dataesr/scientific-paragraphs-categorization huggingface dataset:
1C ) based on the existing crystal structures of Pvs25 (PDB: 1Z27  20  ) and the human C4bp (PDB: 4B0F 21 ). To test the in vitro expression of the antigens (as would occur from the viral-vector vaccines), pENTR4-LPTOS shuttle plasmid DNA  22  expressing Pfs25 or Pfs25-IMX313 (both under the control of the human cytomegalovirus (CMV) promoter  23  ) was used to transfect HEK293 cells. The supernatant was collected and analyzed by western blot using the 4B7 monoclonal antibody (mAb). Pfs25 protein and Pfs25-IMX313 protein-nanoparticle purified from P. pastoris were similarly analyzed using western blot. The western blots were performed under both reducing and non-reducing SDS-PAGE conditions (Fig. 2A  left panel and middle panel). The HEK293 cell and P. pastoris expressed proteins migrated at the predicted molecular weight of Pfs25 (19.
g. recognition of different Pfs25 epitopes and/or better antibody avidity). To this end, anti-Pfs25 antibody levels in the purified IgGs (used for the SMFA) were determined by the standardized ELISA and re-analyzed with the SMFA data. When anti-Pfs25 antibody levels were adjusted, there was no significant group effect (i. e. , either Pfs25 or Pfs25-IMX313) following ChAd63-MVA immunization (Fig. 4C , p = 0. 359). However, in the protein-in-adjuvant study, there was a significant difference between the Pfs25 and Pfs25-IMX313 groups (Fig. 4D , p = 0. 045). To confirm the difference in quality, the purified IgGs from the protein-in-adjuvant study were tested again by SMFA (Fig. S2 ). When data from the two feeding experiments were combined a higher significant difference in the SMFA-quality of antibodies was observed between groups (p = 0.
A long-term memory study of 250 days revealed that the antibody responses were maintained over time which is essential for a TBV. The fusion of Pfs25 to IMX313 does not affect the binding of vaccine-induced anti-Pfs25 to native protein antigen on the surface of P. berghei ookinetes transgenic for Pfs25. The anti-Pfs25 IgG was tested for functional activity in the SMFA and the total IgG from the Pfs25-IMX313 vaccinated groups exhibited stronger TRA largely due to the higher levels of antigen-specific IgG as measured by the standardized ELISA. In addition to the difference in the antibody quantity, there was also a significant difference in the quality of antibody in the case of the protein-in-adjuvant vaccine, calculated from the SMFA data (Fig. 4D ) but this difference was not seen for the viral vectored vaccine immunized groups.
Materials and Methods Generation of viral-vectored vaccines expressing Pfs25-IMX313. Pfs25 sequence (GenBank accession no: AAN35500, from Alanine-22 to Threonine-193) with four potential N-linked glycosylation sites (112, 165, 187 and 202) mutated (as described in  37  ), was codon optimized for expression in humans (GeneArt ® Life Technologies, Germany). The predicted native signal peptide was replaced with the human tissue plasminogen activator (tPA) signal peptide sequence (GenBank Accession No. K03021) as described before  38. For the Pfs25-IMX313 constructs a 229 bp DNA fragment encoding the IMX313 domain was cloned at the C-terminus of Pfs25. The Pfs25 and Pfs25-IMX313 inserts were subcloned into the ChAd63 and MVA destination and shuttle vectors. The recombinant viral vaccines were generated as described previously  18, 39.
Percent reduction in infection intensity was calculated relative to the respective control IgG tested in the same assay. Germinal centre staining. Inguinal dLNs and spleens were prepared as described  42. Cells were transferred to 96 well V-bottom plates (Thermo Scientific, UK) and centrifuged (300 × g, 5 min). Supernatants were then discarded and cells were resuspended with addition of Fc Receptor Block (1:50) (eBioscience, UK) for 15 min. Following a wash in FACS buffer, cells were stained with anti-GL7 AlexaFluor 647 (eBioscience, UK) at 1:100 dilution, anti-CD95 PE (eBioscience, UK) at 1:100 dilution and anti-B220 PeCy7 (eBioscience, UK) at 1:200 for 30 min at RT in the dark. After this incubation, cells were washed twice and resuspended in FACS buffer and data were acquired on a LSRII (BD Bioscience, UK) and analyzed by FlowJo (TreeStar Inc, USA).
