dataesr/scientific-paragraphs-categorization huggingface dataset:
Ongoing studies Multiple of other mAbs are now been tested in RRMM. Combination of elotuzumab, carfilzomib, pomalidomide and dexamethasone in RRMM is actually under investigation in a Phase II trial (NCT03155100). Phase II trial elotuzumab, pomalidomide, bortezomib and dexamethasone in RRMM (Elo-PVd) is also recruiting (NCT02718833). A Phase III study of lenalidomide and dexamethasone with or without elotuzumab in newly diagnosed patients with MM (ELOQUENT-1) is underway (NCT01335399). Elotuzumab is also investigated in combination with bortezomib, lenalidomide and dexamethasone (VRd) in newly diagnosed myeloma (NDMM) eligible for transplant in Phase II trials (NCT02375555, NCT02495922). Elotuzumab combined with carfilzomib, lenalidomide and dexamethasone is investigated in NDMM (NCT02969837).
5 kpc, e. g. NGC 7814-DGSAT-7 with r eff = 1. 49 kpc) and residing in a galaxy group environment based on their projected position in the sky. Therefore we exclude UDGs residing in clusters, because in these environments too many things can affect the velocity dispersion of the UDGs. Also, we only consider galaxies in the nearby Universe (z < 0. 01). While going further would indeed increase the sample  (Greco et al. 2018) , the galaxy's association to a certain galaxy group becomes more difficult to estimate. In Table  1 , we present our sample of nearby UDGs within galaxy group environments. We have compiled the relevant data needed to estimate the velocity dispersion in MOND (see Section 2). For this, we need the total luminosity of the galaxy L , the half-light radius r eff , and the projected separation to the host galaxy ∆ pro j.
2011). From there, the external field at the position of the UDG can be estimated directly from the centripetal acceleration. For elliptical galaxies where no rotation curve data is available, we converted the K band luminosity using a Mass-to-Light (M/L) ratio of 0. 8  (de Blok et al. 2008)  to get the total stellar mass. From there, the gravitational field at the distance of the UDG can be estimated in the context of MOND. This was the case for Cen A (K = -23. 9 mag), NGC 3625 (K = -21. 9 mag), NGC 3669 (K = -22. 3 mag), NGC 7814 (K = -24. 0 mag), NGC 5485 (K = -23. 8 mag), NGC 3384 (K = -23. 4 mag), M 105 (K = -23. 9 mag), NGC 5475 (K = -22. 8 mag), and NGC 3619 (K = -24. 0 mag) using the photometry by the Two Micron All Sky Survey (2MASS,  Skrutskie et al. 2006 ) and a distance modulus given in Table  1.
By varying the Mass-to-Light ratio of the UDG, as well as the distance to its putative host, we give upper and lower limits allowed from MOND. Future observations of these UDGs can therefore test the validity of MOND and test the external field effect. Two of our UDGs -Cen A-MM-Dw1 and M 96-DF6 -have high-precision distance measurements with the HST. In these cases, we have calculated the three dimensional distances to their host and made a more narrow prediction of the expected velocity dispersion in MOND, assuming that they follow a typical M/L ratio of 2. For Cen A-MM-Dw1 we expect a velocity dispersion of σ = 11. 8 +2. 2 -1. 5 km s -1 , and for M 96-DF6 a velocity dispersion of σ = 9. 5 +1. 0 -1. 0 km s -1. For NGC 1052-DF2 high-precision IFU data have become available, taken with VLT+MUSE.
107 For shorter homologue 6CB, resonance shear measurements in confinement detected an increase in viscosity for D < 20 nm. 126 Below 12. 5 ± 1. 3 nm, the orientation of the confined molecules was so large and the rigidity was so high that the LC structure could not be distorted by electric fields. Here, aside from static XRR and in-plane scattering on the LC structure in slit-pore confinement, time-resolved experiments were carried out during compression and decompression cycles. Furthermore, the recorded X-ray scattering and reflectivity data was complemented by simultaneous interferometry-based thickness measurements. Therefore, in contrast to static X-SFA  125  and macroscopic dynamic experiments,  107  our setup provides direct access to the structural relaxation dynamics of the confined LC.
