dataesr/scientific-paragraphs-categorization huggingface dataset:
45 to 14. 65), chronic renal disease (aEHR=4. 86; 95% CI 2. 24 to 10. 53), cirrhosis (aEHR=3. 58; 95% CI 1. 25 to 10. 28), hepatitis C co-infection (aEHR=3. 63; 95% CI 1. 44 to 9. 12), body mass index<18. 5 kg/m² (aEHR=4. 10; 95% CI 1. 61 to 10. 48) and having a CD4 cell count ≤200/mm 3 (aEHR=5. 79; 95% CI 2. 28 to 14. 69). Conclusions ARCs, particularly cardiovascular disease and chronic renal disease, are predictive of HIV-related excess mortality, with an increase in hazard similar to that of CD4 cell count. trial registration number NCT02898987.
MethODs As described in detail previously,  4 5  this study involved all HIV-1 infected patients aged ≥60 years on 1 January 2008 and followed up in the context of the Dat'AIDS cohort that involves 12 French hospitals. Dat'AIDS is a French multicentre prospective cohort that covers inpatients and outpatients treated in French public hospitals, including French overseas territories. It is based on a computerised medical record that is used by clinicians in real time during their consultations since 2000 (Nadis, Fedialis Medica, Marly le Roi, France). 15 All patients were included in the cohort after receiving oral information and giving written consent. All patient information was entered into a database using anonymous, coded identification numbers. The DatAIDS cohort is registered on Clinicaltrials.
gov under the identifier NCT02898987. Patients were excluded if they were infected with HIV-2 or if they did not have at least one CD4 cell count available in the 12 months before or after 1 January 2008. For each patient, follow-up began on 1 January 2008 and stopped on the date of death, or date of last follow-up, or on 1 January 2013 (whichever came first). The study endpoint was 5-year mortality. In patients lost to follow-up (defined as a date of last follow-up prior to 1 January 2013 and alive at last follow-up), vital status was systematically recorded via the Centre for Epidemiology and Population Health , by linkage with the French National Institute of Statistics and Economic Studies, which records nearly all deaths that occur in France by centralised reception of death certificates.
Patients were handled in mortality analyses until their date of death, 1 January 2013, or the date of the last follow-up if it occurred before 1 January 2013 and if the patients were not deceased after the vital status recording. The following data were collected at baseline (1 January 2008): age, gender, clinical centre, risk categories for HIV infection, duration of known HIV infection, AIDS status, CD4 cell count and CD4 nadir. The following ARCs were considered at baseline since they are known to be associated with mortality in the general population  16  : cardiovascular disease (CVD) (history of myocardial infarction, congestive heart failure, cerebrovascular disease), cancer (non-AIDS related), chronic pulmonary disease, diabetes, chronic renal disease (CRD) (defined as a composite criterion comprising documented history of CRD in the patient's medical file or an estimated glomerular filtration rate (eGFR) <60 mL/min/1.
73 m² as calculated using the Modification of Diet in Renal Disease (MDRD) formula) and cirrhosis. The presence or the absence of ARCs was based on the data available in the Nadis computerised medical records. Although hepatitis C virus (HCV) co-infection and hepatitis B virus (HBV) co-infection are not ARCs, they were also assessed since liver-related deaths are the leading cause of death in HCV/HIV and/or HBV/HIV co-infected PLHIV. 17 HBV co-infection was defined as at least one positive hepatitis B surface antigen. HCV co-infection was defined as at least one positive anti-HCV antibody and/or detectable HCV-RNA viral load (recording the value from the assessment closest to the baseline date). Body mass index (BMI) was also assessed as it is significantly associated with mortality in the general aged population, even when adjusted for ARCs.
6%) and does not necessarily reflect active drug injecting and, therefore, could not predict the excess mortality. The HIV population also differs from the general population in terms of tobacco use, exposure to sexually transmitted infections, recreational drug use, and so on, that may also be related to ARCs and mortality. Since the HIV population differs from the general population not only in its HIV status but also in a wide range of sociodemographic and clinical factors, HIV-related excess mortality should not be interpreted as related only to the HIV infection but as related to the HIV population in general. Another limitation is that data are collected before 2013, because the vital status update on patients lost to follow-up was done at that time, which may look a little outdated at the time of the publication of the present study.