Acknowledgements SB is a  NDM Leadership Fellow and Junior Research Fellow   of St Catherine's College, Oxford University. SJD and AVSH are Jenner Investigators. SJD is a  Lister Institute Research Prize Fellow  and a  UK Medical Research Council Career Development Fellow  [grant number  G1000527 ; this Fellowship is jointly funded by the  UK MRC  and the  UK Department for International Development (DFID)  under the  MRC/DFID  Concordat agreement]. This study was supported in part by the  intramural program  of the  National Institute of Allergy and Infectious Diseases/ NIH , and by the  PATH Malaria Vaccine Initiative. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors are grateful for the assistance of  Julie Furze ,  Andrew Blagborough ,  Federica Cappuccini ,  Anna Goodman  and  Alexandre Douglas , as well as the  Jenner Institute Adjuvant Bank ,  Flow Cytometry  and Viral Vector Core Facilities.
Introduction: Response to antiretroviral therapy (ART) among individuals infected with HIV-2 is poorly described. We compared the immunological response among patients treated with three nucleoside reverse-transcriptase inhibitors (NRTIs) to boosted protease inhibitor (PI) and unboosted PI-based regimens in West Africa. Methods: This prospective cohort study enrolled treatment-naı ¨ve HIV-2-infected patients within the International Epidemiological Databases to Evaluate AIDS collaboration in West Africa. We used mixed models to compare the CD4 count response to treatment over 12 months between regimens. Results: Of 422 HIV-2-infected patients, 285 (67. 5%) were treated with a boosted PI-based regimen, 104 (24. 6%) with an unboosted PI-based regimen and 33 (7. 8%) with three NRTIs. Treatment groups were comparable with regard to gender (54.
There have been no randomized trials investigating the response to ART regimens in HIV-2infected patients  [19]. Only a few observational cohort studies with limited sample size have provided information on HIV-2infected patients on ART in Europe and in the United States [20Á26], as well as in West Africa [13Á15, 27Á31]. Moreover, limited data are available on the response to the different first-line regimens used in HIV-2 patients. Whereas the data have generally favoured boosted PI regimens over those comprised of triple NRTIs, to our knowledge, only one report from a European collaboration  [20]  and two from West Africa  [15, 30]  explicitly compared the two first-line regimens. Using data from the International Epidemiological Database to Evaluate AIDS West Africa (IeDEA-WA) HIV-2 collaboration  [32] , we aimed to investigate the impact of first-line ART regimens on immunological response within the first 12 months of ART, for HIV-2 infected patients in the West Africa region where there are limited options for second-line regimens.
Data collection Standardized questionnaires capturing the relevant information on HIV-2 care were developed with an electronic database implemented at the site level. All sites completed the specific questionnaires retrospectively and then prospectively and entered the data into the IeDEA-WA HIV-2 database. The databases from each site are sent every six months to the Regional Centre in Abidjan, Cote d'Ivoire, and Bordeaux, France, using compression/encryption software. Data collected include the following: 1) Baseline demographics and clinical data: birth date, gender, HIV clinical stage (WHO or CDC stage), ART initiated, clinical assessment, medical history; 2) Follow-up: clinical assessment (tuberculosis, other diseases/ infection, HIV clinical stage, weight, height, medications such as antiretroviral drugs and co-trimoxazole); 3) Biological data: CD4 count, haemoglobin, aspartate transaminase, alanine transaminase and plasma HIV RNA viral load (when available); 4) Outcomes: death, loss to follow-up and transferred out.
For degree-2 models unstructured and diagonal covariance matrices were compared. Models with an unstructured covariance matrix were selected, as their Akaike information criterion was smaller. Univariable LMMs were used to assess covariate effects, and a manual backwards selection method was used to select significant variables in a multivariable LMM. To confirm the adequacy of the model, residual homoscedasticity and normality were graphically checked. To address possible informative dropout we performed a sensitivity analysis restricted to patients remaining in care beyond the 12 months of ART (patients deceased or lost to follow-up were excluded). Patients were defined as lost to follow-up if they were not known to have died, not known to have transferred out and not seen at the clinic at least once in the last six months prior to the closure date of the database  [36].
