dataesr/scientific-paragraphs-categorization huggingface dataset:
Data analysis We performed a descriptive analysis. Data were summarized as number (percentage) for qualitative variables and median (interquartile range, range) for continuous variables, as appropriate. We calculated the number (percentage) of RCT where information for each item related to planning (i. e. range of dose allowed, conditions permitting dose modification) or reporting (i. e. number of patients taking the drug at baseline, cumulative/mean intake over time) was completely (reported for all CMs), partly (reported for >0≤50% of CMs) or never (reported for no CM) provided. The same information was provided at drug level. Moreover, we calculated the number (percentage) of RCTs where the minimal set of information (described above) needed to estimate drug exposure over time was reported for all CMs.
Thus, it can be hypothesized that to minimize the risk of poor recruitment or high patient drop-out, the choice not to collect these data has been made at protocol stage. Second, while there is broad consensus on analytic techniques to use for adjusting covariates at baseline, the adjustment for post-randomization imbalance in covariates is more complex and can introduce additional source of error  [18]. However, such adjustment may be warranted when covariates are strongly correlated with the outcome or when there is a high degree of treatment imbalance between arms  [18] [19] [20]. This study has some limitations. First, we included RCTs published in a very short period and in selected journals. An analysis extended to a longer observation time or a wide range of journals could have possibly provided additional information.
Second, we retrieved data from published papers and supplementary material. The analysis of study protocols and e-CRF could have provided more information on how CM use was planned and used. Therefore, study conclusions about how CMs utilization was planned should be interpreted with caution. Third, the choice to label the drugs as 'potentially influencing the primary outcome' on the basis of an expert's opinion can be questioned. However, given the results of the present study, we assume that performing the same survey on a different number of drugs would not have changed the main study conclusions. In conclusion, the description of the use of concomitant medications in rheumatology RCTs is poor and can represent a threat to study conclusion validity. Efforts should be made to enhance trials reporting in the field.
B. Study Design and Methodology The XLH Burden of Disease Survey was designed by a team of researchers employed by or affiliated with Ultragenyx Pharmaceutical Inc. , in partnership with The XLH Network Inc. Questions and assessments in the survey (described in the PROs section below) were included based on recommendations from regulatory authorities, qualitative interviews with patients with XLH or caregivers  [22] , and literature investigating quality of life in diseases similar to XLH (e. g. , osteoarthritis)  [23] [24] [25] [26]. Data from this survey study and the open-label study UX023-CL203 (NCT2312687), which was initiated after the survey (March 2015), were used to validate these instruments (report submitted to the Food and Drug Administration available in an online repository  [27] ).
The XLH Burden of Disease Survey was accessed online and included an electronic consent form. Prospective participants were directed to a Web portal presenting an online consent form that required completion before accessing the survey. The survey was launched in English in June 2014, and was later translated into French, Spanish, Portuguese, and German. Findings from data collected through February 2016 are reported. The adult version of the survey was to be completed by any adult with XLH $18 years of age. The parent/guardian/caregiver of a child with XLH ,18 years of age completed the pediatric version of the survey on their behalf. Parents/guardians/caregivers were first asked to indicate their relationship to the affected child whose disease information was to be collected. Identifying information was not collected to ensure anonymity.
The participant was required to complete the survey in one sitting. The questionnaire was designed to take ;30 minutes. Both versions of the survey, one for children (completed by a caregiver) and one for adults, included demographics, family history, diagnostic history, medical and surgical history, diseasespecific clinical symptoms, treatments, medications, and assistive device use  [27]. PROs were also used to assess pain, disability, and health-related quality of life (HRQoL). Data directly reflected respondents' answers and were not verified against medical records. There was no direct interaction or querying of children, and thus they did not provide formal assent. The protocol, consent form, and participant materials for the XLH Burden of Disease Survey were reviewed and approved by the New England Institutional Review Board.
