dataesr/scientific-paragraphs-categorization huggingface dataset:
Acknowledgments We are grateful to  C. Dubois  and  L. Wimel , the staff of the experimental farm of the  French Horse and Riding Institute (IFCE), 19370 Chamberet , for providing neonatal tissues from selected mares and foals. We thank  Dr. K. Pader ,  Dr JM. Betsch ,  Dr M. Hamon ,  Dr E. Ouachee ,  Dr A. Vitte ,  Dr N. Delalande ,  Dr F. Croisier ,  Dr JC. Meunier ,  Dr D. Lavorel ,  Dr T. Bertholdy ,  Dr F. Martin  and  Dr H. Sorribas  for providing patients and performing clinical evaluations and data collections. We wish to thank  Dr S. Sage  for his contributions to the study protocol.
Inclusion Criteria and Health Status To determine if cows were sick after calving, data were collected from veterinary records, daily rectal temperatures and records of abnormal milk from the milker during the first 3 d after calving. The herd veterinarian visited the farm as needed when farm staff recognized signs of illness in a cow (mastitis, pneumonia or an unknown infection). Rectal body temperatures were taken by the milker twice daily for the first 3 days after calving. Signs of mastitis were recorded twice daily by the milker based on the colour and consistency of the milk. Using these data, we defined 'sick' cows as those with at least one high rectal body temperature (≥39. 1 • C) and one clinical sign of illness diagnosed by the veterinarian and/or milker within 24 h post calving.
Behavioural Data Collection The behaviour of cows and their calves was recorded for 24 h post-partum using a digital video camera (TVCCD-140IR; Monacor UK Ltd. , Milton Keynes, UK) mounted above each individual pen. The moment of calving was recorded for each cow and was defined as the time when the calf's hips were fully expelled from the cow. Table  1  describes behaviours collected in this study; all behaviours were continuously collected from video. The start and end time for each behaviour was recorded using Microsoft Excel during the 24 h after birth. Cow and calf lying bouts were calculated as the number of times animals transitioned from standing to lying. Raw data were used to calculate the latency of each behaviour from the moment of calving (min) and the duration of each bout (min/bout).
Statistical Analysis The cow and calf dyad was considered the experimental unit. Before analysis, behavioural data were summarized into the period 24 h after calving, as well as a sum for each 6 h period after calving (1 to 6 h, 7 to 12 h, 13 to 18 h and 19 to 24 h). All statistical analyses were performed using SAS software (version 9. 4; SAS Institute Inc. , Cary, NC, country). The normality of residuals and of random effect distribution were visually assessed using plots of residuals and quantile-quantile plots of residuals and random effects. Significance was declared at p < 0. 05. We anticipated that parity would impact the behaviours based on previous literature  [18] , thus, parity was forced into all models as a categorical variable (2 and 3 vs. 4). To determine the impact of sickness on the daily duration of cow-calf behaviours, a linear mixed model (PROC MIXED) was used.
Statistical Analysis Means for pen weight gain, feed consumption, feed conversion (adjusted for mortality: feed consumed/(final live weight + mortality weight)), NE lesion scores, and NE mortality were calculated. The mortality was assessed by gross lesions on necropsy enlarged dark-colored livers and the pseudomembrane appearance of classical NE in the small intestine. Statistical evaluation of the data was performed using SPSS v24. 0  [13]. Results on performance of the animals were analyzed by a Mixed Model with treatment as a fixed factor and pen as a random factor. Data on mortality were analyzed using a binary logistics (Generalized Lineair Model).
For extrapolation purposes, systems toxicology models would probably be favoured, being fundamentally mechanistic, like PBPK models. Yet, they can be extremely complex and data hungry. Statistical models (such as linked non-linear regression relationships or Bayesian networks) might be simpler to develop, but they may have more restricted applications. In between, there is a whole range of pharmacodynamic models, such as the effect compartment model, often used in pharmacology, but much less so in toxicology. Research is very active in those areas, and it is likely that, for a quite while, the various approaches will co-exist. PK/PD modelling of the effects of random mixtures of aromatase inhibitors on the dynamics of women's menstrual cycles was assessed. Using high-speed computer code, random exposures to millions of potential mixtures of 86 aromatase inhibitors present both in the US EPA ToxCast and ExpoCast databases were simulated.
