dataesr/scientific-paragraphs-categorization huggingface dataset:
Data sharing Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA (MSD), is committed to providing qualified scientific researchers access to anonymised data and clinical study reports from the company's clinical trials for the purpose of conducting legitimate scientific research. MSD is also obligated to protect the rights and privacy of trial participants and, as such, has a procedure in place for evaluating and fulfilling requests for sharing company clinical trial data with qualified external scientific researchers. The MSD data sharing website (http://engagezone. msd. com/ds_documentation. php) outlines the process and requirements for submitting a data request. Feasible requests will be reviewed by a committee of MSD subject matter experts to assess the scientific validity of the request and the qualifications of the requestors.
In line with data privacy legislation, submitters of approved requests must enter into a standard datasharing agreement with MSD before data access is granted. Data will be made available for request after product approval in the USA and EU or after product development is discontinued. Circumstances might prevent MSD from sharing requested data, including country or regionspecific regulations. If the request is declined, it will be communicated to the investigator. Access to genetic or exploratory biomarker data requires a detailed statistical analysis plan that is collaboratively developed by the requestor and MSD subject matter experts; after approval of the statistical analysis plan and execution of a datasharing agreement, MSD will either perform the proposed analyses and share the results with the requestor or will construct biomarker covariates and add them to a file with clinical data that is uploaded to an SAS portal so that the requestor can perform the proposed analyses.
Acknowledgments This study was funded by  Merck Sharp & Dohme , a subsidiary of  Merck & Co, Rahway, NJ, USA (MSD). We thank the patients and their families and caregivers for participating in the study; the investigators and site personnel; the members of the independent data and safety monitoring committee; and the following employees of MSD:  Melissa Buckland ,  ShuAn Lin , and  Jennifer Villetard  for study support;  Olga Kuznetsova ,  Saidi Palla , and  Shuyan (Sabrina) Wan  for statistical support;  Shital Kamble  for input on healthrelated quality of life; and  Melanie A Leiby  for medical writing and editorial assistance. Editorial note: The Lancet Group takes a neutral position with respect to territorial claims in published maps and institutional affiliations.
Australia's programs for medicines are similar to US and EU programs, while the nascent MD priority program seems modeled on the US Breakthrough program; however, evidence of MDs accessing the program could not be found on website databases (https://www. tga. gov. au/ws-mddesignation-notices-index) [30] [31] [32]. In Europe, accelerated programs for medicines exist (e. g. Priority Medicines or PRIME, Conditional Marketing Authorization), but no specific accelerated or expedited approval processes are currently in place for MDs at the EU level  [12].
Recommendation 2: establish a core set of principles underlying an accelerated access pathway Formulate and publicly share a core set of principles underlying an accelerated access pathway for innovative high-risk implantable MDs, that guarantees: • Transparency and ethics: Provide clear criteria on evidence (or evidence standards) needed to both enter the accelerated pathway and maintain approval. Publish information on how decisions are made to include an MD in the program, using the MDR database (EUDAMED), where applicable, and provide clear labeling for clinicians and patients regarding those technologies that have followed an accelerated pathway. Ensure a role for ethical committees, where appropriate. • Consistency: Guarantee consistent decisions, especially concerning withdrawing approval following negative or ambiguous confirmatory data from post-marketing studies, or the validation of surrogate endpoints.
It takes advantage of provisions in both regulations earmarking innovative high-risk MDs for Expert Panel advice (MDR Article 61(2)) and manufacturer-requested joint scientific consultations (HTA Regulation Article 17) for likely joint clinical assessment candidates (HTA Regulation Article 7), and exploits the European database on MDs, EUDAMED (MDR Article 33), to automate controls on post-market evidence generation, information sharing and updates [1,2].
Study design and participants This multicenter, open-label, randomized, crossover study assessed SL-APO compared with SC-APO in patients with PD and OFF episodes and was conducted in Europe (EudraCT: 2016-003456-7). Herein we provide a brief review of methods, with full methodology available in the Supplementary Methods. Eligible patients were ≥18 years of age with idiopathic PD responsive to and being treated with stable doses of CD/LD and any additional PD medications for ≥4 weeks (>8 weeks for monoamine oxidase-B inhibitors), were stage 1-3 by modified Hoehn and Yahr scale when ON, had ≥1 OFF episode/day and ≥2 h of total daily OFF time, and had a Mini-Mental State Examination score >25. Key exclusion criteria included atypical or secondary parkinsonism; major psychiatric disorder; mouth cankers/sores; prior device-aided treatments; permanent discontinuation of prior SC-APO administration or prior exposure to SL-APO; currently taking selective 5-HT 3 antagonists, selective dopamine antagonists (excluding quetiapine or clozapine), or dopamine-depleting agents; and history of clinically significant impulse control disorders, symptomatic orthostatic hypotension requiring medication, or severe dyskinesia based on MDS-UPDRS Part IV.
