dataesr/scientific-paragraphs-categorization huggingface dataset:
The differential analysis was performed using KissDE, an R package developed as part of the KisSplice post-processing workflow  (Sacomoto et al. , 2012). KissDE works on pairs of variants for which read counts are available in each replicate of each condition and tests if a variant is enriched in one condition. Counts are modeled using a negative binomial distribution. KissDE fits a generalized linear model and tests for the effect of an interaction between the variant and the condition using a likelihood ratio test with a 5% false discovery rate to control for multiple testing. A percent splicing index (PSI or Ψ) value was then estimated for each sample as the ratio of inclusion junction reads to the sum of inclusion and exclusion junction reads. As the datasets are paired, the difference of Ψ values for each event (deltaPSI or ΔΨ) was calculated as the median of ΔΨ values for each replicate.
Purpose: The SERVE-HF study reported a risk of cardiovascular death associated with adaptive servo-ventilation (ASV) for central sleep apnea in patients with chronic heart failure with reduced left ventricular ejection fraction (LVEF). Therefore, we adopted in May 2015 a safety procedure in our 32 patients with ASV since 2006. It led to ASV removal in four patients due to ≤45% LVEF. At the end of the procedure we noted eight cases of death. This high 25% mortality rate led us to study these cases. Methods: The study population was derived from our database of patient follow-up from the sleep unit of our cardiovascular department. Results: All deceased patients but one had cardiac disorders but only one matched the SERVE-HF patient profile. ASV was due to predominant central (n = 4) or mixed (n = 4) sleep apnea.
Material and methods As a cardiovascular department with a sleep unit, uninvolved in the SERVE-HF study, we paid particular attention to the Special Safety Notice received on May 18, 2015 from the American Academy of Sleep Medicine (AASM) relaying a ResMed notification launched five days earlier concerning preliminary results of the SERVE-HF study. Within two weeks a total of 32 patients treated with ASV for sleep apnea were identified from our follow-up database of patients ventilated for sleep apnea, the first patients being equipped with ASV in 2006. Individual consultations were scheduled to explain the ventilator Safety Notice and the necessity to re-assess patients' medical files in light of the SERVE-HF study. The proposal included an echocardiogram to determine their present LVEF, previously measured or not.
Search methods for identification of studies Electronic searches MEDLINE, CENTRAL, Science Direct, Scopus, PEDro, OpenGrey and Greylit were searched from inception up to January 2019 for relevant studies in English or French. Reference list of the included studies were also checked for eligible studies. The following key words were used and combined using Boolean operators and a sensitivitymaximizing method: "COPD"; "pulmonary disease, chronic obstructive"; "chronic respiratory failure"; "high-flow"; "high-flow cannula"; "high-flow nasal cannula"; "nasal cannula"; "humidified high-flow"; "high-flow oxygen"; "humidification therapy"; "HFNC"; "high-flow heated and humidified oxygen". The search strategy for PubMed using a sensitity-maximizing searching method was adapted for the other databases: #1 "COPD"[tiab] OR "pulmonary disease, chronic obstructive"[mh] OR "chronic obstructive pulmonary disease"[tiab] OR "chronic respiratory failure"[tiab] #2 "high-flow"[tiab] OR "high-flow cannula"[tiab] OR "high-flow nasal cannula"[tiab] OR "nasal cannula"[tiab] OR "humidified high-flow"[tiab] OR "high-flow oxygen"[tiab] OR "humidification therapy"[tiab] OR "HFNC"[tiab] OR "high-flow heated and humidified oxygen"[tiab] #3 "randomized controlled trial"[pt] OR "randomized controlled trial"[tiab] OR "controlled clinical trial"[pt] OR "controlled clinical trial"[tiab] OR "randomized"[pt] OR "randomized"[tiab] OR "random"[pt] OR "random"[tiab] #4 #1 AND #2 AND #3 [tiab] denotes a word in the title or abstract.
