in 0. 1 M Hepes-NaOH pH 7. 5, 5% (w/v) PEG 4000, 30% (v/v) methylpentanediol (MPD) by the sitting drop method; for the MsKGD-GarA complex, crystals were obtained from a 10 mg/ml MsKGD solution supplemented with 2 mM ThDP, 5 mM MgCl2 and M. smegmatis GarA (1:1 molar ratio), and crystallized, through the hanging drop method, in 0. 1 M bicine pH 8. 0, 30% (v/v) PEG550MME, 0. 2 M NaCl. X-ray diffraction data collection and structure solution. Diffraction datasets were acquired either on the beamline ID30A-3 at the ESRF synchrotron (Grenoble, France), or on the beamline Proxima-1 at the SOLEIL synchrotron (Saint-Aubin, France). Data integration and scaling were performed with autoPROC  39  , applying anisotropic scaling via STARANISO.
Structures were solved by molecular replacement through the program PHASER  40  , using the previously released coordinates of the MsKGDD115 homodimer (PDB 2XT6;  18  ) as the search model for both datasets (OdhAD97-CoA and MsKGD:GarA). M. smegmatis GarA coordinates were retrieved from the previously published MsKGDD360:GarA complex (pdb 6I2Q;  22  ). Manual model rebuilding and ligand placement in electron density maps was entirely performed with COOT  41. Refinement was carried out with BUSTER, applying local structure similarity restraints for non-crystallography symmetry (NCS)  42  where appropriate, and a Translation-Libration-Screw (TLS) model. Chemical dictionaries for ligands were generated with the Grade server (http://grade. globalphasing. org). Validation of models was performed with MOLPROBITY  43  and the validation tools in PHENIX  44.
Grids were then blotted (during 4 s at blot force 0 for Lacey grids, blot force 2 for UltrAuFoil R1. 2/1. 3 grids) and plunge-frozen into liquid ethane. Data from all samples but OdhAsuccinyl-CoA were collected at the Nanoimaging Core facility in Institut Pasteur on a Titan Krios electron microscope (ThermoScientific), operated at 300 kV and equipped with a K3 direct electron detector (Gatan) operating in counted mode. The OdhA-succinyl-CoA dataset was instead collected on a Titan Krios microscope located at the ESRF (Grenoble, France), also running at 300 kV and equipped by a K3 detector operating in the counted super-resolution mode. The software EPU 2 (ThermoScientific) was used to pilot data collection in all cases. A summary of data collection and model refinement parameters is reported in Table  2.
The OdhA-succinyl-CoA raw data will be available under the DOI 10. 15151/ESRF-ES-514136397. Single particle analysis of cryo-EM data. All single particle cryo-EM datasets were processed through cryoSPARC version 3. 2  45. Motion correction was performed using full-frame motion correction and CTF estimation were performed using patch CTF estimation. Using the curate exposure feature, 12666 out of 13348 for OdhA alone, 7996 out of 12202 for OdhA-CoASH, 8796 out of 11827 for OdhAsuccinyl-CoA, 15025 out of 16647 for OdhA-SP, and 14842 out of 19443 for OdhA-OdhI complex were selected for further analysis. A first round of 'blob particle picking' was performed, and after 2D classification, the most populated classes were selected for template-based particle picking against a dataset containing the selected micrographs.
Particles were extracted applying a box size of 384 Å, except for the OdhA-SP sample for which the box size was set at 448 Å. The extracted particles were cleaned using the 'inspect pick' function of Cryosparc and several rounds of 2D classification with selection of higher resolution classes were applied, selecting classes corresponding to a complete, hexamer shape of OdhA in different orientations. The selected particles were used, after local motion correction, to build an ab-initio model and non-uniform 3D refinement applying D3 symmetry, while optimizing per-particle defocus and per-group CTF parameters. For all datasets, local refinement was performed with a soft mask covering the OdhA E1o domain dimer. A composite map including the three OdhA E1o dimers was generated by the 'combine focused maps' tool in PHENIX (v.
Sensorgrams were processed using the BiaEvaluation software. The concentration-dependence of steady-state SPR signals (Req) was analysed using the following equation: Req = Rmax * C / Kd + C, where C is the SP concentration and Rmax the fitted maximal SPR signal at infinite SP concentration. Analytical Ultracentrifugation. Sedimentation velocity (SV) analytical ultracentrifugation assays were performed using a Beckman Coulter ProteomeLab XL-I analytical ultracentrifuge equipped with UV-Vis absorbance and Raleigh interference detection systems, using an 8-hole Beckman An-50 Ti rotor at 20°C. Experiments were performed at 30,000 rpm. Seven concentrations (from 4 mg/ml to 0. 0625 mg/ml, serial two-fold dilutions) were prepared for this experiment in the OdhA buffer (20 mM Hepes pH 7. 5, 500 mM NaCl) and loaded into analytical ultracentrifugation cells.