dataesr/scientific-paragraphs-categorization huggingface dataset:
 Pathogen identification and susceptibility testing: For the confirmation of the causative pathogen of the bacterial pneumonia, pulmonary, pleural, blood and urine samples will be collected and analysed by any established standard diagnostic method routinely applied at the study site including classical microbiology and/or any other methods. Pulmonary P r o p e r t y o f T a k e d a : F o r S. A. U. Version: Final, Version 7, incorporating Amendment 5 Study Code: Cx611-0204 Date: 19 December 2019 EudraCT No. : 2015-002994-39 samples can be obtained by bronchoalveolar lavage (BAL) and/or mini-BAL/protected specimen brush (PSB) and/or by endotracheal aspiration (ETA) for intubated patients, and sputum production for non-ventilated patients. Samples will be rapidly processed for Gram stain and culture and/or other established standard rapid diagnostic system, e.
2 ) 2 2. 1) please proceed with the following: P r o p e r t y o f T a k e d a : F o r N S. A. U. Version: Final, Version 7, incorporating Amendment 5 Study Code: Cx611-0204 Date: 19 December 2019 EudraCT No. : 2015-002994-39 Pre-study product administration: o Blood samples for anti-HLA/donor antibodies (Abs) o Vital signs: systolic and diastolic blood pressure, heart rate, core temperature (tympanic, rectal or bladder) and respiratory rate (in non-ventilated patients). Start IV administration of study product (Cx611 or placebo) as early as possible and within the first 18 hours of patient fulfilling at least one of the two major criteria of severity for CABP (i. e. from the initiation of invasive mechanical ventilation support or vasopressors, whichever comes first). During and post-study product administration: o Duration of infusion.
o Signs of hypersensitivity reactions or anaphylaxis (the patient will be monitored for skin reactions and episodes of respiratory distress requiring therapeutic intervention during the first 24 hours after the infusion of IMP). P r o p e r t y o f T a k e d a : F o r S. A. U. Version: Final, Version 7, incorporating Amendment 5 Study Code: Cx611-0204 Date: 19 December 2019 EudraCT No. : 2015-002994-39 Page 48 of 130 Post-study medication administration: o 12 lead ECG. 5 hours ± 1h post IMP infusion. o Pre, during and post-study medication administration: AEs/TEAEs assessment and recording including any AESI.
S. A. U. Version: Final, Version 7, incorporating Amendment 5 Study Code: Cx611-0204 Date: 19 December 2019 EudraCT No. : 2015-002994-39 The safety and feasibility of IV eASC administration has been demonstrated in earlier phase I studies: a phase Ia/IIb in rheumatoid arthritis (1) where repeat doses (3 administrations one week apart) of 1, 2 and 4 million cells /kg were tested in 46 patients, and a phase I study in healthy volunteers in a LPS challenge trial, where a single dose of 0. 25, 1 and 4 million cells /kg were tested in 24 healthy volunteers. The dose schedule in the present study consists of two IV administrations of 160 million cells two days apart (Days 1 and 3). This dose is equivalent to a dose of 2 million cells/kg in a subject of 80 kg. No safety concerns have been detected under any of the tested doses, nevertheless in latest phase I LPS response study in healthy volunteers , the highest dose,.
S. A. U. Version: Final, Version 7, incorporating Amendment 5 Study Code: Cx611-0204 Date: 19 December 2019 EudraCT No. : 2015-002994-39 administration procedure or to any undesired experience, whether or not a causal relationship is suspected. SAEs captured by phone contact at Months 6 (Day 180), 12 (Day 365), 18 (Day 545), and 24 (Day 730) will be recorded in the SAE report form.