Data from CTRL and HF diets were provided by SAFE (Augy, France). Concerning P. tricornutum, biomass was analysed for protein, carbohydrate, lipid, dietary fiber, ash, and moisture. Total protein content was estimated as N × 6. 25, where N is the nitrogen content determined through the elemental analysis. Carbohydrate was determined following Dubois et al. [22] , and lipids following Marsh and Weinstein  [23]. Total dietary fiber (TDF), insoluble dietary fiber (IDF) and soluble dietary fiber (SDF) were determined by AOAC Method 985. 29 (AOAC Official Method 985. 29) using commercial kits (Megazyme, Bray, Ireland). TDF was experimentally analysed, not calculated as a sum of SDF and IDF. Moisture and ash were analysed following ISTISAN protocols (ISTISAN Report 1996/34, method B, p. 7; ISTISAN Report 1996/34, pp.
Funding: This research was funded by financial support from the regional program " Food for Tomorrow-Cap Aliment" Research, Formation and Innovation in Pays de la Loire  including a co-financing at 50% of the Ph. D. grant to C. M. The thesis was also co-funded at 50% by  Le Mans University , with joint financial support from the  Conseil Général de la Mayenne, Laval Agglomération  and  CCI de la Mayenne.
Acknowledgments We thank  Manfred Gessler  ( University of Würzburg ),  Francois Guillemot  ( MRC National Institute for Medical Research ) and  David Ish-Horowicz  ( University College London ) for generously providing Heyl, Hes5, and Hes7 mutant strains, respectively. We are grateful to  Bettina Brandt ,  Vivian Schulz , and  Pia Blessin  for excellent technical assistance, and  Petra Stallerow  and  Claudia Päseler  for help with the animal husbandry. We also thank  Hans-Peter Rahn  for advice and help with cell sorting, and  Bastiaan Pierik  for technical help with the imaging setup, respectively. We also acknowledge  Elijah Lowenstein ,  Thomas Müller ,  Minchul Kim , and  Michael Strehle  for critically reading the manuscript. This work was supported by the  Deutsche Forschungsgemeinschaft (DFG) - funded MyoGrad international graduate program , a grant of  AFM-Telethon  and  Agence Nationale de la Recherche (ANR)/DFG  to C.
Gene expression analysis The relative quantification of gene expression was determined using the 2-ΔΔCt method, then normalized to at least an internal control gene (ABL1, GAPDH and/ or HPRT1) and relative to a calibrator control sample corresponding to a mix of cDNA of peripheral blood mononuclear cells (PBMC) from several healthy donors. Statistical analysis using GraphPad Prism Software used Mann-Whitney test.
Somatic mutations assessment We performed the SureSelect targeted-capture strategy from Agilent Technologies (Courtaboeuf, France) using a panel of 34 genes described previously  (22)  with subsequent paired end sequencing on an Illumina HiSeq 1500 Platform (Illumina, San Diego, USA). For variants detection SureCall software from Agilent technologies was used (see Supplementary methods, Tables  S2B  and S3B ).
Acknowledgments This work was supported by an internal grant from the  Hematology laboratory, CHU de Rennes, France , and the  Ligue Régionale contre le Cancer de l'Ouest. The NGS experiments are part of the  RELYSE  project supported by a  National Cancer Institute  translational grant. Sequencing were performed in the  Biogenouest Genomics / Human & Environmental Genomics core facility of Rennes (Biosit/OSUR ). Human samples were obtained from the processing of biological samples through the  Centre de Ressources Biologiques (CRB)-Santé of Rennes  ( BB-0033-00056 , http://www. crbsante-rennes. com). Cell sorting was performed by  Flow Cytometry facility, Biosit, University of Rennes 1. Part of this work was supported by the  Carte d'identité des Tumeurs (CIT) program  (http://cit. ligue-cancer.
Measurements Medical charts of all patients in the present cohort were carefully reviewed and coded within an electronic database. The following information was collected: age, gender, comorbidities, medications (at discharge), laboratory findings, blood pressure, heart rate, physical signs and symptoms (at admission and discharge). In addition, as part of routine care management, all patients underwent standard echocardiography (within 72 hours of admission) and chest X-ray (at admission and a few days before discharge when the treating physician perceived patients as regaining a compensated status (2. 0 [1. 0 -4. 0] days).