Evaluations The primary efficacy endpoint was change from predose to 90 min postdose in MDS-UPDRS Part III score after 4 weeks of dosing in each crossover period, assessed in clinic by a rater blinded to treatment assignment. The blind was maintained by ensuring that the rater did not witness in-clinic dosing, that visible injection sites were covered, and that source data and electronic clinical report forms were protected. Because SL-APO can leave a blue residue on the tongue, a sublingual placebo was administered upon SC-APO in-clinic dosing. Secondary endpoints were evaluated in a hierarchical order and included the following: investigator-rated durability of response (defined as investigator-confirmed achievement of a FULL ON within 30 min postdose and maintenance of that response at 90 min postdose); treatment preference for SL-APO, measured with a 9-item patient self-reported Treatment Preference Questionnaire (TPQ  [23] ; Supplementary Table  1 ); patient-rated durability of response; and Patient Global Impression of Change (PGI-C).
Other endpoints included change in MDS-UPDRS Part III score over time (15-120 min); investigatorrated time to FULL ON and time to partial ON (period of time where medication is providing some improvement with regard to mobility, stiffness, and slowness but the patient does not have adequate motor function to perform normal daily activities); and patients' general level of satisfaction with medication using the validated 14-item Treatment Satisfaction Questionnaire for Medication (TSQM)  [24]. Pharmacokinetic (PK) concentration-time data for apomorphine and metabolites (apomorphine sulfate, norapomorphine) were evaluated and PK parameters, including maximum observed plasma concentration (C max ), time to maximum plasma concentration (t max ), AUC, and parent-to-metabolite ratios of C max and AUC were estimated by noncompartmental methods from plasma samples using actual elapsed time from dosing.
A total of 74 patients were randomized into the treatment phase (treatment phase mITT population: 37 patients randomized to receive SL-APO followed by SC-APO; 37 patients randomized to receive SC-APO followed by SL-APO). The same proportion of patients completed both periods of the treatment phase for each treatment sequence (SL-APO/SC-APO, 81. 1%; SC-APO/SL-APO, 81. 1%). At study baseline (N = 112), patient mean age was 64. 4 years, and 69. 6% were male. Patients were diagnosed with PD a mean of 9. 2 years prior, experienced a mean of 4. 1 OFF episodes per day, and were prescribed a mean daily levodopa dose of 737. 6 mg (Table  1 ). Thirteen (11. 6%) patients had received SC-APO before study enrollment, with a median dose of 4 mg (range, 2-6 mg; data not available for 1 patient) and continued on the same dose of SC-APO during the dose-optimization phase.
0) 0 0 Lip swelling 0 0 1 (1. 4) 0 Nausea 2 (2. 0) 1 (1. 0) 0 0 ON and OFF phenomenon 0 0 1 (1. 4) 0 Orthostatic hypotension 0 1 (1. 0) 0 1 (1. 4) Somnolence 0 0 0 1 (1. 4) Swollen tongue 0 0 1 (1. 4) 0 Syncope 0 1 (1. 0) 0 0 Vomiting 2 (2. 0) 2 (2. 1) 0 0 SC-APO, subcutaneous apomorphine; SL-APO, apomorphine sublingual film. ings were not unexpected given that SC-APO has been shown to have a faster time to peak plasma concentration compared with SL-APO, which was corroborated with current data and suggests a potentially faster time to ON for SC-APO  [22]. Data in this study were not collected before 15 min postdose; thus, additional studies would be needed to demonstrate differential effects at time points before 15 min postdose. Overall, the differences in efficacy observed at time points before and at 30 min in the current study were small and did not meet the threshold of being clinically meaningful, suggesting relatively similar clinical benefit for patients with either treatment at these time points.
Further, it is not possible to draw conclusions about prophylactic versus reactive antiemetic use as the database did not capture the time or reason an antiemetic was taken. A previously published study demonstrated that among 43. 7% of patients who did not use an antiemetic during SL-APO dose optimization, 86. 2% achieved an effective and tolerable dose  [31]. Likewise, an interim analysis of the recently completed, open-label, long-term, phase 3 study of SL-APO (N = 425) demonstrated that nausea and vomiting rates were similar in patients who did versus did not use antiemetics  [32] ; additional information about antiemetic use and nausea and vomiting may be analyzed in the future. Expected differences in route of administration AEs were also noted. Among patients treated with SC-APO, 6.