Clinical Study Protocol Clinical Study Protocol Sponsor: TiGenix S. A. U. Sponsor: TiGenix S. A. U. Version: Final, Version 7 incorporating Amendment 5 Version: Final, Version 7 incorporating Amendment 5 Study Code: Cx611-0204 Study Code: Cx611-0204 Date: 19 December 2019 Date: 19 December 2019 EudraCT No. : 2015-002994-39 EudraCT No. : 2015-002994-39 ! Time to recurrence/reinfection of pneumonia after clinical cure at sCABP clinical response assessments. Survival ! 28-day all-cause mortality. P r o p e r t y o f ! ! e r t CCI ! 28-day sCABP-associated mortality. ! Survival at Days 7, 14, 29, and 90 visits. ! Time to death. Other efficacy endpoints o f ! P r o p e r t y CCI d S u b j e c t t o t h e A p p l i c a b l e T e r m s o at t day dur day du entilation entilatio e of the v of the e of 26, e of 26 of zero).
ICU at least once. When more than one measurement is available for screening, Day 2 and Day 4 onwards only the highest and the lowest value measured for each vital sign for that time period will be recorded in the CRF for that timepoint. 2. Full SOFA: Cardio-vascular, Respiration, Coagulation, Liver, CNS and Renal. Clinical Study Protocol Sponsor: TiGenix S. A. U. Version: Final, Version 7 incorporating Amendment 5 Study Code: Cx611-0204 Date: 19 December 2019 EudraCT No. : 2015-002994-39 CCI CCI CCI CCI Confidential Page 15 of 130 from 3.
2 Patient Records and Source Data. Clinical Study Protocol Sponsor: TiGenix S. A. U. Version: Final, Version 7 incorporating Amendment 5 Study Code: Cx611-0204 Date: 19 December 2019 EudraCT No. : 2015-002994-39 11. 5. 2. Day 365) ay 365. CCI. Signs and Signs an tivity Rea ty R. ram (EC am (EC Safety As afety /donor A onor nts ts. ilator ator-fr f - CABP C CABP APACH APAC ological logica CCI 5. 2 5. 2 CCI Total B otal 7 Appr App ADVER ADVE 11. 1 11. 1. ant Medi nt Med. Immediately Reportable Events (IRE). 94 11. 5. 3 Immediately Reportable Event Reporting. 95 11. 5. 4 Pregnancy Reporting. 96 12 STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE. 98 12. 1 Statistical and Analytical Plans. 98 12. 1. 1 Data Set to be Analysed. 98 12. 1. 2 Summary Statistics. 98 12. 1. 3 Demographic and Other Baseline Characteristics.
SOFA Score. 129 APPENDIX E Conversion Table SO 2 (%) to PaO 2 (mmHg) and O 2 (l/min) to FiO 2 Clinical Study Protocol Sponsor: TiGenix S. A. U. Version: Final, Version 7 incorporating Amendment 5 Study Code: Cx611-0204 Date: 19 December 2019 EudraCT No. : 2015-002994-39 o f U s e T e r m s A p p l i c a b l e t h e S u b j e c t t o a n d O n l y e r c i a l U s e o n -C o m m o f T a k e d a : F o r N P r o p e r t y Table. 123 APPENDIX B CURB-65 Score (Confusion, Elevated Blood Urea Nitrogen Level, Respiratory Rate, and Blood Pressure Plus Age ≥65 Years). 124 APPENDIX C APACHE II (Acute Physiology And Chronic Health Evaluation) Score. 125 APPENDIX D (%). 130 LIST OF TABLES Table 1. Schedule of study assessments. 12 LIST OF FIGURES Figure 1. Study design. 41.
n of Ter n of T Clinical Study Protocol Clinical Study Protocol Sponsor: TiGenix S. A. U. Sponsor: TiGenix S. A. U. Version: Final, Version 7 incorporating Amendment 5 Version: Final, Version 7 incorporating Amendment 5 Study Code: Cx611-0204 Study Code: Cx611-0204 Date: 19 December 2019 Date: 19 December 2019 EudraCT No. : 2015-002994-39 EudraCT No. : 2015-002994-39 E-mail: CCI CCI PPD s e U PPD CCI CCI CCI Authorit Author Name: Address: A P r o p e r t y l: : OORD OORD o f T a k Nam Nam PPD Phone: Fax: Page 22 of 130.