While in the 1970s and early 1980s air pollution was considered as a relatively marginal exposure in terms of attributable risks, the most recent estimate is that it accounts for 7. 6% of global deaths and 4. 2% of global disabilityadjusted life years (DALYs) world-wide  (Vineis and Fecht, 2018). The change in appreciation of the role of air pollution has been mainly due to the refinement of exposure assessment methods and the new generations of longitudinal studies. Mechanistic evidence via 'omic technologies is now rapidly increasing, so lending credibility to previous epidemiological ('black box') associations  (Vineis, 2018; Vineis and Fecht, 2018). In the EXPOsOMICS project, a few priorities for research were selected, with relevant practical implications for policy making and stakeholders: can our knowledge be consolidated on the health effects of those two important exposures, air pollution and water contaminants, reinforcing causal assessment? Can variation in exposures in a finer way than with the standard tools of epidemiology be detected? Can the effects of low and very low levels of exposure using 'omic biomarkers be detected? How can 'omic measurements to study pollutant mixtures be exploited? Can improved exposure assessment to calibrate estimates of risk and burden of disease be used? As a result, developed methodologies for the validation of a set of five 'omics measured in the same subjects (for a total number of more than 2,000 individuals), and statistical tools to allow the analysis of very complex data sets were developed.
In both study arms, animals were terminated at 1 year (interim) and 2 years (terminal). Statistical comparisons were conducted within sex, study arm, and sacrifice time and BPA and EE2 groups were analysed separately. Data collected included survival, body weights, litter parameters, age at vaginal opening, vaginal cytology, including an assessment of the onset of aberrant cycles, clinical chemistry (interim sacrifice only), sperm parameters (interim sacrifice only), organ weights (interim sacrifice only) and histopathology (both interim and terminal sacrifices). The grantee studies assessed a range of molecular, structural and functional endpoints that are not typically assessed in guideline-compliant studies  (Heindel et al. , 2015). As the safety assessment of BPA is outside the scope of this paper, for the results of the core and grantee studies the reader should consult the NTP website (https://manticore.
niehs. nih. gov/cebssearch/program/CLARITY-BPA). The key strengths of this consortium approach included: (i) the identical BPA exposure conditions used for both components of the consortium, which were provided at the same facility (NCTR); (ii) blinding of the core study samples received by the academic grantees, therefore minimising the potential risk of bias; and (iii) the development of an a priori list of endpoints to be collected per study and the requirement that all data be deposited in a private workspace in the NTP's database before decoding. This allowed for confidential data acquisition and blinded deposition of data and also ensured that subsequent public access to data had no bias in end-point data acquisition. There were limitations to this approach though. Academic investigators were limited to using a specific shared design and model that may not have been optimal for the specific endpoints proposed.
The development of databases and softwares for high-throughput screening (HTS) and high content image analysis (HCA) is needed to facilitate international harmonisation and promote the use of NAMs and the large amount of data produced by these technologies. Strategies are required for re-engineering already available data matrices and making them accessible, readable, interpretable, usable and integrable with the new data streams. To facilitate and standardise a transparent risk assessment, electronic submission of toxicological, exposure and epidemiological raw data should be promoted by creating a digital network of relevant information. The successful implementation of NAMs and other new developments in future risk assessment will necessitate cooperation of academia, risk assessors and international bodies such as the OECD, and the identification of these areas as high research priorities for long-term and flexible funding at the European level, this being supported by an effective dialogue between funding bodies, academia and risk assessors.
