dataesr/scientific-paragraphs-categorization huggingface dataset:
FFullA I G U R E 1 Flow diagram of study selection process Records identified through database searching and manual searches (n = 1661) Records screened (n = 1555) systematic review of the literature was conducted in order to identify clinical studies evaluating the use of oral midazolam in pediatric patients in the context either of premedication before anesthesia for surgical procedures or during diagnostic or treatment procedures. Articles were identified from electronic resources including PubMed and ScienceDirect (eg, MEDLINE search ("midazolam"[MeSH Terms] OR "midazolam"[All Fields]) AND "sedation"[All Fields] AND ("child"[MeSH Terms] OR "child"[All Fields] OR "children"[All Fields]) AND ("pediatrics"[MeSH Terms] OR "pediatrics"[All Fields] OR "pediatric"[All Fields])) and by manual searches from further evaluation of key review articles and bibliographies of articles.
Background: The NAPOLI-1 study (NCT01494506) reported that liposomal irinotecan plus 5-fluorouracil and leucovorin (nal-IRIþ5-FU/LV) improved overall survival vs 5-FU/LV with manageable toxicity in patients with metastatic pancreatic adenocarcinoma previously treated with gemcitabine-based therapy. Yet, clinicians need treatment strategies that.
Recently, the US Food and Drug Administration, European Medicines Agency and other regulatory bodies approved liposomal irinotecan (nal-IRI; Onivyde â ; MM-398) in combination with 5-fluorouracil/leucovorin (nal-IRIþ5-FU/LV) for patients with mPDAC who have progressed following gemcitabine-based therapy. nal-IRI is a liposomal formulation of the topoisomerase I inhibitor, irinotecan. Liposomal encapsulation protects irinotecan from premature hepatic conversion to the active metabolite SN-38, resulting in extended availability and enhanced intratumoral drug deposition  [11e13]. After deposition, phagocytic cells convert nal-IRI to SN-38, increasing its activity by approximately 100-to 1000-fold  [11e14]. The NAPOLI-1 study was a global phase III, randomised, open-label, multicentre study (NCT01494506) that tested nal-IRI monotherapy or nal-IRIþ5-FU/LV vs 5-FU/LV alone in patients with mPDAC previously treated with gemcitabine-based therapy.
Two types of missing data, namely domain nonresponse (a patient completed at least one but not all domains of the questionnaire at a particular time point) and unit non-response (a patient completed no domains for a particular time point), were analysed. Patterns of missing data were also evaluated. Monotone (terminal) missingness is unit non-response followed by no subsequent completion of an EORTC QLQ-C30 domain during the treatment period. Monotone missingness occurs when a patient leaves the study and never returns, possibly because of death or study discontinuation  [23]. Intermittent missingness is unit non-response followed by a complete (non-missing) domain at any subsequent time point during the treatment period. Intermittent missingness may occur when a patient misses a particular visit but returns at later scheduled visits  [23].
HRQOL was evaluated in the PRO population (patients in the FPRO population who completed the baseline and at least one subsequent assessment on the EORTC QLQ-C30). Demographic and clinical variables of the PRO and ITT populations were compared for representativeness. Missing data patterns were analysed in the FPRO population. The primary endpoint of the NAPOLI-1 study was OS, and it was not powered for detecting differences in HRQOL, a secondary endpoint. Descriptive statistics are reported for the EORTC QLQ-C30 score and change (%) from baseline, by patient visit and by treatment arm. Response was classified by treatment arm. Duration of improvement was calculated for patients classified as improved. Pairwise treatment group comparisons were performed on response classification for each subscale using CochraneManteleHaenszel testing, and corresponding P values were presented.
The vast majority of missing data were explained by terminal missingness, the most frequent reason being progressive disease. This is consistent with other reports in mPDAC and reflects patient attrition typically observed in end-stage cancer studies  [19, 28, 29]. As patients discontinued the study, EORTC QLQ-C30 compliance decreased. A more frequent HRQOL assessment may have increased data capture. It is unclear whether the improvements in HRQOL at week 12 were due to selection of patients with better HRQOL via attrition of patients with worsened QoL at week 6. It would be expected for this to be noted particularly with 5-FU/LV alone, as treatment discontinuation and progression were observed earlier in this arm  [15]. Another reason could be general amelioration of sideeffects over time  [30].
