dataesr/scientific-paragraphs-categorization huggingface dataset:
5 mm on at least one imaging examination  [12, 16] ; "pulmonary vascular impairment" was defined as pulmonary arteriovenous malformations (AVMs) on computerized tomography scan; "gastrointestinal vascular impairment" was defined as gastrointestinal haemorrhagic telangiectases on endoscopy performed because of gastrointestinal haemorrhage or anaemia not explained by epistaxis; "neurological AVMs" were defined as AVMs in the central nervous system as seen on computed tomography scan or magnetic resonance imaging; and "anaemia" was defined as a haemoglobin level 12 g/dL in women and 13 g/dL in men. The number of telangiectases was estimated by each HHT specialist physician on specific body sites (ears, lips, tongue and hands). A control population, among patients recorded in the database with no echocardiographic suspicion of PH, served for the evaluation of survival and risk factors.
Results Despite current recommendations, only 445 patients had undergone an echocardiographic examination among 2,598 patients with an HHT diagnosis in the database as of June 2014. Echocardiography was performed as part of systematic screening, because of symptoms (dyspnoea, cardiac insufficiency) or because of pulmonary or hepatic AVMs. Of these 445 patients, 119 were suspected of having PH. One hundred and ten patients (4. 2%) fulfilled our criteria for analysis (Fig 1 ), two of whom were children at the time of PH diagnosis. Among these 110 patients, 43 echocardiographic examinations were performed for systematic screening and 67 because of symptoms (54 for dyspnoea, 7 for fainting or chest pain and 29 for cardiac insufficiency). The control population comprised 326 patients.
Echocardiographic and RHC data Of the 110 patients suspected of PH, 47 (42. 7%) underwent RHC (between 1991 and 2014, performed by at least 12 different cardiologist experts and using non-harmonized protocols). In 38/47 (81%) patients, PH was confirmed. Among the 47 patients who underwent RHC, only 11 had been exclusively screened for PH by echocardiography without any recorded symptoms and 9/11 had confirmed PH, all of them with Group 2 PH. Among the 63 patients followed-up exclusively by echocardiography, cardiac index as assessed by echocardiographic estimation was high for the 29/35 (82. 9%) patients with available data.
Treatment and survival comparisons Five out of 7 patients in Group 1 were treated with PAH-specific pharmacotherapies and all patients in Group 2 were treated for high CO consequences (diuretics, salt restriction, atrial fibrillation management, etc. ) and significant hepatic vascular involvement (using bevacizumab and/or in some cases liver transplant). Patients with proven PAH seemed to have a lower life expectancy compared to controls (p = 0. 0009). This seems to be due to heritable Group 1 PAH (p<0. 0001) (Fig  3 ). Age at death and causes of death were collected in the database, as shown in Tables  5  and 6.
Within group 2 PH, as also reported by Lyle et al. [22] , 2 patients (cases 45 and 59) had elevated mPAP, normal PAWP and PVR < 3 WU, suggesting that PH can develop via high PAWP and/or high-flow state. These patients illustrate the difficulty in assigning patients to a specific group after only an RHC and the importance of follow-up. However, we distinguished 2 other groups. Most of the HHT patients had an isolated group 2 PH profile, but the description of more rarely described profiles (heritable Group 1 [4/38], Group 1 with high CO and moderately high PVR  [1/38] , post-and pre-capillary Group 2 [4/38]), may encourage clinicians to perform an RHC in patients with unclear echocardiographic patterns. Despite the recommendations, only 445/2,598 HHT patients had undergone echocardiography, as recorded in the CIROCO database  [23].
Data were not available on all variables of interest, including echocardiography, for every case reported in the database. Sixty-three patients out of 110 (57. 2%) surprisingly never underwent RHC. These were patients with a history of progressive elevation of CO and left ventricle filling pressure, with high sPAP when decompensated. In such cases, sPAP is the marker of stable or unstable heart disease. The natural history of isolated Group 2 PH has been described elsewhere: high CO, leading to left heart impairment, the occurrence of PH, then right heart impairment  [13, 14]. Among 38 patients with confirmed PH, we described 24 (63%) Group 2 PH patients. Of these 24 patients, 17 had complete available haemodynamic data, 13 of whom (76. 5%) had high CO. The threshold for cardiac index is debatable.