C. PROs The adult version of the survey included the following PROs: the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC ® ), the Brief Pain Inventory (BPI) (short form), and the 36-Item Short Form Health Survey version 2 (SF-36v2)  [28] [29] [30]. The WOMAC assessed pain, stiffness, and physical function in adults. The BPI assessed pain severity and pain interference with daily life. SF-36v2 assessed general HRQoL in adults. The pediatric version of the survey included the Pediatric Outcomes Data Collection Instrument (PODCI) developed by the Pediatric Orthopedic Society of North America and the 10-Item Short Form Health Survey (SF-10)  [31, 32]. The PODCI was used to assess disability concepts in children. The SF-10 was used to assess general HRQoL in children. Minimally important differences, defined as the smallest change in an outcome that a patient would identify as important or clinically meaningful, from PRO instrument manuals and the literature were used to interpret PRO results  [28] [29] [30] [31] [32].
B. Current Management At the time of survey completion, 99% (89/90) of children and 49% (114/232) of adults were being treated with oral phosphate; 99% (89/90) of children and 64% (149/232) of adults were being treated with active vitamin D metabolites; 99% (89/90) of children and 47% (110/232) of adults were receiving both oral phosphate and active vitamin D (Table  1 ). At the time of survey completion, 3% (3/90) of children and 10% (23/232) of adults had participated in a clinical trial with burosumab; 1 out of 3 of these children and none of these 23 adults reported currently receiving burosumab. Given the dates of the survey (June 2014 to February 2016), the adults who reported receiving burosumab likely participated in a phase 1 or 2 dose-finding study (NCT01340482, NCT01571596) sponsored by Kyowa Hakko Kirin Co.
, Ltd. Data regarding management of disease was only collected regarding current use and previous participation in a clinical trial with burosumab; information regarding age of initiation with treatment, dose of treatment, adherence to treatment, and duration of treatment were not collected. Because these details were not collected and the survey focused on questions that occurred at any point in the patient's medical history, and not specifically at the time of treatment (with oral phosphate and active vitamin D or burosumab), no subanalyses comparing outcomes by treatment regimen were conducted.
At the time this survey was available, the efficacy of burosumab was not established, only a small number of respondents (8%) reported prior participation in a clinical trial with burosumab, and only one respondent reported current treatment with burosumab during the survey. We also cannot confirm the duration of exposure to burosumab for these respondents, although it is likely limited to that of a dose-finding, phase 1/2 study (NCT01340482, NCT01571596) sponsored by Kyowa Hakko Kirin Co. , Ltd because of the timing for which this survey occurred. Ultragenyx had not initiated clinical trials in adults with XLH, and results from pediatric studies sponsored by Ultragenyx were not yet available. For these reasons and because the survey focused on questions that occurred at any point in the patient's medical history, and not specifically at the time of treatment, no conclusions can be made regarding burosumab's impact on burden of disease.
Acknowledgments The authors acknowledge The  XLH Network Inc. and the Association pour les personnes atteintes de rachitisme vitamino-résistant hypophosphatemique for their advisory role on the survey content and for their assistance with increasing awareness of the survey within the XLH community. The authors thank the responders for providing information on their experience with XLH. Kimberly Denis-Mize  and  Catherine Woods  provided assistance in writing and preparation of this manuscript. Financial Support: This study was funded by  Ultragenyx Pharmaceutical Inc. Author Contributions: A. S. , A. L. , E. A. I. , C. M. , C. T. -O. , M. D. -E,, A. E. , and J. S. M. contributed to design, analyses, and interpretation of the study. A. S. , A. L. , E. A. I. , C. M. , C. T. -O. , M. D. -E,, A.
Methods Population The data that support the findings of this study are available from the corresponding author on reasonable request. Between 2000 and 2015, patients over the age of 18 years with a diagnosis of at least mild AS (aortic valve calcification with restricted systolic leaflet motion and AVA <2 cm 2 ) diagnosed in the echocardiography laboratories of 2 French tertiary centers were prospectively identified and included in an electronic database. The following patients were excluded: (1) patients with more than mild aortic and/or mitral regurgitation; (2)  patients with prosthetic valves, congenital heart disease, supravalvular or subvalvular AS, or dynamic left ventricular (LV) outflow tract obstruction; (3) patients with LVEF <50%; and (4) patients who refused to participate in the study.