* S Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: 10. 1021/acs. langmuir. 9b01215. Experimental description of surface preparation and characterization, material properties, technical details of the X-SFA setup and operation, and complementary 8CB scattering data (PDF) ■ AUTHOR INFORMATION Corresponding Authors *E-mail: valtiner@iap. tuwien. ac. at. *E-mail: mezger@mpip-mainz. mpg. de.
Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic cause of renal failure. For several decades, ADPKD was regarded as an adult-onset disease. In the past decade, it has become more widely appreciated that the disease course begins in childhood. However, evidence-based guidelines on how to manage and approach children diagnosed with or at risk of ADPKD are lacking. Also, scoring systems to stratify patients into risk categories have been established only for adults. Overall, there are insufficient data on the clinical course during childhood. We therefore initiated the global ADPedKD project to establish a large international pediatric ADPKD cohort for deep characterization. Methods: Global ADPedKD is an international multicenter observational study focusing on childhooddiagnosed ADPKD.
This collaborative project is based on interoperable Web-based databases, comprising 7 regional and independent but uniformly organized chapters, namely Africa, Asia, Australia, Europe, North America, South America, and the United Kingdom. In the database, a detailed basic data questionnaire, including genetics, is used in combination with data entry from follow-up visits, to provide both retrospective and prospective longitudinal data on clinical, radiologic, and laboratory findings, as well as therapeutic interventions. Discussion: The global ADPedKD initiative aims to characterize in detail the most extensive international pediatric ADPKD cohort reported to date, providing evidence for the development of unified diagnostic, follow-up, and treatment recommendations regarding modifiable disease factors.
Characteristics of Participants Patients eligible for inclusion are individuals diagnosed with ADPKD before the age of 19 years. Each pediatric center will have the option to include data from their patients who have transitioned to adult clinics. This "transitioned" cohort will allow us to optimize our analysis on long-term progression. The diagnosis is defined by the presence of at least 1 renal cyst with a positive family history  74  and/or a positive molecular assessment of the known ADPKD genes. Also, children diagnosed with the contiguous gene syndrome (TSC2-PKD1) will be included and studied as a subgroup. Patient inclusion is preceded by written informed consent of the patient and/or their parents or legal representatives, after approval of the study and the related study documents, including informed consent forms by the corresponding local ethics committee.
Design of the Study and Study Procedures This global collaborative project is based on interoperable Web-based databases, comprising 7 regional and independent but uniformly organized chapters, each led by their own principal investigator, namely Africa, Asia, Australia, Europe, North America, South America, and the United Kingdom. After signing the informed consent forms, patients' data are pseudonymously entered by the patient's caregiver and/or his or her team member(s) in the Web-based database, accessible via https://www. adpedkd. org/. Local investigators are able to access the ADPedKD Web site at any time for the following purposes: entering and editing data, posing questions, and accessing center enrollment overview. Also, the Downloads section of the Web site gives access to all study-related documents, including a handbook, patient information, and informed consent forms sorted per language for all participating countries and the complete study protocol and ethics committee statement.
Currently, we already have 11 languages available (Dutch, English, French [Belgium], French [France], German, Italian, Polish, Portuguese, Romanian, Serbian, and Turkish). Africa, Asia, and Europe share 1 common database. Its data entry section is secured by restriction to a personal username and password for each investigator. Moreover, the use of Secure Sockets Layer encrypted-connections ensure data protection. Only the responsible local study site is able to identify their own included subjects based on the identification pseudonym, and this will be protected from disclosure as described in both the research protocol and informed consent forms. Therefore, participating centers are exclusively able to review and/or modify data of patients from the corresponding site and are responsible for data protection.
