dataesr/scientific-paragraphs-categorization huggingface dataset:
Patients and Ethical Considerations We screened 34 consecutive patients seeking medical help for persistent symptoms attributed to COVID-19 for participation in this systematic, prospective study. Patients were recruited in the ''Grand-Est'' region of France, the area with the highest incidence of SARS-CoV-2 infection during the first epidemic wave in France (February to April 2020)  [14]. Information about a post-acute COVID-19 syndrome consultation in our tertiary center was advertised through local media and social networks, and interested patients were then asked to participate in the study. All patients provided written informed consent. The data from 17 age-matched patients with a history of nonsevere COVID-19 (confirmed with RT-PCR or serology) at least 3 months before immuno-virologic assays, and without persistent symptoms, were included as controls (these patients were initially recruited as part of the Study ''SeroCOVHUS,'' ClinicalTrials.
gov Identifier: NCT04441684, Ethical Committee authorization from SUD MEDITERRANEE III, No. 2020. 04. 15 bis_ 20. 04. 10. 66856). The sera from 5 patients with acute severe COVID-19 (hospitalized in the intensive care unit) and from 18 patients with active systemic lupus erythematosus were used as a positive control for multiplex cytokine and interferon-a2 measurements, respectively. The present study is part of the ''COVID-HUS'' study, which was approved by the Ethics Committee of the University Hospital of Strasbourg (NCE-2020-51).
The study was conducted in accordance with the Helsinki Declaration of 1964 and its later amendments. This study is part of the ''COVID-HUS'' study, which was approved by the Ethics Committee of the University Hospital of Strasbourg (NCE-2020-51). Individuals with a history of COVID-19 without persistent symptoms, were recruited as part of the Study ''SeroCOVHUS'', ClinicalTrials. gov Identifier: NCT04441684, Ethical Committee authorization from SUD MEDITERRANEE III, Number 2020. 04. 15 bis_ 20. 04. 10. 66856). Data Availability. Data are available upon request to the corresponding authors.
ACKNOWLEDGEMENTS We thank all patients who agreed to take part in the study. We thank  Valle Meyer  for her precious help in planning the study and patient communication. We also thank  COVID-HUS and Strasbourg University Hospital  for their support. Funding. No funding or sponsorship was received for this study or publication of this article. The Journal's Rapid Service Fee was funded by the authors. Editorial Assistance. Editorial assistance in the production of this manuscript was provided by  Dr. Kate Dunning  ( Hopitaux Universitaires de Strasbourg ).
PATIENTS AND METHODS The global, open-label, single-arm phase IIIb PERUSE study (NCT01572038) was designed to evaluate the safety and tolerability of pertuzumab in combination with trastuzumab and a taxane. Eligibility criteria have been described in detail previously. 8 In brief, eligible patients had unresectable HER2-positive LR/mBC, at least one measurable lesion and/or non-measurable disease evaluable according to Response Evaluation Criteria in Solid Tumours (RECIST; version 1. 1), Eastern Cooperative Oncology Group (ECOG) performance status 2, left ventricular ejection fraction (LVEF) 50% and no prior systemic therapy (except 2 lines of endocrine therapy, one of which could have been in combination with everolimus) for LR/mBC. Prior anti-HER2 therapy (approved or investigational) other than (neo)adjuvant trastuzumab and/or lapatinib was prohibited.
Efficacy A confirmed response was recorded in 952 of the 1198 patients with measurable disease, giving an ORR of 79% (95% CI 77-82%). The clinical benefit rate was 86% (95% CI 84-88%). In the 952 responding patients, the median time to response was 2. 5 months (95% CI 2. 4-2. 5 months) and the median duration of response was 20. 0 months (95% CI 18. 2-22. 2 months). By the final data cut-off, 872 of 1436 patients (61%) had experienced disease progression or death. This number is lower than that reported at the interim analysis 8 because of a change before the final analysis to use stricter criteria for defining disease progression to align with the CLEOPATRA trial. Median PFS was 20. 7 months (95% CI 18. 9-23. 1 months) in the ITT population (Figure  2A ). Subgroup analyses showed similar PFS irrespective of HR status (Figure  2B ) or taxane backbone (Figure  2C ) but favoured the subgroup with no prior trastuzumab (Figure  2D ).
