dataesr/scientific-paragraphs-categorization huggingface dataset:
, 2011) ; 4) blood-to-organ transport and drug clearance parameters can be scaled using physiologic information such as volumes or blood flows, although more work is needed in this area to develop a validated scaling method. Sensitivity analyses are then performed to determine the relative importance of model parameters and select the most influential; ones that will be modified for obtaining a patient-specific model. Hence, this analysis may also guide the search of relevant circadian or pharmacological biomarkers to be measured in patients. The human model is then partially recalibrated using individual patient datasets and further serves in optimization procedures to compute personalized administration schemes. As an example, we detail in this work the design of a physiologically-based model of temozolomide (TMZ) brain disposition through a multiscale pipeline integrating PK studies in buffer solutions, cell culture, mice, and patients  (Ballesta et al.
The amount of irreversible complexes was used as an output of irinotecan toxicity, as it was highly correlated with cell death in cell culture  (Ballesta et al. , 2011). Proteins involved in irinotecan efflux, bioactivation, detoxification, and the drug target TOP1 were assumed to display circadian rhythms. In the first study  (Ballesta et al. , 2011) , circadian variations with a period of 26h50 (S. D. 63 minutes) were found in synchronized Caco-2 cells for the mRNA levels of the three clock genes REV-ERBa, PER2, BMAL1, and in that of TOP1, CES2, UGT1A1, and efflux transporters ABCB1, ABCC1, ABCC2, and ABCG2. DNA-bound TOP1 protein amount in the presence of irinotecan also displayed circadian rhythms. The model parameters were estimated from data, and the best-fit model closely reproduced the experimental datasets.
The optimal schemes induced twice as much DNA damage in cancer cells as in healthy ones. Of note, the optimal duration did not exceed, highlighting the need for short exposure durations to optimally exploit the temporal difference between healthy and cancer cells. Irinotecan chronopharmacology was further investigated in a second study in synchronized Caco-2 cells  (Dulong et al. , 2015). Consistently with the first study, large transcription rhythms of period 28 hour 06 minute   Dulong et al. , 2015). This cellular investigation provided the basis for a mouse study and the development of a whole-body model of irinotecan chronoPK-PD explicitly incorporating the cellular model in relevant organs (E)  (Ballesta et al. , 2012). The model was first developed for B6D2F1 male mice in which several chronopharmacology datasets were available, including plasma and colon chronoPK profiles of SN38 after irinotecan at best and worst time of tolerability (F-G).
The next step will consist in fitting intestinal chronotoxicity data available for the same mouse category (H)  (Li et al. , 2013). Dots or bars represent experimental results, and solid lines represent best-fit models. (S. D. 1 hour 41 minute) moderated irinotecan bioactivation, detoxification, transport, and target. These molecular rhythms translated into statistically significant changes according to drug timing in irinotecan pharmacokinetics, in DNA-bound TOP1 amount during SN38 exposure, and in drug-induced apoptosis. Clock silencing through siBMAL1 exposure ablated all the chronopharmacology mechanisms, demonstrating they originated from the molecular circadian clock. The PK-PD model developed in the first study was fitted to these new datasets and achieved a good fit. Parameter sensitivity analysis performed on the model allowed to assess the relative importance of pharmacological proteins with respect to irinotecan chronotoxicity.
The intestine was divided into two compartments, representing intestinal mucosa cells, and intestinal lumen, respectively. A bidirectional transport was assumed between the blood and all organs, except for the transport from the intestinal cells to the hepatic portal vein, which was represented by a flow directly toward the liver. The enterohepatic circulation was also modeled by a drug transport from the liver to the intestinal lumen, which stood for biliary excretion. Renal and intestinal clearance were included, respectively, in the blood and intestinal lumen compartments. Model parameters were either inferred from the in vitro studies or estimated from experimental data available in the three classes of irinotecan chronotoxicity  (Li et al. , 2013). Both PK time-concentration profiles in blood and tissues after administration at the best and worst time of tolerability and circadian expression of pharmacological proteins were integrated in parameter estimation  (Ballesta et al.