To ensure the highest levels of data quality, the online case report forms require mandatory inclusion of key variables and include automated entry checks based on predefined plausibility ranges. Moreover, wherever possible, values are calculated and updated automatically. For instance: body mass index, weight standard deviation score, height SD score, and body mass index SD score are calculated automatically after entry of weight and height, based on the World Health Organization reference standards, as these can be applied to all children regardless of ethnicity, socioeconomic status, or type of feeding. 76 Also, in case of different standard units, laboratory results are converted automatically. By these precautions, the risk of data entry errors or incomplete data is minimized. Next, data entries will be randomly reviewed, during regular interim analyses and for outlying values, a query will be sent to the local investigators.
Data acquisition (Figure  1 ) is subdivided into 3 sections: basic data, visits (initial and follow-up), and study termination (Table  2 ). Australia and the United Kingdom have their separate source databases, namely Australasian Registry of Rare and genetic Kidney disease and National Registry of Rare Kidney Diseases, which are accessible via www. adpedkd. org or directly via www. kidgen. org. au and http://rarerenal. org/rare-disease-groups/adpkd-rdg/, respectively. These databases have a fully interoperable data structure with the ADPedKD database, including a uniform dataset. The Australasian Registry of Rare and genetic Kidney disease is embedded within the local KidGen Collaborative, and its Web site launch will occur within the coming months. It is designed to be a "node" of as well as interact with other global registry efforts.
In North America, the ADPedKD Registry will be implemented under the auspices of the National Institutes of Health-funded Hepato-Renal Fibrocystic Disease database. 77 urrently, the data are stored on a secure server, managed in Köln, Germany, for the European, Asian, African, and South American data. The National Registry of Rare Kidney Diseases (United Kingdom), United States, and Australia have their own secure data storage arrangements that have been established for this registry and other related registries, for example, the ARPKD Database (United States). Depending on the participating center, we expect the number of children enrolled per center to range from a minimum of 10 to a maximum of 100, although this is an open registry with no formal maximal number of centers and patients. The anticipated sample size is 2000 patients.
Basic Data Personal information on the pre-and perinatal period, the initial diagnosis, genetic information, and a detailed family history are documented (Figure  1 , Table  2 ). The latter includes a questionnaire on family history of tuberous sclerosis complex, diabetes mellitus, intracranial aneurysm, gout, colon diverticulosis, heart valvular defects, liver cyst(s), pancreatic cyst(s), and kidney cyst(s) other than caused by ADPKD. Moreover, for all known affected family members, including children already included in ADPedKD (e. g. , siblings or cousins) the age at diagnosis, age at end-stage kidney disease (if applicable), and abdominal imaging results are queried. This enables characterization of family phenotypes in detail.
Initial Visit/Follow-up Visits After completion of the baseline data collection, data can be entered in the "visits" section, starting with the initial visit and further visits, which are suggested to be annual (Figure  1 , Table  2 ). The latter is generated for the registration of clinical, radiologic, laboratory, and other findings of the different organ systems possibly affected in ADPKD (kidney, liver, cardiovascular, neurologic, eye, and others), apart from general information, including biometry (weight, height, blood pressure, heart rate, and Tanner staging  78  ). The patient's medication, even if not directly related to ADPKD, is entered, including dosing and duration. Other therapeutic interventions, such as cyst fenestration, dialysis, nephrectomy, renal transplantation, or other urological/surgical procedure, are noted with date, indication, and possible complications.
Study Termination In case the study is terminated, date and reason for this will be entered (Figure  1 , Table  2 ). The patient might have future follow-up in a pediatric nephrology center not participating in ADPedKD, transition to adult nephrology care, it might be the patient's wish to withdraw his or her informed consent, the patient might be deceased, or the patient might be lost to follow-up for another or unknown reason. In case of transfer to adult nephrology departments, the local site is asked to engage with the future center and provide contact with the adult nephrologist. Also, if patients subsequently participate in an adult ADPKD registry, the registry's name and the patient's registry ID will be requested. As several registries for adult ADPKD data are ongoing, we have added a specific item "termination of the study" in case of transfer to adult nephrology programs.
