dataesr/scientific-paragraphs-categorization huggingface dataset:
| Urine-to-Plasma ratio The plasma DIA concentration is the driving force controlling the DIA urinary concentration ensuring an a priori parallelism of the DIA decay in plasma and urine. Accordingly, after DIA administration, the steady-state urine-to-plasma ratio Rss (U/P) of DIA concentration was estimated by simply adding to the plasma population model an equation expressing the urinary DIA concentration as being proportional to the plasma DIA concentration. Rss, the factor of proportionality, was obtained from the best fit of both plasma and urinary concentrations. For computation of Rss, only urinary data collected at 24h post-administration and afterwards were considered to ensure that the pseudodistribution equilibrium was actually reached and hence the parallelism of plasma and urinary concentrations.
2 mg/kg. These curves were analysed using the non-compartmental tool of Phoenix to compute the DT of interest, that is the time above the IPC for DIA (or NOR). Using this meta-population, the DT corresponding to the LOQ of DIA and NOR in plasma (0. 05 ng/ml) were also estimated. These data were then analysed with the statistical tool of Phoenix to compute the quantiles of interest (10, 25, 50, 75 and 90th), that is the DT for which it can be ensured that from 10 to 90% of all horses are under the IPC or the LOQ.
The situation is different for the control of banned substances (e. g. NOR) where any presence of the analyte may be considered as a rule violation (The Official FEI Equine Prohibited Substances Database of the Fédération Equestre Internationale. , 2020). Here, the difficulty was to distinguish NOR as an expected metabolite of DIA from NOR resulting of an administration of NOR. In the first scenario NOR would result from a horse's legitimate treatment with DIA. However, the application of NOR itself is illegal because it is marketed and used primarily in the treatment of anxiety disorders in human medicine  (Gobbi et al. , 1987). Failing to detect DIA while NOR is present could lead to misinterpretation of an adverse analytical finding (AAF) by the sport authority, when for example NOR is caused by a DIA administration that was carried out, for example 10 days before this positive NOR sample.
Molecular Docking of Compounds IV, IV-a, IV-b, IV-c and IV-d to Hp-Fld Initial structures of compounds IV, IV-a, IV-b, IV-c and IV-d were obtained from their SMILES codes through the online NCI/CADD SMILES translator tool (https://cactus. nci. nih. gov/translate/ (accessed on 10 September 2020), NIH National Cancer Institute, Frederick, MD, USA). They were subsequently optimised at the ab initio level (#HF/6-31G*) with Gaussian 09  [34] , and the resulting structures were docked onto the three-dimensional structure of wild-type Hp-Fld (PDB ID: 1FUE) with AutoDock4. 2. 6 (La Jolla, CA, USA)  [35]. A first round of docking was performed, allowing the compounds to sample the whole protein surface (blind docking), keeping the protein rigid and allowing the compounds' rotatable bonds to freely rotate.
jejuni, and the Gram-positive Bacillus sp. , S. pneumoniae, E. faecalis, S. aureus, C. diphtheriae and C. ammoniagenes. Moreover, these compounds show low MICs for the gastric non-H. pylori Helicobacter species tested (H. felis, H. suis, H. heilmannii, H. ailurogastricus and H. bizzozeronii) and against the enterohepatic Helicobacter species H. muridarum and H. bilis. Globally, the effect of the compounds can be described considering three groups of bacteria: Gram-positive, the Gram-negative bacteria belonging to the Helicobacter and Campylobacter genera, and all other Gram-negative ones. The growth of most Gram-positive bacteria tested-except M. smegmatis and L. monocytogenes-is inhibited by compounds IV and rac-IV-j but not by compounds IV-a, IV-b, IV-c, IV-d, rac-IV-k or rac-IV-l. * Flavodoxins that appear described as essential in the DEG database  [40].
