dataesr/scientific-paragraphs-categorization huggingface dataset:
19] Antiphospholipid syndrome: case reports have highlighted the possible association of anticardiolipin antibodies with sudden sensorineural hearing loss in systemic lupus erythematosus. ] [24] [25] [26]  Whether the presence of antiphospholipid antibodies in patients presenting sudden sensorineural hearing loss is sufficient to establish a diagnosis of secondary antiphospholipid syndrome in the absence of other symptoms (i. e. , thromboembolic or obstetrical complications) remains to be determined. [20, 22, 24, 25] en reviewing the English and French literature in the Medline database, we found 22 documented cases of sudden sensorineural hearing loss in association with systemic lupus erythematosus (Table  1 ). Patients were between 20 and 50 years old, mostly women (16/22). Hearing loss was unilateral in 14 out of 22 cases.
Twelve patients were treated with steroids (0. 5-1 mg/kg equivalent prednisone, 1 was treated with 500 mg methylprednisonolone on 3 consecutive days), 4 patients were prescribed immunosuppressive therapy with azathioprine or cyclophosphamide, 3 were treated with plasmapheresis and 2 with hydroxychloroquine. Anticoagulation or antiplatelet therapy was prescribed to 4 patients. Clinical outcome was reported for 13 patients: recovery from hearing loss was complete in only 4 patients and partial in 2 other cases. None of the patients treated with anticoagulation or antiplatelet therapy recovered. A recent publication of a retrospective cohort study from the Taiwan National Health Insurance Research Database reported 27 cases of sudden sensorineural hearing loss associated with systemic lupus erythematosus, but no detail on clinical and biological data was available.
Yes Fukushima et al  [37]  ; case report 22, F 5 y Unilateral Hematologic involvement, arthritis, lupus nephritis ND Prednisone; plasmapheresis; azathioprime ND Sugiura et al  [38]  ; case report  management of such cases remains empirical, the high risk of permanent hearing loss seems to justify emergency treatment with high dose corticosteroids. If the laboratory criteria of antiphospholipid syndrome are present, antiplatelets agents or anticoagulation therapy shall be considered. Informed oral consent was obtained from the patient. All data were strictly obtained from the patient's medical file.
Purpose: The PRAME tumour antigen is expressed in several tumour types but in few normal adult tissues. A dose-escalation phase I/II study (NCT01149343) assessed the safety, immunogenicity and clinical activity of the PRAME immunotherapeutic (recombinant PRAME protein (recPRAME) with the AS15 immunostimulant) in patients with advanced melanoma. Here, we report the phase I dose-escalation study segment. Patients and methods: Patients with stage IV PRAME-positive melanoma were enrolled to 3 consecutive cohorts to receive up to 24 intramuscular injections of the PRAME immunotherapeutic. The RecPRAME dose was 20, 100 or 500 µg in cohorts 1, 2 and 3, respectively, with a fixed dose of AS15. Adverse events (AEs), including predefined dose-limiting toxicity (DLT) and the anti-PRAME humoral response (ELISA), were coprimary end points.
9 Expansion of PRAME-specific T-cells was observed and no safety issues were identified. In a dose-escalation phase I study, we sought to determine an adequate dose of a recombinant PRAME protein (recPRAME, GSK, Belgium) administered with GSK's proprietary immunostimulant AS15, through evaluation of the safety and immunogenicity of the PRAME immunotherapeutic in patients with PRAMEpositive metastatic melanoma. Here we present safety and immunogenicity data two weeks after dose 4 that led to dose selection according to protocol-defined rules. A phase II study segment is ongoing and will assess clinical activity of the selected dose of recPRAME. Clinical activity observed in phase I will be described at the time of the final analysis.