At the data cut-off, deaths had been recorded in 658 patients (46%), of which 581 (88% of 658) were from progressive disease. Median OS was 65. 3 months (95% CI 60. 9-70. 9 months) in the ITT population (Figure  3A ). OS was similar in the subgroups defined by taxane backbone and the KaplaneMeier curves for docetaxel and paclitaxel were overlapping (Figure  3C ). However, OS was more favourable in patients with HR-positive disease than HR-negative disease (Figure  3B ), and in those with no prior trastuzumab than prior trastuzumab (Figure  3D ). Efficacy in additional subgroups is summarised in Table  2. In post hoc multivariable Cox regression analyses, visceral disease and prior therapy (trastuzumab or other) were associated with worse PFS [hazard ratio 1. 47 (95% CI 1. 26-1. 72) for visceral disease; hazard ratio 1.
DISCUSSION The final analysis of PERUSE represents a mature dataset (median follow-up approaching 6 years) in a large global population of patients representative of routine oncology practice in a wide range of health care settings. The patient population was generally similar to that enrolled in the randomised phase III CLEOPATRA trial, except for a smaller proportion of patients with visceral disease (69% versus 88% in CLEOPATRA) and a larger proportion previously treated with trastuzumab (28% versus 12% in CLEOPATRA). 1  The safety profile of first-line pertuzumab combined with trastuzumab and standard taxane therapy for HER2-positive LR/mBC in PERUSE was consistent with the known safety profile of the individual agents and the results from the phase III CLEOPATRA trial. 1, 2 Safety results in the final analysis of PERUSE were consistent with the preliminary report, in which AEs were reported according to taxane partner.
ACKNOWLEDGEMENTS We thank the patients, their families, the nurses and the investigators who participated in this study, members of the independent data monitoring committee, and  Valerie Easton  (former employee of  F. Hoffmann-La Roche Ltd ). Medical and operational management support was provided by  IQVIA (formerly QuintilesIMSÔ ). Support for thirdparty medical writing assistance for this manuscript was provided by  Jennifer Kelly ,  MA (Medi-Kelsey Ltd, Ashbourne, UK) , funded by  F. Hoffmann-La Roche Ltd, Basel, Switzerland.
NHWS database The NHWS is a self-administered, cross-sectional, internet-based survey of the health of a general population of over 1. 2 million adults (≥18 years of age), the respondents being identified primarily through opt-in online survey panels. The questionnaire included a base component (assessing sociodemographics, health characteristics, and diseases experienced/diagnosed), various diseasespecific modules, and a module specific to pain. The Pearl Institutional Review Board reviewed the 2016 and 2017 NHWS and determined that they meet the exemption requirements under 45CFR46. 101(b) (2), and all respondents provided informed consent. The survey was translated as appropriate for each country. Stratified random sampling, based on sex and age, was used to ensure the demographic composition of the sample was representative of the adult population for each of the five countries.
Study population The current analyses included NHWS respondents who self-reported they had received a physician's diagnosis of lower back pain, and had experienced pain during the prior month, with pain in the past that had lasted for at least 3 months. The current cohort included all those with CLBP who participated in the pain module: in the 2016 NHWS, a probability method was utilized for inclusion into specific disease modules (to reduce respondent burden) and all those with CLBP who were randomly selected to enter into the pain module were identified; while in the 2017 NHWS, all respondents participated in the pain module. Those who reported neuropathic or phantom limb pains were excluded. Since it was possible for a respondent to complete more than one survey during the 2 years, only the most recent data for each respondent were used.
6] [27] [28]  have been reported for various patient populations. Work productivity and activity impairment were assessed using the general health version of the questionnaire (WPAI-GH), a 6-item instrument consisting of four metrics: absenteeism (the percentage of work time missed because of one's health in the past 7 days), presenteeism (the percentage of impairment experienced while at work in the past 7 days because of one's health), overall work productivity loss (an overall impairment estimate that is a combination of absenteeism and presenteeism), and activity impairment (the percentage of impairment in daily activities because of one's health in the past 7 days). 29 Higher scores indicate worse impairment. Only respondents who reported being full-time or part-time employed provided data for absenteeism, presenteeism, and overall work impairment, whereas all respondents completed the activity impairment question.
Statistical analyses The main analysis used data pooled across the five European countries. Supplemental analyses were conducted for the individual countries. To explore differences related to pain severity and prescription medication use, respondents were categorized into four groups: (1) mild pain untreated with prescription medication (mild pain Rx-untreated); (2) mild pain treated with prescription medication (mild pain Rx-treated); (3) moderate/severe pain untreated with prescription medication (moderate/severe pain Rx-untreated); and (4) moderate/severe pain treated with prescription medication (moderate/severe pain Rx-treated). Moderate pain and severe pain were combined for analysis due to sample size considerations for country-level analyses. Sociodemographic data collected during the survey included age, sex, marital status, income, education, and employment status, and health characteristic data included body mass index, smoking status, alcohol consumption, exercise behavior, and self-reported physician diagnosis within the last 12 months of anxiety, depression, insomnia or sleep disturbance.