Results Selection of the study sample As of March 2013 the IeDEA-WA database contained 2005 patients infected with HIV-2 (or dually infected with HIV-1 and HIV-2). Figure  1  shows the different steps of the selection of the study sample. We excluded 590 HIV-2 patients and 344 dually infected patients because they were not treated with ART. We excluded 485 patients because they were dually infected, one patient with an unknown first-line ART regimen and 44 (7. 5%) HIV-2 patients treated with a non-recommended first-line ART regimen. Among these 44 patients, 41 were initially treated with an NNRTI-based regimen and three with only two drugs. Of these 44 patients, 31 (70. 5%) treated with a non-recommended ART regimen had a subsequent drug combination switch reported (28 (90. 3%) switched to a PI-based regimen and three patients (9.
Of 27 (26. 0%) patients initially treated with an unboosted PI-based regimen, 24 were treated with a boosted PI-based regimen, two with an NNRTI combination and one with three NRTIs. The median times from ART initiation to treatment modification were 5. 7 (2. 9 to 8. 9), 4. 9 (2. 8 to 8. 7) and 5. 8 (2. 0 to 8. 8) months for patients initially treated with three-NRTI, unboosted PI-based and boosted PI-based regimens, respectively. Reasons for ART modification were not recorded in the database.
Side effects, tolerability or adherence could not be investigated as they were not available in our database. In the European HIV-2 cohort study, treatment modification was less common with switching reported in 12% of patients in the PI group and 18% in the NRTI group  [20]. A limitation of our study was the small number and limited follow-up duration of HIV-2 infected patients treated with three NRTIs (17 of the 33 patients had at least one CD4 count documented after six months). Indeed, in the WHO guidelines of 2010  [8]  this ART regimen was only recommended for patients with a CD4 cell count !200 cells/ml. In the 2013 WHO consolidated guidelines  [9]  this eligibility criteria has been dropped, which could lead to triple NRTI regimens being prescribed more widely. Another limitation is the use of suboptimal triple NRTI regimens in West Africa.
In conclusion this study further demonstrates the inferiority of unboosted indinavir and triple nucleoside regimens for the treatment of HIV-2 infection. Limitations inherent in this observational design will be addressed by the First-Line Treatment for HIV-2 trial (FIT-2, NCT02150993) already underway in five countries in West Africa and funded by the Agence Nationale de Recherches sur le Sida et les hepatites virales (ANRS). The critical issue of second-line regimens for HIV-2, including the optimal sequence of integrase inhibitors and/ or boosted PIs, could potentially be addressed by a study enrolling the subjects failing therapy in those two arms of the FIT-2 trial.
Acknowledgements We thank the fieldwork team, study sites and participants for their effort. We are indebted to all of the HIV-positive people who agreed to participate in this present study as well as to the health workers and PAC-CI who performed the data collection. Funding This work was supported by the following institutes: the  US National Cancer Institute (NCI) ; the  Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)  and the  US National Institute of Allergy and Infectious Diseases (NIAID) as part of IeDEA  (grant  5U01AI069919 ). This work benefited from the support of the  ART-CC Collaboration  (MM and JS), MM and JS were funded by grant number  MR/J002380/1 , which was jointly awarded by the  UK Medical Research Council (MRC)  and the  UK Department for International Development (DFID)  under the  MRC/DFID  Concordat agreement and is also part of the EDCTP2 programme supported by the  European Union.
Acknowledgements The authors wish to acknowledge and express their gratitude to those who helped access and/or translate rare resources:  Gina G. Canceran , MLIS,  University Librarian , UPM and Librarian-in charge,  College of Medicine Medical Library, Manila, Philippines ;  Önder Ergönül, MD, MPH. Professor  of  Infectious Diseases and Clinical Microbiology, Koç University, School of Medicine, Istanbul, Turkey  ;  Tamer Pehlivan, MD. , MPH ,  Head of Medical Affairs Middle East & North Africa Region, Sanofi Pasteur, Istanbul Turkey ;  Artem Metlin ,  DVM, PhD ,  Virology Unit ,  Institut Pasteur du Cambodge. The National Reference Centre for Rabies is funded by the  Institut de Veille Sanitaire, Saint-Maurice, France  (http://www. invs. sante. fr/),by the  General Direction of Health  (Ministry of health) and the  Institut Pasteur.
Data analysis Images were analyzed using ImageJ (National Institutes of Health, Bethesda, MD), and data were analyzed using a custom-written Matlab (MathWorks, Natick, MA) code. Data are reported as mean ± SD, both in the text and in plots, unless specified otherwise. Samples were deemed statistically significantly different (*p < 0. 05) using Student's unpaired t test. ***p < 0. 001.