Radiographic congestion scoring The severity of lung congestion was quantified by a single physician-cardiologist blinded to the clinical data and to the timing of the assessment, namely admission or prior to discharge. Lung congestion was quantified by chest X-ray (antero-posterior view at admission and postero-anterior view prior to discharge) using a previously validated method  21. To enhance the reproducibility of this scoring with regard to the degree of confluent edema, a part of the divided lung field which visually occupied a density similar to cardiac silhouette was regarded as an intense area whereas the field with weaker density was considered to be a mild area. The grades of congestion in each of the six areas were defined as follows: 0= normal; 1= cephalization, perihilar haze, peribronchial cuffing, or Kerley lines (A, B, C); 2= interstitial pulmonary edema and localized or confluent mild edema; and 3= confluent intense edema [Figure  1 ].
05 by univariable analysis. The increase in discriminative value to predict a 1-year composite outcome following the additional of discharge variables (CSI and BNP) in survival model on a baseline set of covariates including age, a previous history of HF hospitalization, reduced LVEF, hemoglobin and eGFR at discharge were evaluated using continuous NRI and IDI  22. Descriptive analyses, associations with CSI and Cox hazard models were performed using SPSS package version 24. 0 (SPSS Inc. , Chicago, IL, USA). R statistical software (3. 1. 3) was used for ICC, continuous NRI and IDI (ICC and survIDINRI packages).
Methods. We conducted a randomized, double-blind, placebo-controlled, human challenge study (NCT03334695). Healthy adults received 1 × 10 11 vp Ad26. RSV. preF vaccine (active) or placebo (pbo) intramuscularly. After 28 days, volunteers were challenged intranasally with a low-passage clinical strain of RSV-A (0. 8 mL of Memphis 37b) and then quarantined for 12 days. Nasal washes were collected twice daily throughout quarantine, starting 2 days post-challenge (viral load [VL] by qRT-PCR and quantitative cultures). Disease severity was recorded thrice daily using symptom diary cards. Results. Fifty-three volunteers (active, n = 27; pbo, n = 26) were challenged with RSV-A. Quantitative viral assessments were consistently lower in active than pbo. The primary endpoint of the study was met: the area under the curve (AUC) for RSV VL over time (via qRT-PCR) was significantly lower in active pbo (P = 0.
The participants completed Web-based versions of the 9-item Patient Health Questionnaire (PHQ-9), the 7-item Generalized Anxiety Disorder scale (GAD-7), and the Positive and Negative Affect Scale at baseline and 2-3 weeks later (T2). Participants in the Woebot group engaged with the conversational agent an average of 12. 14 (SD 2. 23) times over the study period. No significant differences existed between the groups at baseline, and 83% (58/70) of participants provided data at T2 (17% attrition). Patients in the Woebot group significantly reduced their symptoms of depression over the study period as measured by the PHQ-9 (F = 6. 47; P = 0. 01), in an intent-to-treat univariate analysis, while those in the information control group did not. Another chatbot, Koko, was designed to express empathy, which could be positively leveraged in cancerpatients  [11].
In this study, Morris et al report on the design of a conversational agent that could express empathic support in ways that might approach, or even match, human capabilities. The authors also assessed how users might appraise this system. The authors used responses from an existing pool of online peer support data that were repurposed by the chatbot and presented to the user. Information retrieval techniques and word embeddings were used to select historical responses that best matched a user's concerns. Ratings from 37,169 users were collected to evaluate the system. A controlled experiment (N = 1284) to test whether the alleged source of a response (human or machine) might change user perceptions was performed: the majority of responses created by the agent (2986/3770, 79. 20%) were deemed acceptable by users.
Expression of caring and understanding is valued in supportive human communications. A study recently published by Liu et al. assessed whether humans could perceive empathy from a chatbot: in the first group of people (N = 158), participants simply read a dialogue between a chatbot and a human user. In a second group, participants (N = 88) interacted with a real chatbot. Three types of empathic expression were tested: sympathy, cognitive, and affective empathy, on the individuals' perceptions of the service and the chatbot. Data revealed that expression of sympathy and empathy is favored over unemotional provision of advice, in support of the Computers are Social Actors (CASA) paradigm  [13].
