dataesr/scientific-paragraphs-categorization huggingface dataset:
Methods and findings A search using Ovid MEDLINE and Embase was initially conducted to identify studies on severe Plasmodium falciparum malaria that included information on treatment delay, such as fever duration (inception to 22nd September 2017). Studies identified included 5 casecontrol and 8 other observational clinical studies of SM and UM cases. Risk of bias was assessed using the Newcastle-Ottawa scale, and all studies were ranked as 'Good', scoring �7/10. Individual-patient data (IPD) were pooled from 13 studies of 3,989 (94. 1% aged <15 years) SM patients and 5,780 (79. 6% aged <15 years) UM cases in Benin, Malaysia, Mozambique, Tanzania, The Gambia, Uganda, Yemen, and Zambia. Definitions of SM were standardised across studies to compare treatment delay in patients with UM and different SM phenotypes using age-adjusted mixed-effects regression.
Study inclusion and procedures A comprehensive search of 2 databases, Ovid MEDLINE and Embase, was initially conducted to identify studies of SM (inceptions to 22nd September 2017). Details of the search strategy, as well as the inclusion and exclusion criteria, are found in S1 Text (Table  A  and Table  B , respectively). In brief, we included case-control studies of uncomplicated and severe P. falciparum malaria with available data on delay to treatment, quantified as either duration of illness or fever prior to hospital admission. Large studies of severe disease that did not have a casecontrol design, such as cohort studies, were still considered if they were sufficiently large (n > 100) to allow comparisons between different severe disease types. The research questions were formed as part of an MRC UKRI project, and the protocol is registered with protocols.
All analyses were done separately for children aged <15 years and for ages 15 and over. A separate subset analysis included young children aged between 6 months to 5 years (excluding <6-month-olds to minimise any biases that may arise from differences in case definitions between infants and children). In all analyses, a likelihood ratio test was performed to compare the difference between a model with and without the term for illness duration. We explored confounding by education of the caregiver (less than primary versus at least primary) and effect modification by transmission intensity using estimates of parasite prevalence of P. falciparum in 2-to 10-year-olds (PR 2-10 ) obtained from the Malaria Atlas Project database at the upper administrative area level for the year of admission for each individual  [39].
all associations). The distribution of severe disease symptoms varied between study sites (S2 Fig) and by age (Fig 1). In areas of moderate-to-high Table  1. Characteristics of studies used in IPD meta-analysis. Table includes study site, study period, age ranges included, and frequencies and percentages of uncomplicated and SM groups amongst the study sample. Percentages with a given phenotype amongst severe cases are shown in brackets and omit missing values for that phenotype. The denominator only includes those who were assessed for that phenotype. 'NA' entries indicate that information on the phenotype in that study was not collected (for example, data on RDS were not collected in the Zambian study). Percentages may add up to more than 100% because the same study subject may present with more than 1 phenotype.
4%, 4/168). Data on time since first fever or any symptoms prior to arrival at the study health facility, as reported by the patient or caregiver, were available for a total of Data on duration of severe symptoms were also obtained from 5 studies, including information on duration of coma, unconsciousness, convulsions, respiratory distress, fast breathing, or difficulty in breathing (N = 1,323). Care was sought within the first day of severe symptom onset for most cases because the median delay was <1 day after onset of any severe symptom (S7 Table ). However, onset of fever or other symptoms of uncomplicated illness for those who later developed SM occurred, on average, between 1 to 3 days before they developed signs of severe disease, depending on the symptoms (S7 Table ).
8% of SMA cases in children under 15, 46. 8% of SMA cases in children under 5, and 48. 5% in adults aged 15 or over. In the UK study of imported adult cases, similar results were observed to those in adults from the pooled analysis (S7 Fig) , with the odds of any severe disease being 3-4 times higher in those with a delay of 5 to 7 days compared with those being admitted in the first 24 hours after symptom onset (χ 2 (7) = 17. 59,. Amongst 5 studies with information on blood transfusions during hospital admission, 27. 7% (1,520/5,496) of children aged under 15 with available data had received a blood transfusion. ORs (and 95% CIs) for receiving a blood transfusion was estimated for each additional day of illness duration amongst all uncomplicated and severe cases. All ORs shown were obtained from a mixed-effects logistic regression adjusted for age as a linear predictor and allowed for random study effects.