However, all patients had a clinical evaluation. Despite the screening recommendations for pulmonary AVMs, only 445 patients underwent echocardiographic screening, as shown in the database. Nonetheless, this is the largest cohort reported to date  [39, 40]. Another limitation, resulting in a major selection bias, is that only 43% of the patients with suspected PH underwent RHC. With the development and improvement of echocardiography, the need for RHC has decreased. This limits our results on the frequencies of the haemodynamic forms of PH. Performing RHC more systematically in HHT would help to understand the mechanisms of PH. A standardized protocol of evaluation should be proposed, as has been done for other pathologies presenting this risk  [41] [42] [43] [44]. In conclusion, group 2 PH is far more frequent than other groups, but several mechanisms can lead to PH.
Study design In France, the public health authorities created a national pharmacosurveillance system in 1994 for FVIII and factor IX products administered to hemophiliacs. 23 Clinicians of all hemophilia treatment centers were invited to include all hemophilia patients in an observational open cohort. In 2003, this system was renamed FranceCoag and inclusion was extended to other hereditary bleeding disorders. The high observed average prevalence of hemophilia A at birth (23. 3 cases per 100 000 male live births for 1991-2008) compared with prevalences in other industrialized countries supports the exhaustiveness of this registry. 11, 24 Since 1994, PUPs with hemophilia (FVIII or factor IX <2 IU/dL) have been enrolled in a sub-cohort with detailed follow-up and data collection to investigate risk factors for inhibitor development and the impact of prophylaxis.
F8 gene defect, family history of hemophilia and inhibitor, ethnic origin) were recorded at inclusion or shortly thereafter. Quarterly visits were recommended until ED-150. At each follow-up visit, hemorrhagic events, surgical procedures, treatments received and results of all inhibitor assays since the previous visit were accurately recorded. All data were centralized via a dedicated website. In parallel, details of the first 75 EDs [date, reason(s) for treatment, FVIII product, dose and body weight] were recorded on a spreadsheet for each patient from his own booklet and hospital records. Data were automatically checked for inconsistencies and closely monitored by three dedicated clinical research assistants who compared the database with the original files in the centers.
Follow-up was censored upon any switch of product, so this factor was considered as fixed and Factane was chosen as the reference. 0] [31]  Crude and adjusted hazard ratios with 95% confidence intervals (95% CI) were reported for Advate versus Factane and then for Kogenate versus Factane. Stata statistical software release 13. 1 (College Station, TX StataCorp LP, USA) was used for all analyses and figures. For cofactor definitions, grouping, missing data procedures, and propensity score analyses, see the Online Supplementary Methods.
Selection and characteristics of the patients In all, 649 children with hemophilia A were included by 35 centers in the FranceCoag PUP cohort between 1994 and 2016. For this analysis, 120 ineligible patients were excluded (Figure  1 ). The 29 patients excluded due to insufficient data were first treated with nine well-balanced FVIII products. An inhibitor was diagnosed before ED 75 in five of them (first treated with five different FVIII products). Among the remaining 529 patients, 144 were first treated with plasma-derived FVIII products and 385 with recombinant products. We analyzed three product groups (Factane, Advate and Kogenate) which were sufficiently large to provide informative comparisons. Calendar period being a potential confounder, we excluded two patients first treated with Kogenate 2 years before its marketing authorization.
Acknowledgments The authors thank  Dominique Costagliola  for critical review of the manuscript and helpful discussions. We also thank all the contributors from the  FranceCoag Network , patients and their parents or legal guardians for their participation. TC thanks  Jennifer Markovic  for English editing assistance. The French hemophilia surveillance system (" Suivi thérapeutique National des Hémophiles " since 1994 and "FranceCoag" from 2003 onward) is fully supported by the public health authorities. Additional data collection for the first 75 exposure days was partially supported by the  French National Clinical Research Program  (2009) and by  Assistance Publique -Hôpitaux de Marseille.
Functional Analysis The multimodal measurement setup used in this study enables reproducible and highly accurate measurements of multiple aspects of the phonatory process within an ex vivo setting. 10  The frozen harvested larynges were thawed overnight, prepared as previously described,  11, 12  and mounted in the ex vivo setup in which measurements of the sound produced during phonation were made while adjusting air flow through the larynx and the loading of the vocal apparatus A detailed protocol is described in the Supplemental Information. In total, 768 measurement runs were performed. The analysis was performed in MATLAB version R2017b (The MathWorks, Inc, Natick, MA, USA). IBM SPSS software package version 28 (IBM, Armonk, NY, USA) was used for statistical analysis (Mann-Whitney U test).