Statistical Analyses SPSS version 25 software (IBM, Armonk, NY) was used for statistical analysis. The study population was divided into 2 groups according to the type of AS: NF-LG-SAS or MAS. Continuous variables were expressed as meanAESD or median (interquartile range), and categorical variables were expressed as numbers (percentages). The relationship between continuous baseline variables and the various groups was explored using 1-way ANOVA or Kruskal-Wallis test. Pearson chisquared statistic or Fisher exact test was used to examine the association between baseline categorical variables and the various groups. The start of follow-up for survival analysis was baseline echocardiography. Event ratesAEstandard error in the 2 groups were estimated using the Kaplan-Meier method and were compared using 2-sided log-rank tests.
20 ropensity scores were used to match each NF-LG-SAS patient with a unique control with a propensity score within 2%. Each patient with NF-LG-SAS was first matched with another patient with MAS with a similar 5-digit propensity score, and matched patients were removed from the database. This procedure was repeated in the remaining patients with successive matching by 4-, 3-, and 2-digit scores. One hundred thirteen (73. 4%) of the 154 patients with NF-LG-SAS were successfully matched. Baseline characteristics of the 2 resulting groups after matching were compared using Student t tests and chisquared tests, as appropriate. Mean propensity scores between patients with NF-LG-SAS (0. 66844 [0. 59532-0. 75897]) and patients with MAS (0. 66859 [0. 59563-0. 75882]) were not statistically different (P=0.
97). Patients with NF-LG-SAS were also compared with the 1055 consecutive patients diagnosed with high gradient (MPG ≥40 mm Hg) severe AS (not operated on during the first 3 months after the baseline echocardiography) of our database. Univariate and multivariate analyses of times to events were performed using the same Cox proportional hazard models as those described above. The limit of statistical significance was P<0. 05. All tests were 2-tailed.
47 In contrast to SF2a, SD1 conjugates made of an average of 23 1RU-core O-AgCs per BSA were antigenic and immunogenic. 47 our fractions were isolated following SF6 LPS acidmediated detoxification. BSA conjugates featuring O-AgCs with an average of one RU and 2. 5 RUs, respectively, were antigenic but poorly immunogenic. In contrast, those encompassing O-SPCs with an average of seven RUs bound at an average density of 3. 5 per BSA induced anti-LPS Ab titers equivalent to those induced by a "lattice"-type pmLPS conjugate in mice receiving three injections of 2. 5 μg OSequivalent conjugate. In the latter case, the number of RUs per chain was in the range of 15-20. 47 rom the data available for O-AgC-protein conjugates targeting four different Shigella species and types, it was concluded that the conjugates were easy to prepare, characterize, and standardize.
sonnei O-AgC conjugate were significantly higher than those elicited by the pmLPS conjugates. The immunization regimen consisted in volunteers receiving a single dose of conjugate equivalent to 25 μg sugar amount, as in previous clinical trials with S. sonnei pmLPS conjugates, or to 10 μg carbohydrate amount, which more closely resembles doses used in commercial polysaccharide conjugate vaccines. As part of the dose-escalation study protocol, vaccine-induced Abs were to be measured at 1 and 6 months after immunization, and compared to those elicited by S. sonnei pmLPS conjugate vaccines. The study is completed but data are yet to be disclosed (ClinicalTrials. gov Identifier: NCT01369927).
Analogously, analysis of Ab lymphocyte supernatants (ALS) isolated 7 days after the first and second shots, respectively, revealed that the majority of the response was detected after the first injection. These findings suggested that, with a capacity to induce a 16-fold and 14-fold increase in anti-LPS IgG and IgA Ab titers over baseline in 92-100% subjects, respectively, a single 10 μg saccharide equivalent dose may provide the required immunity. Still, data from a SBA, indicated that delivery of a second vaccine dose could impact the development of functional Abs. Besides, Ab functionality differed substantially between subjects and could not be directly correlated to the anti-LPS IgG response. 49 As a major step forward, detailed data from the phase IIb, double blind, placebo-controlled, efficacy challenge study with the bioconjugate vaccine candidate Flexyn2a (ClinicalTrials.
gov, Identifier: NCT02646371), a Controlled Human Infection Model (CHIM) study, shall be very instructive. Undoubtedly, information communicated to date  50  provides significant support to the bioconjugate technology. As a remarkable achievement, the Flexyn2a vaccine was shown to induce a protective immune response in naïve adult volunteers, who had received twice, 4 weeks apart, a 10 μg saccharide equivalent dose of nonadjuvanted Flexyn2a, and were challenged with 1500 cfu of the virulent SF2a strain 2457T 4 weeks after the second injection. These promising data pave the way to the production of a Shigella tetravalent bioconjugate vaccine candidate, featuring the S. sonnei, SF2a and SF6 components in combination with a S. flexneri 3a (SF3a) constituent. 49.