Ongoing trials A search on ClinicalTrials. gov returns four trials evaluating chatbots in healthcare. In the United Kingdom, a non-randomized trial is being performed by the National Health Service to compare the Babylon chatbot to the non-emergency 111 telephone number  [19]. Patients can interact with an automatic agent in order to describe their symptoms. Advices and information are given in return by the chatbot. Randomized studies demonstrating the superiority (or at least non-inferiority) of chatbots, compared to an intervention performed by a physician, do not exist. If chatbots are to be safely used by a large number of patients, they must be evaluated like a medical device, or even a drug. The Buddy Study (NCT02742740) evaluates an ECA Oncology Trial Advisor for Cancer Trials that acts as an advisor to patients on chemotherapy regimens, promoting protocol adherence and retention, providing anticipatory guidance and answering ques- tions.
The chatbot also serves as a conduit to capture information about complaints or adverse events. Usability metrics will include session time, satisfaction, and error rates. Subjects will be identified from among patients on chemotherapy regimens at the Boston Medical Center  [20]. All subjects will be enrolled for 2 months and randomized to the chatbot group or control group. Baseline data will be collected after enrollment and before randomization and will include: sociodemographic data, mental and social health, medical diagnosis (cancer type and stage), the Short Assessment of Health Literacy and the Short Portable Mental Status Questionnaire (SPMSQ) for cognitive impairment. The exit interview will be conducted 2 months after baseline. Data collected at the exit interview will include: mental and social health and the satisfaction with ECA Review of the subject's medical chart will be performed bi-weekly while the subject is enrolled.
Chart review will be performed by a staff member who is blinded to the subject's group (intervention vs control). Primary outcome will be treatment protocol adherence, defined by the number of treatment visits attended/number of treatment visits scheduled. The secondary outcome will measure: subject satisfaction, number of adverse events as reported through the ECA and directly to clinic by patient, time to detect and resolve adverse events as reported through the ECA and directly to clinic by patient, adverse event false alarm rate, as reported through ECA and directly to clinic by patient. A third study, the RAISE project (NCT01458002)  [21] , is designed to promote exercise and sun protection. The primary aims are to develop and assess the effectiveness of a tailored internet intervention on a national sample, to develop and assess the effectiveness of the internet intervention enhanced by a relational agent, and to determine if the intervention with the relational agent can outperform the regular tailored internet intervention.
The study will include three groups (Control, Internet, Internet plus Relational Agent). A representative national sample of 1639 individuals at risk for both behaviors will be recruited. A fourth study, INCASE, a randomized, controlled, blind study will be launched in France, comparing the information given by the Vik chatbot vs a multidisciplinary group of physicians (from medical, radiation and surgical oncology) to breast cancer patients (NCT03556813). One hundred and forty patients will be randomized in this non-inferiority trial. The EORTC QLQ-INFO25 questionnaire, that was validated to assess cancer patients' information  [22] , will be used to compare the quality of the information provided to the two groups of patients by the physician or the chatbot.
study design Analyses of studies in the IAI clinical trial database that included pharmacokinetic and/or pharmacodynamic data were conducted; the following trials were included: VGFT-OD-0702. PK, VGFT-OD-0512, VIEW 2 and VIVID-DME. VGFT-OD-0702. PK was a pharmacokinetic extension study of the US-based clinical trial VGFT-OD-0702 (NCT00527423), a randomised, single-masked phase II study comprising patients with nAMD previously enrolled in clinical trials of IAI. Patients were treated with 2 mg IAI every 8 weeks after their previous treatment in study VGFT-OD-0702. Pharmacokinetic samples were taken after first injection only. VGFT-OD-0512 (NCT00320814) was a phase I, US-based exploratory, 6-week open-label study in patients aged ≥18 years with DME who were treated with IAI 4. 0 mg. Blood samples for pharmacokinetic analysis were collected at screening (visit 1) through day 155 (visit 8).
VIEW 2 (NCT00637377) was a phase III, randomised, double-masked, active-controlled trial conducted in in Europe, Asia, Australia and South America. Patients aged ≥50 years with nAMD were included in this trial. IAI was administered monthly at a dose of 0. 5 mg every 4 weeks Open access or 2 mg every 4 weeks, or 2 mg every 8 weeks after three initial monthly injections, and compared with monthly 0. 5 mg ranibizumab. 10 IVID-DME (NCT01331681) was a phase III, randomised, double-masked, active-controlled, 148-week trial conducted in Europe, Japan and Australia. Patients aged ≥18 years with DME were included and randomised 1:1:1 to receive either IAI 2 mg every 4 weeks, IAI 2 mg every 8 weeks (after five initial monthly doses) or macular laser photocoagulation. The study designs of VIEW 2 and VIVID-DME have previously been fully described.