3, 13 ] [16]  Among azoles, fluconazole is effective against Cryptococcus and Candida spp. , whereas voriconazole has good CNS penetration and has been shown to be effective against a broad spectrum of fungal pathogens but is ineffective against Mucorales. 12, 17 savuconazole is a novel triazole with a similar mode of action to voriconazole but with broad-spectrum activity encompassing a wider range of fungal species, including Mucorales. Isavuconazole demonstrates blood-brain barrier penetration in animal models,  18  and clinical efficacy has been reported in a single patient with disseminated mucormycosis and CNS involvement, who was treated with isavuconazole under the Emergency Investigational New Drug program. 19 The phase III VITAL trial (NCT00634049) evaluated isavuconazole as primary therapy in patients infected with rare fungi, principally mucormycosis, or renally impaired patients with aspergillosis.
20 A subgroup analysis of this trial evaluated the efficacy of isavuconazole against Cryptococcus species and dimorphic fungi. 21 The phase III SECURE trial (NCT00412893) compared isavuconazole with voriconazole as a primary treatment for infections caused by Aspergillus species or other filamentous fungi. 22 Isavuconazole was also made available as part of a named patient program (NPP), ahead of country-specific approvals for use in IFD. 23, 24 he aim of this analysis was to assess the effectiveness of isavuconazole in the treatment of CNS IFDs, by examining relevant cases from the two isavuconazole phase III clinical trials and the NPP.
Methods Data were collated from the VITAL  20  and SECURE trials  22  as well as from the NPP. Disseminated IFD or CNS IFD were regarded as proven by histopathology or culture of fungal species from sterile body sites including cerebrospinal fluid, brain fineneedle aspiration, or brain biopsy using EORTC/(Mycoses Study Group [MSG] criteria. 25 In both trials, patients with probable IFD were also included. For cases of probable disseminated IFD, confirmation by CNS imaging, either by magnetic resonance imaging (MRI) or computed tomography (CT), in conjunction with a positive direct or indirect mycology test from another site (blood, sinus, lower respiratory tract), was regarded as evidence of CNS involvement. Both trials and the NPP excluded patients with Candida infections. Adult dosages were consistent with the prescribing information.
28 The effectiveness of isavuconazole as salvage therapy for infections of the CNS was also assessed in a retrospective series of patients with coccidioidal meningitis. 29 A total of nine patients were initially treated with fluconazole and switched to voriconazole. All nine patients subsequently received isavuconazole as salvage therapy, with the majority of voriconazole patients switching to isavuconazole due to adverse events (one patient switched after voriconazole treatment failure). All nine patients achieved treatment success (three patients) or stable disease (six patients) during a follow-up with isavuconazole therapy ranging from 138 to 810 days. These data further support the utility of isavuconazole in fungal infections of the CNS. In the present retrospective study, treatment with isavuconazole was effective against CNS infections caused by a wide range of different fungi.
32 Furthermore, a relationship between trough isavuconazole plasma concentrations, fungal isolate minimum inhibitory concentrations, and key outcomes could not be identified in VITAL, although this may have been due to the small number of patients with data available. 20 Therefore, additional clinical data in different localizations and stages of infection are needed to better understand brain tissue and CNS fluid penetration of this azole. Voriconazole is another azole used for the treatment of invasive fungal infections, for which effectiveness against CNS IFD was evaluated in an analysis similar to the current study. 33 A total of 192 cases were accumulated from the voriconazole clinical trial database and published case reports and case series. Treatment with voriconazole resulted in complete or partial responses in 63% of cases as primary therapy and 45% of cases as salvage therapy, and outcomes improved significantly with antifungal combination therapy and with surgery.
Clinical responses were more frequently observed in published versus database cases treated with voriconazole for CNS IFD suggesting a publication bias. A publication bias is unlikely true for the present analysis as we have included patients from clinical databases only. In an earlier study that retrospectively analyzed the effectiveness of voriconazole in 81 patients with Aspergillus infections of the CNS,  34  the survival rate was 31%. While this is lower than the survival rate in Aspergillus infections observed in the current analysis (day 42: 87. 5%; day 84: 62. 5%), comparisons may not be meaningful because of differences in study populations and the considerable time that has elapsed between the studies, which may have allowed for improvements in other aspects of care. In SECURE,  22  only two patients were treated with voriconazole for infections with CNS involvement, both as primary therapy.