Those continuous circadian individual datasets combine to patient general information (age, sex, lifestyle habits, chronotype, concomitant medications. ), clock and pharmacology gene polymorphisms, cancer stage, phenotype, and molecular characteristics. Such multidimensional features can be integrated into dedicated physiologically-based models enabling patient-tailored anticancer chronotherapy computation on a real-time basis. Thus, the quest for personalized chronotherapeutics has favored the development of Domomedicine platforms, allowing for the continuous monitoring of circadian and disease-specific markers in nonhospitalized patients. A first successful conceptual, technological, and clinical investigation was conducted within the European Project InCASA (http://www. incasa-project. eu) in 31 metastatic cancer patients on treatment  (Innominato et al.
) at home or during his or her daily activities. Authorized users can access record information via a secure web interface, add different type of patient information (health, nutrition, psychology, etc. ), and communicate with other caregivers via the same interface. Automatic preanalysis of data is coupled to notifications sending to care professionals, which they can reset. According to the data, professional caregivers can also propose adapted dietician or psychologic support services to their patients. The PiCADo project has also allowed the design of the PiCADomo clinical study, which aims to establish the first multidimensional database on the health relevance of circadian rhythms, measured in real-life condition in people receiving complex circadian chemotherapy outside the hospital.
Thus, the development of reliable quantitative techniques measuring the absolute protein levels and activities on a 24-hour basis is needed. The arising of "omics" technologies may have huge implications for the molecular understanding of the CTS and its interplay with diseases and treatments, and for the implementation of personalized chronotherapy into the clinics. Recent in vitro and in vivo investigations have provided insights into tissue-specific circadian organization through transcriptomic, proteomic, and metabolomic circadian datasets (reviewed in  Dallmann et al. , 2016; Gumz, 2016). In particular, systems approaches involving high-throughput preclinical studies in the mouse liver have been useful for characterizing the circadian molecular determinants of the clock control on hepatic drug metabolism.
Furthermore, circadian "omics" technologies have now been tested in various biologic samples from laboratory animals, such as blood, saliva, urine, and exhaled breath (reviewed in  Dallmann et al. , 2016). These investigations present a great translational potential as such samples can realistically be collected around the clock in a noninvasive manner in individual patients. Such large-scale datasets could then be combined, through systems methodologies, with other patient data such as rest-activity and temperature rhythmic profiles or genetic polymorphisms toward the prediction of individualized optimal drug timing. Pharmaceutical and biomedical industries also have great interest in endorsing multidisciplinary systems chronotherapeutic as a cost-effective mean to improve drug development, which currently has a high failure rate  (Rosenblatt, 2017).
Indeed, physiologically-based mathematical models can be developed to assess patient-specific drug chronoefficacy and chronotolerability from multitype datasets measured through dedicated biomedical devices. Thus, this type of modeling allows for a priori in silico test of therapeutic response of individual patients to a specific drug combination and/or timing, thus providing a critical tool to assist the clinicians' decision to include a particular patient in a clinical trial. Ultimately, physiologically-based models can be used in optimization procedures to design personalization frameworks taking as inputs multitype datasets in the individual subject and outputting patient-tailored chronomodulated treatments. After its design though preclinical and clinical steps, the personalization algorithm needs to be validated through several clinical stages.
Signals are collected on an EEG recorder, via other electrodes also inserted into the medium. In this article, the influence of two different media, an electrolyte or a sponge wet with an electrolyte, are compared. An electrical circuit including so-called Constant Phase Elements (CPE)  (Diard et al. , 2013) ,  (Jorcin et al. , 2006) ,  (Zoltowski, 1998)  in order to capture the non-integer order of the system is proposed and its theoretical transfer function and properties are calculated. This enables to fit the experimental data and identify the parameters of the theoretical proposed system, from the arc paths of the transfer functions observed in the Nyquist representations. The article is constructed as follows: first the experimental setup and related empirical transfer function estimates are presented in section 2.
