dataesr/scientific-paragraphs-categorization huggingface dataset:
Acknowledgements: the authors would thank  Anaïs Saintigny  ( Pharmacy Student ),  Nathalie Borel  ( Medical Assistant ),  Professor Rode Gilles  ( Dean, School of Medicine, Université Claude Bernard Lyon 1, France ),  Professor Debra Roter  ( Johns Hopkins Bloomberg School of Public Health ) and all participating medical practitioners experienced in oncology ( Centre Leon Berard, Lyon, France :  Astrid Morel ,  Armelle Vinceneux ,  Helene Vanacker ,  Violette Mesdag ,  Waisse Waissi ,  Mellie Heinen ,  Amandine Bertrand ,  Cécile Renard ,  Clémence Santana ,  Clélia Coutzac ,  Audrey Couillet ,  Aurélie Dupre ,  François Gouin ,  Clémence Santana ,  Anne-Sophie Michallet ,  Pamela Funk Debleds ,  Bénédicte Mastroianni ,  Giraudet Anne-Laure, Laude Cécile, Yazigui Alexandre ) for their support.
This new regulation was provided to promote the correct use of zolpidem and limit the risks of abuse and dependence. Different effects of this regulation were evaluated by the CEIP-A of Nantes, with the ZORRO (ZOlpidem and the Reinforcement of Regulation of prescription Orders) national study, which aimed to evaluate the overall impact of the zolpidem regulatory change on the prescription of hypnotic/sedative and anxiolytic medications  [15]. The ZORRO study used an epidemiological approach, combining (i) an analysis of the French national healthcare claims database  [16, 17]  and (ii) a clinical field study, including data collection among general practitioners (GPs) and consumers at risk for zolpidem use. The first results from the healthcare claims database approach showed a decrease of half in zolpidem consumers in the general population, and we identified four specific trajectory patterns in long-term consumers: zolpidem continuation (approximately 40% of the population), zolpidem discontinuation without replacement with another sedative (a third of the population), and zolpidem replacement with zopiclone or another hypnotic benzodiazepine (a quarter of the population)  [16, 17].
These results, using databases, are valuable for assessing the impact of the regulation on zolpidem delivery in the general population, but they are not sufficient to address other specific questions, such as the impact on specific patterns of zolpidem use by problematic consumers and replacement of zolpidem with nonprescribed medications or licit and illicit psychoactive substances. Thus, the clinical part of the ZORRO study was expected to be complementary to previous results in evaluating the impact of the new zolpidem regulation on subjects at risk for zolpidem use. It provides an original study design with an individual evaluation of subjects directly recruited at their care centers. Data are scarce in the literature concerning the impact of drug regulations on specific patterns of consumption using clinical data.
Study Oversight This study was a part of the multimodal ZORRO study. The study was funded by a grant from the French National Agency for Medicines and Health Products Safety and was monitored by a pluridisciplinary steering committee with pharmacologists, psychiatrists specialized in addiction, pharmacoepidemiologists, and general practitioners. This study was approved by the French Committee for the Protection of Persons (CPP, 2018-A01070-55) on 11 June 2018 and conducted in accordance with the National Commission of Information Technology and Liberties (CNIL) rules, regarding data management and analysis. The study was registered under the reference NCT03584542, and the study protocol is available as a publication  [15].
The same data were collected from the patients recruited by GPs and users recruited by SCDDs. Participants were asked about the following: their sociodemographic data (age, sex); their knowledge about the change in zolpidem prescription rules; evolution in their zolpidem consumption since the regulatory change (continuation without any change, discontinuation, or a reduction with or without replacement); their zolpidem consumption characteristics before the regulatory change (frequency, dose, duration, effects sought and felt, way of obtaining, limitation of the prescription, route of administration); their molecule of replacement and molecule of preference to replace zolpidem, if applicable; their characteristics of consumption of zolpidem or preferred molecule (when replacement) after the regulatory change (same criteria as characteristics of consumption before); and their consumption of other psychoactive substances.