Comorbid burden was assessed using the Charlson Comorbidity Index. 30 ivariate analyses of sociodemographics and health characteristics across the four groups were conducted using chi-square (categorical variables) or analysis of variance (continuous variables). 31 egression modeling using generalized linear models, specifying a normal distribution and identity function (SF-12v2, SF-6D utility score, EQ-5D-5L, and EQ VAS) or negative binomial distribution and log-link function (work productivity and activity impairment and healthcare resource utilization) as appropriate,  32  was used to estimate differences across groups, controlling for age, sex and country, and other sociodemographic and health characteristic covariates identified as being significantly different in bivariate analyses. Complete data were available for all items except those allowing a "don't know" response.
In such cases, if those variables were included as covariates in multivariable models or as outcome measures in bivariate analysis, missing values were included as a separate, defined category, or assimilated into another category or omitted altogether (depending on whether either approach was conceptually interpretable [e. g. , mean differences on a continuous measure] or necessary [e. g. , due to problems with model convergence]). If those variables were analyzed as outcomes (e. g. , work productivity was only assessed for employed respondents), respondents with missing data were excluded from analysis (and the subsample for analysis was reported). Statistical analyses were conducted using SPSS v23. 0 or later, with p ≤ 0. 05 considered statistically significant. No correction was made for multiple testing.
PCS and MCS scores are normed to a mean of 50 and a standard deviation of 10 for the US population. Covariates included: severity/treatment group, country of residence, age, sex, marital status, education, income, employment status, alcohol use, exercise, body mass index, smoking status, anxiety diagnosis, depression diagnosis, insomnia diagnosis, diagnosed with sleep difficulties, and CCI. A total of 18 respondents had missing data and were excluded from multivariate analyses. ] [27]  It is interesting to note that the mild pain Rx-treated group had worse health-related quality of life than the moderate/severe pain Rx-untreated group in the current study. Although prescription medication status differed between the groups, there was also disparity between the pain categorization (as mild or moderate/severe) and the groups' mean SF-MPQ scores.
594) was used for all countries based on the publisher's recommendation. The EQ VAS ranges from 0 (worst imaginable health state) to 100 (best imaginable health state). Generalized linear models specifying a normal distribution and identity function assessed differences in health status by group. Covariates included: severity/treatment group, country of residence, age, sex, marital status, education, income, employment status, alcohol use, exercise, body mass index, smoking status, anxiety diagnosis, depression diagnosis, insomnia diagnosis, diagnosed with sleep difficulties, and CCI. A total of 18 respondents had missing data and were excluded from multivariate analyses. CCI, Charlson Comorbidity Index; EQ VAS, EQ visual analog scale; LS, least squares; Rx, prescription medication; SE, standard error; SF-6D, Short Form-6 Dimensions of the mild pain group than the moderate/severe pain group used prescription medication in the current study, and an explanation for this is not clear from the current data.
Higher scores indicate greater impairment (worse outcome). Generalized linear models specifying a negative binomial distribution and log-link function assessed differences in work and activity impairment by group. Covariates included: severity/treatment group, country of residence, age, sex, marital status, education, income, employment status, alcohol use, exercise, body mass index, smoking status, anxiety diagnosis, depression diagnosis, insomnia diagnosis, diagnosed with sleep difficulties, and CCI. A total of 18 respondents had missing data and were excluded from multivariate analyses. Only respondents who reported being full-time or part-time employed provided data for absenteeism, presenteeism, and overall work impairment, whereas all respondents completed the activity impairment question.
Covariates included: severity/treatment group, country of residence, age, sex, marital status, education, income, employment status, alcohol use, exercise, body mass index, smoking status, anxiety diagnosis, depression diagnosis, insomnia diagnosis, diagnosed with sleep difficulties, and CCI. A total of 18 respondents had missing data and were excluded from multivariate analyses. CCI, Charlson Comorbidity Index; LS, least squares; Rx, prescription medication; SE, standard error.