Images were analyzed using the ImageJ software. Jurkat cells (clone 20; obtained from A. Alcover, Pasteur Institute, Paris, France) were grown in GlutaMAX-containing RPMI 1640 (Invitrogen Life Technologies, Carlsbad, CA) supplemented with 10% fetal calf serum as described previously  (Blanchard et al. , 2002). Primary human aortic endothelial cells (HAECs) were purchased from ThermoFisher Scientific and cultured in medium 200 (M200500; ThermoFisher Scientific, Waltham, MA) supplemented with low serum growth supplement (S00310; ThermoFisher Scientific). They were passaged three times a week using trypsin, followed by resuspension in fresh medium.
All patients in the historical control group were assessed at the same three time points as those in C1-INH patients: at the time of initial diagnosis of ABMR (eGFR, proteinuria, graft biopsy, and anti-HLA DSA assessments), at the end of the first-line treatment (eGFR, proteinuria, graft biopsy, and anti-HLA DSA assessments), and at the end of the second-line treatment (eGFR). Clinical and biological data were obtained from a prospective database, Donn ees Informatiques Valid ees en Transplantation (DIVAT, official website: www. divat. fr), in which data were entered at specific points for each patient (at day 0 and 6 months and 1 year posttransplantation and at the time of allograft biopsies); follow-up was updated annually thereafter. This database is approved by the National French Commission for Bioinformatics Data (CNIL, registration number: 1016618, validated  June 8, 2004).
Recently, C1-INH Berinert was evaluated in a phase 1/2 study for the prevention of ABMR  (23)  and demonstrated a safe reduction of C1q-binding anti-HLA DSA. An ongoing study is assessing the efficacy of the C1-INH Cinryze in the treatment of ABMR (NCT01147302). In our study, Berinert was administered at 20 IU/kg per infusion, according to the prescribing information  (21) , twice weekly for 50 doses. This schema provides a stable serum concentration of C1-INH within the treat- ment period and is able to inhibit complement activation  (23). In the present study, five (83. 3%) of six C1qpositive DSA in the C1-INH group became negative after treatment, together with a significant decrease in C4d positivity in allograft capillaries. The decrease in C4d deposition, which reflects the local activation of the complement, is important because there is no systemic marker of complement involvement in the ABMR disease and because no relevant dosage can prove inhibition of the classic pathway for patients receiving the C1-INH.
Methods We searched the databases MEDLINE (via Ovid, from 1950 to 2015), EMBASE (via Scopus, from 1980 to the present) and the Cochrane Central Register of Controlled Trials for eligible studies. Search strategies are shown in Additional file 1. No language restrictions were set. In addition, we searched three trials registers (www. controlled-trials. com, www. clinicaltrials. gov and www. who. int/trialsearch/) to identify further published or unpublished studies or data for completed or ongoing studies. We included randomized controlled trials (RCTs) and non-randomized studies (NRSs) evaluating pharmacological treatment of children (age <18 years) with clinically diagnosed Lyme neuroborreliosis. Studies were eligible for inclusion if they reported a comparison of a pharmacological treatment against another pharmacological treatment, against placebo or against no treatment.
Secondly, each full text was evaluated independently by two reviewers (RD, SS or TH) for eligibility. Disagreements were resolved by discussion or with a third reviewer (JM). Two review authors independently extracted data from the full texts of included studies using a specifically developed extraction form, which had been piloted previously. Data was entered into Review Manager (RevMan 5. 3) by one of the reviewers and checked by a second reviewer. Discrepancies in data extraction or entry were resolved by discussion with a third reviewer. Reviewers were not blinded to study author, journal, or institution. Risk of bias was assessed by two reviewers independently using the Cochrane risk of bias (RoB) tools for RCTs and for NRSs, respectively  [23, 24]. According to the recommendations for the Cochrane RoB-tool for NRSs, no studies assessed as having a 'critical' risk of bias were included in the quantitative data synthesis.
We initially planned to assess the primary outcome 'neurological symptoms' as a continuous outcome. However, the majority of included studies reported the outcome dichotomized, so the results are presented accordingly. If neurological symptoms were reported as continuous or categorical variables, data was appropriately dichotomized according to the measurement scales and categories used. Data was analyzed on an intention-to-treat basis. If this was not possible, data was used as reported by the primary authors. If data was only available in graphical format, we thoroughly estimated the numeric values. Heterogeneity among studies was investigated by using the Chi 2 test and I 2 test, see protocol for details  [22]. Risk for publication bias was reduced in our systematic review by ensuring a comprehensive search for eligible studies including three trial registries.
