dataesr/scientific-paragraphs-categorization huggingface dataset:
Background: At present, the flexible endoscopic evaluation of swallowing (FEES) is one of the most commonly used methods for the objective assessment of swallowing. This multicenter trial prospectively collected data on the safety of FEES and also assessed the impact of this procedure on clinical dysphagia management. Methods: Patients were recruited in 23 hospitals in Germany and Switzerland from September 2014 to May 2017. Patient characteristics, professional affiliation of the FEES examiners (physicians or speech and language therapists), side-effects and cardiorespiratory parameters, severity of dysphagia and clinical consequences of FEES were documented. Results: 2401 patients, mean age 69. 8 (14. 6) years, 42. 3% women, were included in the FEES-registry. The most common main diagnosis was stroke (61%), followed by Parkinson's disease (6.
In addition, FEES is also being increasingly used in paediatrics  [21] , geriatrics  [22]  and intensive-care medicine  [23, 24]. The growing interest in this technique is also reflected by the development of systematic educational curricula put forward by different medical societies. Remarkably, these curricula are not confined to a specific medical profession but are all designed as interdisciplinary concepts involving a variety of healthcare professionals being engaged in the management of dysphagia  [25] [26] [27]. In spite of the increasing dissemination of FEES, there are only few studies that evaluate procedure related side effects and the clinical benefits related to providing this tool for objective dysphagia evaluation. This multicenter trial, the FEES-registry, therefore prospectively collected data on the safety of FEES and also assessed the impact this procedure had on dysphagia management in the studied patient cohort.
Patients and methods Patients were prospectively recruited in 23 hospitals in Germany and Switzerland from September 2014 to May 2017. Trial sites were identified among those hospitals actively supporting the German FEES education initiative. Trial sites included 10 neurological departments, 9 rehabilitation facilities and 4 geriatric departments. Patients were considered eligible for this study if a FEES was scheduled during their treatment either within the in-or outpatient service. There were no in-or exclusion criteria with regards to the patients' main diagnosis or treatment facility. The study protocol was approved by all involved ethics committees, and all patients or their legal representative provided written informed consent. The FEES-registry was registered as NCT03037762.
Fourth, this study showed that a simple FEES-based algorithm grading dysphagia severity according to efficiency and safety of swallowing with regards to different consistencies correlates well with the less swallowing specific FOIS score. In the past, this algorithm was used in patients with movement disorders  [16, 31]. However, since the present multicenter trial has demonstrated that the algorithm (i) is readily applicable in different diagnostic groups and (ii) is able to grade dysphagia in a clinically meaningful way, it may be assumed that this FEES-score could be helpful in everyday patients' care and might be useful as an endpoint in clinical studies devoted to the topic of neurogenic dysphagia  [38]. Finally, the present study also collected data with regards to the impact of FEES on dysphagia management.
Motivation The ongoing BETADOSE study (NCT02897076) aims to demonstrate that a 50% reduced betamethasone dose regimen is not inferior to a full-dose in preventing neonatal severe respiratory distress syndrome  [8]. Several studies have proven the benefice of antenatal corticosteroids, such as betamethasone, so it is used worldwide in pregnant women at risk  [9] [10] [11] [12] [13]. However, concerns persist regarding long-term adverse events of antenatal corticosteroids, mainly dose-related  [14] [15] [16]. The trial plans to include 1571 women per arm in 37 French centres. A sequential data analysis has been planned after every 300 newborns reach the primary outcome. As a safety secondary objective, the protocol plans to monitor, at each interim analysis, the absence of an excess of four other neonatal complications, i.
, E]. The acceptable difference between arms according to the e th expert is: d j,e = h j,e -fj. For each event, the distribution of the acceptable difference among the E experts was modeled using a mixture of beta distributions, with a maximum of 3 distributions. Using the betamix function (betareg package on R software  [18, 19] ), 3 different estimation methods were adopted (the first mathematically driven and the other two empirically driven). See Table  1  for details as well as Section 1 of the Additional file 7. As results, the distribution of D j will be denoted as D j ∼ f (a 1,j , b 1,j , a 2,j , b 2,j , a 3,j , b 3,j , w 1,j , w 2,j , w 3,j ), where (a 1,j , b 1,j ), (a 2,j , b 2,j ) and (a 3,j , b 3,j ) are parameters for the 3 beta distributions, and (w 1,j , w 2,j , w 3,j ) the corresponding weights.