106 The detailed molecular analysis of the O-Ag recognition pattern by the five mIgGs was achieved by use of synthetic non-O-acetylated 2-to 15-mer glycosides corresponding to all frame-shifted sequences within the SF2a O-Ag RU and up to a 3RU O-Ag portion. In addition to highlighting the importance of the E 1 C 1 D 1 trisaccharide for IgG binding, data revealed that the minimal sequence necessary for recognition by all five mAbs was the branched B 1 (E 1 ) C 1 D 1 tetrasaccharide flanked by residue A 1 /A 1ʹ at either end. 106, 107 Chain extension from 1RU-to 2RU-segments correlated with a significant increase in OS binding to all mAbs, which was not significantly influenced by further extension to OSs larger than a 10-mer. Analysis of Ab binding to the frame-shifted 10-mer segments [A 1 B 1 (E 1 )C 1 D 1 ] 2 and [D 1°A1 B 1 (E 1 )C 1 2 also revealed divergence between the IgG fine specificity suggesting that chain length is not the sole important parameter.
92 In this respect, the unique behavior of IgG F22-4, which was also the only mAb showing measurable affinity to E 1 C 1 D 1 , was outlined. Crystallographic data for Fab F22-4 in complex with a synthetic 10-mer [A 1 B 1 (E 1 )C 1 D 1 ] 2 and 15-mer [A 1 B 1 (E 1 ) C 1 D 1 ] 3 , corresponding to a 2RU-and 3RU-segment of the SF2a O-Ag, respectively, provided structural evidence in support to E 1 C 1 D 1 driving Ab binding. 108 The binding modes of the two OSs to IgG F22-4 were almost identical, showing a 9-mer epitope featuring six residues within two consecutive O-Ag RUs in direct interaction with the mAb. This original observation provided strong indication that synthetic glycans acting as O-Ag surrogates to be included in a SF2a glycoconjugate vaccine may require a minimum of two contiguous RUs.
In contrast, mIgG F22-4 was the only Ab able to recognize diversely O-acetylated segments of the SF2a O-Ag with micro-to submicromolar IC 50 , which shed extra light on its unique recognition specificity. 110 Interestingly, the observation that none of the acetyl groups added significantly to broad Ab recognition substantiated previous conclusions on the absence of serological variation between the SF2a LPS and its O-deacetylated counterpart. 57 It comforted original findings suggesting that SF2a O-Ag mimicry was achieved by synthetic non-O-acetylated OSs. Moreover, the demonstration that O-Ag epitopes recognized by sera from patients naturally infected with SF2a were, to some extent, displayed in non-substituted OSs corresponding to a small number of RUs, 111 corroborated conformational, physicochemical and structural data unraveling the basis for accurate molecular mimicry of SF2a O-Ag by non-O-acetylated OSs featuring two to three consecutive RUs.
Key parameters, the control of which is essential for robustness, were identified and optimized. The established two-step process allows full control of the density of OSs per TT molecule. With an improved reproducible yield of 70% relative to [A 1 B 1 (E 1 )C 1 D 1 ] 3 -SAc, a comparable efficiency of the conjugation step relative to TT Mal , and substantial margin in terms of applicable variables, the process complies robustness and efficiency criteria. 52 s a major step forward, SF2a-TT15 (Institut Pasteur, Paris, France) has completed a single blind, dose-escalating, placebocontrolled phase I clinical trial (ClinicalTrials. gov, Identifier: NCT02797236). This investigational vaccine was evaluated for safety and immunogenicity in young healthy adult volunteers, administered the vaccines three times, via intramuscular injection, on days 0, 28, and 56, and followed up to 3 months post the third injection.