Signals are simulated in Python with Scipy modules  (Jones et al. , 2016). They are binded to an own-purpose library in C linked to the National Instruments library interfacing the DAC. Python and C codes are available in  (Becq, 2016). Home-made pure platinum electrodes are used in this study in order to avoid reduction-oxidation reactions at the contact of the electrodes with electrolytic solutions for potentials lower than E • Pt = 1. 2V at 25 • C  (Didier, 1984). Each electrode consists of a thin cylinder of platinum with a diameter of 0. 5 mm and a length of 1 cm, soldered on a copper wire. The solder junction is covered by a thin layer of epoxy resin for insulation. Two media are tested to compare their influences on the system: an electrolytic solution; a sponge fully wet with an electrolytic solution.
Thawing the tissue at room temperature for ~12 h and paring away the underlying fat layers using a scraping knife prepared samples (25 × 25 × 5 mm) for testing. Soaking in a bath of phosphate-buffered saline (pH = 7. 4) led to gradual uptake of water. The epidermal sensors and an analytical balance allowed measurements of thermal characteristics and the mass, respectively, of samples removed from the bath at several time points. Each evaluation involved three measurements from three separate sensors, for a total of nine measurements. The error bars in Figures  2c-f  represent the full range of these data. The process of fitting the data to determine the thermal conductivity and diffusivity involved a custom algorithm (MATLAB, Mathworks, Natick, Massachusetts, USA) based on the solution to the heat diffusion equation for a transient plane source.
Simulation of thermal and electrical fields Finite element analysis. Computational studies of the thermal and electrical responses relied on commercial software from ABAQUS 9 and COMSOL  10  , respectively. For the former, the encapsulation layer (Ecoflex), skin, and heater used axisymmetric heat transfer elements (DCAX4). For the latter, the encapsulation layer (Ecoflex), skin, and capacitor used axisymmetric electrical current elements.
Data consisted of recordings before, immediately after, and at 30, 60, and 270 min after application of the compound. A final measurement (300 min after initial application) on these same regions followed immediately after thorough cleaning and drying with an absorbent pad. At each measurement time, the epidermal devices yielded thermal and impedance data. A corneometer probe (Cutometer MPA 580; Courage+Khazaka GmbH, Köln, Germany) yielded hydration levels, captured in three sequential measurements. Additional standard sensors (Tewameter TM 300; Courage +Khazaka GmbH) provided data on transepidermal water loss. Thermal transport data included transient temperature responses from 14 individual thermal actuator/sensor elements, each sequentially activated with input power of 7 mW mm -2 for 2 s using custom data acquisition electronics.
Statistical analysis Scatterplot matrices of the descriptors as a function of time reveal pairwise relationships (Supplementary Figure  S2 ). Box plot representations (Supplementary Figure  S3 ) illustrate, for the different descriptors, raw responses and changes associated with treatments using creams with various glycerin content. Values corresponding to areas under the curves (AUC; Supplementary Figure  S4 ) summarize individual profiles, and appear for different glycerin content using density plots. All statistical analyses used SAS software release 9. 3, SAS Institute Inc. , Cary, NC, USA, and JMP statistical software release 10. 0 (JMP is a trademark of SAS Institute).
8, 9 andard protocol approvals and patient consents. Institutional ethical approval was obtained from all sites. Written informed consent was obtained from parents/guardians, and children provided assent. Statistical analysis. Clinical and MRI data were collected using a standard template. We report mean values (6SD) and/or medians (with interquartile ranges, IQRs) for continuous variables and frequency (percentage) for categorical variables. We created Kaplan-Meier survival curves to illustrate time to either a first clinical event consistent with CNS demyelination (defined as a new neurologic symptom and sign lasting $24 hours) or radiologic evolution where zero time was the date of the initial scan that met the 2010 criteria for DIS. We used Mann-Whitney U tests (continuous variables) and Fisher's exact tests (categorical variables) to examine the statistical significance of unadjusted associations between the outcomes of either a first clinical event or radiologic evolution, and demographic variables (e.
Two multicenter clinical trials, 1 using dimethyl fumarate and 1 using teriflunomide, are currently underway to test whether immunomodulatory treatment prevents or delays clinical evolution in adults with RIS. 24, 25 Treatment for children with RIS should be considered, after adequate controlled trials are performed, if our finding that RIS in children is associated with a substantial risk of developing a first clinical event is confirmed. One limitation of our study is that we analyzed historical data, and therefore, all clinical, MRI, and laboratory data were obtained in the past using nonstandardized MRI techniques, and timing and methods for the collection of clinical and laboratory data were not uniform. Prospective studies with standardized protocols are planned and will necessitate continued multinational collaborations.