The local site is asked to fill in the future center, the contact of the nephrologist, and if the patients will participate in an adult ADPKD registry, the registry's name and the patient's registry ID will be requested. This approach will allow us to trace the patient in the future and to merge registry data in collaboration with the adult nephrologist community. We note that the National Registry of Rare Kidney Diseases and Australasian Registry of Rare and Genetic Kidney disease initiatives include patients from all the ages on a national basis and it will be easier to track their course in the same database. Importantly, in case of a transfer to another pediatric nephrology center participating in ADPedKD, the patient is not terminating the study. The local study site then informs the destination center about the transfer by filling in a transfer form available in this patient's data entry section.
Statistical Analysis Initially, we will perform a descriptive analysis, including the calculation of relative and absolute frequencies for binary/categorical variables and of mean, SD, median, interquartile range, minimum, and maximum for the continuous variables. Further longitudinal data regarding outcomes of markers of renal function, renal size and volume, and cardiovascular morbidity will be analyzed using appropriate statistical methods, such as mixed modeling. Missing data will be handled by means of multiple imputation. Also, the aspect of multiple testing and potential sources of bias will be examined and considered in all analyses. If required, the distribution of variables will be normalized by appropriate transformation. Methods will also include multivariable adjusted linear and logistic regression analysis for cross-sectional data, and linear regression and proportional hazards regression for longitudinal data.
DISCUSSION The global ADPedKD initiative aims to remedy the current paucity of information regarding pediatric ADPKD, especially from regions other than Europe and the United States (Table  1 , Supplementary Table  S1 ). Patient registries are well-recognized tools to advance epidemiological characterization of patient cohorts and to evaluate clinical therapies. 79 Future analyses of the ADPedKD Registry will be conducted to increase the understanding of disease progression from early disease stages. Data gathered during the follow-up period will be collected from clinicians worldwide and will be valuable to help describe childhood ADPKD prevalence, presentation, progression, and current management and its effect on the disease history (e. g. , strict versus standard blood pressure control) and patient outcomes.
Initial focus will be placed on undertaking a descriptive analysis of the dataset, once enrollment reaches 1000 patients. These initial cross-sectional analyses will focus on the prevalence of renal and extrarenal disease manifestations, the current practices in different regions of the world regarding monitoring and treatment. For this, data at inclusion, including sonomorphological markers, family history, and genetics, will be analyzed. The documented prevalence might be different from adult ADPKD prevalence, given the controversy about testing for disease presence in minors  22  and the fact that the ADPKD diagnosis in children might have different origins: by coincidence via ultrasound for another reason, or by a presenting symptom such as a urinary tract infection, hematuria, or bedwetting.
44 Also, children might be diagnosed prenatally, and in some cases because of screening by means of renal ultrasound or genetic analysis of the ADPKD genes on parental request. Moreover, diagnosis of the disease and its different renal and extrarenal manifestations might be region-specific, as this is dependent on patients' and caregivers' awareness, availability of resources, and organization of health care. 80 These will be important confounders in our analysis of region-specific differences and their effects on outcomes. Longer term, we will focus on longitudinal data to assess disease progression and evaluate risk factors that distinguish slow versus rapid disease progression. These analyses will facilitate appropriate patient selection for future clinical trials. As part of these analyses, we will assess whether hypertension of varying grades and other possible disease features, such as proteinuria and left ventricular hypertrophy, should be regarded as modifiable risk factors, early treatment of which can slow disease progression.
CLINICAL RESEARCH the numerous potential benefits inherent with such an initiative and approach. The immediate goal of ADPedKD is to describe current clinical practices and to analyze the patient population that is already under care in reference centers and tertiary hospitals. Although this approach might bias the cohort toward more severe cases, the lack of a validated approach for screening asymptomatic at-risk offspring suggests that this limitation is identifiable but unable to be minimized at present without clearer understanding more broadly of ADPKD in the pediatric age group. Moreover, ADPedKD, like any registry study, will be limited by the use of real-life clinical data resulting in missing, incomplete, or inaccurate data entry, even despite the established automated plausibility checks.