Statistically significant ORs are denoted in red (dashed purple line: OR = 1). OR, odds ratio; SM, severe malaria; SMA, severe malarial anaemia; UM, uncomplicated malaria. https://doi. org/10. 1371/journal. pmed. 1003359. g003 p = 0. 014). In this study, case numbers of individual phenotypes were too small to separate out. In the overall data set, no relationship was observed between duration of illness and presentation with any other SM phenotypes for either children or adults (Fig 5, S7 and S8 Figs). However, caregivers may have reported the time of onset of severe symptoms if asked about duration of illness rather than initial onset of UM symptoms. We therefore also repeated the analysis restricted to a subset of 9 studies that specifically recorded onset of fever, the most common UM symptom (N = 1,866, including 1,689 children aged under 15 years).
Secondary antibodies coupled with Alexa fluorochromes from Molecular Probes (Thermo Fisher Scientific) and Alexa-Fluor 488 Alpaca anti-mouse IgG1 (Chromotek) were diluted at 1/100. Images were acquired on a Leica SP8 confocal microscope or, where specified, on an LSM 510 Zeiss. Image treatment, analysis and quantification were performed with ImageJ or Fiji software. Jurkat T-cell and Raji B-cell conjugates for microscopy. Raji B cells were resuspended at 2 × 10 6 cells/ml in PBS and stained with CellTrace Violet Dye (5 μM Thermo Fisher Scientific) for 20 min at 37 °C. Labelling was stopped with the addition of full IMDM medium, cells were resuspended at 2 × 10 6 cells/ml and incubated with wt or IRAP ko Jurkat T cells also at 2 × 10 6 cells/ml for 30 min at 37 °C. Cells were resuspended at 6 × 10 6 cells/ml in full IMDM medium with SEE (100 ng/ml, Toxin Technology) and incubated at RT for 30 min on poly-L-Lysine slides.
Images were acquired on Leica TCS SP8 SMD (Single Molecule Detection), and GFP average lifetime was measured on a Leica TCS SP8 SMD system equipped with the FRET analysis tool and the SymPhoTime Software. Image analysis. Marker colocalizations were evaluated using only non-saturated images and the ImageJ software. A manual threshold was established for each channel before image analysis. Individual cells were delimitated with the freehand selection tool, and considered as region of interest (ROI) in ImageJ. For colocalization studies, all images were first translated to a binary image (black pixel intensity = 0; white pixel intensity = 1). The binary images for independent channels were multiplied to create a mask that encompasses the pixels present in both channels. The areas of pixels for each colour and of mask pixels were calculated using the plugin "measure stack" of ImageJ.
The percentage of pixels for one colour that colocalized with pixels for another colour was calculated as the ratio: sum of area of pixels in the mask divided by sum of area of pixels from the first colour. Statistical analysis was performed with GraphPad Prism software using unpaired t tests. Tri-dimensional reconstitution of images was realised with Imaris Software. Proximity ligation assay (Duolink). Duolink™ (OLINK Bioscience) was performed according to the manufacturer's instructions. Briefly, the cells were incubated for 30 min on IBItreat μ-channels (IBIDI) coated with poly-L-Lysine, fixed for 10 min in 4% paraformaldehyde prewarmed at 37 °C, permeabilized in PBS, 0. 2% saponin for 10 min and blocked with 0. 2% BSA in PBS, 0. 1% saponin. Primary antibodies used were: mouse anti-CD3ε (OKT3, Biolegend), mouse anti-CD3ζ (6B.
rAAV1-pseudotyped vectors were then prepared by co-transfection, in 293 cells, of the pSMD2-cOVA plasmid with the pXX6 and pAAV9-pITRCO2 plasmids, encoding, respectively, for the adenovirus helper functions and the rep and cap genes. Vector particles were purified on iodixanol gradients from cell lysates obtained 48 h after transfection, and titers were measured by quantitative real-time PCR. For intramuscular immunisation, mice were anaesthetised and 10 10 vg of rAAV2/1-cOVA, diluted in a final volume of 25 μL of 1× phosphatebuffered saline (1X PBS), was injected into the tibialis anterior using a 30-G RN Hamilton syringe. Ovalbumin-specific CD8 + T cells were detected in the blood on day 14 using K b -SIINFEKL pentamers. Statistical analysis. Statistical analysis was performed with GraphPad Prism software using unpaired two-tailed Student's t test.