Not being in the DEG database does not necessarily mean they are essential. The other Gram-negative bacteria tested, which belong to the class gamma-proteobacteria, are generally non-susceptible to any of the compounds, including isogenic LPS mutants of P. aeruginosa, S. maltophilia and K. pneumoniae tested to address potential permeabilization issues of the compounds across the outer membrane of the parental wild-type strains. However, most Gram-negative bacteria of the Helicobacter genus (9 species tested) and the closely related C. jejuni species (they both belong to the class epsilon-proteobacteria and the order Campylobacterales) are inhibited, at least by compounds IV and rac-IV-j. Within this group, H. pylori is inhibited by all the compounds tested (lead compound IV was initially discovered as an Hp-Fld inhibitor); the five remaining gastric species (H.
Acknowledgments: We acknowledge  Pilar Mañas  from the  University of Zaragoza (Spain)  and  Mirko Rossi  from the  University of Helsinki (Finland)  for donating some C. jejuni and H. bizzozeronii strains, respectively. We would like to thank  Manuel Hein  and  Dörte Grella  ( Research Center Borstel ) for their excellent technical assistance.
Horses remained standing in stocks during the entire procedure with the head attached on both sides of the front gate. The GP catheter was removed at the end of each treatment session. Follow-up URTE (Figure  1C ) was performed eight times (T1-T8): before Aspergillus inoculation (T1 on D-5), just before the first TOT session on D0 (T2), and at days D2 (T3), D4 (T4), D6 (T5), D8 (T6), D20 (T7), and D60 (T8). All data were recorded with a PC AIDA system, Karl Storz, Guyancourt, France. Each URTE follow-up period included images captured of nine locations: one of the pharynx including both pharyngeal GP orifices; the epiglottis and arytenoids for each GP; one general view; one image centered on the proximal third of the stylohyoid bone and the roof of the GP; one image of the ventral lateral compartment; one of the ventral medial compartment.
Statistical Analysis Statistical analyses were performed for the phase-1 pilot study. To control for the possible effect of the evaluator on image evaluation (when scoring for the presence of macroscopic inflammatory lesions), a measure of agreement was calculated between the six evaluators. Due to a multiple judgment problem with ordinal data with replicates, the agreement was tested using Krippendorff's alpha coefficient. A Krippendorff's alpha of <0 indicates a poor agreement, 0 to 0. 2 indicates a slight agreement, 0. 21 to 0. 40 indicates a fair agreement, 0. 41 to 0. 60 denotes a moderate agreement, 0. 61 to 0. 80 indicates a substantial agreement, and between 0. 81 to 1 indicates near-perfect agreement. To assess the difference between GP treated and untreated, the Kolmogorov-Smirnov test was used.
Experimental design: The experimental design is summarized in Figure  1. Anticoagulated blood was used in this study. Blood and urine were spiked (stock solutions) with PGME or PGBE at two concentrations: A and B. These concentrations were obtained in a human controlled study where participants (n=11) were exposed 6 hours to 129 mg/m 3 (35 ppm) and 81 mg/m 3 (15 ppm) of PGME and PGBE, respectively (data not shown, ongoing study). Blood and urine samples were collected during and after participants' exposure. The concentration A corresponded to low concentrations observed in blood and urine (around 0. 4 mg/L), whereas J o u r n a l P r e -p r o o f concentration B represents high PGME concentrations quantified in urine (around 4 mg/L). The stock solution was first prepared in a 200 mL glass beaker, and then directly into headspace (HS) glass vials to provide controls (t0, in three replicates).
Statistical analysis: There is a mean +/-15% analytical uncertainty with the HS SPME technique. This is the variability we accept in this paper and is according to the U. S. food and drug administration (FDA)'s guidance  (Food and Administration (FDA), 2001). The variability of the respective concentration of PGME and PGBE in J o u r n a l P r e -p r o o f blood and in urine was analysed using a standard anova with the time point and the storage material and their interaction as independent factors. The concentration was expressed in percentage of the mean concentration at t0 so that the target concentration was 100%. Statistical analyses were performed using Stata software (StataCorp LP, College Station, TX, USA).