METHODS The open-label, phase I dose-escalation study (http:// www. clinical trials. gov NCT01149343) study protocol was approved by institutional review boards at each participating centre. Written informed consent was obtained from each patient prior to the performance of any studyspecific procedures, including PRAME screening. Overall, this study was conducted in accordance with the principles of 'good clinical practice', the principles of the Declaration of Helsinki and all applicable regulatory requirements. During the course of the study, whenever potential or actual issues with regard to the conduct of the study were identified, either via site monitoring activities or brought to GSK's attention by other oversight mechanisms, these issues were investigated and, where possible, appropriate corrective and/or preventive actions were taken.
Acknowledgements The authors thank the patients who participated in this study and their families. They also acknowledge the investigators and their clinical teams for their contribution to the study and their support and care of patients, in particular  Federica Baldini ,  Dirk Debus ,  Monica Dinulescu ,  Claus Garbe ,  Christoffer Gebhardt ,  Oleg Gladkov ,  Massimo Guidoboni ,  Janusz Jaskiewicz ,  Ivana Krajsova ,  Sina Krengel ,  Eugen Kubala ,  Antonella Marasco ,  Andrea Maurichi ,  Sandrine Monestier-Gasmi ,  Laurent Mortier ,  Alexander Roesch ,  Igor Samoylenko ,  Mario Santinami ,  Ester Simeone ,  Patrick Terheyden ,  Maria Chiara Tronconi ,  Rostislav Vyzula  and  Lisa Zimmer. The authors thank the global and regional clinical operations, in particular  Geneviève Ramaekers , and safety teams of  GSK Vaccines  for their contribution to the study, the scientific writer for clinical protocol and clinical report writing and the team of statisticians at  GSK  for the statistical analysis, in particular  Carline Vanden Abeele.
Results Sequencing depth and alpha diversity indices. After initial quality filtering, removal of chimeras and "contaminants" sequences, 3,692 to 26,518 effective sequences were collected from each sample, resulting in a final dataset of 161,417 high quality sequences from the eleven samples. The average read length was 170 bp. For the downstream alpha and beta diversity analyses, the sequence number was normalized at 3,692 by randomly subsampling to standardized sampling effort. The subsampling of the sequences retained a sufficient resolution to compare the bacterial communities, as suggested by an average Good's coverage of 97. 44% ± 1. 28% (mean ± SD, Table  1 ) and by the rarefaction curves (Figure  S1 ). After sample-size standardization, 40,612 sequences remained, which clustered into a total of 1,184 OTUs at the 97%-similarity level.
A phylogenetic tree was constructed based on representative sequences of these five OTUs assigned to Aeromonas by neighbor-joining (MEGA program version 6. 0; Figure  S3 ). Two of these OTUs (00001 and 00013) were clustered with A. salmonicida, and remained distinct from the other reference strains (A. hydrophila, A. sobria, and A. veronii), and from the other OTUs that corresponded to same genus (00002, 00004 and 000011). Interestingly, two reference pathogenic strains of A. salmonicida were isolated and identified in samples from C. guichenoti affected by furunculosis (strains YTU1 and YTL1, isolated from ulcer and liver, respectively). In an additional experiment, pathogenicity of YTU1 and YTL1 strains were studied using zebrafish as infection model, and the LD 50 values were determined to be 1.
Sample collection and DNA extraction. A severe disease outbreak of cage-cultured C. guichenoti occurred in the upper reaches of the Yangtze River in Luzhou, Sichuan province, Southwest China in late March 2012. The cumulative mortality was approximately 42% during the epidemic at a water temperature ranging from 15 °C to 20 °C. The fish were 18 cm to 20 cm in length. The major symptoms of the diseased fish were swollen dorsal muscle, shallow ulcerations, swollen mouth, slight exophthalmia, and slight hemorrhage on the body surface. The causative agent was identified as Aeromonas salmonicida subspecies salmonicida by conventional bacteriological methods and molecular sequence data (data not shown; GenBank identifiers: KC254647, KC254648). The fish studied in the present study were reared in net cages (3 m × 3 m × 3 m) in the upper reaches of the Yangtze River.