Only a small set of studies was available for comparisons, so we did not provide a funnel plot. Pooling of data and meta-analysis of studies was only considered among studies with similar design (e. g. , RCTs were only combined with other RCTs) and limited heterogeneity. Combined estimates were not provided for studies with considerable differences in the included population or differences regarding interventions. We planned to provide estimates of treatment effects on a fixed effect model. We planned to calculate pooled risk ratios and 95 % confidence interval across comparable studies using Review Manager (RevMan 5. 3). Subgroup analyses were planned to consider dosage of drugs, geographical origin of studies, length of treatment, and likelihood of diagnosis. Sensitivity analyses were planned to assess the effect of risk of bias in included studies.
3  Risk of bias in non-randomized studies Fig. 4  Forest-plot for the comparison of betalactam antibiotics versus doxycycline for residual neurological symptoms in non-randomized studies group. Millner and colleagues reported no adverse events for the penicillin G group, but moderate allergic skin rash (n = 1), elevated liver enzymes (n = 2), and asymptomatic bile concrements (n = 6) in the ceftriaxone group. Bile concrements were actively sought via sonography in the ceftriaxone group but not in the penicillin G group, which diminishes comparability. Adverse events reported in other studies could not be attributed to an intervention, so no comparison could be performed. No data regarding other secondary outcomes could be extracted. One retrospective cohort study with critical risk of bias reported data on neurological symptoms after treatment with combinations of antibiotic treatments against single drugs.
Discussion A strength of this review is the comprehensive search of the available literature, including three databases for clinical trials and screening the reference list of included studies, minimizing the risk of bias in study selection. Due to the small number of studies included in these meta-analyses and considerable risk of bias, only limited conclusions can be drawn from them. We were unable to assess publication biases due to the low number of available studies for each of the comparisons. Literature on pharmacological treatment of Lyme neuroborreliosis in children is scarce and with very limited quality. Most of the available studies were performed several decades ago when pharmacologic treatment was less rigorously assessed as it would be performed today in case of new drugs or indications.
Patients The study participants comprised 23 HBsAg-positive and HBeAg-negative CHB patients treated by analogs who had undetectable HBV-DNA for at least one year and who were enrolled in a multicenter, randomized, phase 3 study of Peg-IFN-α (ANRS HB06-PEGAN: NCT01172392). Fourteen patients remained on NA alone (control group) and nine received an additional 180μg of Peg-IFN-α (Pegasys; F Hoffmann-La Roche) once a week for 48 weeks (Peg-IFN-α group) (Table  1 ). Seven out of 14 patients in the control group and 7 out of 9 patients in the Peg-IFN-α group were HLA-A Ã 02:01+ (Table  1 ). The study protocol was conducted according to the Declaration of Helsinki and French law for biomedical research, and approved by the Ethics Committee "Comite de Protection des Personnnes" (CPP) Sud-Méditerranée-I and the French Regulatory Authority "Agence Nationale de Securite du Medicament et des produits de sante" (ANSM).
Acknowledgments We are indebted to the patients who agreed to participate in this study. We thank the co investigator coordinator  Dr Yves Benhamou , the methodologist  Pr Fabrice Carrat , and all the investigators belonging to the  ANRS   HB06   PEGAN study group  (leader:  Dr Marc Bourlière , contact: mbourliere@hopital-saint-joseph. fr):Pr. Dominique Roulot ,  Unité fonctionnelle d'Hépatologie, Hôpital Avicenne, Bobigny ; Pr. Dominique Valla ,  Pr. Patrick Marcellin ,  Service d'Hépatologie, Hôpital Beaujon, Clichy ;  Pr. Catherine Buffet ,  Dr. Pierre Attali ,  Service d'Hépato-gastro-entérologie, Hôpital Bicêtre, Le Kremlin Bicêtre ;  Pr. Stanislas Pol ,  Dr. Fontaine Hélène ,  Pôle d'Hépato-gastroentérologie, Hôpital Cochin, Paris ;  Dr. Ariane Mallat ,  Dr. Christophe Hezode ,  Service d'Hépato-gastroentérologie ,  Hôpital Henri Mondor , Creteil; Pr.