CONTRACT RESEARCH ORGANISATION (CRO) Clinical Study Protocol Sponsor: TiGenix S. A. U. Version: Final, Version 7 incorporating Amendment 5 Study Code: Cx611-0204 Date: 19 December 2019 EudraCT No. : 2015-002994-39 PPD s e o f U s PPD T e r m PPD PPD l y Name: PPD Address: Phone: Fax:.
5 INTRODUCTION 5. 1 Background: Severe Community-acquired Bacterial Pneumonia Clinical Study Protocol Sponsor: TiGenix S. A. U. Version: Final, Version 7 incorporating Amendment 5 Study Code: Cx611-0204 Date: 19 December 2019 EudraCT No. : 2015-002994-39 inspired oxygen (PaO2/FiO2) ratio < 250; multilobar infiltrates; confusion; blood urea nitrogen level >20 mg/dL; leukopenia; thrombocytopenia; hypothermia; or hypotension requiring aggressive fluid resuscitation) may also suggest a severe CABP (4). To aid in Community-acquired pneumonia (CAP) is the most common cause of death associated with infectious disease and the sixth most common cause of death in the United States (2,3). When deciding whether a given patient can be treated as an outpatient or should be admitted to the hospital, severity scores (such as the Pneumonia Severity Index [PSI]; the confusion, elevated o f U s e CAP is caused by bacterial pathogens, it is named a community-acquired bacterial pneumonia (CABP).
soon as sCABP is clinically diagnosed and indication for initiating mechanical ventilation and/or treatment with vasopressors is met, written informed consent to participate in the study must be obtained from the patient's legally acceptable representative, as required by local laws and guidelines (written informed consent should be sought from the patient as soon as he/she becomes capable of comprehending the scope of the trial). Clinical Study Protocol Sponsor: TiGenix S. A. U. Version: Final, Version 7, incorporating Amendment 5 Study Code: Cx611-0204 Date: 19 December 2019 EudraCT No. : 2015-002994-39 7. 2. 2. 1 Screening Period Screening visit will take place promptly once the patient presents clinical evidence that one of the two major criteria of severity for CABP are being met (i. e.
inclusion/exclusion criteria. Clinical Study Protocol Sponsor: TiGenix S. A. U. Version: Final, Version 7, incorporating Amendment 5 Study Code: Cx611-0204 Date: 19 December 2019 EudraCT No. : 2015-002994-39 mutation, hyperhomocysteinemia], thrombophilia; fracture of pelvis, hip or long bones; lower limb orthopaedic surgery; malignancy; major general surgery).  Prior antibiotic and non-antibiotic treatments for CABP and treatments for other diseases s e o f U (within the last 2 weeks); concomitant treatments for sCABP and other diseases (concomitant medication page will be completed, including all medication taken by the patient at the time of the visit).  Physical examination including weight and height.  Assessment of clinical signs and symptoms of pneumonia. s T e r m A p p l i c a b l e t h e S u b j e c t t o a n d O n l y e r c i a l U s e o n -C o m m  Demographic data and complete medical history including previous and current diseases and allergies, immunological status (i.
6 Visit 8: Study Days 8-10  Concomitant medication page will be updated with treatment for sCABP and other diseases as it applies.  Physical examination including assessment of clinical signs and symptoms of pneumonia.  Vital signs: systolic and diastolic blood pressure, heart rate, core temperature (tympanic, rectal or bladder) and respiratory rate (in non-ventilated patients). On Days 8-10 if patient is in the ICU at least 4 times daily (i. e. every 6h±1h), if discharged from ICU at least once. When more than one measurement is available only the highest and the lowest value measured for each vital sign for that time period will be recorded in the CRF for that timepoint. Clinical Study Protocol Sponsor: TiGenix S. A. U. Version: Final, Version 7, incorporating Amendment 5 Study Code: Cx611-0204 Date: 19 December 2019 EudraCT No.