Accurate demographic knowledge of the equine population is needed to assess and model equine health events. France is one of the few European countries with an operational centralized database (SIRE) recording individual data on all declared equines living in France and on their owners and keepers. Our study aimed to assess SIRE database quality concerning the updating of information by equine owners and keepers with a view to its improvement and use in surveillance and research. Two online surveys were conducted with the participation of 6244 registered keepers and 13,869 owners. Results showed some inconsistencies between SIRE records and survey responses. The inconsistency rate for equines whose castration and death were not registered in the database was 28. 7% and 5. 9% respectively. Concerning owners, 11% of respondents did not own the reference equine selected considered by the survey, 33% had changed address without updating it in the SIRE.
Concerning premises hosting equines, the keeper survey's inconsistency rate was 7. 3%, of which 57 respondents had closed and 32 had opened premises without reporting it. Comparatively, the owner survey's inconsistency rate was 40. 7% including respondents who owned and hosted an equine without reporting these equine premises, and owners who did not keep any equines on their premises. In conclusion, the SIRE database proved to be a valuable and reliable source for epidemiological research as long as some bias is taken into account. On the contrary, its use in surveillance is currently limited due some shortcomings in updating and/or reporting by owners and keepers.
Introduction The absence of reliable and complete data on the equine population can have significant economic and health consequences, especially in the event of a rapidly-spreading epizootic. The example of the equine influenza epidemic in Australia in 2007, when nearly 4,500 premises hosting equines were infected in less than two months  (Brendan et al. , 2009; Callinan, 2007)  has shown the importance of knowing the location of equines in order to control disease  (Garner et al. , 2010). Demographic data are also needed for research, in particular for modeling the spread of diseases, evaluating control measures and quantifying economic consequences  (Lo Iacono et al. , 2013; Robin et al. , 2012). However, in most countries, demographic knowledge of the equine population is limited. In fact, the equine sector is divided into several sub-sectors managed by different organizations with multiple separate databases.
European regulations impose all traceability obligations on the keeper, whereas French regulations place the onus of traceability on the owner. European keepers are thus responsible for applying to the competent authorities to identify an equine, while in France, owners can also apply. Similarly, when the equine dies (except at slaughter), European keepers must return the identification document (passport) to the competent authorities within 30 days of the animal's death, while French owners are asked to return it, the important point being that the passport is invalidated by the competent authority to avoid any fraudulent use and update traceability database. To complete the traceability system, European regulations (Regulation, 262/2015) made it compulsory to set up a central database in each European state by June 30, 2016 at the latest.
France is one of the few European countries with a centralized database that has been operational for many years  (Engelsen, 2017). The French central database is known as "SIRE" from the French acronym for equine-related information system. It was created in 1976 and is managed by the French horse and riding institute (IFCE). The SIRE database records information on equines in France (unique SIRE identification number, microchip number, date of birth, sex and breed, date of death) whose owners (95%) have complied with regulations  (Dornier, 2010; Ifce, 2015). This declarative collection of information is mandatory. It also records information on "equine premises", where equines are kept, because French regulations require keepers to notify the authorities of the opening and/or closing of such premises (Article R215-14 of the French Rural Code).
The SIRE database also records contact information for both owners and keepers  (address, email, etc. ). The IFCE must be notified of any change in information concerning equines (such as castration or a change in ownership), owners or keepers (contact information) so it can update the SIRE database. However, owners and keepers do not systematically comply with these regulations, or take a long time to do so, which means that some of the information in the database is incomplete or not up to date. The IFCE carries out annual communication campaigns targeting owners and keepers in order to encourage them to update information (through emails to all keepers in the database, web news, Facebook posts, phone calls (Reinforced-healthprotection), but their impact is known to be limited. Until now, no major survey has ever been carried out to evaluate the global quality of the SIRE database.