HRQOL improvements could also be due to adequate dose reductions and supportive measurements, improvement of disease symptoms via treatment of side-effects, or a combination of all these factors. Other study limitations include a potential reporting bias because of the open-label design of the NAPOLI-1 study and a limited power to detect significant HRQOL differences between the two treatment arms. Additionally, the EORTC QLQ-C30 is a general questionnaire and may have failed to capture all nuances of mPDAC. Despite these limitations, this study provides randomised trial data on HRQOL, an important clinical insight.
Acknowledgements and role of the study sponsor The authors thank the patients and their families for their participation in the study. The NAPOLI-1 study (ClinicalTrials. govidentifier:  NCT01494506 ) was sponsored by  Merrimack Pharmaceuticals, Inc. , Cambridge, MA,  USA. The HRQOL analyses and first data presentation were performed by  Merrimack Pharmaceuticals, Inc. ; the rights for nal-IRI now reside with Ipsen in the USA (April 2017);  PharmaEngine, Inc. holds the rights in Taiwan; Servier holds rights in the rest of the world through a licensing agreement with  Ipsen. Bruce Belanger  ( Merrimack Pharmaceuticals, Inc. at the time of the study, now Ipsen) was responsible for statistical analyses of the HRQOL data. Medical writing and editorial support were provided by  Doyel Mitra, PhD , of  ApotheCom (Yardley, PA, USA ) and  Florian Szardenings  of  Physicians World Europe GmbH, Mannheim, Germany , and funded by  Shire, Zug, Switzerland.
To ensure the accuracy of injection and precision in the quantity of the cells injected, we used highresolution echocardiography to guide the needle into the left ventricle. In Fig. 5e , the needle's position is discernible. Mice were imaged for firefly luciferase expression in the tumor cells at multiple time points post-injection. Quantitative bioluminescence imaging data show a marked decrease in lung cancer brain metastasis in Mito-LND-treated mice but not in those treated with LND (Fig. 5f, g ). Similar effects of Mito-LND were also observed in the A549 brain metastasis mouse model (Supplementary Fig. 11C, D ). Maximum tolerated dose and safety of Mito-LND. We conducted an 8-week toxicology study of Mito-LND in mice, including a Modified Irwin Screen (a comprehensive observational battery to screen for central nervous system effects)  38.
Based on our results, we propose that Mito-LND decreases cell viability and induces autophagic cell death in H2030, H2030BrM3, A549, and NCI-H460 lung cancer cells. The role of autophagy in human lung cancer progression, metastasis, and prognosis is still an emerging area of research. In a study of >100 patients, high BECN1 expression correlated with well-differentiated NSCLC and reduced lymph node metastasis. The same study reported that low BECN1 expression coupled with high P62 expression is significantly associated with shorter patient survival time  51. Similarly, an mRNA expression database (containing 440 lung adenocarcinoma cases) for pro-autophagy markers was queried and the results showed that high expression of BECN1, ATG12, and DRAM1 are closely linked to increased survival among lung adenocarcinoma patients (Fig.
Immunoblotting was performed as described for the cell lines. Statistical analysis. GraphPad Prism software was used for evaluating statistical differences between treatments. Student's t-test was applied for pairwise comparisons. For assessing multiple comparisons (e. g. , inhibition of viability data) we used ANOVA with Tukey's post-hoc test. p-Values of < 0. 05 were considered significant. Reporting summary. Further information on research design is available in the Nature Research Reporting Summary linked to this article.