More than a third of variation in spot urinary As concentrations was attributable to dilution. Conventional SG and osmolality correction removed significant dilution variation from As concentrations, whereas conventional creatinine over-corrected, and modifications of all three removed measurable dilution variation. Modified creatinine and both methods of SG and osmolality generated stronger correlations of urinary and drinking water As concentrations than conventional creatinine, which gave weaker correlations than uncorrected values. A disparity in optima between performance criteria was observed, with much smaller improvements possible for Criterion B relative to A. Conventional corrections -particularly creatinine -limit the utility spot urine samples, whereas a modified technique outlined here may allow substantial improvement and can be readily retrospectively applied to existing datasets.
Statistical analysis Statistical analysis and graphics were generated using R version 3. 4. 3 (base package) and the RStudio GUI. Urinary analyte data were positively skewed, so geometric means (GM) were calculated. For this reason, Pearson correlations of urinary As IMM concentrations against creatinine, SG, osmolality and drinking water As concentrations were calculated on natural log (ln) transformed data with significance tests (p-values) and 95% confidence intervals (CI). Linear regression models for trend lines were also performed on ln-transformed variables. To test the significance of the difference between correlations of, for example, drinking water total As and urinary As IMM yielded by different correction methods, the Williams's test was performed using the psych package (these correlations are not independent from one another if they share a common variable -drinking water total As).
For some analytes, this might be limited to a modest increase in the strength of association between exposure and biomarker concentrations, but it is plausible, for chemicals with very different excretion kinetics relative to dilution markers, that greater influence will be observed. Readers wishing to employ these methods can download R scripts made freely available in our previous publication  (Middleton et al. , 2016a). Further research in this area should address the derivation of correction coefficients (z values) by generating concentrations slopes for a broad range of analytes against UFR for single individuals over varying states of hydration. This should be conducted on a study group large enough to facilitate analysis of demographic and anthropometric variation. This will enable further optimisation of corrections and could be tailored to specific analytes of interest and population subgroups.
Funding This work was undertaken during a  NERC-funded University of Manchester/BUFI  ( Centre for Environmental Geochemistry) PhD studentship  ( GA/125/017 , BUFI Ref:  S204. 2 ) and completed during a Postdoctoral Fellowship at the  International agency for Research on Cancer (IARC) , partially supported by the  European Commission FP7 Marie Curie Actions -People -Co -funding of regional, national and international programmes (COFUND).
After the indicated time, plates were fixed with 4% paraformaldehyde (PFA) in PBS containing 2 µg mL -1 Hoechst 33342 (Thermo Scientific, Waltham, MA, USA) overnight at 4 °C. After 3 additional washing steps plates were filled with 50 μL PBS per well and subjected to automated image acquisition and subsequent image analysis. For automated fluorescence microscopy, a robot-assisted Molecular Devices IXM XL BioImager (Molecular Devices, Sunnyvale, CA, USA) equipped with a Sola light source (Lumencor, Beaverton, OR, USA), adequate excitation and emission filters (Semrock) a 16-bit monochrome sCMOS PCO. edge 5. 5 camera (PCO, Kelheim, Germany) and a 20X PlanAPO objective (Nikon, Tokyo, Japan) was used to acquire a minimum of 4 view fields of each well. Following images were processed and segmented with the MetaXpress software (Molecular Devices) to analyze GFP-LC3 granularity, CALR-RFP granularity at the cellular membrane, the decrease of nuclear HMGB1-GFP intensity, as well as nuclear shrinkage to indicate apoptotic cell death.
Data mining was conducted using the freely available software R (https://www. r-project. org). Data was intra-plate normalized as the ratio to plate means for each data point, while Z-scores were employed for inter-plate normalization. In vitro validation of CALR exposure, ATP release and HMGB1 release. U2OS, MCA205 or TC1 cells were seeded in 6 well plates and allowed to adapt for 24 h. Following, cells were treated with MTX (2 µM), CDDP (150 µM), MitoC (150 µM), (R) or (S)-crizotinib (1, 5, or 10 µM), alone or in combinations, for 6 h. Following the cells were washed and fresh medium was added for additional 24 h. Cells were collected and washed for staining with an anti-CALR antibody (ab2907, Abcam) diluted 1:100 in flow cytometry buffer (1% BSA in PBS) for 45 min. Then the cells were washed and incubated with an Alexa Fluor 488®-conjugated goat-anti-rabbit antibody (Invitrogen, Carlsbad, CA, USA) diluted 1:250 in flow cytometry buffer for 30 min.
