dataesr/scientific-paragraphs-categorization huggingface dataset:
Surface water and groundwater in the basin showed isotopic values ranging from -10. 9 to + 3. 3 ‰ and from -71. 0 to -3. 3 ‰ for δ  18  O and δ 2 H respectively (Table  1 , Methodology for units). In a δ 2 H vs δ  18  O diagram, these data defined a local meteoric water line (LMWL) with an equation intermediate between those of the two closest GNIP stations in Diyarbakir (Turkey) and Tehran (Iran; IAEA/WMO, 2022; Figs. 1  and 3A ). The present-day isotopic value of the Shahr Chay River is very close to that of the winter precipitation recorded by these two stations. Without neglecting direct lake recharge, we can therefore conclude that groundwater recharge takes place during winter, which may confirm the relationship between a wet, cold climate and lake level fluctuations  23, 26. The stable isotope contents of the G2-G5-G6 sludge and lake surface water samples define a clear evaporation line intercepting the LMWL at the point corresponding to the source of the Shahr Chay River samples, indicating that these waters and sludges originate via a single evaporation process from river water (Fig.
Precipitation In order to define the local Meteoric Water Line (LMWL) corresponding to rainwater on the Shahr Chay River basin, data from the GNIP database (IAEA/WMO GNIP Network, 2022) were used for the three main stations surrounding Lake Urmia: Diyarbakir and Dalbahce (Turkey) and Tehran (Iran). See Fig. 3  for station location.
Acknowledgements This work was funded by the  2016-2017 French-Iranian Gundishapur Project  (Project No. 35633ZB ), the  Center for International Scientific Studies and Collaboration (CCSIS, Iran) , the  French Embassy in Iran , the  TelluS Program of CNRS/INSU (France) , and the  China Scholarship Council (CSC)  for T. Kong's PhD fellowship.
The primary outcome measure will be high-contrast best-corrected visual acuity (HC-BCVA) at months. In addition, multimodal data will be collected in subjects with any ON (CIS-ON, MS-ON, AQP -IgG+ON or MOG-IgG+ON, and seronegative non-MS-ON), excluding infectious and granulomatous ON. Secondary outcomes include low-contrast best-corrected visual acuity (LC-BCVA), optical coherence tomography (OCT), magnetic resonance imaging (MRI) measurements, serum and cerebrospinal fluid (CSF) biomarkers (AQP -IgG and MOG-IgG levels, neurofilament, and glial fibrillary protein), and patient reported outcome measures (headache, visual function in daily routine, depression, and quality of.
Structural biomarkers as an aid to tailor ON treatment To explore possible means to aid hyperacute treatment decisions, the ACON study will collect data on and evaluate the potential of structural biomarkers as methods to enhance timely diagnoses. These structural biomarkers will be explored using magnetic resonance imaging (MRI) and optical coherence tomography (OCT). MRI of the brain and the orbits is one of the most established clinical tools for investigating acute ON. The radiological features of ON differ between the three disease etiologies: optic nerve lesions in AQP4-IgG+ON and MOG-IgG+ON are more frequently bilateral and more extensive than in MS-ON  (26) (27) (28). AQP4-IgG+ON typically affects posterior parts of the optic nerve and the chiasm, while MOG-IgG+ON typically affects long segments of the anterior optic nerve  (10, 28).
g. , visual acuity) and structural measurements (e. g. , pRNFL) of visual outcome in NMOSD  (16). The long-term visual function in daily routine and Qol following ON is an understudied aspect, which may be explored through a highquality detailed database of questionnaires filled in by patients in a prospective fashion. In summary, ACON will build a broad dataset to serve as a platform to revise and tailor acute ON treatment recommendations, improve the differential diagnoses between neuroimmunological disease entities, and identify determinants of disease progression and QoL in subjects after inaugural MS-ON, AQP4-IgG+ON, and MOG-IgG+ON.
Study objectives The primary objective of ACON is to investigate whether MS-ON, AQP4-IgG+ON, and MOG-IgG+ON patients treated with early high-dose corticosteroids for visual loss have better visual outcomes than those with late treatment. Treatment with both IVMP and oral high-dose corticosteroids is currently used as the standard of care in ON and will be included. According to previous data  (24) , subjects will be stratified into three groups: those presenting within 3 days of the onset of visual loss, those presenting between 4 and 7 days from the onset of visual loss, and those presenting between 8 and 30 days from onset of visual loss (daysto-Rx). The stratification will be performed within each respective disease group (MS, AQP4-IgG+NMOSD, and MOGAD). Secondary objectives will consist of the interaction between clinical and para-clinical parameters, as well as their association with patient-reported QoL aspects (see Table  1 ; Figure  2 ).