Acknowledgements The authors are grateful to  Dr. Joan Massage  ( Memorial Sloan Kettering Cancer Center ) for providing the H2030BrM3 cells. This work was supported by  NIH   R01CA232433  (to M. Y. , B. K. and L. K. ),  NIH   R01CA208648  (to M. Y. and B. K. ),  NIH   R01CA152810  (to B. K. ),  NIH   CA205633  (to M. Y. ) and  NIH   R01CA158319  (to L. K. ). The authors would like to thank the  University of Michigan Flow Cytometry Shared Resource Laboratory  which is supported by the  University of Michigan Rogel Cancer Center support  Grant  P30CA046592.
1 Cycle Sequencing Kit on an ABI PRISM 3100 automatic sequencer (Applied Biosystems). Nucleotide sequences were then compared with those present in leBIBI  [23]  and National Center for Biotechnology Information (NCBI) databases. For all specimens of the spondylodiscitis group (cases and controls), specific detection of M tuberculosis was performed with the Artus M tuberculosis RG PCR kit in a Rotorgene-300 PCR cycler (QIAGEN) according to the manufacturer's instructions.
Acknowledgments Financial support. This study was funded by a grant from  Assistance Publique des Hôpitaux de Paris (Direction de la Recherche Clinique et du Développement ;  CRC 06 057 ). Potential conflicts of interest. All authors: no reported conflicts of interest. All authors have submitted the  ICMJE Form for Disclosure of Potential Conflicts of Interest. The MOLOS study Group is composed of  Nicole Desplaces  ( La Croix Saint Simon Hospital ),  Thomas Bauer  ( A. Paré Hospital ),  Fréderique Larousserie  ( Cochin Hospital ),  Edouard Pertuisset  ( Pontoise Hospital ),  Valérie Chicheportiche  ( La Croix Saint Simon Hospital ), and  Martin Rottman  ( Raymond Poincaré Hospital ) and the collaborators of the study in  Saint-Louis-Lariboisière-Fernand Widal University Hospital (Laurent Sedel ,  Philippe Orcel ,  Thomas Bardin ,  Anne Allard ,  Jérémy Ora ,  Hang-Korng Ea ,  Olivier Peyr ,  Olivia Tran ,  Abdourahmane Diallo ,  Laurence Guery ,  Véronique Jouis ,  Laurent Raskine ,  Faiza Mougari ,  Gauthier de Ponfilly ,  Hanaa Benmansour ,  Emmanuel Lecorche ,  Marie-José Sanson-Le-Pors ,  Jacques Riahi ,  François Camelena ,  Thibault Poncin ,  Bassam Hamze ,  Jean-François Bergmann ,  Anne-Lise Munier , and  Amanda Lopes).
Human skeletal muscle FAP and MP isolation FAPs and MPs were isolated by a standard method  [13, 14]. Adherent cells derived from the digestion and amplification of healthy and DMD skeletal muscle biopsies were sorted by flow cytometry with the BD FACSARIA II sorter equipped with 4 lasers and the FACSDiva software (Becton, Dickinson and Company, Franklin Lakes, USA). Briefly, about 2 000 000 cells were labelled with anti-CD56-APC and CD140a-PE (PDGFRα) antibodies or the relevant isotype control in PBS 1X, EDTA 2mM and 10% FBS for 30 minutes at 4°C. The labelled-cell suspension was filtered through 40-µm cell strainers, pelleted by centrifugation and re-suspended in PBS/EDTA/Fetal bovine serum for isolation by the flow cytometer. For CD140a-PE, fluorescence was excited with the 561-nm laser and measured with a 586/15 bandpass filter.
Immunofluorescence analysis Cells plated on slides were fixed with Histofix 4% (Carl Roth, Lauterbourg, France) for 10 minutes, permeabilized and saturated with 0. 1 % Triton X-100 / 3% bovine serum albumin for 30 minutes at room temperature, and sequentially incubated with primary antibody (Sigma-Aldrich) overnight at 4°C then with secondary antibody for 45 minutes at room temperature. PBS wash was performed three times between all steps. Cells were finally mounted in Mowiol containing DAPI and visualized with an Axiovert microscope (Carl Zeiss, Le Pecq, France) under oil immersion and pictures were captured and treated with AxioVision software (Carl Zeiss).