Acknowledgements We thank the  Agence Nationale pour la Recherche  ( ANR grants Cytoendostor, ECLIPSE  and  Help2Kill ,  IDEX  EMERGENCE  ANR-18-IDEX-0001 ) and the  Fondation pour la Recherche Medicale (FRM)  for financial support. We also thank  A. Weiss ,  A. Alcover ,  J. Rossy ,  L. Chamberlain  and  M. Schindler  for recombinant plasmids,  S. Chai  for providing the IRAP loxlox mice,  F. Faure  for providing Daju-A2 melanoma cells and  Meriem Garfa-Traore  for help with FLIM-FRET analysis. We finally thank  Gregory Gautier  and  Olivier Pellé  for help with cell sorting experiments.
Genes with low expression (TPM , 4 for , 4 samples), non-protein-coding genes, genes on sex chromosomes, and gene model genes were removed from TPM tables. Differential analysis was performed with Sleuth. 25 Gene set enrichment analysis (GSEA) was used to evaluate enriched molecular signatures (either gene ontology (GO) biological processes or BL signatures from Hummel et al  26  and Sha et al  27  ). RNAseq data were deposited in the Gene Expression Omnibus database with accession number GSE132721.
Transcriptome analysis of nonmalignant and malignant B cells To document molecular signatures of tumors in the 3 IgH-c-myc transgenic models, RNA sequencing of 28 B-cell samples (B220 1 IgM 1 IgD 1 ) was performed, and normalized expression data were obtained for all protein-coding genes. In Figure  4A -B, PCA and hierarchical clustering clearly defined groups of samples with similar transcriptome signatures. Nonmalignant (resting and LPS-stimulated) B-cell samples appear as distinct clusters from tumor samples. These samples segregate as 2 distinct groups (of, respectively, 6 and 13 samples) both in PCA and hierarchical clustering representations. We thus define group I as the 6-sample cluster that shares more similarities with LPS-stimulated B-cell samples and group II as the other 13-sample cluster.
Functional profiling of tumor samples was achieved by analyzing differential gene expression between the 2 above-defined groups (group II vs group I; Figure  5A ). Among 9995 genes that passed the minimum-expression filter, 2236 genes exhibit significantly different expression (adjusted P ,. 05), most of them with slight to moderate differences. Limiting to genes changing by more than 2-fold, we found 225 upregulated genes and 588 downregulated genes in group II compared with in group I samples (. 4-fold: 68 up genes, 231 down genes). The set of differentially expressed genes indeed segregates samples according to expected groups, as emphasized in Figure  5B. GSEA software identified upregulated biological processes (as defined in gene ontology) in each group (Figure  5C ). Distribution of genotypes according the group I and group II classifications showed a significant commitment of c-myc-KIE m samples to group II (Figure  5C ).
Acknowledgments The authors are " Equipe Labellis ée LIGUE 2018. "This work is also supported by  Agence Nationale de la Recherche (ANR)  " Epi-Switch 2016. "N. G. is supported by a grant from " Soci ét é Française d'H ématologie " and  ANR  " Epi-Switch 2016. "H. I. is supported by  University of Limoges (France)  and  ANR  " Epi-Switch 2016. "M. F. is supported by  "R égion Nouvelle Aquitaine" (France). F. B. is supported by  Fondation Partenariale de l'Universit é de Limoges and Association Limousine pour l'Utilisation du Rein Artificiel à Domicile.
Pimasertib is an orally bioavailable, selective small-molecule MEK1/2 inhibitor. At the recommended phase II dose (RP2D) of 60 mg twice-daily (bid) it has an acceptable safety profile in patients with solid tumors and potential efficacy in patients with BRAFand/or NRAS-mutated melanoma tumors  [15]. This phase II study (NCT01693068) aimed to confirm the efficacy and safety of pimasertib at the RP2D in patients with NRAS-mutated cutaneous melanoma, and to compare this with DTIC, the SOC at the time of study initiation.
Study Design and Treatment This phase II, multicenter, randomized, open-label trial was conducted in compliance with the principles of the Declaration of Helsinki, the International Council for Harmonization Note for Guidance on Good Clinical Practice (ICH topic E6, 1996) and all applicable regulatory requirements. this research has been approved by the Quorum Review IRB on 07/03/12 (ethic code: NCT01693068). Patients were randomized 2:1 (permuted block randomization using an interactive voice response system performed centrally by PPD under the supervision of the Sponsor) to receive pimasertib (60 mg; oral bid) or DTIC (1000 mg/m 2 ; intravenously) on Day 1 of each 21-day cycle (Figure  S1 ). Randomization was stratified by Eastern Cooperative Oncology Group performance status (ECOG PS; 0 versus 1).