Cells were washed and resuspended in flow cytometry buffer containing 2 µg mL -1 4',6-diamidino-2-phenylindole (DAPI) and then immediately subjected to flow cytometry (BD LSRFortessa, BD Biosciences, San José, CA, USA). Data were further processed with the FlowJo software (Tree Star, Inc. , Ashland, OR, USA) to assess the percentage of CALR + DAPI -cells. ATP concentrations in the supernatant of cells upon the indicated treatment were measured by means of an ENLITEN ATP Assay kit (Promega, Fitchburg, WI, USA), based on the ATP dependent luciferin-conversion, that yields detectable bioluminescence, according to the manufacturer's protocol. HMGB1 concentrations in the supernatant of cells following the indicated treatment were measured by means of an enzyme-linked immunosorbent assay (ELISA) kit (Shino test corporation, Tokyo, Japan), according to the manufacturer's protocol.
Luminescence and absorbance were measured using a SpectraMax I3 multi-mode microplate reader (Molecular Devices). Clonogenic assay. MCA205 or TC1 cells were seeded in 6-well plates (200 cells per well in 2 mL medium) and let adapt for 24 h before the treatment with different concentrations of (R)/(S)-crizotinib, alone or in combination with CDDP. Another 24 h after the treatment, medium was replaced, and the plates were incubated for additional 12 days before fixation and crystal violet staining (0. 05% crystal violet, 1% PFA, 1% methanol in PBS). The plates were scanned and the area of clones was quantified with the free software image J (https://imagej. nih. gov/ij/). Quantitative Quantification of cell death by flow cytometer. Cell death was assessed by means of the FITC-Annexin V detection kit I (BD Biosciences) following the manufacture's procedures.
Briefly, cells treated in 6-well plates were collected and washed in PBS before the cell pellet was resuspended in 50 µL staining buffer containing FITC-conjugated AnnexinV antibody. Samples were then incubated in the dark for 15 min before adding 400 µL staining buffer supplemented with 2 μg mL -1 DAPI. Acquisitions were performed on a CyAn ADP cytofluorometer (Beckman Coulter, Indianapolis, USA), and data were statistically evaluated using FlowJo. In vitro analysis of PD-L1 and MHC Class I/II expression by flow cytometry. Cells were seeded in 96-well plates (10,000 cells per well for murine cells) in 100 μL growth medium and let adapt for 24 h before treatment. Cells were then treated by different concentrations of crizotinib, alone or in combination with cisplatin, for another 24 h, recombinant murine IFNα (2000 IU) or IFNγ (100 ng mL -1 ) was used as positive controls.
Membranes were washed 5× times with TBST and revealed with suitable horseradish peroxidase-conjugated secondary antibodies (Southern Biotechnologies, Birmingham, AL, USA) for another 2 h at room temperature, followed by additional washing steps and chemiluminescence-based detection with the Amersham ECL Prime detection reagent kit and the ImageQuant LAS 4000 software-assisted imager (GE Healthcare, Piscataway, NJ, USA). Immunofluorescence of cells. Cells were seeded into 384 wells black microplates and treated as indicated. After washing twice with PBS, plates were fixed with 4% PFA/PBS containing Hoechst 33342 (2 µg mL -1 ) for 10 min, washed twice with PBS and incubated with quenching solution (2. 67 g NH 4 Cl in 1 L PBS, pH 7. 4) for 5 min. Then cells were washed with PBS and permeabilized with 0.
5 μM) were loaded for OCR assessment on the Seahorse XFe96 Analyzer. ECAR and OCR were analyzed by the Wave Desktop software (Seahorse Bioscience) and reported as step line chart or histogram (mean ± s. d. ). Pharmacokinetic of (R)-crizotinib kinetics in murine plasma. Female C57Bl/6 mice (8 weeks) received a single i. p. injection of (R)-crizotinib (50 mg Kg -1 , dissolved as described above) before blood sampling via cardiac puncture. Blood was collect in BD Microtainer™ Capillary Blood Collector (BD bioscience) containing lithium heparin and was spun to obtain plasma. Plasma was mixed with extraction buffer (methanol, H 2 O, chloroform; 9:1:1, v:v) at a ratio of 1:10 (v:v) vortexed and centrifugated (10 min at 15,000 × g, 4 °C). Then extracts from the supernatant were dried by evaporation at 40 °C in a pneumatically assisted concentrator (Techne DB3, Staffordshire, UK).