Covariates included: severity/treatment group, country of residence, age, sex, marital status, education, income, employment status, alcohol use, exercise, body mass index, smoking status, anxiety diagnosis, depression diagnosis, insomnia diagnosis, diagnosed with sleep difficulties, and CCI. A total of 18 respondents had missing data and were excluded from multivariate analyses. CCI, Charlson Comorbidity Index; LS, least squares; Rx, prescription medication; SE, standard error 100 90 80 70 59. 71 62. 83 60 49. 02 48. 58 51. 00 50 39. 48 39. 59 44. 00 40 35. 10 29. 71 29. 76 0 20 30 10 Absenteesim 8. 81 19. 20 * #  † 4. 75 * # P resenteeism 21. 44 O verall work impairment 24. 27 Activity impairment Mild pain Rx-untreated Moderate/severe pain Rx-untreated Mild pain Rx-treated Moderate/severe pain Rx-treated AC K NOW L E DGE M E N T S The authors acknowledge the medical writing assis- tance of Urmila Rao, PhD, and Ramu Periyasamy, PhD, Indegene Pvt Ltd, Bangalore, India with preparation of initial drafts, funded by Kantar.
Statistically significant conclusions for the viral titer in hamsters were only based on quantitative measures of viral RNA. Interestingly, while the MR3-MR3-ABD was similarly potent with Fc-MR3 in vitro, it was less efficient than Fc-MR3 when tested in hamsters. This may be related to their difference in A sensor coated with streptavidin was saturated with 2 μg mL -1 of biotinylated RBD. The sensor was then soaked in 200 nM of the indicated sybody before further soaked in sybody-containing buffer with (black) or without (red) 25 nM of ACE2 for BLI signal recording. As a control, the ACE2-RBD interaction was monitored in the absence of sybodies (magenta). e, f Alignment of the SR4-RBD (e) and MR17-RBD (f) to the "up" conformation of the RBD from the cryo-EM structure of the trimer S (PDB ID 6VYB)  2.
The three subunits are colored yellow (A'), white (B'), and light blue (C'). Synthetic nanobodies are colored deep blue. RBM (red) marks the ACE2-binding motif. g, h Binding kinetics of SR4 (g) and MR17 (h) to S. BLI assay was performed with sybodies immobilized and S as analyte at the indicated concentrations (nM). Source data for c, d, g, h are provided as a Source data file. ACE2 angiotensinconverting enzyme 2, BLI biolayer interferometry, RBD receptor-binding domain, RBM receptor-binding motif. half-life. As shown in Supplementary Fig. 11c , Fc-MR3 had a much longer half-life than MR3-MR3-ABD, although we note that the stability was tested in mice (Supplementary Fig. 11c ) while the protection was compared in hamsters (Fig. 5c-i ). The possible difference of tissue distribution of the sybody forms, and pharmacokinetic stability modulated by the binding affinity to Fc receptors and the binding affinity to albumin from different species, may need to be investigated to explain their differences in in vivo efficiency.
Source data for a-d are provided as a Source data file. BLI biolayer interferometry, N. D. not determined. Ni-Sepharose Excel column was desalted to remove imidazole using a desalting column (Cat. 732-2010, Bio-Rad) pre-equilibrated in Buffer A. The desalted RBD was mixed with home-purified His-tagged 3C protease at 1:100 molar ratio (3C protease:RBD) at 4 °C for 16 h. The mixture was then passed through a Ni-NTA column, which binds 3C protease, undigested RBD, and the cleaved His-tag. The flow-through fractions were collected and concentrated to 8-10 mg mL -1. The protein was either used directly for crystallization or flash-frozen in liquid nitrogen and stored at -80 °C before use. For crystallization, fresh RBD or thawed from -80 °C was mixed with desired sybodies at 1:1. 5 molar ratio (RBD:sybody).
Statistical analyses were performed using one-way ANOVA followed by Tukey's multiple comparisons test on log-transformed data (d-g) or raw data (h, i). ns not significant; *p < 0. 05; **p < 0. 01; ****p < 0. 0001. Source data of a-i and exact p values of c-i are provided as a Source data file. 20 mM Tris-HCl pH 7. 5. The eluted fractions were pooled, concentrated using a 100-kDa cut-off membrane concentrator, and further purified using SEC. Fractions containing S were pooled, quantified using a ε 280 of 138,825 M -1 cm -1 , concentrated to 2 mg mL -1 , and mixed with a 4-fold molar concentration of MR3 sybody for cryo-EM sample preparation. Protein expression and purification-sybodies in E. coli. Sybodies were expressed with a C-terminally His-tag in E. coli MC1061 cells. Briefly, cells carrying sybody genes in the vector pSb-init  24, 25  were grown in Terrific Broth (TB, 0.