Acknowledgments: The authors would like to thank the patients and their families, investigators, co investigators and the study teams at each of the participating centers, and at  Merck Healthcare KGaA, Darmstadt, Germany. Trial monitoring, primary quality assurance, data management, statistical analyses and overall operational trial conduct were performed by  Pharmaceutical Product Development (PPD), Cambridge, UK. Medical writing assistance was provided by  Helen Swainston ,  Bioscript Science ,  Macclesfield, UK  and funded by  Merck Healthcare KGaA, Darmstadt, Germany.
The solution was allowed to polymerize for 60 min at 37 °C. Five hundred microliters of culture media (2% charcoal-stripped FBS) containing either IL-1β and/or TNFα at the indicated concentrations or vehicle only were added to the three-dimensional solidified collagen gels, and plates were returned to the incubator. Collagen gel contraction was monitored over a period of 24 h, and the surface area of the contracted gels was measured at 24 h using ImageJ software (version 1. 41) developed at the National Institute of Health. All experiments were performed in duplicate, because only limited number of Ectopic-ES were available for analysis. Immunofluorescence staining. Endometriotic or endometrial stromal cells were seeded onto glass coverslips (22 mm × 22 mm) (3 × 10 4 cells per coverslip), and were incubated with 2 mL culture media (2% charcoal-stripped FBS) containing IL-1β and/or TNFα at the indicated concentrations or vehicle only for 48 h.
Statistical analysis. The STATA program version 12 (StataCorp, College Station, TX, USA) was used for statistical analysis. Comparisons between groups were made using one-way analysis of variance (ANOVA) following Scheffé's method, the Mann-Whitney U test or the Wilcoxon matched pairs signed-ranks test. According to the results of the present cell proliferation assays, effects of the highest dose of IL-1β (100 pg/mL) on cell migration, collagen gel contraction, mRNA and/or protein expression of Col I, MMP-1, and αSMA in menstrual endometrial stromal cells of patients with endometriosis (M-ES-endo) and those of healthy fertile women (M-ES-healthy) were excluded for further analyses, due to markedly reduced cell viability. Statistical significance was defined as p < 0. 05.
Acknowledgements We are most grateful to all of the patients who participated in the present study. We acknowledge use of the confocal imaging platform (ICCF, https://www. gred-clermont. fr/directory/platform/)at the  GReD laboratory, Faculty of Medicine, University of Auvergne. We also thank the staff at the  Department of Gynecology  and operating room,  CHU Estaing, CHU Clermont-Ferrand. This study was supported in part by  KARL STORZ SE & Co. KG (Tuttlingen, Germany ).
Data on PROs were collected through face-to-face questionnaires administered to participants after the clinical visit at baseline and then quarterly. The following instruments were used: (1) the Justice index  [16]  complemented with 12 items on neuro-sensorial symptoms known to be associated with EFV (see the Online Resource, p. 4)  [17] ; (2) the short-form version of the Depression, Anxiety and Stress Scale (DASS-21)  [18] ; and (3) the 12-item Medical Outcomes Study Short-Form General Health Survey (MOS SF-12, 2nd version)  [19]. The 21 items of the DASS-21each response having a 4-point ordinal severity/frequency scale-enabled the construction of depression, anxiety, and stress scores (ranging from 0 to 42, with higher values corresponding to poorer outcomes). These scores were used to classify patients according to their severity of depression, anxiety, and stress, based on validated cut-offs  [18].
We computed costs incurred from enrolment to W96 or, if follow-up time was shorter, to the last visit  [23]. The following cost items were included: antiretroviral drugs (ARV), outpatient consultations (including non-routine visits), laboratory tests, concomitant drugs, and hospitalisations. For each arm, total costs were computed as the sum of all individual healthcare resources used by patients during followup (as reported in standardised case report forms) multiplied by their respective unit cost. Data on unit costs were obtained using data collected prospectively in the study sites during the trial period complemented by the most recent relevant national sources for concomitant drugs and laboratory tests, and international sources for ARV (Online Resource, p. 6). In the base-case analysis, considering the most recent ARV prices (3rd quarter 2020), the monthly prices of DTG-and EFV400based FDC regimens were $5.
11 and 1. 25, respectively  [15]. For each arm and each health state, the mean cost and the mean number of QALYs per 3-month cycle were estimated using the trial data from 24 to 96 weeks. The total cost and number of QALYs per arm over 5 and 10 years were computed by adding the cumulated costs and number of QALYs obtained over the total 13 and 35 simulated cycles to the cost and number of QALYs accrued over the first 96 weeks of follow-up. We estimated the 95% CI for incremental costs, incremental QALYs, NHB, as well as CEAC using a nonparametric bootstrapping technique. We tested the internal validity of our model by simulating a cohort receiving the EFV400-based (DTG-based) regimen  (1)  with the same transition probabilities as its counterpart (life-years saved were equal to 0),  (2)  with the same transition probabilities and QALYs per cycle and health state as its counterpart (incremental QALYs were equal to 0), and (3) with the same transition probabilities and costs per cycle and health state as its counterpart (incremental costs were equal to 0).