) were used at 1:200 dilution after washing three times for 5 min with TBST. After additional washing steps, samples were mounted with cover slides using Fluoroshield™ with DAPI (Sigma-Aldrich), which allowed nuclear counterstaining. For each sample, 10 viewfields from different sections of different layers were captured with a HR-SP8 Confocal Microscope (Leica). Image analysis was performed with the LAS X software (Leica). Urethane induced lung cancer model. This protocol was approved by the Ethics Committee of Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences (No: 2017AWEC011). Naive FVB mice (female, aged between 6-7 weeks, weighing 20-22 g) were purchased from Charles River, Beijing, China. All mice received i. p. injections of urethane (dissolved in 0. 9% NaCl saline solution, 1 g per Kg of body weight) once per week, for total of 6 weeks.
A stereo microscope (Motic SMZ168TP) equipped with a high-resolution camera (Sony HD 1/1. 8 inch color CCD) was used to record the images of all lung lobes (two sides). The number and sizes of all neoplastic nodules were quantified with the supporting software EZ-NET™. All samples were then fixed in 4% PFA and embedded in O. C. T to be frozen at -80 °C for tissue sections. Frozen sections were adapted to room temperature and washed 3 times before hematoxylin-eosin staining using a hematoxylin-eosin staining kit, Sangon Biotech (Shanghai, China). Alternatively, samples were permeabilized with 0. 5% Triton X100 and incubated with Alexa Fluor 488conjugated anti-mouse IFN-γ antibody (clone XMG1. 2, 5 μg ml -1 ) before Alexa Fluor 647-conjugated anti-mouse CD3 antibody (clone 17A2, 5 μg ml -1 ).
Prior to surface staining of fluorescent antibodies, samples were incubated with LIVE/DEAD® Fixable Yellow Dead Cell dye (Invitrogen) to discriminate viable cells from damaged/dead cells, and incubated with antibodies against CD16/CD32 (clone 2. 4G2, BD Biosciences) to block Fc receptors. Finally, cells were incubated with a panel of fluorescenceconjugated antibodies (surface staining) before permeabilization and fixation with Foxp3/Transcription Factor Staining Buffer Set (eBioscience, San Diego,CA, USA) for the staining of intracellular Foxp3, IFNγ, and IL-17. Data were acquired on a BD LSRFortessa flow cytometer (BD Biosciences) and analyzed by means of FlowJo software. Absolute counts of tumor-infiltrating lymphocytes were obtained taking in account the weight of the harvested tumor, total volume of the dissociated tumor cell suspension (cell concentration typically set to 250 mg ml -1 in PBS), proportion of the whole cell suspension stained (typically 200 µl containing 50 mg of bulk tumor cell suspension) and proportion of the stained cell suspension ran through the flow cytometer (typically ~300 out of 400 µl of the stained cell suspension).
Antibodies for RNA-Seq data analysis was performed by GenoSplice technology (www. genosplice. com). Sequencing, data quality, reads repartition (e. g. , for potential ribosomal contamination), and insert size estimation were performed using FastQC, Picard-Tools, Samtools, and rseqc. Reads were mapped using STARv2. 4. 0  47  on the mm10 Mouse genome assembly. Gene expression regulation study was performed as already described  48. Briefly, for each gene present in the Mouse FAST DB v2016_1 annotations, reads aligning on constitutive regions (that are not prone to alternative splicing) were counted. Based on these read counts, normalization and differential gene expression were performed using DESeq2  49  on R (v. 3. 2. 5). Only genes expressed in at least one of the two compared experimental conditions were further analyzed.
Livers were fixed in 4% PFA and subjected to hematoxylin and eosin staining for morphology observation. Statistical analyses. Unless specified, results were expressed as mean ± s. e. m. Statistical tests included unpaired one-tailed and two-tailed Student's t-tests using Welch's correction and one-way ANOVA followed by multiple comparison tests. When applicable, two-way ANOVA followed by multiple comparison tests were used for analysis of interleaved box whiskers plot and scatter dots plots; comparison of tumor growth curves was performed by means of the ANOVA Type 2 (Wald test); Comparison of survival curves was performed with the Likelihood ratio test. P-values of 0. 05 or less were considered to denote significance (*p < 0. 05; **p < 0. 01; ***p < 0. 001; ns, not significant). In vivo data was analyzed using the freely available TumGrowth software (https://github.