Clinical Response assessment and recording. Clinical Study Protocol Sponsor: TiGenix S. A. U. Version: Final, Version 7, incorporating Amendment 5 Study Code: Cx611-0204 Date: 19 December 2019 EudraCT No. : 2015-002994-39 s e o f U up T e r m s on n as as a b l e ording rding CCI ry y requi requ y y ESI ESI. update upda g assess g asse di diastol asto d respi d respir i ast 4 tim ast 4 t than than ed d fo for r mepoint epoint SOFA SO Page 53 of 130.
10 Long-term safety follow-up (phone calls at Month 6 [Day 180 ± 30 days], Month 12 [Day 365 ± 30 days], Month 18 [Day 545 ± 30 days] and Month 24 [Day 730 ± 30 days] ). Blood samples for haematological, coagulation and biochemical tests (according to local laboratory requirements) and anti-HLA/donor Abs (4. 5 mL EDTA). Urine samples for urinalysis (according to local laboratory requirements). Clinical Study Protocol Sponsor: TiGenix S. A. U. Version: Final, Version 7, incorporating Amendment 5 Study Code: Cx611-0204 Date: 19 December 2019 EudraCT No. : 2015-002994-39 TEAEs assessment and recording, including any AESI. 7. 2. 2. CCI h t t h reatm rea of clinic of clini d press pre rate (in rate (in ily (i. e. y (i. e asurem sure tal tal sign sig le and and nce ce): ): e C CRF) CRF) Pneu Pne P Page 54 of 130.
July 1996), adopted in the European Union (EU) by CPMP EU Commission Directive 2005/28/EC (GCP, April 2005) and the ethical principles of the latest revision of t he Clinical Study Protocol Sponsor: TiGenix S. A. U. Version: Final, Version 7, incorporating Amendment 5 Study Code: Cx611-0204 Date: 19 December 2019 EudraCT No. : 2015-002994-39 ( o f U s e T e r m s A p p l i c a b l e t h e S u b j e c t t o a n d O n l y e r c i a l U s e o n -C o m m o f T a k e d a : F o r N P r o p e r t y The study will be conducted in compliance with the protocol, regulatory requirements, GCP, consolidated guidelines Committee for Proprietary Medicinal Products (CPMP)/ICH/135/95.
Although these advances in mouse models have provided critical insights into the physiological importance of this complex, its relevance in humans remains unknown, as no disease variant has been identified in humans. Using whole-exome sequencing (WES), here we report the identification of 3 autosomal recessive variants, SEL1L p. Gly585Asp, p. Met528Arg, and HRD1 p. Pro398Leu, in 6 children from 3 unrelated families with similar neurodevelopmental disorders -termed Similarly, allele frequency of HRD1 p. Pro398Leu was low in the population and was predicted to be benign to damaging in various prediction databases (Table  1 ). SEL1L and HRD1 genes are located on chromosomes 14 and 11, respectively (Figure  1, G  and H ). Using Sanger sequencing, we confirmed that the 3 variants were found to be homozygous in all patients, but heterozygous in all parents (Figure  1 , G and H).
Indeed, neither of the SEL1L variants was found in public genetic variants databases, such as 1000gp3 (https://www. internationalgenome. org/), ESP6500 (https://esp. gs. washington. edu/drupal/), ExAC (https://gnomad. broadinstitute. org/), and gnomAD (https://gnomad. broadinstitute. org/), and both variants were consistently predicted to be damaging using various prediction tools, such as Combined Annotation Dependent Depletion (CADD) (https:// cadd. gs. washington. edu/), PolyPhen2-HVAR (http://genetics. bwh. harvard. edu/pph2/), Sorting Intolerant from Tolerant (SIFT) (https://sift. bii. a-star. edu. sg/), LIST-S2 (https://list-s2. msl. ubc. ca/?session=838295C8507C38640C29677123B49248), Mendelian Clinically Applicable Pathogenicity (M-CAP) (http://bejerano. stanford. edu/mcap/), BayesDel addAF (https://fenglab.