Data sources and sample selection The SIRE database was consulted in December, 2018 to select owners and keepers having filled in their email address and specified their agreement to be contacted in this way. The 6404 keepers meeting these criteria were included in the keeper survey. This corresponded to 8. 4% of the 76,501 keepers who had declared one or more equine premises, regardless of the premises' status (open or closed) or the date of registration. Similarly, the owner survey included the 13,869 contactable owners, representing 1. 9% of the 737,789 owners known as the last owner of at least one equine recorded in the SIRE database. The 4,400 people registered as both owner and keeper received both questionnaires. As an owner could have several equines in the database, we selected a single equine for each owner (subsequently referred to as the "reference equine").
This simplified the questionnaire, thus encouraging responses, while providing us with additional information on one specific equine. The reference equine was selected as follows: -If the owner had only one equine registered in the SIRE database, this was the reference equine, regardless of its status (dead or alive); -If the owner had several equines, all of which were alive, the reference equine was randomly selected among them; -If the owner had several equines all registered as dead, the equine that had died most recently was selected to limit memory bias; -If the owner had several equines of different statuses (alive or dead), the reference equine was randomly selected among the live equines. Two SIRE datasets were used to evaluate the quality of data: -the "equine premises" dataset that has been used since 2006 to register the identification number of the keeper, the location(s) of the equine premises including the commune (smallest French administrative unit), the commune's INSEE code (unique identification number) and the date the premises were opened and closed (if applicable).
Data collection and analysis The questionnaires were designed with Sphinx iQ2® software to collect information needed to evaluate how up-to-date the information on owners and keepers recorded in the SIRE database actually was, and the degree of compliance of declarations of changes in the status of equines (castration, death) which must be declared by owners or keepers. The owner survey focused on information on the owner (commune of residence, equine ownership and whether the owner was also a keeper) and on the reference equine (dead/alive, gender, date of death if relevant). The keeper survey aimed to characterize the keeper and the premises on which the equine was kept, including whether or not these premises had been declared. The emails were sent by the IFCE. Each recipient was given a unique identification code that was used to link survey responses to SIRE information.
Results and discussion We based our selection on the availability of an email address and contact agreement, and only 1. 9% of owners and 8. 2% of keepers registered in the SIRE database were reachable. This was the main limitation of our study, as we had little explanation for the lack of an email address and none for the lack of agreement. It also revealed an significant problem, namely that it is not possible to contact quickly all owners and keepers individually in the event of an outbreak.
, 2013; Hotchkiss et al. , 2007; Knubben et al. , 2008; McGowan et al. , 2010; Merlin et al. , 2020). Compared to these studies, the lower response rates obtained in our study could be linked to the differences in survey procedures (email rather than direct contact). Additionally, we were not able to check the validity of the email address, and some of the owners and keepers selected probably never received the email, especially those that had not updated their personal information in the SIRE database for a long time. Indeed, respondents had updated their information on average more recently than nonrespondents (2. 2 years vs. 2. 7 years, Wilcoxon Test, p < 0. 05).
Estimation of sampling and response biases People having recently updated information in the SIRE database were more likely to have provided an email address and a contact agreement, so were selected more often (Wilcoxon test, p-value <0. 05). Nevertheless, the proportion of owners and keepers selected was almost identical in each département (a French administrative unit), with an average of 1. 2% for owner and 8. 4% for keeper surveys (Fig. 1 ). In contrast, the response rates of both surveys varied greatly depending on the département. They ranged from 0 to 32% for the keeper survey (Fig. 1C ) and from 0 to 50% for the owner survey (Fig. 1D ). Any recent updating of information in the SIRE database had a positive influence on the probability of response (Wilcoxon test, p-value <0. 05, see above).
Updates of castration and death of equines Out of 1041 geldings belonging to owner survey respondents, only 690 (66. 3%) were registered as castrated in the SIRE database. This suggests that about 1/3 of castrations are not declared by owners. This high percentage of non-compliance with notification regulations is probably due to the absence of any checks on castration except for equines participating in official events (jumping, dressage, races, etc. ), and to the fact that castration cannot be notified online. The owner has to send to the IFCE, by email or ordinary mail, a copy of the identification page from the equine's passport modified either by the veterinarian who performed the castration or by another veterinarian who certifies it. Concerning the 2613 reference equines for which the owners knew the life status (dead or alive), the information given by 2450 (93.