An open-label, long-term study of SL-APO (NCT02542696) was recently completed, and results may provide additional information on the occurrence of oral AEs during long-term SL-APO treatment. There are several limitations to consider. The primary and secondary endpoints were assessed using a statistical hierarchy. As the primary endpoint was not statistically significant, all subsequent endpoints were evaluated descriptively. Efficacy endpoints were assessed by a rater blinded to treatment assignment, and every effort was made to maintain that blind by preventing the rater from witnessing dosing, covering visible evidence of route of administration, and protecting source data and electronic clinical report forms. However, the open-label administration of SL-APO and SC-APO may have introduced bias.
ACKNOWLEDGMENTS The study was supported by funding from Sumitomo Pharma America, Inc. (Marlborough, MA, USA). The authors would like to thank all coinvestigators, including Dr. Valentina Leta, for their contributions to the study. Medical writing and editorial assistance were provided by Maureen Wallace-Nadolski, PhD, and Jessica Deckman, PhD, CMPP, of The Lockwood Group (Stamford, CT, USA) and were supported by funding from Sumitomo Pharma America, Inc. (Marlborough, MA, USA).
CONFLICTS OF INTEREST FS is an Editorial Board member of this journal, but was not involved in the peer-review process nor had access to any information regarding its peer review and has received grants and/or research support from Zambon and honoraria or consultation fees from Bial, Biogen, Britania Pharmaceuticals, Chiesi, Cynapsus Therapeutics, Kyowa Kirin, Lundbeck, NeuroDerm, Sunovion Pharmaceuticals Inc. , and Zambon. OR has received grants and/or research support from Agence Nationale de la Recherche (ANR), CHU de Toulouse, France-Parkinson, INSERM-DHOS Recherche Clinique Translationnelle, Michael J. Fox Foundation, and Programme Hospitalier de Recherche Clinique, European Commission (FP7, H2020) and honoraria or consultation fees from AbbVie, Adamas, Acorda, Aguettant, Alkahest, AlzProtect, ApoPharma, AstraZeneca, Bial, Biogen, Britannia Pharmaceuticals, Bukwang, Cerevel, Clevexel, Irlab, Eli-Lilly, Lundbeck, NeuroDerm, ONO Pharma, Orion Pharma, Osmotica, Oxford Biomedica, Pfizer, Prexton Therapeutics, Sanofi, Servier, Sunovion Pharmaceuticals Inc.
Here we report on the preclinical evaluation of VLA2001, a vaccine intended for active immunization to prevent carriage and symptomatic infection with SARS-CoV-2. We demonstrate here the capacity of the vaccine to induce neutralizing antibodies against several VOCs in mice and non-human primates  (NHP)  and protection in a NHP challenge model. The VLA2001 vaccine induced high levels of anti-SARS-CoV-2 antibodies in mice VLA2001 is a highly puri ed inactivated virus derived from a single plaque of the clinical isolate hCoV-19/Italy/INMI1-isl/2020 (National Institute for Infectious Diseases, Rome, Italy, GISAID Accession EPI_ISL_410545). VLA2001 was formulated with alum (17 µg Al 3+ /0. 1 mL) and CpG 1018™ adjuvant, which is used in the US FDA-and EMA-approved vaccine HEPLISAV-B®  [27]  and was added cage-side prior to injection (10 µg CpG 1018/0.
Non-human primate study design Twenty-four male cynomolgus macaques were randomly assigned into three experimental groups. The vaccinated High dose group (Group High) received 35 AU of SARS-CoV-2 inactivated VLA2001 vaccine, adjuvanted with 0. 5 mg alum and 1 mg CpG 1018™ adjuvant, by i. m. route. The vaccinated Medium dose group (Group Medium) received 7 AU of SARS-CoV-2 inactivated VLA2001 vaccine, adjuvanted with 0. 5 g alum and 1 mg CpG 1018™ adjuvant, by i. m. route. Remaining animals were used as controls and received the equivalent volume of PBS by i. m. route. All animals received two injections of the vaccine at weeks 0 and 3, into the right thigh (0. 5 mL per dose). Seven weeks following rst vaccine injection (day 0), animals were inoculated with 1x10 5 PFU SARS-CoV-2 WA1 strain (BetaCoV/France/IDF/0372/2020 strain, EPI_ISL_410720 (GISAID ID)) by intranasal (i.