Strengths and Weaknesses The unique multimodal design of the ZORRO study combining complementary approaches (a clinical approach and a database approach) provides valuable knowledge regarding the overall impact of the health regulation. No clear guidelines are provided in the methodology application to assess the impact of a regulatory action at an individual level. Indeed, two systematic reviews in 2013 and 2018 investigated the scientific literature regarding methodologies used to assess the impact of regulatory actions, notably for the Food and Drug Administration in the USA and Europe  [25, 26] , and revealed the heterogeneity of the methodologies employed. None of the studies focused on hypnotics/zolpidem, and only a few studies concerned a patient-centred evaluation. In these studies, the data collected were not compared to medico-administrative data and, to our knowledge, never compared from a global perspective integrating database and individual evaluations.
This clinical part of the ZORRO study is the first to assess the impact of a health regulation on specific populations of problematic zolpidem consumers. This field study provides complementary results to previous results on a database regarding (i) a specific population of zolpidem users at risk and (ii) clinical data about consumption that are unavailable in medico-administrative data (type of consumption and use of nonprescribed substances). We especially identified that some licit or illicit substances for replacing zolpidem were reported by users in SCDDs. However, the majority of the time, the preferred substance was a medication in GP offices and SCDDs. This explains why we found a close proportion of patients with replacement substances in a context of discontinuation or reduction of zolpidem in this clinical study, compared to our previous results using a healthcare database (18% in GP offices and 28% in SCDDs versus a quarter in database study  [17] ).
However, we found a higher proportion of patients who continued zolpidem use (any change or reduction without a replacement), compared to the healthcare database results (80% in GP offices and 64% in SCDDs versus approximately 40%). The main factor appears to be the differences between the study populations: at-risk users of problematic zolpidem consumption in our study versus more broadly chronic users in the healthcare database. We can assume that at-risk zolpidem users may have much difficulty stopping zolpidem and, moreover, stopping zolpidem without a drug replacement. Taking this into account, off-prescription zolpidem intake in our study may also have played a role in the difference, but to a lesser extent because it was only reported by SCDD users. A major limitation is the relatively small size of the study populations, which can limit the generalizability of our results.
(I) A XBP1 binding site is present in SMN gene. CORE sequence of the consensus XBP1s binding from JASPAR database  [39]  (XBP1 JASPAR_CORE_2016, MA0844. 1, MA0844. 1) (I1). Alignment of the 5 0 UTR of human SMN2 gene contains a XPB1s binding site conserved among mammals (analyse done on ConTrav3 web site  [40] ) (I2). XBP1s binding site labelled in red is located in the first exon of SMN2 gene. (J, K) qPCR performed to detect SMN2 (J) and BiP/GRP78 (K) promoters following ChIP against flag-XBP1s in SMA type I patient-derived immortalised fibroblasts transfected 48 h with 0. 5 μg of pCMV5-flag-XBP1s or the empty pFlag-CMV2 vectors (n = 3). Data are expressed as mean AE SD *p < 0. 05. Non-parametric Mann-Whitney U test. Vertical dotted lines indicate that the pictures have been spliced from the same blot confirming the efficiency of the 4μ8c treatment as an IRE1α RNase inhibitor.
We previously reported a CRE sequence in the human SMN promoter (GenBank accession AF187725), in the first exon of SMN (+105 to +118 base pairs)  [30]. This site, which can be also bound by the CREB protein, is considered as a crucial positive regulator of SMN gene expression  [30]. Therefore, we performed an in silico analysis to determine if XBP1s could bind the SMN2 promoter and particularly on this CRE site  [40]. As shown in Figure  4I , the CRE site is also a consensus XBP1s binding site that is highly conserved in mammals. Therefore, we investigated whether XBP1s could bind this site by performing ChIP experiments in SMA fibroblasts overexpressing Flag-XBP1s using Flag antibody. We found that XBP1s binds to the SMN promoter, as well as the BiP/GRP78 promoter used as a positive control (Figure  4J, K ).