chpc. utah. edu/BayesDel/BayesDel. html), DEOGEN2 (http://babylone. 3bio. ulb. ac. be/MutaFrame/), Functional Analysis through Hidden Markov Models (FATHMM-MKL) (http://fathmm. biocompute. org. uk/), MutationAssessor (http://mutationassessor. org/r3/), MutationTaster (https://www. mutationtaster. org/), and PrimateAI (https://github. com/Illumina/PrimateAI) (Table  1 ). cyst without other notable findings. When repeated at the age of 21 years, an abnormal signal was detected in the globus pallidum and substantia nigra (not shown). Cardiac and abdomen ultrasounds were both normal. The patient has been on risperidone (Table  1 ) since the COVID-19 outbreak because of worsening of her behavior with agitation and aggression. and dysmorphic facial features (Figure  2F ). Physical examination at 16 years of age revealed that she was underweight (37.
Structural modeling of the human SEL1L-HRD1 complex showed a great similarity to the cryogenic electron microscopy (Cryo-EM) structure of the yeast Hrd1p-Hrd3p complex (PDB ID 6VJZ) (12) (Supplemental Figure  5A ). ConSurf conservation analysis (57) of SEL1L confirmed that both Met528 and Gly585 residues were in highly conserved patches (Supplemental Figure  5B ). (RING-finger) domain (Figure  4K ). This proline-rich region is disordered based on IUPred2 prediction (58) (Figure  4L ), with no predictable structure. SEL1L and HRD1 variants impair ERAD function via distinct mechanisms. We next explored how these variants cause ERAD defects using KI HEK293T cells. We first measured protein levels of the SEL1L-HRD1 ERAD complex. Noticeably, SEL1L M528R KI HEK293T exhibited reduced SEL1L and HRD1 protein levels, by approximately 80% and 60%, respectively (Figure  5, A  and B ), uncoupled from their gene transcription (Figure  5 , C and D).
Acknowledgments We are deeply grateful to all patients and their families for their consent and willingness to participate in this study;  Chih-Chi Andrew Hu  ( Houston Methodist Hospital ) for reagents; members of the  Qi ,  Arvan , and  Pletcher  laboratories; and  Jiwon Hwang  and  Ryan Baldridge  at the  University of Michigan Medical School  for technical assistance and insightful discussions and constructive comments on the manuscript. This work was supported by  R01DK128077 ,  R01DK132068  (to SS), the  Telethon Foundation , the  Telethon Undiagnosed Diseases Program   GSP15001  (to NBP),  R01DK120330 ,  R35GM130292 , and the  Michigan Protein Folding.
Information sources We searched Medline (National Library of Medicine, Etats-Unis), the Cochrane Library (Wiley Interscience, USA), Embase (Elsevier) and LiSSA from January 2008 to January 2022. Bibliographic monitoring of studies reported in English or French continued until September 2022. This systematic research was completed by a manual search of the websites of international journals and congresses on MT and BS (i. e. , to identify potential abstracts of unpublished trials). The literature search strategy with the list of websites is detailed in Supplement 1 (see supplementary materials associated with this article online). We also conducted a manual search of ClinicalTrial. gov to find potentially eligible trials or any additional information about trials identified by database searches.
Outcomes DR was selected as the primary outcome. It was defined according to American diabetes association (ADA) consensus report  [12]  as glycated hemoglobin (HbA1c) <6. 5 % (48 mmol/mol) measured at least three months after the intervention (MS or MT) at least three months after cessation of all glucose-lowering pharmacotherapy including insulin. We chose to study DR that persisted at least 24 months after surgery. The primary outcome was expressed as the number of individuals who experienced the event of interest (i. e. , DR). We extracted data for the intention-to-treat population as described in the protocol of each trial or in the first ancillary publication of the trial. The analysis included all patients allocated to MS versus all patients allocated to MT management. In case of missing data, we considered that patients did not meet the primary outcome (i.