Study design ACON is an international, multicenter non-interventional study network aiming to optimize treatment decisions in subjects with acute ON and to improve understanding of the underlying pathologies. It currently includes 28 teaching hospitals from Africa (Botswana, Zambia), Asia (India, Korea, Thailand, and Vietnam), the Middle East (Israel), North America (USA), South America (Argentina, Brazil, and Colombia), Australia, and Europe (Denmark, France, Germany, Italy, Spain, and United Kingdom) (for details see Supplementary material). ACON centers will recruit and prospectively collect data from all subjects with inaugural acute ON (see study population). Local staff will have confirmed up-to-date training in the conduct of studies according to the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and good clinical practice (GCP) standards.
For the primary analysis, we collect data from subjects with MS-ON, AQP4-IgG+ON, and MOG-IgG+ON. For the secondary analysis, multimodal data will be collected in subjects with any demyelinating ON (CIS-ON, MS-ON, AQP4-IgG+ON, or MOG-IgG+ON and seronegative non-MS-ON) with the aim of exploring clinical, structural, and laboratory biomarkers to expedite the diagnosis and tailoring of treatment. This data will include OCT measurements, an MRI of the visual pathway including orbital cuts, questionnaires (headache, visual function in daily routine, depression, and QoL), basal metabolic index (BMI), IVMP, and oral corticosteroid treatment duration, utility of escalation therapy with PLEX or IVIG, and serum and CSF biomarkers (AQP4-and MOG-IgG levels, NFL, and GFAP). We expect between 30 and 50% of subjects will be ineligible due to the rigorous exclusion criteria.
Magnetic resonance imaging Cerebral MRI with dedicated orbital cuts at the baseline will be performed as part of the clinical routine diagnostic tests. Patients will receive 1. 5 or 3-Tesla imaging, including a cerebral 3D T2-weighted and/or Fluid Attenuated Inversion Recovery (FLAIR) sequence, and, if available, a 3D T1-weighted Magnetization Prepared Rapid Gradient Echo (MPRAGE) sequence. In the acute setting and at 6-month follow-up, 3D T1-weighted, fat suppression (FS) sequences and/or MPRAGE will be performed following gadolinium administration. Radiological analysis parameters include brain lesion number and volume, location, and extension (for details see Supplementary material Questionnaires and Data Collection CRFs). The MRI characterization score of the optic nerve developed by Ramanathan et al.
Data management All clinical results and MRI imaging data will be pseudonymized and stored in electronic case report form (eCRF) in an electronic database hosted by Research Electronic Data Capture (REDCap), a secure web application developed by Vanderbilt University, for building and managing academic databases (73) on a secure server at Charité-Universitätsmedizin Berlin, Germany. Regular monitoring in the form of independent data quality checks is ensured. OCT image data will be analyzed at Charité-Universitätsmedizin Berlin, Germany.
Statistical analysis For data analysis, subjects will be assigned into groups according to their diagnosis at the 6-month follow-up. For the primary objective, data from subjects with a diagnosis of MS, AQP4-IgG+ NMOSD, and MOGAD will be analyzed. Data from subjects with other diagnoses (other autoimmune, e. g. , CIS-ON, seronegative non-MS-ON) will be described and characterized separately but not included in the primary analysis.
Discussion ACON is the first global prospective longitudinal study on acute ON that includes participating centers from Africa, America, Asia, Australia, and Europe. It intends to build up a comprehensive, systematic, multimodal database of ON patients both in the acute phase and during longitudinal follow-up. Since the publication of the ONTT results in 1992  (21) , no large-scale international multicenter study has investigated the treatment of acute ON. In particular, the effect of time to treatment on visual outcomes has not been examined prospectively, either in a multi-racial cohort or with regard to different ON etiologies. Therefore, clinical treatment decisions are largely based on individual choices but lack scientific evidence. ACON will address the question of the potential benefit of hyperacute high-dose corticosteroids on visual acuity, visual function in daily routine, QoL, and optic nerve structural outcomes in acute MS-ON, AQP4-IgG+ON, and MOG-IgG+ON.
ACON will investigate the viability of early clinical clues as potential indicators, both for the underlying diagnosis and the respective disease course. The medical history is the first step in the diagnostic workup. To investigate pain scores as a means of distinguishing MS-ON and AQP4-IgG+ON from MOG-IgG+ON, we will carry out a semi-structured interview to assess the chronology of visual symptoms and characterize pain patterns. Data obtained from this interview, collected from multiple countries, including a wide range of races, are expected to result in an easily accessible clinical tool to accelerate the diagnosis with regard to etiology. Furthermore, ACON aims to explore the implications of early dynamics in levels of NfL and GFAP in the serum of patients with acute ON and their potential prognostic value for a subsequent disease conversion to MS, NMOSD, and MOGAD.