Bridging the study with established data for existing similar vaccines-Quimi-Hib® is licensed for use of doses equivalent to 10 μg saccharide-or related studies-Flexyn2a was evaluated at the same dose-and going one step beyond, volunteers have received doses of SF2a-TT15 equivalent to 10 or 2 μg saccharide, the high dose and the low dose, with or without alum adjuvant, respectively. Undeniably, information communicated to date  53  provides considerable support to further development of the synthetic glycan conjugate strategy. Before all, they encourage the design of a Shigella tetravalent synthetic glycan conjugate vaccine candidate, featuring the S. sonnei, SF2a and SF6 components in combination with a S. flexneri 3a (SF3a) constituent. Active developments toward this aim are in progress at Institut Pasteur.
Funding This work has received funding from the Institut Pasteur (GPF project FlexBiVac, Vaccinology Program), the French National Research Agency (grant # ANR-15-CE07-0019-01). Louis Antoine Barel (L. A. B) is the recipient of an ANR PhD fellowship (contract Nb ANR-15-CE07-0019-01), he is affiliated to the Médicament, Toxicologie, Chimie, Imageries (MTCI) doctoral school.
PCR amplification of resistance-encoding genes Detection of antimicrobial resistance genes was performed by Conventional PCR using the forward and reverse primers for the ESBL genes (bla TEM , bla SHV , bla CTX-M , bla VEB , bla PER and bla GES ) (9) , Fluoroquinolone resistance genes (qnrA and qnrB)  (10) , aminoglycosidemodifying enzymes (AMEs) (armA, aac3, aac(6΄), ant(2΄΄), aph(3΄), aad, and rmtA)  (11)  and carbapenemases, for the strain resistant to imipenem, (bla VIM, bla IPM, bla KPC, bla NDM-1, bla OXA23, bla OXA24). Positive PCR products obtained were sequenced using the Big Dye ® terminator chemistry on an automated ABI 3730 sequencer (Applied Biosystems, Foster City, California, United States). The sequences obtained were analyzed using BlastN and BlastP against the NCBI database (http:/www.
Follow-up Patients were followed up from the time of CRT implantation until 1 January 2017. The primary endpoint was cardiovascular events, which was a composite of cardiovascular death, ventricular arrhythmia requiring defibrillator therapy or hospitalization for heart failure. The secondary endpoint was cardiovascular death. Data were collected using hospital archives and hospital software that archived medical data. All the hospitalization and consultation reports were examined. If necessary, general practitioners and referring cardiologists were contacted to provide missing information. An independent cardiologist blinded to SonR™ evolution adjudicated all the events. Events that occurred within the first 6 months were not considered when the predictive value of SonR™ evolution during the first 6 months was assessed.
The associations between SSE and cardiovascular events and deaths were evaluated in univariate and multivariable Fine and Gray regression analyses. The proportional hazards assumption was assessed using log-log plots. Multivariable analysis used a backward elimination procedure performed on an initial model, including every factor associated with prognosis at the P < 0. 20 level in the univariate analysis. Analyses were performed using SPSS 22 (SPSS, Inc. , Chicago, IL, USA) and SAS 9. 3 (SAS Institute, Inc. , Cary, NC, USA) statistical software. Two-sided P values < 0. 05 were considered statistically significant.
We included the following variables in the analyses: age, sex, body mass index (BMI), antiretroviral therapy (ART), seriously ill as per clinical exam, CD4 count, and severe anaemia. We initiated the model with all the listed variables, and we selected the most parsimonious model using the Akaike Information Criterion (AIC) as the final multivariable model. The only variable of interest that had missing data was anaemia. AIC and Bayesian Information Criterion (BIC) were calculated for a complete case analysis excluding the missing values and including the missing values as a separate category (S3 Appendix). In addition, to assess the impact of missing values on the point estimates, we fitted a separate multivariable regression where missing values were imputed with multiple sequential imputation using chained equations (S4 Appendix).
Acknowledgments We are grateful to the patients who participated in this study, and to the  Medecins Sans Frontières and Ministry of Health  staff teams in Malawi and Mozambique who provided care to the patients. We would like to thank the  Ministry of Health  and national TB control programs in Mozambique and  Malawi  for their support of this study. Thanks to  Ankur Gupta-Wright  for his advice and to  Emily Lynch  for editing the text.