Choice of the prior and thresholds for the final analysis The posterior distributions of θ 1,j -θ 0,j of the final L th analysis, were obtained through the Hamiltonian-Monte Carlo method, using the rstan package  [20, 21]  carried out in R among the 5000 simulated trials. The posterior probability that it is higher than the acceptable difference distribution was calculated. Table  2  Prevalence of events assumed in each trial, according to the scenario and to the application data set, and weight and maximal rates of misclassifications assigned to each event to build the decision rule Event Death IVH [1]  NEC [2]  Retinopathy Good decision [3]  U U A c c A c c Scenario D Prevalence in HD arm 0. 78 0. 30 0. 12 0. 08 Good decision [3]  U U U U Scenario E Prevalence in HD arm 1. 00 0. 45 0. 18 0.
Application to data We applied our method to a simulated dataset for the BETADOSE trial. In this dataset, we considered that the final sample size was 1571 per arm, with n i = 162 for children born before 28 weeks. The prevalence of events was sampled as detailed in Table  2. For all events, a good decision of this trial was considered to conclude an "Unacceptable" difference using the same explanation given before (Section 3 of the Additional file 7). Table  6  summarizes the results at the end of the trial (expressed as observed prevalence) and the Bayesian sequential results, using the rule built in the previous step (Table  5 ). At the 6 th analysis, since the posterior probabilities became higher than the prespecified threshold τ * 6 j for death, the trial was stopped because of a potential unacceptable increase of deaths in the experimental arm.
Funding This research received no specific grant from any funding agency in the public, commercial or not-f or-profit sectors. The BETADOSE study is supported by a research grant from the  French Health Ministry  and sponsored by the  Direction de la Recherche et de l'Innovation, APHP  ( Programme Hospitalier de Recherche Clinique ,  AOM15158 ) after a peer review process, but the research work covered in this manuscript has been conducted independently from this funding of the BETADOSE trial.
Data source This retrospective healthcare study utilized data from The UK Health Improvement Network (THIN), a large primary care database  (18)  of anonymized medical records of more than 13 million patients (3. 5 million active patients) from 587 general practices across England, Wales, Scotland, and Northern Ireland. Of note, the data from the THIN database are representative of general practitioners and not specialists in dermatology. The study protocol was reviewed and approved by the UK Independent Scientific Review Committee, and the study was conducted in accordance with the ethical standards of the 1964 Declaration of Helsinki.
Population The THIN database contains anonymized records of more than 11 million patients from more than 500 general practitioner practices in the UK  (19, 20). The analysis population comprised a cohort of eligible adults (18 years of age) with a diagnosis of AD recorded during the study period, validated by at least one medical-claim evidence of AD diagnosis. Patients were eligible if they received at least one prescription for a systemic IMM within 12 months of the first AD diagnosis. The cohort identified by this approach was therefore deemed to be representative of those cases with moderate-to-severe AD. Patients who died during the study period or who received an organ transplantation, bone marrow transplantation, or stem cell transplantation before or during the study period were excluded.
Prescribing patterns Prescribing data were evaluated during the follow-up period. The mean number of prescriptions and the prevalence of at least one prescription for topical corticosteroids, topical calcineurin inhibitors, phototherapy, OCSs, and IMMs were reported. In addition, the relationship between IMM exposure and OCS prescribing was explored. Systemic IMM exposure was defined as the number of once-daily tablets prescribed during the 1-year follow-up period divided by 365 days. To determine the quartile of IMM exposure, concomitant OCS prescribing was stratified according to IMM exposure (25% vs. >25%; 50% vs. >50%; and 75% vs. >75%).