Quality control was performed by spiking a monoclonal human anti-SARS-CoV-2 S Glycoprotein S1 antibody (clone CR3022; Abcam ref. ab273073) into negative serum samples to compare different inactivation protocols (0. 1 % Triton; 30 minutes at 56 °C). Data acquisition was performed on a MESO Quickplex SQ120 imager and the results were analyzed with the associated software (Discovery Workbench).
Evaluation of anti-SARS-CoV-2 neutralizing IgG antibodies in cynomolgus macaque sera The analysis of the SARS-CoV-2 neutralizing antibody responses was performed in a VeroE6-TMPRSS2 cell  [40]  culture assay in presence of live virus. Pre-incubated mixtures (at different dilution ratios) of NHP heat-inactivated sera (56 °C for 30 minutes) and SARS-CoV-2 virus (strain SK-BMC5/2020 supplied through the European Virus Archive -Global [EVAg] platform) were placed on plated cells. A reference standard control was included (WHO International Standard First WHO International Standard for anti-SARS-CoV-2 human immunoglobulin NIBSC code 20/136, corresponding to pooled plasma obtained from eleven convalescent individuals recovered from SARS-CoV-2 infection). Data acquisition was performed on an Operetta reader (Perkin Elmer), using the colorimetric CellTiter 96® AQueous Non-Radioactive Cell Proliferation Assay following the manufacturer's protocol (Promega, ref.
Pulmonary histopathology in cynomolgus macaques At necropsy, and caudal lobes of macaque lungs were xed by immersion in 10 % formalin solution for 24 hours. Formalin xed samples were para n embedded (FFPE) with vacuum inclusion processor (Excelsior, Thermo), cut in 5 µm (Microtome RM2255, Leica) slices, mounted on coated glass slides (Superfrost+, Thermo) and stained with haematoxylin and eosin (H&E) with automated staining processor (Autostainer ST5020, Leica). Each slide was scored in 20 different spots at 20× magni cation. On each spot, 5 different parameters were assessed: Septal cellularity, Septal brosis, Type II pneumocytes hyperplasia and alveolar macrophages and neutrophils. A systematic histopathology scoring was used and described in supplementary data (Fig. S5 ). Each score was then cumulated for each assessed eld of view for cranial and caudal lobes.
Acknowledgements We thank  Alexandra Skritek  and  Ingmar Stoll  for support with the mouse studies. We thank  Benoit Delache ,  Quentin Sconosciuti ,  Victor Magneron ,  Pauline Le Calvez ,  Maxime Potier ,  Jean-Marie Robert ,  Nina Dhooge ,  Manon Rimlinger ,  Jiahao Qiu ,  Thierry Prot ,  Kévin Tirmarche ,  Marjorie Ben  ssa and  Cristina Dodan  for the NHP experiments;  Laetitia Bossevot ,  Laurine Moenne-Loccoz ,  Suzie Hecquet  and  Loïc Pintore  for the RT-qPCR, ELISpot and MSD serology assays, and for the preparation of reagents;  Mario Gomez-Pacheco  and  Jérôme van Wassenhove  for the ow cytometry assays,  Blanche Fert  and  Nidhal Kahlaoui  for the in vivo imaging;  Sophie Luccantoni  and  Camille Ludot  for histology analysis. We thank  Julia Pilot ,  Karen Storck ,  Céline Aubenque  and  Mickael Jegat  for the MSD serology assays and neutralization assays;  Elodie Guyon ,  Julien Dinh ,  Tracy Abauzit  and  Alexis Gomes  for the NHP sample processing;  Sylvie Keyser  for the transports organization;  Frédéric Ducancel ,  Alicia Pouget  and  Yann Gorin  for the logistics and safety management;  Pauline Maisonnasse  for ethics management;  Isabelle Mangeot  and  Camille Morice  for help with resources management and  Brice Targat  and  Karl-Stefan Baczowski  who contributed to data management.