Overall, our findings should be interpreted with caution as our analysis featured a relatively low number of highly selected patients and was retrospective in nature. Furthermore, this analysis included data from two different trials and a separate database and covered a range of fungal pathogens. Our report suggests that isavuconazole may be a valuable option in the treatment of CNS IFDs. To improve outcomes, future research should focus on advances in diagnostic methods (e. g. , molecular detection, fungus identification with susceptibility testing), CNS pharmacokinetics of antifungal compounds, development of antifungal compounds with enhanced CNS-directed efficacy, and further investigation of crucial host defense mechanisms.
Bioinformatic Analysis Raw sequencing reads (fastq) were filtered and trimmed using the FASTQ trimmer tool of the FASTX-Toolkit (Hannon Lab, Cold Spring Harbour Laboratories, Cold Spring Harbor, NY, USA) applying a threshold PHRED score of 25. To identify SNPs in genes conferring resistance, fastq files were analysed using the ARIBA pipeline  [30] , querying a custom-made database of gene sequences derived from the H. pylori reference strain 26695 (NCBI reference sequence: NC_000915. 1). For the evaluation of metronidazole resistance, all SNPs in rdxA, frxA, mdaB, omp11, and rpsU that occurred more frequently in metronidazole resistant than susceptible H. pylori isolates were assessed. In order to identify probable plasmid-encoded resistance genes, trimmed and filtered FASTQ sequencing files were analysed using the plasmidSPAdes pipeline (Version 3.
Statistics and Data Analysis We used the 2 × 2 contingency table to calculate the agreement between WGS and phenotypic DST results  [32, 33]. In this context, specificity describes the likelihood that SNPs identified in a target gene lead to phenotypic drug resistance, while sensitivity describes the proportion of resistant cases that are identified through that set of SNPs. A major error occurred if a H. pylori strain that was identified as susceptible by phenotypic DST was determined resistant by WGS. In this case, an alternative antimicrobial regimen would have been prescribed to the patient, though first line treatment could be administered. A very major error occurred if an H. pylori strain that was identified as resistant by phenotypic DST was determined susceptible by WGS. In this case, the organism would be falsely assessed as susceptible, resulting in the administration of an ineffective first-line antibiotic therapy.
Distribution of P. columella in cuba. The updated distribution of P. columella was obtained from the National Reference Malacological Database for freshwater snails in Cuba, held by the Laboratory of Malacology of the Institute of Tropical Medicine in Havana, through the revision of 496 sampled sites ( = populations) from 1982 to 2018. Each record includes the presence of a given freshwater snail, geographic coordinates, habitat type, date and collector. Nationwide malacological surveys are carried out by our laboratory on a 10-year sampling period basis complemented with annual expeditions covering smaller areas. All sites positive for P. columella were plotted on a map differentiating each record according to a 11-year time interval, to account for new and historical data, using MapInfo v.
The plate was mixed in vortex, incubated overnight at 56 °C and placed for 10 min at 95 °C. The mixture was centrifuged at 6000 × g for 6 min and the supernatant containing the DNA was collected and stored at -20 °C until use. PCR amplifications were performed in a 96-well MJ-Research PTC 100 for all samples. Six microsatellite loci, previously described for P. columella species by Nicot et al. 27  , were amplified (GenBank Access number): PCO01 (EU04295), PCO02 (EU049296), PCO07 (EU049299), PCO12 (EU049303), PCO13 (EU049304) and PCO20 (EU049309). Each locus was amplified through PCR using 1 µL of extracted DNA in 10 µL of reaction volume containing 2 µL buffer 5 × (Promega), 1 µL of 25 mmol/L MgCl 2 , 0. 5 µL of 2 mmol/L dNTP (Invitro-gen/ Life Technology), 0. 2 µL of each primer (10 pmol) and 0.