Acknowledgments We thank  Axel Petzold  for the discussions and comments on the manuscript. We thank the administrative office of the  NeuroCure Clinical Research Center (NCRC) , funded by the  Deutsche Forschungsgemeinschaft (DFG, German Research Foundation ) under Germany's Excellence Strategy-EXC-2049-390688087 and  Charité-BIH Clinical Study Center  for their support. and  Roche. JB reports payment for consultation from  Horizon Therapeutics, Alexion, Antigenomycs, BeiGene ,  Chugai ,  Clene Nanomedicine ,  Genentech ,  Reistone Bio ,  Roche , Imcyse, and TG; grants from  Alexion ,  Novartis , and the  National Institutes of Health. In addition, JB has a patent on Compositions and methods for the treatment of neuromyelitis optica. YB has received speaker honoraria from  Novartis ,  Roche ,  Genzyme-Sanofi ,  Merck , and  Biogen.
ML-P has received funding for travel and speaker honoraria from  Novartis ,  Biogen , and  Roche. MLei was funded by  NHS (Myasthenia and Related Disorders Service and National Specialized Commissioning Group for Neuromyelitis Optica, UK)  and by the  University of Oxford, UK. She has been awarded research grants from the UK association for patients with myasthenia-Myaware and the  University of Oxford. She has received speaker honoraria or travel grants from  Biogen Idec ,  Novartis ,  Argenx ,  UCB , and the  Guthy-Jackson Charitable Foundation. MLei serves on scientific or educational advisory boards for  UCB Pharma, Argenx, and Viela/Horizon. SL has received consulting fees and speaker honoraria from  Biogen ,  Novartis ,  TEVA, Genzyme, Sanofy , and  Merck. PL has received reimbursement for developing educational presentations, educational and research grants, consultation fees, and/or travel stipends from  Biogen Argentina and LATAM, Genzyme Argentina, Merck Argentina ,  Roche Argentina ,  Novartis Argentina , and  LACTRIMS.
He is holding patents for the 3D printing of computed tomography models and is a shareholder of PhantomX and  MSC3D. All unrelated to this work. PSu has served on advisory boards for  Horizon Therapeutics ,  Viridian Therapeutics ,  Invex Therapeutics ,  Kriya Therapeutics , and  GenSight Biologics. He  receives research support from the  NIH, DOD ,  Horizon ,  Invex , and  Viridian. AM has received a grant for  Biopas Laboratories  and reports speaking fees from  Chiesi. HZ received research grants from  Novartis  and speaking fees from  Bayer Healthcare , unrelated to this project. FP served on the scientific advisory boards of  Novartis  and MedImmune; received travel funding and/or speaker honoraria from  Bayer ,  Novartis ,  Biogen ,  Teva ,  Sanofi-Aventis/Genzyme ,  Merck Serono, Alexion ,  Chugai ,  MedImmune , and Shire; is an associate editor of Neurology: Neuroimmunology & Neuroinflammation; is an academic editor of PLoS ONE; consulted for  Sanofi Genzyme, Biogen ,  MedImmune ,  Shire , and Alexion; received research support from  Bayer ,  Novartis ,  Biogen ,  Teva ,  Sanofi-Aventis/Geynzme, Alexion , and  Merck Serono ; and received research support from the  German Research Council, Werth Stiftung of the City of Cologne, German Ministry of Education and Research, Arthur Arnstein Stiftung Berlin ,  EU   FP7 Framework Program ,  Arthur Arnstein Foundation Berlin, Guthy-Jackson Charitable Foundation , and  NMSS.
Data collection Data for this retrospective multicenter study were retrieved from the registry of the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT), a nonpro t, scienti c society representing > 600 transplant centers, mainly located in Europe. Centers commit to reporting all consecutive HSCT and follow-ups once a year. Data are entered, managed, and maintained in a central database and validated by veri cation of the computer printout of the entered data, cross-checking with the national registries, and on-site visits to selected teams. All patients gave informed consent authorizing the use of their personal information for research purposes. This study was approved by the ALWP of the EBMT institutional review board and conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines.
All tests were two-sided with the type 1 error rate xed at 0. 05. SPSS 27. 0 (IBM Corp. , Armonk, NY, USA) and R 4. 0. 2 (R Core Team 2020. R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria, https://www. Rproject. org/)), were used for all statistical analyses.