Funding: The  Infectious Diseases Models for Innovative Therapies (IDMIT) research infrastructure  is supported by the " Programme d'investissements d'avenir ", managed by the  ANR  under reference  ANR-11-INBS-0008. The NHP model of  SARS-CoV -2 infection have been developed thanks to the support from  REACTing (ANRS-MIE)  and the " Fondation pour la Recherche Médicale " (FRM;  AM-CoV-Path ). Valneva  received funding from the  Secretary of State for Business, Energy and Industrial Strategy, UK.
facility authorization #D92-032-02, Préfecture des Hauts-de-Seine, France) and in compliance with European Directive 2010/63/EU, the French regulations and the Standards for Human Care and Use of Laboratory Animals of the O ce for Laboratory Animal Welfare (OLAW, assurance number #A5826-01, US). The protocols were approved by the institutional ethical committee "Comité d'Ethique en Expérimentation Animale du Commissariat à l'Energie Atomique et aux Energies Alternatives" (CEtEA #44) under statement number A20-037. The study was authorized by the Research, Innovation and Education Ministry under registration number APAFIS#24434-2020030216532863v3. VLA2001 vaccine VLA2001 is a highly puri ed inactivated virus derived from a single plaque of the clinical isolate, hCoV-19/Italy/INMI1-isl/2020 (National Institute for Infectious Diseases [INMI], Rome, Italy, GISAID Accession EPI_ISL_410545.
Pharmacokinetic Analysis After the first blood sampling for trough concentration (C 0 ), approximately 24 h after the previous morning dose, the fasting patients took their usual TacQD dose together with their concomitant immunosuppressive medication. Then, blood samples were collected at 20 ± 15 min (T 1 ), 60 ± 15 min (T 2 ), 120 ± 15 min (T 3 ), and 180 ± 30 min (T 4 ), and the exact sampling times were recorded. The C 0 /D ratio was calculated by dividing the Tac C 0 by the corresponding daily Tac dose (D). Whole blood Tac concentrations were analyzed by liquid chromatography with tandem mass spectrometry using isotopically labeled standards on an XEVO TQMS instrument from Waters. Afterward, these data were sent to the laboratory of Pharmacology at the University Hospital of Limoges, where, based on the Immunosuppressant Bayesian Dose Adjustment system, an AUC 24 estimation was delivered.
Statistical Analysis Statistical analysis was performed using SPSS 28. 0 (SPSS, Inc, Chicago, IL). Data with a normal distribution were presented as mean values with their SD. Nominal data were presented by the number of patients and the percentage of total patients. Categorical variables were compared between groups with the chi-square test; differences in continuous variables between groups were tested using the independent sample Student t test (parametric variables). All tests were 2-sided, and a P value below 0. 05 was considered significant. To assess whether the association between C 0 and AUC 24 changes according to dose level, a multiple linear regression model was used with AUC 24 as the dependent variable and C 0 , Tac dose, and interaction between both as independent variables.
CT scans and measurements Pelvic CT scans of the pelvis of 128 children aged 0-15 years old of both genders (sex ratio = 1) were obtained. For all CT scans, a multidetector scanner (HITACHI Medical System Europe, 16 raw multidetectors) was employed. The examination was carried out in helical mode with the acquisition parameters 120 kVp, 250 mAs, pitch 1. 75. The pixel size was 0. 33*0. 33 mm with slice thickness 0. 625 mm. Data were exported in Digital Imaging and Communication in Medicine (DICOM) format. Measurements were performed with the Radiant 2000. 2 software. One sagittal and one transversal views were used for measurements. The sagittal plane passes through the pubic symphysis, which allows the concomitant visualization of the sacral canal, posterior sacral foramina, and intervertebral foramina.
Conclusions Rectal prolapse is a benign pathology but with great concern for the child's family. Mucous prolapse is the most frequently observed as compared with total prolapse and is often a complication of constipation. In the present study, morphological parameters of the sacrum, mostly SL and SC were determining. The SL was greater in cases compared to controls. The SC was more pronounced in controls than children with rectal prolapse. Thus, long and flat sacrum are probably anatomical factors favoring the occurrence of rectal prolapse in children and also probably related to growth retardation. Increased knowledge of the child's pelvis, especially morphological variations, could provide a better understanding of the state of the pelvic viscera, particularly the rectum. This data must be confirmed in future research.
The ten most intense peptide ions from the preview scan in the Orbitrap were fragmented by collision-induced dissociation (normalized collision energy of 35% and resolution of 17,500) after 50,000 ions accumulated. Maximal filling times were 250 ms for the full scans and 60 ms for the MS/MS scans. We enabled the precursor ion charge state screening to reject all unassigned charge states, as well as singly, seven and eight charged species. The dynamic exclusion list was restricted to 500 entries at most, with a maximum retention period of 40 s and a relative mass window of 10 ppm. We enabled the lock mass option survey scans to improve mass accuracy. We retrieved the data using the Xcalibur software  (version 4. 3. 73. 11).