Data synthesis We conducted meta-analyses when at least three studies reported our primary outcome. We used the Cochrane Collaboration's Review Manager (RevMan) [Computer program] v5. 4 (2020). We calculated relative risk (RR) and 95 % confidence intervals (CIs) using the Mantel-Haenszel random-effects approach. Statistical heterogeneity was quantified with I 2 and Tau 2. The selected studies were grouped in three different groups according to the length of follow-up (24, 36, and 60 months after intervention). Meta-analyses were then performed within these three groups. We therefore conducted two main meta-analyses, each with five trials taking into account the results for 323 and 404 patients with a follow-up of and 36 months respectively. Furthermore, we conducted a meta-analysis of three trials, including 321 patients, with a 60-month follow-up and a sub-group analysis in patients assigned to RYGB or MT with a 36-month follow-up.
Diabetes remission in patients with overweight Given that only two studies included patients with overweight  [15, 22] , it was not relevant to conduct a MA focusing on this subgroup. Moreover, in  [22] , the authors pooled data from overweight patients and patients with class I obesity. It was therefore impossible to extract data only for patients with a BMI of less than 30 kg/m 2. Wentworth et al. [15]  only included patients with overweight (n = 51), of whom 25 underwent MS (LAGB in all cases). This trial presented a high risk of bias. At 24 months, the DR rate was significantly different (P < 0. 01): 52 % [95  %CI 30; 73]  in the LAGB group compared with 8 % [0. 98;26] in the control group. Patients lost to follow-up represented % of the study population.
Policy decisions on the reimbursement of MS care in each country should be based on health technology assessments incorporating longterm clinical efficacy and safety data with particular attention to the organization of country-specific care systems providing for appropriate mandatory follow-up throughout life  [31]. When HAS added MS to the treatment algorithm of uncontrolled type 2 diabetes, it concluded that the long-term, real-life data were necessary to potentially reassess the relevance of MS in the future and therefore revise or confirm its conclusion in five years' time. Indeed, previous work using the French national health insurance database on BS have provided information at national level on long-term complications  [32]  and loss to follow-up after BS  [33]. Moreover, this database, which collects longitudinal data on medication use, has also been used to assess improvements in type 2 diabetes, hypertension, and dyslipidemia, as well as changes in medication use after BS  [34, 35].
Therefore, we are convinced that this database provides us with a comprehensive set of data on changes in the general health of patients' after MS, allowing us to assess safety and efficacy, as well as to describe in depth changes in medication use during follow-up including the occurrence of death and cardiovascular events and the impact on healthcare consumption with information on the specific risks associated with surgery (type 2 diabetes relapse, adverse events, revision surgery, etc. ). Further studies are needed to evaluate quality of life. Type 2 diabetes has historically been considered as a homogeneous entity, which was also the case for all the RCTs included in our metaanalysis. There is now increasing evidence that the disease exists as distinct subtypes, with specific clinical presentation, disease progression, and therapeutic response.
Yet, it remains unclear to what extent the complementation of CanRisk-based BC risk prediction with data on further genetic (PRS)  [6]  and non-genetic risk factors (NGRFs) affects clinical recommendations on an individual level according to country-specific guidelines. In this study, we assessed the clinical implications of a comprehensive CanRisk-based BC risk prediction in comparison to a risk prediction that only considers cancer FH and PV status. The study sample comprises 425 cancer-free women with a FH of BC and/or OC consecutively enrolled at three study sites in Germany, France and the Netherlands.
Detection and classifications of rare variants Detection of rare (likely) PVs was carried out using the SeqNext module of the SeqPilot Software Package (JSI medical systems GmbH, Ettenheim, Germany). The Alamut Visual version 2. 13 analysis software tool (Interactive Biosoftware, Rouen, France) was applied for variant annotation and integration of up-to-date classifications from the ClinVar database (www. ncbi. nlm. nih. gov/clinvar/). Variant classification was performed using the criteria of the GC-HBOC for the classification of germline sequence variants in predisposition genes for hereditary BC and OC  [15] , which are based on the guidelines by the Evidence-Based.