2 µL of Taq DNA polymerase (Promega). Thermocycling consisted of 10 min of initial denaturalization at 94 °C, 30 cycles at 94 °C for 30 s, annealing at 55 °C (for each locus) for 30 s, 60 s at 72 °C and a final elongation step at 60 °C for 30 min. Primers were fluorescently labelled to be used in an ABI automated sequencer (ABI Prism 310 Genetic Analyser, Applied Biosystem, Perkin-Elmer, USA). Amplified products for each individual were used for sequencing where 1 µL of diluted amplicon (1/100) was added to a mix containing 15 µL of Hi-Di Formamide and 0. 27 µL of internal size standards (GENESCAN 500 LIZ, Applera). Each allele's length was read using GeneMapper ® v. 4. 0 software (Applied Biosystems TM ).
The obtained distance matrix was used to build a neighbour-joining network of all MLGT in SplitsTree4 34. The genotypic diversity was calculated in each population with an adaptation of the Simpson index using GENCLONE 2. 0  35. ecological patterns of resistant and susceptible P. columella. The ecological patterns of the two phenotypes of P. columella were explored using three approaches: laboratory field records, field study and experimental life tables. Revisiting laboratory field records of resistant and susceptible P. columella populations. A thorough literature review which included published papers and 37 years of unpublished data from our laboratory's field notes, was conducted. We gathered data for species composition of the mollusc assemblage and field abiotic factors (phosphates, nitrates, dissolved oxygen, pH and total hardness) measured for resistant and susceptible populations investigated within this study.
Distribution of P. columella in cuba. Knowing the distribution of a snail species is particularly important to assess its epidemiological significance and to attempt its effective control. The National Reference Database contains nearly 500 records in Cuba (Fig. 2A ), from which 68 verified sites harbour P. columella species (Fig. 2B ). The distribution of P. columella ranges from the westernmost region (Pinar del Río province) to the east-central (Camagüey province) region of Cuba (Fig. 2B ). No records exist for the easternmost provinces. Notably, 59% of sampled populations were documented in the last 15 years. Overall, earliest records are more abundant in the west-central region while populations from east-central Cuba correspond mostly to newer samplings. From the 68 verified P. columella populations, only six are acknowledged as resistant to F.
columella in the mollusc assemblage and their interaction with the abiotic factors, which could explain the differential distribution observed, are lacking. Considering that such resistance could hold promise as a control strategy to disengage F. hepatica transmission in the field, it is important to account for its ecological or demographical patterns. Thus, we analysed the occurrence of each phenotype in the wild in association with different environmental factors and we carried out experimental life tables to address this topic. Reviewing data from natural populations. Since no apparent pattern concerning the type of habitat was found in either resistant or susceptible P. columella (see section 3. 1), we aimed to identify specific ecological features associated with the occurrence of each phenotype.
Acknowledgements This study is set within the framework of the  "Laboratoires d'Excellences (LABEX) "  TULIP  ( ANR-10-LABX-41 ). Partial financial support for this investigation was provided by the subventions granted to AA by the  French Embassy in Cuba  and to AAV by  Institut de Recherche pour le Développement  ( BEST grant ). BG was supported by  ANR  JCJC  INVIMORY  (number  ANR 13-JSV7-0009 ) from the  French National Research Agency (ANR). The authors would like to thank  Dr. Jérémie Vidal-Dupiol , for his suggestions on the experiment of the life history traits. The authors also acknowledge the valuable comments and suggestions made by the anonymous reviewers and the editor that greatly helped in improving the manuscript.
Statistics After validation of the normal distribution of the data and their residues, a mixed linear statistical model  [31]  (R version 3. 1. 3) was used to test the relationship between DIPJ cartilage thickness and area and several independent variables. The differences in thickness and area between weight-bearing and non-weight-bearing acquisitions were assessed, in both the frontal and sagittal acquisitions. The difference in thickness between medial, sagittal and lateral aspects and between dorsal, central and palmar aspects of the articular cartilage during the same acquisition were assessed, in both the weight-bearing and non-weight-bearing conditions. The differences in cartilage thickness and areas between the middle and distal phalanges was also tested, when available (5 feet for frontal measurements, 9 feet for sagittal measurements).