8 μL of nuclease-free water, 4 μL of solution I, 0. 5 μL of solution II, 1 μL of solution III, 0. 5 μL of 10 mM cysteine, 0. 5 μL of 80 mM reduced glutathione, 0. 5 μL of 60 mM oxidized glutathione, and 0. 5 μL of 1. 875 mg mL -1 disulfide bond isomerase DsbC (DS supplement, Cat. PF005-0. 5-EX, Genefrontier) was warmed at 37 °C. After 5 min, 0. 7 μL of mRNA library, corresponding to 1. 6 × 10 12 mRNA molecules, was added to the pre-warmed mix for in vitro translation at 37 °C for 30 min. The reaction was diluted with 100 μL ice-cold Panning Solution (150 mM NaCl, 50 mM magnesium acetate, 0. 5% (w/v) bovine serum albumin (BSA), 0. 1% (w/v) Tween 20, 0. 5% (w/v) heparin, 1 μL RNaseIn, and 50 mM Tris-acetate pH 7. 4) and cleared by centrifugation at 20,000 × g for 5 min at 4 °C. Biotinylated RBD was added to the supernatant and the mixture was incubated on ice for 20 min.
5, 25, 50, and 100 nM. The sensor was then moved into a sybody-free buffer for dissociation and the signal was monitored for 600 s. Data were fitted for a 1:1 stoichiometry for K D , k on , and k off calculations using the built-in software Data Analysis 10. 0. For the binding between MR3 and RBD mutants, MR3 was first chemically biotinylated using an amine-reactive crosslinker (Cat. 21338, Thermo Fisher). Briefly, MR3 purified in PBS buffer at 2. 9 mg mL -1 was incubated with equimolar of the crosslinker for 30 min at RT (20-22 °C). The reaction was quenched by Tris. Desalted MR3 (2 μg mL -1 ) was immobilized onto an SA sensor and the BLI assays were carried out essentially as above with slight differences in association (120 or 240 s) and dissociation time (220 or 300 s) using RBD wild type and mutants as analytes at a 100-nM concentration.
45-μm membrane before been used for neutralizing assays. DNA encoding the human ACE2 (hACE2, NCBI accession number: NM_001371415) was cloned (from cDNA of Caco-2 cell) and constructed into pLVX-IRES-Puro lenti-vector (Addgene ID 6401). Then G glycoprotein of the vesicular stomatitis virus (VSV-G)-enveloped lentivirus pseudoparticles were packed using this vector with the human immunodeficiency virus gag pol and used to transduce VeroE6 cells. The cells were selected with 5 μg/mL puromycin. For neutralization assays, VeroE6-hACE2 cells (10 4 cells/well) were seeded in a 48-well plate and infected 24 h later with 100 μL of virus supernatant in a final volume of 150 μL. Sybodies were preincubated with the pseudotype samples for 1 h at 37 °C prior to cell/virus co-incubation. After 6 h of co-incubation, the supernatants were removed and the cells were incubated in a medium for 72 h at 37 °C.
Specifically, the gradient was 4-10% Buffer B over 3 min, 10-30% Buffer B over 8 min, 30-90% Buffer B over 1 min followed by isocratic flow with 90% Buffer B for 1 min. The online digestion, trapping, and desalting process was performed at 4 °C and the separation process at 0. 5 °C in a temperature-controlled compartment in the HDX PAL system. Data were acquired using a Thermo LTQ Orbitrap-Elite mass spectrometer (San Jose, CA) with a Thermo H-ESI II probe. For peptide identification, mass spectra were acquired in a data-dependent scan using FTMS mode in MS1 (one microscan, 100 ms max injection time, 60k resolution at 400 m/z) at the m/z range of 300-1500 followed by 10 CID MS2 scans in the ion trap with a ±2. 0 m/z isolation width. Once the peptides were identified, the deuterium uptake in HDX experiments was conducted using FTMS mode in MS1.
The whole HDX-MS procedure was repeated three times for each sample and for each time point. The MS spectra were searched in PEAKS Studio X against a homemade database including target protein with a precursor mass tolerance of ≤20 ppm and MS/MS fragment ≤0. 02 Da. Retention time and sequence information for each peptide were exported to Microsoft Excel. HDX-MS data analysis was carried out using HDExaminer 2. 0 (Sierra Analytics Inc. , Modesto, CA). The number of D taken up (D-uptake) by each peptide at each exchange time was calculated by matching the theoretical isotope distribution pattern to the observed isotope distribution pattern and plotted as a function of exchange time. Data from triplicates were analyzed using Student's t test at a 95% confidence level. D-uptake, expressed as a percentage of the theoretical value, was used to generate heat maps, butterfly comparisons, and difference plots.