Discussion This retrospective study based on the UK THIN primary care database  (18)  characterized the real-world treatment patterns in UK adult patients with AD treated with systemic IMMs. In the UK, prescribing of IMMs for AD is initiated by dermatologists in secondary care, but usually prescribing is then continued by primary care physicians under joint supervision. We showed that in this cohort of 9969 adult patients with AD, 6. 6% were prescribed a systemic IMM. The data indicated that ciclosporin, the only approved IMM for AD in the UK, was prescribed to just 16. 9% of patients treated with IMMs seen by general practitioners. This relatively low rate of use concurs with the observations of ciclosporin use found through an online survey of UK dermatologists  (22) , which found that ciclosporin was not the preferred first-line systemic agent, with only 37% of dermatologists prescribing the drug as first line.
a Two patients were prescribed three unique IMMs. The data for these patients were not included due to the small sample size. b Among patients with 1 OCS prescription in the follow-up period. c Ciclosporin was the reference drug. Phototherapy/photochemotherapy had a negligible prescription rate in the current study. This is because the THIN database only reports patients seen in general practice, and phototherapy can only be prescribed by a consultant dermatologist or accredited practitioner working under the supervision of a consultant dermatologist  (30) , and delivered in secondary care as a hospital day case treatment. By contrast, the study by Taylor et al. (22)  was conducted among specialists, who can prescribe phototherapy, and in this study phototherapy was the most common therapeutic modality.
In addition, the number of IMM prescriptions received per year does not necessarily correlate with the length of time a patient spends on treatment, as clinical practice is highly variable and can differ for each IMM. For example, clinicians may provide monthly prescriptions for ciclosporin (equivalent to 12 prescriptions per year) or 3-monthly prescriptions for methotrexate (equivalent to four prescriptions per year). Finally, as the dataset does not allow confirmation of the disease being treated, some of the OCS prescribing may have been directed towards conditions identified here as co-morbidities (e. g. rheumatological disease, respiratory, and non-AD skin disease). However, in the UK, psoriasis is not treated with OCS. For the 7. 9% and 5. 8% of patients with concomitant rheumatological disease, or upper respiratory disease (including asthma), respectively, OCSs may have been prescribed to treat the comorbidity rather than AD.
However, we want to highlight that OCS usage in the ciclosporin-and azathioprine-treated groups, treatments that are only used for AD, was equivalent to that in the methotrexate/ mycophenolate groups. Thus, although this does not exclude the possibility that some patients in the cohort had AD requiring IMM treatment and another unrelated condition requiring OCS treatment, we suspect that this potential error in interpretation is small. Despite these limitations, THIN provides a valid  (34) (35) (36)  and generalizable source of data to study treatment patterns in the general UK adult population  (37)  and has been used extensively in other disease areas to address similar objectives  (36, (38) (39) (40) (41). In conclusion, this analysis of data from the THIN primary care database of more than 13 million patients in the UK indicates a high prescription rate of systemic IMMs among adults with AD (6.
Structure modeling of CA mutants. Hexameric CA structural models of each CA mutant were constructed using the Modeller program  (83)  based on a hexameric CA crystal structure (PDB accession number 3H4E)  (84). The figures with the model structures were generated with the PyMOL program (https://pymol. org/). Time-of-addition assay. Time-of-addition experiments were performed by infecting Jurkat cells with VSV-G-pseudotyped viruses encoding the GFP reporter gene by spinoculation (1,200 ϫ g for 30 min) in the presence of 20 g per ml of DEAE-dextran. Cells were washed and cultured in fresh medium. Nevirapine at 2 M (final concentration; Sigma-Aldrich) was added at the time points indicated above. Viral infectivity was measured by determining the percentage of GFP-positive cells 2 days after infection using the EC800 cell analyzer (Sony).
Live imaging analysis. z-stacks were deconvolved and z-projected using SoftWorx software (GE Life Sciences), before individual tdTomato-Vpr particle tracking over time was performed using Fiji/ImageJ software (NIH). The mean intensities of HIV-iGFP were automatically measured on the same x-y coordinates to which the Vpr particle was tracked. Centered particle video recordings were automatically generated by in-house-made Python scripts using the Pims (http://soft-matter. github. io/pims/) and Matplotlib libraries, with the data being analyzed and exported from Fiji/ImageJ software as described by Mamede et al. (12). Fixed imaging. Jurkat cells were treated overnight with or without 200 U per ml of IFN-␤. The cells were then allowed to settle on poly-L-lysine-treated glass coverslips for 2 h at 37°C in a 5% CO 2 incubator.