Micro Computed Tomography After the completion of the functional analyses, the larynges were immersed in 4% phosphate-buffered formalin solution for fixation and processed further as previously described,  11  with minor modifications. Bruker SKYSCAN 1276 X-Ray Microtomograph (Bruker Corporation, Billerica, Massachusetts, USA) with a maximum spatial resolution of 20 μm was used to generate CT images, whereas the scanning protocol was set using SKYSCAN 1276 measurement software. Volumes and diameter of the left and right TAM were averaged to obtain one value per sheep, except for one sheep, were a large sarcocystis was found within the right TAM. Statistical analysis was performed with SPSS (Mann-Whitney U test).
Triple Immunofluorescence Labeling of Cryosections Cryosections (10 μm) were prepared from frozen muscle samples and correct orientation of specimens was confirmed via standard haematoxylin and eosin staining. Subsequently, sections on Superfrost Plus microscope slides (Thermo Scientific, Waltham, MA, USA) were subjected to triple immunofluorescence labeling based on a previously described method. 7, 13  A detailed protocol can be found in the Supplemental Information. In total, 34,558 fibers of the TAM were analyzed, 15,694 in the stimulated and 18,864 in the sham group. A total of 31,483 PCAM fibers were analyzed, 14,195 in the stimulated and 17,288 in the sham group. A Generalized Estimating Equations model  14, 15  was used to compare treatment, fiber type, and minimum feret diameter using SPSS.
Introduction The Antarctic balloon-borne experiment Cosmic Ray Energetics And Mass (CREAM) has successfully completed seven flights between the years 2004 and 2017, and collected data for a total of 191 days during these flights. It observed a discrepant hardening in the energy spectra of cosmic rays  [1]. The International Space Station (ISS) is an ideal platform to further investigate the unexpected hardening as well as explore fundamental issues like the acceleration mechanism and the origin of energetic cosmic rays because of the high duty cycle of experiments on the ISS platform. Thus, the space-borne experiment ISS-CREAM stationed to be deployed to the ISS is an obvious next step towards further investigation and exploration of the outstanding issues with high-statistics. The ISS-CREAM experiment adapts the detector concept and technology proven with the balloon-borne CREAM experiment.
4  shows the distribution of pedestal tail plus muon signals in each pixel of the sensor from the data taken before the space environment tests, while the unshaded histogram shows the distribution from the data taken after all space environments tests. Before and after the space environment tests, muon data were taken for 4 hours and 22 hours, respectively. Obviously the statistics of the data taken before the environments tests were poor, but the number of pixels with muon signals observed remained the same before and after the space environment tests. Shown in the right of Fig. 4  are the zoomed distributions of pedestal tail plus muon signals detected in the thirteenth pixel where open and solid circles represent the distributions from data taken before and after the space environment tests, respectively.
Acknowledgments The authors thank  NASA GSFC WFF  for project management and engineering support, and  NASA   JSC ISS Program Office  for launch support and the  ISS accommodation. This work was supported in the U. S. by  NASA  grants  NNX11AC52G ,  NNX08AC15G ,  NNX08AC16G  and their predecessor grants, as well as by directed RTOP funds to  NASA GSFC WFF. It was supported in Korea by the  Creative Research Initiatives of MEST/NRF , and by  National Research Foundation  Grants  NRF-2014R1A2A2A01002734 ,  NRF-2014R1A1A2006456 ,  NRF-2015R1A2A1A13001843. It was supported in France by  IN2P3/CNRS  and  CNES  and in Mexico by  DGAPA-UNAM  and  CONACYT. The authors also thank  H. S. Choi ,  Korea Institute of Industrial Technology , for contributions to the SCD thermal vacuum tests,  M. Geske ,  Penn State , for contributions to the  BSD , and  M.