The PCR reactions were duplicated for each sample, and the two products were pooled before migration on 1% agarose gel electrophoresis. The PCR products were re-extracted from the gel, and purified by using the QIAEX II Gel Extraction Kit (QIAGEN). All the samples were sequenced in one paired-end MiSeq run (Illumina Inc. , San Diego, CA). Statistical and bioinformatics analysis. The sequence data were processed using QIIME Pipeline-Version 1. 7. 0 (http://qiime. org/)  44. The sequences with an average phred score lower than 20, ambiguous bases, homopolymer runs exceeding 8 bp, primer mismatches, or sequence lengths shorter than 150 bp were removed. Only the sequences with an overlap longer than 10 bp and without any mismatch were assembled according to their overlap sequence. The reads that could not be assembled were discarded.
All the sequence reads were trimmed and assigned to each sample, based on their barcodes. The barcode and sequencing primers were trimmed from the assembled sequence, and aligned with the Bacterial SILVA database (SILVA SSU 123), resulting in 14,956 bacterial sequences  45. The chimeric sequences were excluded by using the Uchime algorithm  46, 47. Taxonomy was assigned using the Ribosomal Database Project classifier, with a confidence threshold of 50%  48, 49. The "contaminants" sequences classified as "Mitochondria, " "Eukaryota, " or "unknown, " as well as those from archaeal and eukaryotic 16S/18S rRNA genes were removed to focus as closely as possible on bacterial diversity. The remaining sequences were clustered into operational taxonomic units (OTUs) at 97% identity threshold. All the samples were randomly resampled to 3,692 reads.
The rarefaction curves were generated from the remaining numbers of OTUs, before analyzing both alpha-diversity (phylogenetic distance on whole tree; number of OTUs; Chao1 estimator of richness; Shannon and Simpson diversity indices) and beta-diversity with Principal Coordinates Analysis (PCoA) and UniFrac. The microbial communities were visualized using Circos  50. A phylogenetic tree was generated with MEGA program (version 6. 0). The heatmap was constructed using the heatmap 2 function of the R gplots package  51. The bacterial communities were compared by p test on the Fast UniFrac metric matrix and PCoA, based on phylogenetic information  52. LEfSe (http://huttenhower. sph. harvard. edu/galaxy/) was also utilized, the significance threshold of the alpha parameter for the Kruskal-Wallis test among classes was set to 0.
Acknowledgements Julio Pascual is supported by grants  PI13/00598  ( Spanish Ministry of Health ISCIII FIS-FEDER) ,  Marato   TV3 137/C/2012  and  RedinRen RD12/ 0021/0024. Medical writing support was funded by a grant from  Sanofi. Conflicts of interest:  Dr. Julio Pascual  has received honoraria from  Sanofi. Andreas Zuckermann  is a member of a speaker's bureau and advisory board for Sanofi, is a member of a speaker's bureau for  Novartis , and has received a scientific grant from  Roche. Arjang Djamali  has received travel support from  Sanofi  and grants from  BMS  and  Takeda. Alexandre Hertig  has received speaker's honoraria from  Sanofi ,  Novartis  and  Astellas. Maarten Naesens  is a member of advisory boards for  Roche ,  Novartis  and  Sanofi , has received speaker's honoraria from  Novartis ,  Astellas  and  Shire , and has received travel support from  Sanofi ,  Novartis  and  Astellas.
Study designs Integrated data from two Phase III multicenter, randomized, double-blind, placebo-controlled, parallel-group trials (UNCOVER-2 and UNCOVER-3) were used in this analysis. For the first 12 weeks of the trials, UNCOVER-2 and UNCOVER-3 compared the efficacy and safety of ixekizumab vs. etanercept, and vs. placebo. We evaluated the efficacy and safety of ixekizumab in patients with or without prior exposure to biologic drugs relative to etanercept using these integrated data in which patients received placebo (N = 361), or ixekizumab every 2 weeks (IXE Q2W; N = 736) or 4 every weeks (IXE Q4W; N = 733) following a 160-mg initial ixekizumab dose. Etanercept (50 mg twice weekly; N = 740) was administered as active control. Efficacy and safety data in the overall population have already been reported.