Acknowledgements We thank  JY. Kurzenne  ( Hôpitaux pédiatriques de Nice CHU-Lanval, Nice, France ) for providing muscle biopsies from healthy donors, and  Myobank-AFM Institut de Myology, Paris, France  for providing muscle biopsies from Duchenne muscular dystrophy donors. The authors greatly thank  Agnès Loubat  from  Institut de Biologie Valrose, Nice , for FAP and MP purification from human skeletal muscle biopsies.
Funding Sources This work was supported by the  Association Française contre les Myopathies (AFM) , (through grants # 15294 , # 16063 , and # 17708  and a PhD fellowship for CM) and the  Netherland Duchene Parent Project. The  French Government (National Research Agency, ANR)  supported this work through the  "Investments for the Future" LABEX SIGNALIFE: program  reference #  ANR-11-LABX-0028-01.
STAR+METHODS METHOD DETAILS Plasmids for protein expression EGFP-GPHN was previously described  (Fossati et al. , 2016)  and it was used to visualize inhibitory synapses. HA-tagged mouse grid1 (gift from Ludovic Tricoire, IBPS, Paris, France) was inserted into pCAG vector by PCR between XhoI and BsrGI to obtain pCAHA GluD1 or between XhoI and KpnI to obtain pCAHA GluD1-EGFP. EGFP was then replaced by mOrange between KpnI and NotI to generate pCAHA GluD1-mOrange. pCAG_PSD95. FingR-EGFP-CCR5TC and pCAG_GPHN. FingR-EGFP-CCR5TC were purchased from Addgene  (plasmids #46295 and #46296, respectively). Mouse ppp1r12a (GenBank: BC125381, cDNA clone MGC:159084 IMAGE:40129896) and human CDC42BPA (encoding MRCKa, GenBank: BC136333, cDNA clone MGC:167943 IMAGE:9020320) cDNAs were obtained from Dharmacon and subcloned by PCR into pCAG vector between AgeI and BsrGI or AgeI and NotI, respectively.
Both constructs were Myc-tagged by inserting a DNA cassette containing a start codon and 3x-Myc between AgeI and KpnI. Human ARHGEF12 (gift from Moritz B€ unemann, Marburg University, Germany) was inserted into pCAG vector by PCR between AgeI and BsrGI. Indicated mutations were introduced in grid1, CDC42BPA, ppp1r12a, and ARHGEF12 using the QuickChange mutagenesis kit (Agilent). Mouse cbln2 (GenBank: BC055682, cDNA clone MGC:66500 IMAGE:6412317) and cbln4 (GenBank: BC094540, cDNA clone MGC:106619 IMAGE:5708067) cDNAs were obtained from Dharmacon and subcloned by PCR into pCAG vector between AgeI and NotI. The three constructs were Myc-tagged at the N terminus by inserting a DNA cassette containing a start codon, the signal sequence of Cbln1 (for Cbln2) or of Cbln4 (for Cbln4) and one Myc tag between EcoRI and AgeI.
Confocal image acquisition Confocal images were acquired in 1024x1024 mode using Leica TCS SP8 confocal laser scanning platforms controlled by the LAF AS software and equipped with a tunable white laser and hybrid detectors (Leica Microsystems) or, for slices infected with AAVs expressing TagBFP, in 512x512 mode using an inverted microscope (Nikon Ti PSF) equipped with a CSUX1-A1 Yokogawa spinning disc and an EMCCD camera and controlled by the Metamorph software (Molecular Devices). We used the following objective lenses: 10X PlanApo, NA 0. 45 (identification of electroporated neurons and low magnification images) and 100X HC-PL APO, NA 1. 44 CORR CS (Leica) or 100 X HC-PlanApo, NA 1. 4 (Nikon) (images of spines, gephyrin and PSD-95 clusters and association between GluD1, immunostained gephyrin and PS-D95 or Gephyrin.