Pharmacokinetics/pharmacodynamics Non-compartmental analysis of concentration-time data obtained with dense sampling was undertaken in VGFT-OD-0702. PK and VGFT-OD-0512. With this type of analysis, pharmacokinetic parameters like area under the curve (AUC) and maximum observed concentration (C max ) are calculated based directly on the measured concentration-time data without model-based assumptions about body compartments of the drug. Plasma samples for free and bound aflibercept concentrations were collected at prespecified time points up to 28 and 154 days after administration, respectively. Sparse sampling for pharmacokinetics was used in VIEW 2 and VIVID-DME. Sampling time points are described in online supplementary appendix table 1. All samples for pharmacokinetic analyses were collected, processed and stored under conditions proven to ensure adequate analyte stability.
Pharmacodynamics After IVT aflibercept administration, there were no meaningful changes from baseline in systolic blood pressure over the duration of the studies, and no clinically relevant differences between treatments or indications (online supplementary appendix figure  1 ). Similar results were observed for diastolic blood pressure (data not shown). In patients treated with IAI in VIEW 2, blood pressure was evaluated relative to free or adjusted bound aflibercept concentrations in plasma. For this analysis, time points of C max were selected, that is, week 1 for free aflibercept and week 12 for adjusted bound aflibercept. Systemic concentrations of free or adjusted bound aflibercept did not correlate with blood pressure changes (figure  2 ). Blood pressure changes in patients with free or bound aflibercept concentrations below the LLOQ were in the same range as those with free aflibercept concentrations >LLOQ and up to the individual observed maximum of about 110 µg/L of free aflibercept and about 410 µg/L for adjusted bound aflibercept.
These results are also in line with postmarketing data, which do not support a causal association between IAI and development or worsening of renal impairment (Bayer data on file). The current analyses were conducted for both free and bound aflibercept. Following IVT administration, aflibercept is slowly released from the eye into the systemic circulation, where it is predominantly observed in its biologically inactive bound form. While free aflibercept is detectable in plasma 1-2 weeks after administration and does not accumulate after repeated administration every 4 weeks, bound aflibercept accumulates after repeated administration and reaches a steady state 4 weeks after the third IAI administration, that is, at week 12. The ratio of free and bound aflibercept is not constant, but decreases over time as the concentration of free aflibercept increases to C max at a faster rate than bound aflibercept and then decreases quickly thereafter, while bound aflibercept concentrations plateau.
As such, total aflibercept concentrations (defined as the sum of free and bound aflibercept) should not be used as a surrogate for active drug concentrations (as it is often used for small molecules bound to plasma proteins that show no concentration dependence of protein binding). Overall, systemic pharmacokinetic and pharmacodynamic parameters of aflibercept were similar across both nAMD and DME indications and consistent across the four studies included in this analysis as well as with recently published data on free aflibercept concentrations after IAI. 22 Free aflibercept concentrations obtained 1 week after the first IAI administration were used to explore the potential pharmacokinetic/pharmacodynamic relationship for the pharmacologically active moiety. Although pharmacologically inactive, the relationship between bound aflibercept and potential systemic pharmacodynamic markers of VEGF inhibition at week 12 were also explored for the sake of completeness.
Acknowledgements We thank  Leigh Prevost  and  Albert Balkiewicz  of PAREXEL for medical writing support. Contributors All authors (PKK, LK, JFK, JW, AT, OZ, RV, CA, TZ, ATD and JH) had full access to the data in the study, contributed to the concept and design of the analysis, participated in the acquisition, analysis or interpretation of the data, drafted and provided critical revision of the manuscript for intellectual content and confirmed submission of the manuscript for publication. PKK, CA, OZ, TZ, ATD and JH contributed to and provided input to the statistical analysis. PKK and JH are responsible for the overall content as guarantors of the information presented. The sponsor Bayer was involved in study design, collection, analysis and interpretation of data, writing the report and in the decision to submit the article for publication.