Pharma; received travel funding and/or speaker honoraria from  Biogen ,  Bayer ,  Novartis ,  Sanofi ,  Almirall ,  Merck , and  Teva  and received research support from  FP7  and  PHRC. C. Carra-Dalliere  received travel funding from  Genzyme ,  Biogen , and  Novartis. J. de Seze  served on the editorial board for  Revue Neurologique. W. Du  reports no disclosures. F. Durand-Dubief  served on the scientific advisory board for  Merck Serono and Roche  and received travel funding and/or speaker honoraria from  Biogen ,  Merck Serono, Sanofi-Aventis ,  Genzyme ,  Novartis Pharma ,  Roche , and  Teva. O. Kantarci  received speaker honoraria from  Novartis Pharmaceuticals and Biogen ; did a grant review for the  National Multiple Sclerosis Society ; received research support from  European Regional Development Fund, National Multiple Sclerosis Society, Biogen ,  Multiple Sclerosis Society, Mayo Foundation ,  Hilton Foundation , and  Mayo Clinic ; received compensation for consulting activities from  Teva ; his spouse serves on the data safety monitoring board of  Takeda Global Research and Development Center, Inc , and the data monitoring boards of  Pfizer Inc and Janssen Alzheimer Immunotherapy ; and is funded by the  NIH and Minnesota Partnership for Biotechnology and Medical Genomics.
Six patients carrying a single pathogenic variant were further analysed on the gene panel. Patient S1760, who was homozygous for the p. Met34Thr variant, was also included for further studies because the clinical data were not coherent with the identified genotype (profound HL and enlarged vestibular aqueduct: EVA). The 49 DFNB1 pathogenic genotypes included 20 different variants: although c. 35delG represented 58% (57/98) of the pathogenic alleles, genetic heterogeneity was notable as most of the other variants were encountered only once or twice. Other NSHL genotypes. In 50 additional patients, pathogenic genotypes were identified in 18 different genes using MPS strategy (Supplementary Table  2 ). The data were categorized according to genotypes identified in truly non-syndromic genes and in those of the NSHL mimics (i.
Nominative licensing in the name of Dr. Roux was delivered by Agence de la Biomédecine. Hearing loss assessment. Audiometric data were collected from the various departments and obtained using calibrated audiometers according to the International Organization for Standardization ISO  28. In adults and children of at least 6 years old, bilateral air and bone conduction hearing thresholds (dB HL) were obtained for 0. 25, 0. 5, 1, 2, 4 and 8 kHz frequencies. For young children unable to undergo bilateral evaluation, open-field air and bone conduction thresholds were assessed using age-appropriate procedures (behavioural observation audiometry, visual reinforced audiometry or play audiometry). An electrophysiological assessment completed the audiological evaluation if necessary (i. e. auditory brainstem response thresholds, auditory steady state response, acoustic otoemission).
Data from universal newborn screening were collected for the youngest patients. Hearing loss degree was analysed according to the International Bureau for Audiophonology audiometric classification (https://www. biap. org/en/recommandations/recommendations/tc-02-classification/213-rec-02 -1-en-audiometric-classification-of-hearing-impairments/file), whereas other phenotype features were analysed according to the recommendations for the description of non-syndromic hearing loss  29. Sensorineural hearing loss was found in all cases. DFNB1 locus screening. The screening was performed as recommended by the EMQN DFNB1 guidelines  30  and included Sanger sequencing of GJB2 exons 1 and 2 and their flanking intronic regions and multiplex PCR as designed by del Castillo et al. 31  to detect the two large deletions encompassing part of the GJB6 gene, del(G-JB6-D13S1830) and del(GJB6-D13S1854).