ACKNOWLEDGMENTS This work was supported by grants from the  Japan Agency for Medical Research and Development (AMED) Research Program on HIV/AIDS  (grant  JP17fk0410015  to  E. E. Nakayama ), from the  Ministry of Health, Labor, and Welfare of Japan  (to E. E. Nakayama ,  Y. Iwatani , and  T. Shioda ),  JSPS   Grant-in-Aid for Young Scientists (B)   17K15701  (to A. Saito),  CRDF Global  grant  JP16jk0210012  (to  T. Shioda  and  T. J. Hope ), and  NIH  grants  R01AI100720  (to M. Yamashita) and  P50GM082545-7294  (to T. J. Hope ). We thank  Jeremy Luban  for  Jurkat Luc  knockdown [ Jurkat Luc  (k/d)] cells. The pNL4-3. Luc. R Ϫ E Ϫ plasmid was obtained from  Nathaniel Landau  through the  NIH AIDS Reagent Program. We thank  Debbie Walker ,  Kananart Kongsakon ,  Mana Kuwabara , and  Kumi Yamamoto  for their assistance.
Processing of high-throughput sequencing data The data were demultiplexed using CASAVA software (Illumina, San Diego, USA). After primer removal, the sequences with a low Phred quality score (Q<30) were removed and the overlapping paired-end reads were assembled using FLASH software  (Magoč and Salzberg, 2011). Finally a QIIME 2 2018. 11 pipeline was used to remove chimeric sequences, cluster the sequences in operational taxonomic units (OTUs; quality-filter and deblur plugins; q-score and denoise-16S/denoise-other functions) and taxonomically classify the obtained OTUs (plugin feature-classifier; function classify-consensus-vsearch;  (Bolyen et al. , 2018) ). The taxonomic classification of bacterial, fungal and eukaryotic OTUs was achieved using Greengenes database  (McDonald et al. , 2012) , the UNITE database  (Nilsson et al.
Possible replacement of the main agent of rosy discoloration by Nitriliruptor sp. The main data about Nitriliruptor in relation with this study is that this species is not known to produce pink pigment, with available strains described as colorless  (Goodfellow et al. , 2012b). Moreover, the colorimetric assessment of the white and the pink areas showed no evolution of the color in each area during the period of monitoring from the day the stone was scratched in September 2014 and January 2018. The only significant change in color was recorded at the beginning of the experiment between the measurements before scratching and the measurements after scratching. This suggests that the process leading to the formation of the rosy discoloration of stones was already finished at the beginning of the experiment and that the presence of Nitriliruptor may indicate a subsequent evolution of this process.
Measurement of live body weight, variation of empty body weight, milk yield, dry matter intake, back fat thickness and energy balance (EB) During the dry period, the animal housing was not equipped with defined feeders, so it was not possible to determine energy balance (EB. Thus, animals were kept in groups in loose housing where the total DMI from feed was estimated from the given amount. After calving, cows were milked twice daily and weighed automatically after each milking (software RIC version RW1. 7). Only live body weight (LBW) data measured following morning milking were used in subsequent analyses because the afternoon LBW was submitted to high variations. As LBW is affected by digestive contents, the estimation of empty body weight (EBW) was corrected for the digestive tract content.
A change of 4. 5 kg of digestive contents per kg of DMI was assumed  [31]. Variation of EBW (VEBW) was calculated d after d: EBW of the previous d was taken as reference weight. Live body weight and VEBW as compared to one month before calving were measured from-4 wk peripartum (wkpp) to 16 wkpp in females during their first lactation. All cows were milked twice daily. At the entrance of the milking parlour, cows were identified by an electronic collar and milk yield (MY) of each cow was automatically recorded (software R-Manufeed 500 pro, vc5 version 2. 011. 14, 1996, France). Dry matter intake was determined from the intake of fresh matter and the DM content of each feed of the ration. The diet was distributed twice daily, at 9 am and at 3 pm, and each cow had access to several defined feeders (Insentec B.
V. , Marknesse, The Netherlands). On average, there was one feeder for two cows. When a cow arrived in front of the feeder, it was recognized by a unique passive transponder attached to her ear tag. If the cows were allowed, the feeder opened and the quantity of food eaten was automatically recorded (software RIC version RW1. 7). Animals had access to their diet all the time. Dry matter intake was calculated daily for the HE and LE diets, from calving to 16 wkpp. The chemical composition of each feed is shown in S1 Table. The nutritional values of the different ingredients composing the diets were available from chemical analysis. Energy balance (expressed in Mcal/d) was calculated during the lactating period only (from calving to 16 wkpp), as it was not possible to measure DMI during the dry period.