ACKNOWLEDGEMENTS The authors wish to thank  Claire Mader  and her team (Animal facility,  BioMedTech Facilities ,  CNRS UMS 2009, INSERM US 36 ) for taking care of all the mice used in this study,  S. Lefebvre  for the kind gift of immortalised fibroblasts,  J. Coté  ( University of Ottawa, Canada ) for the kind gift MN-1 cells and  S. Nedelec  for the kind gift pEF1aFlagbiotagSMN-PGKpuro. We also thank the  Cyto2BM Molecular Biology Platform of BioMedTech Facilities. C. B. is the recipient of a CIFRE fellowship with Biophytis company.
Study design We investigated inter-rater reliability in one cohort of healthy subjects (N = 34) who performed the tabled tasks twice with two raters. Validity of task measures was studied in another cohort (N = 54) by correlating the tablet measures with age, clinical dexterity assessments (BBT and MPUT) and with measures obtained using a finger force-sensor device. First, a repeated-measures design was employed to assess inter-rater reliability of tablet measures. To do so, data was collected on two separated test sessions by two different raters (rater 1 and rater 2). The minimal time interval between the two sessions was 2 h, the maximum was 19 days. For about one third of the subjects, the two measurements were obtained on the same day. Session circumstances and instructions were held constant.
Tablet-based dexterity tasks A standardized set of written and oral instructions was provided before each task (during both sessions and by each rater). Each session started with a brief introductory instruction, basic personal data collection, and familiarization with the tablet. At the beginning of each task the subject had to position his/her dominant hand within the dark blue rectangle of the tablet (Fig. 1A ). Subjects were asked not to lift the hand off the screen until each task was completed. The position of each finger was detected  within this rectangle for all five tasks. Specific instructions for each task were provided prior to each task. The order of the tasks was identical for all subjects (FiRec, RhyTap, MFTap, SeqTap and LineTr). Altogether, execution of the five tasks lasted about 20 min.
Force sensor dexterity testing using Dextrain device The Dextrain Manipulandum (www. dextr ain. com) was used as a separate and different procedure to quantify manual dexterity in the subjects. This device is equipped with a piston for each finger connected to a force sensor. The force applied by each finger on the corresponding piston was recorded using National Instruments acquisition card and tasks running on Labview (tasks same as in  [32] ). Only one of the original tasks was used, a visuomotor multi-tapping task, to assess independence of finger movements in order to compare it to the tablet data obtained by the similar (but not identical) MFTap tablet task.
Data analysis: pre-processing MATLAB (www. mathw orks. com, v2019) was used for data analysis. Figure  2  shows example raw data for the Finger recognition (Fig. 2A ) and Line tracking task (Fig. 2B ). First, data were scrutinized for outliers: Finger Recognition task data from two subjects were removed since they performed less than 50% of the total number of trials (i. e. , < 45 trials per condition). Furthermore, trials with RT < 150 ms were considered anticipatory  [51]  and removed (this concerned 17 trials from four subjects out of a total of 23,760 trials). Multi-Finger Tapping task data from two subjects were excluded since they responded in less than 50% of trials. Data from one more subject were excluded from the twofinger-tap condition due to responses in < 50% of trials. Again, single trial data with RT < 150 ms, or RT > 1 s were excluded.
As a result, more than one hundred values were eliminated across the total of 7920 trials recorded across all subjects, i. e. , < 2%. Certain two-finger tap combinations were noticeably difficult to perform and resulted in missing data. When > 50% of these trials from a given two-finger combination were missing, data were eliminated. On complicated two-finger combinations we also remarked high variability between trials. In this case averages were calculated from the three fastest trials. Otherwise, the average was based on the five fastest two-finger combinations. Sequence Tapping task visual data inspection revealed that some subjects did not follow the instructions, e. g. anticipated the memorized sequence prior to the starting cue, resulting in artefacts. This was corrected for by hand.