8%) of them was consistent with that in the SIRE database. For the 162 for which inconsistencies were observed (Fig. 2a ), either the death had not been declared to the IFCE, or the death occurred between the date we extracted datasets and the date the questionnaire was returned. The rate of non-declaration of an equine's death in our survey (6. 2%) was much lower than that estimated by the IFCE. Indeed, only some 30 to 40% of owners return the passport of their animal (IFCE, personal communication). It has been estimated that 40% of equines that died between 2011 and 2017 were still alive according to SIRE information. In the United Kingdom, it has been estimated that only 27% of owners complied with the mandatory process of returning the passport either to the issuing authorities (the Department for Environment, Food and Rural Affairs) directly or indirectly via the fallen stock disposal representative  (Defra, 2018).
Concerning delays in notifications of death, the difference between the date of death indicated by the owner and the date of death recorded in the database (most of the time this was the date on which the passport was returned) was calculated for 41 equines. The delay was under one year for the majority of equines (68. 3%, n = 28) and it was between one and four years for 24. 4% (n = 10). A recent French survey  (Merlin et al. , 2020)  had noted various reasons for the non-return or late return of the passport after death. These included the fact that the keepers do not necessarily return the passport themselves to the IFCE but entrust it to the rendering company; secondly, the keeper rarely has the original passport, which is kept by the owner; and thirdly, some owners want to keep the passport in memory of their animal.
In fact, owners can ask for the passport to be returned once invalidated as long as they enclose a stamped addressed envelope, but many people are not aware of this procedure, despite regular IFCE communication campaigns. This explains part of the under-notification and the long delay sometimes observed between the animal's death and its notification. This could also explain why surveyed owners whose reference equine was dead were less likely to respond to our survey, leading to an underestimation of the proportion of dead equines recorded as still being alive in the SIRE database. The under-declaration of equine deaths and the long delays in notifications of deaths severely limit knowledge of the size of the equine population living in France. Different multi-stakeholders working groups are underway in order to improve the updating of deaths in the SIRE database: improvement of the collection of the microchip number during the cadaver removal, interconnection of regulatory traceability databases (fallen stock database, slaughterhouse database) (Tapprest   , 2015)  and possibility of exchanging information between the SIRE database and private databases (cremation companies, insurers, etc.
Quality of ownership status data We checked not only whether the ownership of the reference equine was up to date but also the ownership of other equines potentially owned by the respondents. Concerning the reference equine, 11% (n = 307) of the 2788 respondents stated that they no longer owned this equine (Table  3 ). Concerning ownership in general, of the 50 owners that were not linked to any living equine in the SIRE records (but only dead ones), 16 indicated that they currently owned at least one equine (Fig. 2b ). On the other hand, of the 2738 respondents linked to at least one living equine registered in the SIRE database, 3. 6% (n = 99) reported that they no longer owned any equines (Fig. 2b ). These inconsistencies are mainly due to the lack of or late notification to the IFCE by owners of a change in ownership, leading to a delay in the ownership records being updated.
Quality of personal information on owners We evaluated the updating of the address of residence of owners through a question on the commune of residence (open question, not compulsory). Among the 2303 respondents concerned (current owner), 64. 7% (n = 1490) had the same postcode in the survey and the SIRE  database. For 2. 3%, the commune was either not registered in either the database or in the survey (n = 33), or erroneous in the survey (n = 21) (Table  3 ). The inconsistency rate for the location of the owner highlighted in our study is high (33%), and suggests that the knowledge of equine owners' location in France is noticeably incomplete. In the absence of a valid email or postal address, it is questionable as to whether the IFCE could contact an owner if necessary.