A gephyrin or PSD-95 cluster labeled with EGFP-tagged FingRs was considered associated with GluD1 if it overlapped with a GluD1-mOrange puncta. mEPSC and mIPSC analysis Data were sampled at 10 kHz and filtered at 2 kHz. Miniature currents were analyzed over 1 min periods using pClamp 10. 0 (Molecular Devices). Cells showing > 20% change in access and input resistance upon application of 5 mV hyperpolarizing steps of current were excluded from the analysis. Overlapping events were excluded from amplitude analysis. Cumulative probability graphs were obtained by taking the first 200 events within the analyzed time window of each recorded cell.
Proteomic analysis For protein identification, data were searched against the Mus musculus (Mouse) UniProt database using Sequest HF through proteome discoverer (version 2. 1). Enzyme specificity was set to trypsin and a maximum of two missed cleavage site were allowed. Oxidized methionine, N-terminal acetylation, and carbamidomethyl cysteine were set as variable modifications. Maximum allowed mass deviation was set to 10 ppm for monoisotopic precursor ions and 0. 6 Da for MS/MS peaks. The resulting files were further processed using myProMS  (Poullet et al. , 2007) v3. 6 (work in progress). FDR calculation used Percolator and was set to 1% at the peptide level for the whole study.
Statistics Data are a minimum of three independent experiments. For in utero electroporations and AAV injections, data were obtained from at least three experiments or three animals from two independent litters. For statistical analysis, we first checked the normality of the distributions using the D'Agostino-Pearson normality test. In case of normal distributions, we used unpaired Student's t test or one-way analysis of variance followed by Tukey's post test. Non-normal.
ACKNOWLEDGMENTS We thank members of  A. Triller's laboratory (IBENS, Paris, France) ,  D. Stroebel ,  P. Paoletti ,  M. Casado ,  F. Selimi , and  F. Polleux , for helpful discussions and comments on the manuscript;  P. Rostaing  for his help with electron microscopy;  L. Tricoire  for kindly providing anti-GluD1 antibody and HA-GluD1 plasmid; M. B€ unemann for ARHGEF12 plasmid; and  B. Roska ,  D. B. Arnold , and  F. Zhang  for plasmids available through Addgene. This work was supported by  INSERM , the  Agence Nationale de la Recherche  ( ANR-13-PDOC-0003  and  ANR-17-ERC3-0009  to C. C. ), the  European Research Council  ( ERC starting grant   803704  to C. C. ), the  Fyssen Foundation  (to C. C. ), the Region  Ile-de-France  (to D. L. ), and the  Fondation pour la Recherche Medicale  (to D.
L. ). We are grateful to the  IBENS Imaging Facility (France BioImaging , supported by  ANR-10-INBS-04 ,  ANR-10-LABX-54  MEMO  LIFE , and  ANR-11-IDEX-000-02 PSL* Research University , ''Investments for the future''; NERF 2011-45; FRM DGE 20111123023; and  FRC Rotary International France) , the IBENS acute transgenesis facility, and the imaging unit of the  Humanitas Clinical and Research Center.
SBF-SEM imaging and correlation of optical and EM datasets To maximise the chances of successful correlation (i. e. revisiting the same structure in both LM and SBF-SEM), we used a dual monitor workstation that allows both the optical sections and 'live' acquisition of EM data to be viewed simultaneously (Fig. S3A ). Consecutive survey sections (∼200 nm thick) were acquired (Fig. 2A ) until biological fiducials were revealed, present in both the LM and EM datasets (Fig. 2Bi ,ii, red arrows). These 'landmarks' allowed the position of yet-to-be-sectioned targets to be accurately estimated, in both X-Y (Fig. 2Biii ) and Z planes (Fig. S1 ). At this stage the structures of interest were 'gated', meaning the field of view was decreased and the magnification increased. The section thickness was now also decreased (80 nm), to improve the Z-resolution (Fig.