This is especially true for retrospectively entered data. Also, laboratory and molecular investigations are performed using multiple techniques. Finally, entering data is labor intensive and time-consuming, jeopardizing the completeness of reporting. Based on our beta-testing, completion of the case report form requires approximately 1 hour per patient visit, with some variation introduced by differences in how patient data are stored at each referral center storage. Going forward, we expect that with the global transition to electronic health records, data entry increasingly will be automated; however, funding will be sought to support centers with data entry. In summary, the global ADPedKD registry aims to establish a large longitudinal pediatric ADPKD cohort, which will be jointly evaluated by the partners of the global ADPedPKD consortium.
ACKNOWLEDGMENTS Patient inclusion is preceded by informed consent of the patient and/or his or her parents or legal representatives, after approval of the study by a corresponding local ethics committee. The registry study protocol and patient informed consent forms have been reviewed and approved by the Ethics Committee of University Hospitals Leuven (S59638). The study is conducted according to the 1964 Declaration of Helsinki, the guidelines of Good Clinical Practice, and with all applicable regulatory requirements, including the recently enforced European Union General Data Protection Regulation. 35 M is supported by the Clinical Research Fund of UZ Leuven. LGW is supported by the UAB Hepatorenal To date, ADPedKD has been supported by an initiation award from the University Hospitals Leuven coordinating center, as well as a research grant from the European Society of Pediatric Nephrology and the European Renal Association-European Dialysis and Transplant Association.
Plasmids were isolated from E. coli using the NucleoSpin Plasmid EasyPure kit (Macherey-Nagel). Restriction enzymes were obtained from New England Biolabs. DNA fragments were separated in 1% (w/v) agarose gel. DNA fragments were purified using the NucleoSpin Gel and PCR Clean-up kit (Macherey-Nagel). DNA concentrations were measured with a NanoDrop spectrophotometer. Yeast transformations were performed with the lithium acetate method. 37 Yeast plasmid and genomic DNA was extracted as previously described. 38 lasmid Construction. The episomal expression vector pMEN2 was assembled in vivo from five separate DNA fragments using 60 bp homologous recombination sequences. The S. flavescens Sf FPT (coSf FPT; GenBank accession number AHA36633) gene was ordered as a yeast codon-optimized synthetic gBlock gene fragment from Integrated DNA Technologies.
The truncated HMG1 gene fragment (tHMG1) was amplified from genomic DNA of S. cerevisiae IMK393. The fragments TEF1 T -AmpR-2 μm, GAP P -TEF1 P , and 2 μm-HIS3-CYC1 T were amplified from plasmid pUDE188. 26 Correct assembly of the plasmid was confirmed via restriction enzyme analysis and sequencing (Macrogen). All plasmids used in this study are listed in Table  3. Strain Construction. Integration of gene fragments and knockout of genes was obtained using CRISPR-Cas9, as previously described. 39. cerevisiae strain PATW066 was transformed with p414-TEF1p-Cas9-CYC1t, yielding strain PATW083. The native open reading frame of TSC13 was replaced by its gene orthologue from Malus × domestica (MdECR; GenBank accession number XP_008382818), as described previously. 39 Strain PATW083 was transformed with the gRNA.
TSC13 plasmid and the coMdECR integration fragment. Correct integration of coMdECR was verified by colony PCR and sequencing. After gRNA. TSC13 and Cas9 plasmid removal, this resulted in strains PATW088 and PATW089 (Table  1 ). The integration of Rhodobacter capsulatus coTAL1 (RcTAL1; GenBank accession number WP_013066811) was combined with a SPR1 knockout, as described previously. 39 Strain PATW089 was transformed with the gRNA. SPR1 plasmid and the coTAL1 integration fragment. Correct integration was verified by colony PCR and sequencing. After gRNA and Cas9 plasmid removal, this resulted in strains PATW103 and PATW104 (Table  1 ). Strains IMK393, PATW066, PATW088, and PATW103 were transformed with construct pMEN2, resulting in strains PPF3, PPF4, PPF5, and PPF6, respectively (Table  1 ).