Baseline demographics and disposition In the overall population, patient baseline characteristics were well balanced among the different treatment groups across the individual studies included in the analysis (Supplementary Table  S1 ). Table  1  provides details on previous psoriasis therapy for UNCOVER-2 and UNCOVER-3. Table  2  displays patient demographics and other baseline characteristics examined by previous biologic status (biologicnaive vs. biologic-experienced) for the integrated dataset. Key characteristics, including weight and disease severity at baseline, were similar between patients with and without prior biologic exposure. As expected, some baseline variables and clinical characteristics were significantly different between the two groups, including age (P < 0. 001), geographical region (P < 0.
Lastly, the analysis only included data from the first 12 weeks of the studies. Further investigations could possibly target later time points to see if different profiles of the biologic-naive and biologic-experienced populations are observed. Both doses of ixekizumab were significantly superior to etanercept for biologic-naive and biologic-experienced patients. Treatment differences in IXE Q2W vs. etanercept increased for patients with previous exposure to biologics compared to patients who were naive, with comparable safety findings. The IXE Q2W dosing regimen consistently provided greater benefit with more predictable treatment outcomes across subgroups relative to the IXE Q4W dosing regimen.
Data collection at inclusion The following demographic, clinical and biochemical data were collected at patient admission and/or inclusion in the protocol: 1. Demographic characteristics: age and sex 2. Clinical scores: Simplified Acute Physiology Score II (SAPS II) (range 0-163  [14] , calculated at inclusion), Sepsis-related Organ Failure Assessment (SOFA) score (range 0-24  [15] , calculated at inclusion and at D3) and Charlson comorbidity index (range 0-32  [16]  for which age was not taken into account). S1 ). The second derivative maximum method was used with the LightCycler software to automatically determine the crossing point for individual samples, as previously described. Standard curves were generated by using quadruplicate cDNA standard. Relative standard curves describing the PCR efficiency of selected genes were created and used to perform efficiencycorrected quantification with the LightCycler Relative Quantification software (Roche Diagnostics).
Acknowledgements MIP-REA study group  Dr. Guillaume Marcotte  and  Dr. Christian Guillaume  ( Hospices Civils de Lyon, Department of Anaesthesiology and Critical Care Medicine, Groupement Hospitalier Edouard Herriot, University Claude Bernard Lyon 1, Lyon, France );  Dr. Romain Hernu ,  Sylvie De La Salle ,  Dr. Marie Simon , and  Dr. Thomas Baudry  ( Hospices Civils de Lyon, Medical Intensive Care Unit, Groupement Hospitalier Edouard Herriot, Lyon, France );  Elisabeth Cerrato ,  Emmanuelle Gallet-Gorius ,  Audrey Larue , and  Christine Alberti-Segui  ( Hospices Civils de Lyon -bioMérieux Joint Research Unit, Groupement Hospitalier Edouard Herriot, Lyon, France );  Nathalie Panel  and  Marion Provent  ( Hospices Civils de Lyon, Intensive Care Unit, Centre Hospitalier Lyon Sud, Pierre Bénite, France );  Prof.