Recently, the randomized phase III PADA-1 trial (NCT03079011) has shown the usefulness of periodic monitoring for the emergence or rise of ESR1 mutations in ctDNA in order to trigger the shift from AI to fulvestrant in hormone receptor (HR) positive/HER2-MBC patients treated by first line AI-palbociclib without radiologic progressive disease. After a median follow-up of 26 months, the median PFS of patients who switched to fulvestrant was over twice as long as that of those who remained on an AI treatment (11. 9 months, compared with 5. 7 months, respectively) after ESR1 mutation detection  [13]. Another phase III randomised study (SERENA-6, NCT04964934) is currently underway to assess switching to AZD9833 (a next-generation oral SERD) plus CDK4/6 inhibitor versus continuing AI plus CDK4/6 inhibitor treatment in HR+/HER2-MBC with a detectable ESR1 mutation in plasma.
Patients A total of 138 plasma samples from 109 HR+/HER2-MBC female patients treated at the Department of Medical Oncology of the Centre Eugène Marquis (CEM) in Rennes were included in this study (Supplementary Dataset). A blood sample was prospectively collected from each patient at the time of disease progression for circulating cell-free DNA (cfDNA) extraction. The results obtained from the cfDNA samples were compared to the results obtained at the Institut Curie (IC) using their own multiplex assay for a subset of 33 samples from 30 patients. The research protocol was conducted under French legal guidelines and was approved by the medical ethics committee, CREDO, in the CEM. Written informed consent was obtained from all patients.
Design of ESR1-mutated cfDNA-like positive controls We designed gBlock® Gene Fragments (gBlock) (Integrated DNA Technologies) of 166 bp to serve as positive controls (Supplementary Table  S4 ). For the Drop-Off 536-540 system, we selected the seven most frequent mutations occurring on codons 536-540, representing 98% of all of the pathogenic mutations identified on this hotspot for breast carcinoma tumor samples in the Catalogue of Somatic Mutations in Cancer (COSMIC) database (Supplementary Figures  S1  and S2 ).
PCR programs included an initial "partition" step allowing for the formation of 15,000 to 30,000 droplets of 0. 59 ± 0. 03 nl, self-arranged into a crystal-like pattern, followed by PCR amplification cycles (Supplementary Table  S5 ). The chips were imaged with the naica® Prism3 scanner using Crystal Reader TM software v2. 4. 0. 3 with optimized parameters (Supplementary Table  S6 ), and the analyses were performed using Crystal Miner TM software v2. 4. 0. 3. Notably, thresholds for the classification of WT and mutated (MUT) droplet clusters for patient samples were set manually using the polygon gates on 2D dot plots based on the positions of the positive control clusters. These results were then "LOB-corrected" to account for the potential presence of false-positive droplets using the equation presented in  [15].
ESR1 assays results in patients The median cfDNA concentration for the 138 plasma samples from the 109 patients was 10. 1 ng/ml of plasma (range: 2. 4-568 ng/ml of plasma; mean: 23. 1 ng/ml of plasma) (Supplementary Dataset). Thirtyone patients (28. 4%) harboured at least one mutation. A total of 39 mutations were found, with the simultaneous detection of two mutations per sample occurring in five patients and the detection of four mutations occurring in one patient (Supplementary Figure  S7 ). Among the 11 pathogenic mutations potentially detected, six were detected in our series of plasma samples with the following results: D538G (16/39, 41. 03%), Y537S (10/39, 25. 64%), E380Q (4/39, 10. 26%), Y537N (4/ 39, 10. 26%), Y537C (1/39, 2. 56%), and L536R (1/39, 2. 56%). Three mutations on codons 536-540 were revealed in the ESR1(S) assay but could not be identified: "(536-540)" (3/39, 7.
69%) (Fig. 6a  and 6b ). Moreover, the relative frequencies obtained from our series of patients were rather consistent with the frequencies listed in the COSMIC database (Supplementary Table  S8 ). The distribution of the quantifications obtained was quite broad in regards to copies/ml of plasma with the following results (median (min-max)): D538G (59 (3-712)), Y537S (38 (7-1,727)), E380Q (16 (3-246)), Y537N (10 (7-12)), Y537C  (11) , L536R  (13, 821) , and "(536-540)" (41 (15-64)). The distribution was similarly broad for MAFs (%), with the following values (median (min-max)): D538G (1. 10 (0. 13-11. 07)), Y537S (1. 22 (0. 22-14. 07)), E380Q (0. 25 (0. 09-5. 55)), Y537N (0. 25 (0. 16-0. 33)), Y537C (0. 14), L536R (28. 68), and "(536-540)" (0. 59 (0. 18-1. 87)) (Fig. 6c ). In a double-blind comparative study, we used a subset of 33 samples from 30 patients of this study to compare the results obtained from the ESR1 assays to those obtained with the IC assay  [16]  (Fig.