Data processing and statistical analysis. Peaks were manually integrated on chromatograms using the Qual Browser module of Thermo XCalibur version 2. 1. 0 mass spectrometry software, based on mass spectra and the retention time of each integrated peak relative to fluorobenzene. Both peak detection and intensity relative to fluorobenzene were recorded. Compounds found in control samples (clean towel or Milli-Q water) were excluded from further analysis. Peak identities were determined by comparison of their averaged, baseline subtracted mass spectra with those contained in the NIST 2011 / Wiley 9 Combined Library of Mass Spectra using NIST MS Search Version 2. 0 g R1 software. Peak matches with a score greater than 900/1000 were considered valid. Statistical analyses were carried out in Primer v6  55.
Following a fourth root transformation of the dataset, we ran one-way ANOSIM analyses (based on a Bray-Curtis index), to look for differences in the presence and relative abundance of chemical compounds between marsupial and placental predators, and among the predator species sampled. We conducted pairwise comparisons to further investigate species differences. A nonmetric multidimensional scaling (nMDS) plot was used to visualize differences between tested groups (created using package VEGAN 56 in R 3. 2. 2  57 ). Similarity percentage analyses (SIMPER  55  ) were conducted to determine whether differences among groups were determined by a few or multiple compounds. Finally, PERMDISP was run for each analysis (as recommended by Clarke & Gorley  58  as an accompaniment to ANOSIM procedures), to confirm that the different groups had similar levels of dispersion to one another -i.
EC preparation Mouse lung ECs were isolated from three adult mice per genotype, as previously described  [13]. The purity of ECs prepared with our method has been established  [2]. Anti-ICAM2 clone IC2/4 (3C4), (Abd Serotec, Martinsried, Germany); anti-VECAD clone 11D4. 1; (BD Biosciences San Joe, CA, USA) were used to assess EC purity by flow cytometry on a Becton Dickinson, Oxford, UK, FACSCalibur instrument. As a negative control, IgG-matched isotypes were used (data not shown). Cells were immortalized by two rounds of infection with polyoma virus middle T  [14]. To ensure maximal Cre-induced recombination, lung ECs isolated from Cre-positive mice were transfected with a Cre-encoding plasmid (pCAG-Cre-IRES2-GFP; Addgene, Cambridge, MA, USA 26646), and cells isolated from Cre-negative mice were transfected with the corresponding plasmid backbone (pCAG-GFP; Addgene 11150).
Quantitative polymerase chain reaction (qPCR) analysis demonstrated loss of endogenous mouse FAK mRNA in Cre+;FAK WT/WT but not Cre-;FAK WT/WT ECs and hearts (Figure  2B ). Together, these data indicate that the knockin WT chicken FAK was expressed and that the endogenous mouse FAK was deleted in ECs from ECCre+;FAK WT/WT mice and in vivo. Loss of EC FAK in adult mice reduces tumour growth and tumour angiogenesis  [2]. To show that WT chicken FAK could reproduce the effects of endogenous mouse FAK in vivo, we first examined tumour growth and angiogenesis in Pdgfb-iCre ert ;FAK fl/fl ;R26FAK WT/WT mice. ECCre-;FAK WT/WT and ECCre+;FAK WT/WT mice were injected subcutaneously with 1 million syngeneic mouse B16F0 melanoma cells, and tumour growth was measured over time. There was no difference in tumour growth between ECCre-;FAK WT/WT and ECCre+;FAK WT/WT mice (Figure  2C ).
Bioinformatics considerations The bioinformatic process, used to analyze and interpret BRCA1/ 2 mutational analysis results, is a critical part of the whole testing process and requires as much consideration, validation, and accreditation (eg, ISO15189 or CLIA) as the laboratory methods selected to perform the BRCA1/2 mutation analysis. Individual samples in a pooled reaction must be identified and de-multiplexed according to the indices used in the library preparation and the raw data aligned to the reference sequence. Any variations between the reference sequence and the test samples need to be identified by appropriate variant-calling algorithms, correctly annotated using human genome variant society (HGVS) nomenclature, and classified through interrogation of internal and external databases (list provided in Appendix A).
Information security management is important where sensitive information is shared, such as in database queries or variant annotation processes, and local and international legislation relating to this issue must be adhered to. The ISO 27001 is an internationally recognized best practice framework for an information security management system, which is important for bioinformatics platforms that share information among users or manage information from clinical scenarios. Mutation detection threshold levels that are suitable for detecting germline mutations will need to be modified to detect potentially low-variant frequencies of somatic mutations. There is no set recommendation to where this level should be, as this depends on the performance criteria for the test, including any pre-analytical steps such as DNA yield, test DNA input, and neoplastic cell content.