Segmentation of SBF-SEM data to generate 3D models A further strength of the SuperCLEM imaging pipeline is the ability to generate nanometer accurate 3D models or renders from the SBF-SEM data. Surface volumes were created by segmenting structures of interest in the SBF-SEM datasets using the 'blow tool' (Fig. S3Gi ) across multiple layers (Fig. S3Gii-iv ). Three extended regions of myelinated axon, with a combined length of ∼400 µm were modelled (see also Movie 1). This included surface volumes of both the axon (Fig. 3Aii ) and myelin (Fig. 3Aiii ), allowing a variety of useful parameters to be retrieved, including compartment volumes (Fig. 3Aiv ). Next, a surface renders of a node of Ranvier, including the axon (Fig. 3Bii ), myelin (Fig. 3Biii ) and paranodal loops (Fig. 3Biv ,vi) was generated.
The resolution of the model allowed us to detect that both clusters of paranodal loops (red and blue renditions in Fig. 3B , from either side of the node) each was comprised of 10-11 lamellae. This number of lamellae is expected for a small diameter axon (1-2 µm) and importantly corresponds to empirically derived numbers  (Friede and Samorajski, 1967). Using SuperCLEM to study morphometrics Next, we exploited the LM and SBF-SEM datasets to retrieve and compare a variety of diagnostic geometric parameters which allow for the g-ratio to be calculated (Fig. S5A ) including myelin diameter (Fig. S5B ) and axon diameter (Fig. S5C ). The g-ratio (=d/D) relates the inner diameter of the myelinated fibre (d=axon diameter) with the outer diameter (D=axon+myelin diameter) and has a relatively constant value of ∼0.
6, as observations have revealed that myelin thickness grades with axonal diameter  (Donaldson and Hoke, 1905). We acquired line scans at set intervals along the length of the imaged axon from both longitudinal (Fig. 4A, B ) and digitally resectioned orthogonal SBF-SEM datasets (Fig. 4C ). The resulting traces revealed inner diameter (d) and outer diameter (D) used for calculating the g-ratio (See Fig. S5  for raw diameter data). Mean g-ratios of 0. 66±0. 06 and 0. 69±0. 05 were found for the longitudinal and orthogonal EM data respectively (Fig. 4D ). Same area analysis in data acquired using the Airyscan (super resolution) retrieved mean g-ratios of 0. 43±0. 1 and 0. 55±0. 08 for orthogonal and longitudinal sections respectively (Fig. 4D ). Mean g-ratios of 0. 37±0. 1 and 0. 33±0. 13 were calculated for orthogonal and longitudinal sections obtained in confocal mode (Fig.
4D ). Thus, our data showing that g-ratios derived from most LM data deviate significantly from the empirical values as well as the theoretical value (Fig. 4D , red bar) clearly indicate the poor diagnostic value of LM in accessing structural aspects of myelin in culture. We next revisited our SBF-SEM data to compare g-ratios measured using alternative parameters. We calculated and compared g-ratios using diameter (d axon/D fibre), cross-sectional area (ca axon/CA fibre), and volume from three myelinated fibres. The mean g-ratios from diameter (0. 69±0. 07), cross-sectional area (0. 64±0. 04) and volume (0. 61±0. 01) were directly compared (Fig. 4E ). Thus, whereas all three methods yield g-ratios that fall within the empirical range, the volume-based method produces the most accurate value (lowest standard deviation) that corresponds exactly with theoretical predictions.
Microscopy improvements leading to SuperCLEM Volumetric EM datasets can be obtained through a variety of techniques involving transmission or scanning EM. Whereas serialsection TEM in principle offers higher resolution, it is technically more demanding than the available scanning blockface techniques FIB-SEM and SBF-SEM (see  Kremer et al. , 2015  for an historic oversight and in-depth discussion of the pros and cons of the different techniques). Since its introduction by  Denk and Horstmann (2004) , SBF-SEM has been widely used to obtain nanometer scale renderings of large multi-cellular structures/tissues  (Peddie and Collinson, 2014). The application of both FIB-SEM and SBF-SEM have had a particularly large impact in the neurosciences, a development that was aided by the introduction of improved staining procedures  (Ohno et al.