7a , Supplementary Dataset). Out of the 20 mutated samples, 17 were also found to be mutated in the IC assay, while the three remaining samples had "indeterminate" results (i. e. , few mutant droplets detected at first pass, a setting in which more cfDNA must be analysed to reach a conclusion about sample positivity status). These three samples had relatively low ESR1 MAFs (0. 89%, 0. 22% and 0. 13%) and the remaining 13 samples were detected to be non-mutated by both assays. Thus, we obtained 91% (30/33) concordance in this double-blind cross-validation experiment. Overall, the results obtained by the two assays showed a good correlation with a coefficient of determination, calculated for the linear regression performed between the MAFs obtained in the CEM and in the IC, of R 2 = 0. 9822 (Fig.
As not all mutations have the same effect on resistance to hormone therapy and/or the same prognostic impact, it is important to identify them precisely. Depending on the type of mutation, Toy et al. [17]  observed varying levels of in vitro receptor activity in the absence of estradiol. The Y537S mutation conferred the most potent estrogendependant activity and was the only type of ER mutant that could not be further activated by the addition of estradiol. Certain ESR1 mutants altered fulvestrant sensitivity, with the Y537S mutant, again, requiring the highest dose for full inhibition  [17]. The clinical translation of this has been reported in the PALOMA-3 phase III trial (NCT01942135) of palbociclib plus fulvestrant versus placebo plus fulvestrant in pretreated ER+/HER2-MBC patients: in both arms of treatment a positive selection of ESR1 Y537S (and not for the other mutants) was observed, which is consistent with the possibility that ESR1 Y537S promotes resistance to fulvestrant  [18].
Partly corroborating this, in the MONARCH2 phase III trial (NCT02107703) of abemaciclib plus fulvestrant versus placebo plus fulvestrant in pre-treated ER+/HER2-MBC patients, in the placebo arm, PFS was similar for D538G-mutant and wild-type tumors but shorter in patients harbouring Y537C/N/S mutations. However, OS was longer in patients with an ESR1 mutation, and this was particularly so for the subgroup of the D538G mutant. In this study, only four mutations (Y537C, Y537N, Y537S and D538G) were searched for  [19]. In the plasmaMATCH study (NCT03182634), patients Fig. 3. Evaluation of the sensitivity of the ESR1 assays. DNA mixtures were prepared through serial dilutions of MUT gBlocks in a constant WT gDNA background of 10,000 copies/PCR to reach theoretical MAFs of 5%, 2. 5%, 1%, 0. 5%, 0.
with Y537S mutations were not less sensitive to fulvestrant than those with other ESR1 mutations. It should be noted that, in this trial, patients were heavily pre-treated and fulvestrant was not very effective (median PFS of two months), regardless of the presence of ESR1 mutation  [20]. Other differential effects by the type of ESR1 mutations have been reported. In the BOLERO-2 phase III trial (NCT00863655) of exemestane plus everolimus versus placebo plus exemestane after a first line of ET, D538G and Y537S were analysed with ctDNA in a subgroup of patients. The ESR1 D538G mutant and wild-type derived a PFS benefit from addition of everolimus, unlike the Y537S mutant  [11]. These results therefore further evidence the necessity for precise identification of ESR1 mutations. Using our test for our study population, we found that 28.
4% (31/ 109) of patients had one or more ESR1 mutations detected in their ctDNA. This is comparable to the data found in the literature, although it is interesting to note that there were significant differences in  prevalence between studies: 25% (195 patients, PALOMA-3 study)  [18] , 26% (1,017 patient, PADA-1 study)  [14] , 29% (541 patients, BOLERO-2 study)  [11] , 30% (377 patients, SOFEA (NCT00253422) and EFECT (NCT00065325) studies)  [21] , 31% (144 MBC HR+ patients after first line AI failure  [22] , 37% (153 patients, FERGI study (NCT01437566))  [8] , 38% (659 patients, plasmaMATCH study)  [20] , and 59% (248 patients, MONARCH2 study)  [19]. In all cases, except one that used OncoBEAMing Digital PCR with a DNA pre-amplification, the analysis of at least Y537S and D538G mutations was done with a classical dPCR.