Library templates were amplified clonally using an ion one touch 2 ™ , following the manufacturer's protocol. Recovered template-positive ion sphere particles were subjected to enrichment according to the manufacturer's instructions. Samples were subjected to the ion PGM 200 sequencing v2 protocol using ion 318 v2 chips (Life Technologies). Thirty-two barcoded samples were loaded per chip to ensure an average depth of 1500. For data analysis, alignment of the sequences to the human genome build 19 reference genome and base calling were performed using Torrent Suite software. Identification of variants was performed with an ion torrent variant caller and coverage analysis was generated using coverage analysis plugins (Life Technologies). Allelic frequencies and their association with anti-S.
cerevisiae antibody and mannose-binding lectin levels were determined with Haploview software  41. Statistical analysis. Statistical analysis was performed using Prism 4. 0 from GraphPad and XLSTAT. Data were analysed using either the Kruskal-Wallis or Mann-Whitney U test to compare pairs of groups and the Chi 2 -test for comparison of two independent groups with categorical data. Differences were considered significant when the P value was as follows: P < 0. 05; P < 0. 01; P < 0. 001. Fitting the Hardy-Weinberg equilibrium, allelic frequencies and their association with Crohn's disease or anti-S. cerevisiae antibody levels were determined with Haploview software.
Acknowledgements The authors thank  Ms. Shéhérazade Sebda  and  Ms. Nadine François  for their excellent technical assistance. The authors would like to thank the digestScience  Foundation  for their support. This work was funded by the  FP7 Health 260338 "ALLFUN" project  " Fungi in the setting of inflammation , allergy and auto-immune diseases: translating basic science into clinical practices".
These data demonstrate the essential the role for IL-12Rβ1 to generate IFN-γ + ILC2 in humans. ILC2 have been identified in several mucosal sites, including human lung, skin, and nasal cavity, where type 2 immune response are involved in barrier function and tissue total number of clones obtained from each donor. (F) Analysis of intracellular IL-13 and IFN-γ production in ILC2 clones after PMA/iono stimulation. Clones were expanded using irradiated PBMCs and cytokines (IL-2, -7, -25, and 33) and analyzed on day 14 and 28. Data in A-C and F are representative of five independent experiments with one donor each. (D and E) Each dot represents one ILC2 clone from five independent donors (mean ± SD). regeneration  (Mjösberg et al. , 2011; Monticelli et al. , 2011; Salimi et al. , 2013). Our results on cytokine stimulation of peripheral blood ILC2 suggest that inflammatory tissues might be a site where plastic ILC2 could be generated under the influence of soluble factors such as IL-12.
(F and G) FACS-sorted bulk ILC2 were cultured in feeder-free or irradiated PBMCs in IL-2, -7, -25, -33 with or without IL-12 for 4 d. (G) Culture supernatants were collected to analyze soluble IFN-γ. (F) Expanded ILC2 were analyzed for IFN-γ production after stimulation in medium or with PMA/iono. Data in A-C and E-G are representative results from three independent experiments with one donor each. Data in D and G are obtained from three independent donors. ns, P > 0. 05; *, P < 0. 05; **, P < 0. 01; ****, P < 0. 0001 using unpaired Student's t test (mean ± SD). We focused our attention on CRTh2 + ILC2 to understand possible functional heterogeneity of this subset. ILC2 have multiple functional attributes (production of IL-4, -5, -13, amphiregulin, and GM-CSF), and we wished to know if these were contributed by distinct ILC2 subsets.
Samples were acquired on LSRFortessa (BD) and analyzed by FlowJo software (Tree Star). For cell sorting, PBMCs were depleted of T cells, B cells, pDCs, and monocytes by labeling with biotin-conjugated anti-CD3, anti-CD4, anti-CD19, anti-CD14, and anti-CD123, followed by antibiotin microbeads (Miltenyi Biotec) according to manufacturer's instructions. Bulk populations were sorted to a purity ≥99% or as single-cell index sorting (both using FAC SAria III; BD). Bulk and single ILC2 cell culture. Sorted bulk ILC2 and NK cells were plated in 96-well round-bottom plates with irradiated allogeneic PBMCs (45 Gy; combined from 6 healthy donors) and purified phytohemagglutinin (0. 2 µg/ml; Oxoid) in Yssel's medium  (Yssel and Spits, 2002)  supplemented with 2% human AB serum (Establissement Français du Sang).