Funding This project was supported by Fondation Deniker and Fondation de l' Avenir pour la recherche médicale, the Fondation pour la Recherche sur les AVC, and by the French government's "Investissements d' Avenir" programme, which is managed by the Agence Nationale de la Recherche (ANR), under the reference PsyCARE ANR-18-RHUS-0014. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
Introduction Status epilepticus (SE) is a common lifethreatening neurological emergency that can cause longterm impairments. Overall outcomes remain poor. Major efforts are required to clarify the epidemiology of SE and the determinants of outcomes, thereby identifying targets for improved management. Methods and analysis ICTAL Registry is a multicentre open cohort of critically ill patients with convulsive, nonconvulsive or psychogenic non-epileptic SE. Observational methods are applied to collect uniform data. The goal of the ICTAL Registry is to collect high-quality information on a large number of patients, thereby allowing elucidation of the pathophysiological mechanisms involved in mortality and morbidity. The registry structure is modular, with a large core data set and the opportunity for research teams to create satellite data sets for observational or interventional studies (eg, cohort multiple randomised controlled trials, cross-sectional studies and shortterm and long-term longitudinal outcome studies).
The availability of core data will hasten patient recruitment to studies, while also decreasing costs. Importantly, the vast amount of data from a large number of patients will allow valid subgroup analyses, which are expected to identify patient populations requiring specific treatment strategies. The results of the studies will have a broad spectrum of application, particularly given the multidisciplinary approach used by the IctalGroup research network. Ethics and dissemination The ICTAL Registry protocol was approved by the ethics committee of the French Intensive Care Society (#CE_SRLF 19-68 and 19-68a). Patients or their relatives/proxies received written information to the use of the retrospectively collected and pseudonymised data, in compliance with French law. Prospectively included patients receive written consent form as soon as they recover decision-making competency; if they refuse consent, they are excluded from the registry.
Strengths and limitations of this study ► The multicentre open cohort design including critically ill patients with convulsive, non-convulsive or psychogenic non-epileptic status epilepticus. ► The modular nature of the cohort with the establishment of satellite databases around the core set of variables. ► The multidisciplinary approach used by the IctalGroup research network. ► The inclusion criteria restricted to critically ill patients. ► The registry is on a modular-based structure that allows the establishment of satellite databases around the core set of variables. Open access dearth of information on neuroprotective strategies. 10 e urgently need to identify new therapeutic targets to improve the outcomes of SE. One means to achieving this goal consists in collecting epidemiological data about patients with SE at all stages of management.
METHODS AND ANALYSIS ICTAL Registry objectives The ICTAL Registry collects observational data on adults admitted to intensive care units (ICUs) at multiple healthcare institutions for CSE, NCSE or psychogenic non-epileptic SE (PNESE). The primary objectives are to record extensive information on the causes, circumstances of onset, clinical and electroencephalographic (EEG) patterns, treatments, adverse treatment effects and outcomes in adults with CSE, NCSE or PNESE. These data will allow us to identify different patient phenotypes that may require different treatments. The secondary objectives are to provide the data needed for nested-cohort studies using a variety of designs including cohort multiple randomised controlled trials; observational cross-sectional, prospective or retrospective studies and patient-reported outcome studies.
Design and patients The ICTAL Registry collects retrospective data (from January 2005 to December 2017) and prospective data (from January 2018 onward) from 23 ICUs in France. Expansion to international centres is planned. All patients admitted to any of the participating ICUs with any seizure activity are screened for eligibility by the ICU physicians around the clock and 7 days a week. Inclusion criteria are age 18 or older and admission to any of the participating ICUs for CSE, NCSE or PNESE as defined below. Patients with post-anoxic SE are not included.
Data collection For each patient, the registry collects a set of core variables. Over time, as the registry data or other new events suggest clinical questions requiring specific studies, additional data to allow such studies will be obtained. Figure  1  is a graph showing these satellite data sets and examples of the types of investigations they will allow. A standardised case report form is used for each patient (figure  2 ). The form includes definitions of variables (see below) and data validation rules. The core variables were chosen based on an adaptation of Utstein-style guidelines. 24 They include demographic data, baseline autonomy, history of epilepsy, comorbidities and characteristics of the current episode (circumstances of onset, dates and times of onset and of seizure control, clinical features of the seizures, prehospital and hospital care providers and timing of all given ASMs and adjuvant antiseizure or supportive treatments).