The length of the cycle was calculated by combining the results from ovarian scans and data from oestrus detection. After AI, ovulation was confirmed by measuring progesterone three times per week until 21 days post-AI. The postpartum commencement of luteal activity (CLA) was defined as the first day that the plasma progesterone concentration was > 0. 70 ng/mL; this threshold was defined from our full data set as the value at which 95% of the minimum concentrations flanking the supposed day of oestrus were higher than this concentration. Pregnancy was determined on day 35 by ultrasonography and on day 90 by transrectal palpation. The pregnancy rate was calculated as the number of pregnant females divided by the total number of inseminated females.
Read mapping and gene identification Reads were mapped onto the cow's reference genome bosTau8. fa (downloaded from the UCSC database, http://hgdownload. soe. ucsc. edu/goldenPath/bosTau8/bigZips/) with TopHat2 (using default parameters). The corresponding filtered annotation file from UCSC contained 13,896 genes. Since samples were treated with a ribosomal depletion protocol rather than a polyA selection of mRNAs, a high proportion of reads was found to map on introns. However, it has been shown that there is a strong correlation of the read coverage levels between exon and intron  [34]. Thus differential expression analysis was performed twice, either only on exonic parts of each gene or on the entire gene sequences. Mapped reads were assigned to features with htseq-count (intersection-nonempty mode) (S2 Table ).
Bioinformatics analysis of DEGs Differentially expressed genes (DEGs) according to week (-4 vs. 1 wkpp or 1 vs. 16 wkpp) were determined from the RNAseq data collected at three time points (-4, 1 and 16 wkpp) and analyses were performed separately for the two NEB groups. DEGs related to the NEB status (SNEB vs MNEB) were determined from RNAseq data generated at 1 and 16 wkpp. The variation in gene expression was determined according to DESeq analysis. The over-expressed genes were genes that were highly expressed at -4 compared to at 1 wkpp, or at 1 compared to at 16 wkpp, or in SNEB cows compared to MNEB cows. The under-expressed genes were genes that were less expressed at -4 compared to at 1 wkpp, or at 1 compared to 16 wkpp, or in SNEB cows compared to MNEB cows (S1 Fig).
Gene network analysis and biomarker identification A downstream effects analysis including a gene network analysis was performed in 2016 using the Ingenuity Pathway Analysis propriety tool (IPA; http://www. ingenuity. com, Redwood City, CA). The purpose of downstream effects analysis is to identify biological processes and functions that are likely to be causally affected by up-and down-regulated genes. In addition, it is also predicted whether those processes are increased or decreased as described by  [35]. The build version and the content version used were 366632M and 26127183 (release date 2015-11-30), respectively. The IPA database included those following data sources: BIND, BIOGRID, Cognia, DIP, Gene Ontology (GO), Ingenuity Expert Findings, Ingenuity Exper-tAssist Findings, INTACT, Interactome studies, MINT, MIPS, Online Mendelian Inheritance in Man (OMIM).
The calculation of the overlap P-value and the activation Z-score is essentially the same as in standard enrichment functional analysis, based upon Fischer's exact test, and is well detailed by  [35]. Consequently, only direct interactions (known interactions from published studies with humans and rodents referenced in the IPA database) and metabolic downstream biological processes that are increased or decreased based on gene expression results (filtered under the "diseases & functions" section) among the genes analysed in the present study were included in the analyses for the identification of main biological functions and gene networks. Relevant biomarker candidates were also identified in 2018 using IPA under preset parameters, and references that indicate expression or function related to reproductive parameters were extracted from the NCBI database.
Progesterone ELISA assay The progesterone concentration in serum-free medium from primary bovine granulosa cells was measured after 48 h of treatment using ELISA assays  [37]. The limit of detection for progesterone was 12 pg/tube. The intra-and inter-assay coefficients of variation for progesterone were less than 10% and 11%, respectively. The results were expressed as the concentration of progesterone (ng/mL) per mg of protein per well. Data were obtained from three independent cultures, and each treatment (recombinant human CCL21: 10, 50, 100, 200 ng/mL) had four replicates.