As the two instruments have a similar output, the number of samples per run was the same (12 samples). The secondary analysis (mainly alignment and variant calling) was performed using the commercial software MiSeqReporter (v2. 5) for the MiSeq runs and LocalRunManager (v1. 3. 1) for the MiniSeq runs, these workflows being very similar. Variant Calling Files (VCFs) were automatically included in our in-house database system (USHVaM2), which also handled variant annotation. In addition, when the pathogenic genotype was unclear, the samples were re-analysed using an in-house pipeline (Nenufaar, https://github. com/mobidic/nenufaar), which performed the secondary analysis and annotation of the variants. In particular, Nenufaar uses more recent software than the commercial pipelines and is better at retrieving small indels.
For potential short STRC CNVs, binary alignment map (BAM) files were loaded into the integrative genomics viewer (IGV) software (v2. 3. 55)  34 in order to globally inspect the aligned sequence reads between the STRC gene and the ψSTRC pseudogene. Point mutations were validated with a long-range PCR assay specific to the STRC gene (specificity of the amplification was ascertained by the absence of the divergent c. 4057C > T base pair) followed by nested PCRs.
Variant classification. Variants were classified using a fully described method  35  (Supplementary Figure  1 ) that includes six classes from neutral to pathogenic and four classes of variants of unknown clinical significance. Variants predicting the inclusion of a PTC or located at canonical splicing positions (-2,-1, +1, +2 positions around exons) of isoforms described in pathology were considered a priori pathogenic. The main characteristics for missense classification were the familial segregation of the variant, its frequency in public databases, evolutionary conservation throughout orthologs and paralogs (domain conservation) and, when available, the impact on the 3D structure. 3D analysis of NP_002691. 1: p. (Phe322Ser) was performed using human Oct-1 homeodomain encoded by POU2F1 (Protein Data Bank ID: 1E3O) binding DNA as the model.
1E3O shares 56% amino acids identity with pou4f3 through residues 182-332 and 66% (12/18) for residues surrounding pou4f3 position 322 in helix 3 (residues 141-158). The pictures were built using the PyMOL software (The PyMOL Molecular Graphics System, Version 1. 8 Schrödinger, LLC). The potential impact on splicing for rare missense, isosemantic and intronic variants was also assessed using a local implementation of the MaxEnt algorithm  36  and, when available, using dbscSNV results  37. Minigene analysis was performed to experimentally verify the impact of selected variants on the splicing process, as described alsewhere  38.
Acknowledgements The authors are grateful to the patients and families. The authors acknowledge the clinicians  Dr. Khau Van  kien,  Dr. Dollfus ,  Dr. Perthus ,  Dr. Boucher ,  Dr. Leheup ,  Dr. Moutton ,  Dr. Drumare  and  Dr. Collignon , for referring patients. GGG was a recipient of the E-rare " EURUSH " project at the time of the study.
Electronic collection of VAS data in AR When a paper-based format is used, VAS readings (measuring the score with a ruler) takes up the greatest amount of time in terms of data analysis  [3]. This time expenditure is dispensed with by means of automatically programmed analysis of online data, e. g. , in the context of an app. The project group "MASK-Rhinitis" (MACVIA-ARIA Sentinel network) has developed a free smartphone app for patients called Allergy Diary and is currently developing a companion tablet-based app for healthcare providers (Allergy Diary Companion), both of which use a digitized VAS (Fig. 1 ;  [58] [59] [60] ). Daily symptom assessments are recorded in the MACVIA-ARIA app using a simple VAS, and VAS scores categorized as the degree of AR control. As recommended the VAS used is a simple line, with no incremental lines, with simple word anchors at either end.
Jean Bousquet et al. have tested and evaluated use of the app in real life, and the data obtained using the app, in a feasibility study. To this end, the data from the first 730 allergy diary users were tested. Analysis of the results attested to the app's high user friendliness, since all participants had answered the basic questions correctly. Furthermore, it was possible to identify simple phenotypical characteristics based on the app that helped rate rhinitis. For example, daily impairments, as well as impairments in working life, in patients with rhinorrhea appeared to be more pronounced the higher the number of symptoms noted by the user in the allergy diary app. However, the authors of the study concluded that their results need to be supported by the analysis of larger volumes of data obtained using the app (more app users), as well as further investigations.