Acknowledgements G. K. is supported by the  Ligue contre le Cancer Comité de Charente-Maritime  (équipe labelisée);  Agence National de la Recherche (ANR)-Projets blancs ;  ANR  under the frame of E-Rare-2, the  ERA-Net for Research on Rare Diseases; Association pour la recherche sur le cancer (ARC) ;  Cancéropôle Ile-de-France ;  Chancelerie des universités de Paris  ( Legs Poix ),  Fondation pour la Recherche Médicale (FRM) ; a donation by Elior; the  European Commission (ArtForce) ; the  European Research Council (ERC) ;  Fondation Carrefour; Institut National du Cancer (INCa) ;  Inserm (HTE) ;  Institut Universitaire de France ;  LeDucq Foundation ; the  LabEx Immuno-Oncology ; the  RHU Torino Lumière ; the  Seerave Foundation ; the  SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE) ; the  SIRIC Cancer Research and Personalized Medicine (CARPEM) ; and the  Paris Alliance of Cancer Research Institutes (PACRI).
Data availability The RNASeq data have been deposited in the NCBI GEO database under the accession code GSE126988, The source data underlying Figs. 1  and 6  are provided as a Source Data file. All the other data supporting the findings of this study are available within the article and its supplementary information files and from the corresponding author upon reasonable request. A reporting summary for this article is available as a Supplementary Information file.
Materials and methods This was a multicenter, multinational, randomized controlled trial to determine the effectiveness and safety of lumbar discectomy with a bone-anchored implant designed to provide annulus fibrosus occlusion in patients at high risk for reherniation (ClinicalTrials. gov NCT01283438). Local ethics committees reviewed and approved the protocol. All participants provided written informed consent before trial participation. The design  [9]  and 2-year primary endpoint results  [17]  of this trial have previously been described. This report presents 3-year clinical and radiographic results from the trial. Preoperative imaging included magnetic resonance imaging (MRI) with T1-and T2-weighted axial and sagittal images, index-level low-dose multiplanar computed tomography (CT), and anteroposterior/lateral and flexion/extension x-rays.
3-point increase from baseline for MCS  [18]. Neurological status and adverse events were assessed at each follow-up visit. Investigators classified adverse events by seriousness and relation to the device or procedure. Neither patients, surgeons, outcome assessors nor imaging core laboratory readers were blinded to group allocation, with the exception of patients in the Netherlands due to regional regulations. An independent data safety monitoring board provided safety oversight during the study and adjudicated all adverse events. Statistical analyses were performed on a modified intention-to-treat population consisting of randomized patients in whom the intended procedure was attempted. Preoperative group characteristics were reported as mean and standard deviation for continuous variables, and count and percentage for categorical variables.
Group comparisons were performed with Student's t test for continuous data, Fisher's exact test for categorical data, and log-rank tests for survival data. In patients who underwent a reoperation prior to the 3-year follow visit, leg pain, back pain, ODI, PCS, and MCS values at 3 years were substituted with baseline values. Statistical significance was set at P < 0. 05 and hypothesis testing was two-sided. Statistical analyses were performed using SAS v9. 4 (SAS Institute, Cary, NC, USA) and R v3. 3. 2 (R Foundation for Statistical Computing, Vienna, Austria).
Materials and Methods The PETG filament is a polyester-based material provided by the FDBI company (Asnières sur seine, France) under the tradename 3DFilTech. The filament has a diameter of 1. 75 ± 0. 05 mm. The supplier recommends the use of a heated bed with typical temperatures between 40 • C and 65 • C. The supplier does not provide more technical data about the filament. Differential scanning calorimetry (DSC) experiments are performed to study the thermal behaviour of the as-received filament (Figure  1a ). Two thermal scans are considered within a temperature range of (-40 • C to 300 • C) with a rate of 10 • C/min using DSC823e equipment from Mettler Toledo SAS (Viroflay, France). In addition, tensile performance on single filaments is performed using a universal testing machine (Zwick Roell, Ulm, Germany).
X-ray micro-tomography imaging is performed on the dog-bone specimens using UltraTom Xray micro-CT from Rx-Solutions (Chavanod, France) under a fixed voxel size of 14. 31 µm and a detector resolution of 1920 × 1536 pixels. Up to 1440 radiographic images are needed to build the tomogram of the printed PETG using X-Act software from Rx-Solutions. The processed images represent a volume of 17. 5 × 11. 5 × 5. 1 mm 3 , which is based on a resolution of 1224 × 804 × 354 voxels. The raw images are processed using ImageJ software from NIH to isolate the features of interest and measure the amount and distribution of the defects within the printed PETG. The printing duration varies depending on the type of geometry between 7 min and 29 min. The density of dog-bone specimens is measured to derive the porosity content using the formula.