The bioinformatics processes should be validated on all BRCA1/ 2 mutation types. If laboratories do not have access to a sufficient spectrum of data, there is an increasing repository of NGS data in the public domain. This data could be a useful tool to ensure that all variants are being identified, characterized and classified using a laboratory's own pipeline. There are a number of international initiatives for the sharing of genetic data: ENIGMA is a consortium of investigators focused on determining all unclassified variants and variants of unknown significance (VUS) in BRCA1 and BRCA2. The BRCA Challenge is a joint initiative of the Global Alliance for Genomic and Global Health and the Human Variome Project, involving several hundred institutes and academic organizations around the world, which aims to pool global available data on BRCA1/2 genetic variants to further the understanding of BRCA1/2 genetic variation.
Reporting tumor BRCA1/2 results Recommendations for information to include when reporting BRCA1/2 testing results are listed in Table  4. The minimum dataset required in a clinical report for tumor BRCA1/2 testing should include: • Suitability of the tumor sample, including neoplastic content estimation, cellularity, and whether these are acceptable for the specific testing method • Targets analyzed (ie, BRCA1 and/or BRCA2) • The regions covered for each gene (eg, coding region only or intronic and exonic regions) • Overall results: either pathogenic or deleterious variants present or absent • Mutation details (when present): cDNA and amino acid change according to HGVS nomenclature • Reference sequence, including version used for annotation and HGVS nomenclature • Summary and interpretation: including pathogenic or likely pathogenic classification of the identified variants.
Should genetic testing be limited to BRCA1/2 testing? Currently, genetic testing in OC should be limited to BRCA1/2 for clinical-and therapeutic-driven decisions, as indications to date are restricted to these genes. However, additional genes involved in the HRR pathway are being evaluated in a number of clinical trials (NCT02422498, NCT02489058, and NCT01434316) and are likely to become part of the standard testing methodology in the future  [73]. A recent study has shown increased efficacy of PARPi in OC with HRD without a germline BRCA1/2 mutation  [14].
Recommendations for information to be included when reporting tumor BRCA1/2 results. College of American Pathologists; CLIA, Clinical Laboratory Improvement Amendments; DNA, deoxyribonucleic acid; EMQN, the European Molecular Genetics Quality Network; EQA, external quality assessment schemes; LOH, loss of heterozygosity; NGS, next generation sequencing; PARPi, poly (adenosine diphosphateribose) polymerase inhibitor; PGM, personal genome machine; QUIP, Arbeitsgruppe für Qualitätssicherung in der Molekularpathologie der Österreichischen Gesellschaft für Pathologie; UK NEQAS, United Kingdom National External Quality Assessment Service; UMD, Universal Mutation Database; VUS, variants of unknown significance.
If the tools are web based, include the https address Requested databases for grading of detected mutation UMD and ClinVar-DB, etc. Variant allele frequency It is important to correlate with neoplastic tumor content and potential LOH, which is present in the vast majority of cases Explanation of therapeutic consequence of mutations Mutation class 4 or 5 ~pathogen ¼ possibility of therapy with PARPi; mutation class 1-3 or wild according to the classification of the variants type ¼ no therapeutic consequence and should not be reported (see text for VUS) A recommendation of germline analysis and genetic Germline analysis should be always considered if not already performed counseling in cases of pathogenic mutations Accreditation of the laboratory ISO15189, CAP, CLIA or equivalent Participation in EQA For example: EMQN, QuIP, UK NEQAS Abbreviations: CAP,.
Acknowledgment:  L. Hawelek  is acknowledged for a grant from the  National Science Center, Poland  ( 2011/01/D/ST5/07816 ). A. Kolano-Burian ,  P. Wlodarczyk ,  M. Kowalczyk  and  M. Polak  are acknowledged for a grant from  NCBR ,  Poland  (grant No. PBS2/A5/36/2013 ). Acknowledgments:  L. Hawelek  is acknowledged for a grant from the  National Science Center, Poland  ( 2011/01/D/ST5/07816 ). A. Kolano-Burian ,  P. Wlodarczyk ,  M. Kowalczyk  and  M. Polak  are acknowledged for a grant from  NCBR ,  Poland  (grant No. PBS2/A5/36/2013 ).