Gene expression profiling was assessed using a Biomark (Fluidigm) with EvaGreen Supermix (Bio-Rad Laboratories) according to the manufacturer's protocols. Primers (Fluidigm) used are listed in Table  S1. Mean and SD of Ct values from housekeeping genes (B2M, ACTB, and GAP DH) for all cells were calculated. Cells with Ct values of housekeeping genes exceeding the SD by more than twofold were eliminated from the analysis. 182 freshly isolated single ILC2 and 176 single ILC2 after 3-h culture in TL1A, IL-25, and IL-33 (R&D Systems; 100 ng/ml each) were included in the dataset shown in Fig. 2. Frequency of expression of each gene was calculated by number of cells with detectable signal (Ct value ≤ 38) from total cells in each group. Heat maps of two-dimensional hierarchical clustering analysis were performed by Qlucore Omics Explorer software.
Dot plots were obtained by analyzing Ct values in Prism software (GraphPad Software). Quantitative RT-PCR analysis of IL-12R subunits from cultured cells was performed using Power SYBR Green Cells-to-Ct kit (Thermo Fisher Scientific) according to manufacturer's instructions. Primer 5′-GCC ATA TCC GGA TGC AGAC-3′ and 5′-AGG AGC ACT CGT AAC GAT CA-3′ for IL12RB1 and 5′-GGA GTG AAT CAT TGA GAG CAC AA-3′ and 5′-TGC CGT TTC ATG TAC CAG AC-3′ for IL12RB2 were used. Expression levels of genes of interest were normalized to GAP DH. ELI SA. Human IFN-γ in culture supernatants was quantitated by ELI SA (Thermo Fisher Scientific). Statistical analysis. Experimental results are reported as mean ± SD unless otherwise specified. Statistical differences between groups were determined using unpaired Student's t test.
Statistical analysis of cultured ILC2 was compared with fresh ILC2. (E) FACS-sorted bulk ILC2 were cultured without feeder cells in IL-2, -7, -25, -33, and 12 at different time-point as indicated. Intracellular IFN-γ and IL-13 expression was analyzed after PMA/iono stimulation. (F and G) FACS-sorted bulk ILC2 were cultured in feeder-free or irradiated PBMCs in IL-2, -7, -25, -33 with or without IL-12 for 4 d. (G) Culture supernatants were collected to analyze soluble IFN-γ. (F) Expanded ILC2 were analyzed for IFN-γ production after stimulation in medium or with PMA/iono. Data in A-C and E-G are representative results from three independent experiments with one donor each. Data in D and G are obtained from three independent donors. ns, P > 0. 05; *, P < 0. 05; **, P < 0. 01; ****, P < 0. 0001 using unpaired Student's t test (mean ± SD).
ACK NOW LED GME NTS We thank the  Centre d'Immunologie Humaine (Institut Pasteur)  for technical assistance. This work is supported by the  Institut Pasteur ,  Institut National de la Santé et de la Recherche Médicale , and  FP7  under grant agreements  305578  (PathCO) and 317057 (HOM IN). A. I. Lim is a scholar in Pasteur- Paris University (PPU) International PhD program  and supported by a  PhD International Training Network grant  from  European Union 's  Seventh Framework Program  under grant agreement n°317057 (HOM IN). J. P. Di Santo  is a founder and stakeholder in AXE  NIS (Paris, France). The other authors declare no additional competing financial interests. Submitted: 6 November 2015 Accepted: 9 February 2016.
Acknowledgements The work performed in MPP, PLB and DR laboratories was supported by the  European NoE EMBIC  ( LSHM-CT-2004-512040 ), MPP was supported by  Intramural Scientific Research  (ex-60 %) of the  University of Florence. Work performed in PLB lab was also supported by  INSERM ,  CNRS  and  Toulouse III University. DR was supported by  University of Rijeka  ( 13. 06. 1. 1. 06 ).