Acknowledgements We thank all the patients and staff from the HIV centres who participated in the NAMSAL trial. Our thanks also to  Sylvie Legac  and  Jules Eric Adjedi Emadoua  at the  ANRS Cameroon site  for their support with the data collection, to  Nelly Feukeng ,  Serge Bibeki ,  Martine Mbog , and  Bara Nibilla , who collected the socioeconomic data, to  Jude Sweeney  for the English revision and editing of the manuscript, and to the editor and two anonymous referees for their valuable comments. Members of the  NAMSAL Study Group: TransVIHMI, University of Montpellier-IRD-INSERM , Montpellier, France:  A. Ayouba ,  A. Agholeng ,  C. Butel ,  A. Cournil ,  E. Delaporte ,  S. Eymard-Duvernay ,  B. Granouillac ,  S. Izard ,  A. Lacroix ,  S. Leroy ,.
Structural model The structural model of the CD22-hCD22. 7-scFv complex was obtained using directed docking as follows. The structure for CD22 was taken for the PDB databank  29  (identification code 5vkj  30  ) and the structure of the scFv anti-CD22 was derived by homology modeling using M4T  31  and templates 4h0h, 32 1dqd 33 and 4okv. 34 The initial docking conformations were inferred using Patch-Dock  35  by selecting the complementarity-determining regions of anti-CD22-scFv and mapped epitope of CD22 as docking interfaces. Resulting docking conformations Open access were further refined and minimized using Rosetta  36  and the top 200 poses were visually inspected. A more detailed description of the structural analysis is shown in online supplementary information.
Acknowledgements We thank  CERCA/Generalitat de Catalunya and Fundació Josep Carreras-Obra Social la Caixa  for their institutional support. Contributors TVH conceived the study, designed and performed experiments, analyzed data, and wrote the manuscript. SRZ designed and performed experiments. HRH, FGA, PP, MLB, OM, and DSM performed experiments. NFF generated the structural model. PE generated the CD22 hybridoma and performed experiments. JLF and PB provided primary samples. CB supported the study technically and financially. PM conceived the study, designed experiments, wrote the manuscript, and financially supported the study. Funding This work was supported by the  European Research Council  ( CoG-2014-646903 ,  PoC-2018-811220 ), the  Spanish Ministry of Economy and Competitiveness  ( MINECO-SAF2016-80481-R ), the  Fundación Uno entre Cienmil , the  Obra Social La Caixa  ( LCF/PR/HR19/52160011 ), the  Spanish Cancer Association and Leo Messi Foundation  to PM.
Il10 -/-mouse model of colitis At 9 weeks of age, C57BL/6 Il10 -/-female and male mice were exposed to BPA, BPS, BPF, or vehicle (0. 1% ethanol in corn oil, controls) for 6 weeks. Data from male and female were compiled because previous studies have shown no incidence of sex in the susceptibility to develop colitis in this mice model  (Riba et al. , 2017). Previous studies in C57BL/6 wild-type mice showed no sign of spontaneous colitis after BPA direct exposure  (DeLuca et al. , 2018). Mice were exposed to bisphenols for 6 weeks to reproduce comparable exposure BPs treatment as oral tolerance. Mice were euthanized by cervical dislocation; blood was collected by intra-cardiac puncture and spleens and colons were sampled. Colon length was measured.
Cytokine measurements Cytokines were measured in supernatants of primary cell cultures of spleen, in feces and in colonic tissue segments. Frozen colonic fragments or feces were suspended in RIPA buffer (0. 5% deoxycholate, 0. 1% SDS, and 1% Igepal in TBS) containing complete anti-protease cocktail (Roche, Indianapolis, IN, USA), and protein concentrations were determined using BCA protein Assay kit, Uptima (Interchim, Montluçon, France). IFN-γ, IL-17 and TGF-β in primary cell culture supernatants, and lipocalin and TNF-α in fecal and colonic tissues, were assayed using commercial ELISA kits (Duoset R&D Systems, Lille, France) according to the manufacturer's instructions. Data are expressed as picograms of cytokine per milligram of protein in colons or feces, and in picograms per milliliter of supernatant of cell cultures.