Special attention is paid to treatment-related complications (eg, respiratory and/or cardiac side effects of ASMs, haemodynamic side effects of anaesthetics and airway-management difficulties). The characteristics (sequential and/or continuous) and results of EEG monitoring are collected according to the most recent Open access international guidelines. 20 The following data describing the ICU and hospital care are also collected: severity and description of SE and organ failures according to the STESS score, Simplified Acute Physiology Score II (SAPS-II) and Logistic Organ Dysfunction (LOD) score and use of mechanical ventilation, inotropic support and/or renal replacement therapy. Follow-up data are recorded for all registered patients not known to have died before or after discharge. The Glasgow Outcome Scale (GOS) score and functional impairments at ICU and hospital discharge are collected.
Data quality control For each patient entered into the registry, the data are manually verified by an IctalGroup member and any queries are resolved with participating-centre investigators. For patients with missing data, the available information is checked again to ensure that only high-quality data are kept in the registry. When data are missing, out-of-range or inconsistent, the IctalGroup coordinator routinely contacts the participatingcentre investigator to obtain clarification. Outcome data recorded at ICU and hospital discharge then 90 days and 1 year after SE onset are routinely verified. The registry data are regularly checked against source data, and random audits are conducted every 100 included patients by the IctalGroup coordinator.
Data security The ICTAL Registry complies with the standards set by the French health authorities (INDS #MR5821231120 and #MR0314241018) and the General Data Protection Regulation (GDRP) 2016/679 of European Union law aimed at protecting the confidentiality of personal data. According to the GDRP, all data are pseudonymised, that is, made unattributable to a specific patient without additional information. Only the participating-centre investigator can identify the patients managed at that centre, using a mapping table of inclusion numbers. Other important measures further improve data security. The registry data are accessible only to authorised individuals who need the access for logistic or scientific purposes. The pseudonymised data are stored on a secure local server approved for hosting health data.
A lumbar puncture is performed in patients with a fever, neck on June 24, 2022 by guest. Protected by copyright. http://bmjopen. bmj. com/ Open access stiffness, an immunodeficiency or negative findings from all other etiological investigations. MRI may be considered if the other etiological investigations are negative. The aetiology is diagnosed jointly by the intensivists and consultant internists and neurologists. Continuous or sequential EEG monitoring is performed routinely as soon as possible,  32  and is particularly valuable in patients with a deep coma, long-lasting postictal state and/or progression to refractory SE. [33] [34] [35]  The future One of the purposes of the ICTAL Registry is to allow nested observational and interventional studies (figure  1 ). The collection of core data followed by that of satellite data as dictated by the identification of unresolved issues will make these studies easier, faster, and less costly.
Ethics and dissemination The ICTAL Registry protocol was approved by the ethics committee of the French Intensive Care Society (#CE_ SRLF 19-68 and 19-68a). Patients or their relatives/proxies received written information to the use of the retrospectively collected and pseudonymised data, in compliance with French law. Prospectively included patients receive a written consent form as soon as they recover decisionmaking competency; if they refuse consent, they are excluded from the registry. The ICTAL Registry is being created and maintained by the IctalGroup, a non-profit organisation of physicians, nurses and other healthcare professionals dedicated to teaching and research in neurocritical care. The Ictal-Group is responsible for managing and coordinating the database and for conducting the statistical analyses of the registry data.
DISCUSSION The development of the ICTAL Registry is a major collaborative initiative aimed at allowing retrospective and prospective studies of mechanisms associated with shortterm and long-term outcomes, notably disabilities, in critically ill patients with SE. The large size of the cohort, the breadth and quality of the data and the inclusion of patients over time should result in management changes capable of improving the currently poor outcomes of SE. The data collected for each patient include potential demographic and biological risk factors and health events occurring over time. Whereas closed cohorts collect longitudinal data in a population determined at a given time point, our registry will remain open to the inclusion of all adults with non-postanoxic SE newly admitted to the participating ICUs.