dataesr/scientific-paragraphs-categorization huggingface dataset:
Palmar-plantar erythrodysesthesia syndrome (PPES), as well as stomatitis, are common with TKI therapy, especially with sunitinib and regorafenib; even Grade 2 severity of these common TEAEs can have significant impact on activities of daily living  [4, [8] [9] [10]. Therefore, it is critical to evaluate patient-reported outcome (PRO) measures in patients with GIST receiving TKI therapy. In a systematic review of the current literature on TKI therapy in GIST, only 13 of 104 studies evaluated health-related QoL; common issues negatively affecting QoL were severe fatigue and fear of recurrence or progression of disease  [11] [12] [13]. Most patients treated with sunitinib reported a decrease in health-related QoL whereas patients reported mostly stable QoL while receiving other TKIs  [13]. Ripretinib, a novel switch-control TKI designed to broadly inhibit KIT and PDGFRA kinase signaling through a dual mechanism of action  [14] , is approved for the treatment of adult patients with advanced GIST who have received prior treatment with three or more TKIs, including imatinib, based on the results of the phase 3 INVICTUS study (NCT03353753)  [15, 16].
1. Patients randomized to placebo could cross over to ripretinib 150 mg once daily at the time of confirmed PD and patients who progressed on ripretinib 150 mg once daily could dose-escalate to ripretinib 150 mg twice daily, continue treatment at the same dose, or discontinue treatment  [17, 18]. Treatment cycles were 28 days. The protocol for the INVICTUS study is published online  [19]. This analysis only includes PRO assessments from patients conducted during the placebo-controlled, double-blind portion of the trial (data cutoff: May 31, 2019).
The two functional scales (EORTC QLQ-C30 physical and role function) and the self-reported health status (EQ-5D-5 L VAS) were prespecified because they illuminate critical aspects of the patient experience not covered otherwise. The additional function and symptom scales of the EORTC QLQ-C30 were not prespecified analyses to avoid alpha-split issues. Additional data from the PRO questionnaires (including symptom items) are presented in the Supplementary information (Tables  S1  and S2 ). In scoring the EORTC QLQ-C30, the overall health and QoL scales may be combined into a single score  [23]. However, since the scales measure fundamentally different aspects of the patient experience, one could improve while the other deteriorates. Thus, reporting the average of the two scores would be problematic and is not done in the prespecified analysis.
Patient population Of 84 patients who received ripretinib during the doubleblind period, the PRO-evaluable population included 73 patients with an available baseline assessment and 71 patients with an available C2D1 assessment. Of the 43 patients who received placebo during the doubleblind period, the PRO-evaluable population included 42 patients with an available baseline assessment and 32 patients with an available C2D1 assessment (Fig. 1 ). The declining number of patients with PRO data over time reflects the number of patients who remained progression-free as previously reported  [16].
Acknowledgements We would like to thank the patients, their families and caregivers, the investigators, and the site staff. The authors would also like to thank  Elva Cha, DVM, PhD  for her input on the analysis and outline review. Medical writing support was provided by  Lauren Hanlon, PhD ,  CMPP of AlphaBioCom, LLC , and was funded by  Deciphera Pharmaceuticals, LLC. MCH received partial salary support from a  VA Merit Award Grant  ( 2I01BX000338-05 ).
Structural studies of short peptidyl-tXNA bi-substrates in complex with FemX We determined the crystal structure of FemX bound to compounds 26, 27, 28 and 29 (Figure  7 ). Complex crystals were grown under conditions similar to those used to obtain the complex with our first 8-nt peptidyl-RNA (PDB: 4II9). Analysis reveals that in the four complexes, the enzyme structure is almost identical to that in the complex with a peptidyl-RNA. R. M. S. D. values between the RNA-based complex and the complexes with compound 26 (2 F-RNA), 27 (HNA), 28 (2 F-ANA) and 29 (DNA) were 0. 204, 0. 131, 0. 144 and 0. 116 Å, respectively (including all residues, Supplementary Figure  S2 ). The only minor conformational change observed consisted of a 1. 8 Å shift of the Met 260 -Thr 264 loop (Supplementary Figure  S2 ) for the two complexes containing the bi-substrates 28 and 29 containing 2 F-ANA and DNA nucleic acids, respectively.
ACKNOWLEDGEMENTS This work was supported by the  French Infrastructure for Integrated Structural Biology (FRISBI)   ANR-10-INBS-05. Mass spectrometry of unmodified oligonucleotides was made possible by the support of the  Hercules Foundation of the Flemish Government  (grant  20100225-7 ). X-ray diffraction data were collected at the  SOLEIL Synchrotron (Saint-Aubin, France ;  PROXIMA-2A  and PROXIMA-1 beamlines) and at the  ESRF Synchrotron (Grenoble, France ;  ID23-2  beamline). We thank the beamline staff for their assistance and advice during data collection. This work has benefited from the expertise of the  Crystallization Platform of I2BC (Gif-sur-Yvette, France ).
FUNDING French Infrastructure for Integrated Structural Biology (FRISBI)  [ ANR-10-INBS-05 ];  Hercules Foundation  of the Downloaded from https://academic. oup. com/nar/advance-article/doi/10. 1093/nar/gkac1023/6814473 by guest on 05 December 2022 10 Nucleic Acids Research, 2022  Flemish Government  [20100225-7]. Funding for open access charge: INSERM.
Should GH replacement (dosing, serum IGF-I target, monitoring, and transition) be different in patients surviving cancer? Key statement: GH replacement dosing and monitoring in cancer survivors follow general recommendations, but a higher degree of vigilance is required to avoid overtreatment. There are no data to support management recommendations for cancer survivors that differ from those available for other populations of patients with GHD  (7). In children, monitoring height velocity is central, and an acceptable growth response can be achieved in most children with a low starting dose of GH followed by slow dose up-titration  (3, 7). Serum IGF-I is an important safety marker during GH replacement in childhood and adult cancer survivors and should be measured after making a dose adjustment, approximately every 3 months during dose titration and at least annually thereafter.
lecture fees and/or consultancy honoraria from  Merck ,  Pfizer ,  Sandoz ,  Novo Nordisk. L E C: lecture and/or consultancy honoraria from  Novo Nordisk and Sandoz ,  Pfizer  site PI on long-acting growth hormone study and sub-PI on investigator-initiated research grant to  Boston Children's Hospital. A R H: consultant for  Novo Nordisk and Ascendis. M P: Research support from  Pfizer ,  Novo Nordisk , IPSEN,  Sandoz ,  Merck-Serono, Lilly ,  Sanofi ,  National French Grants , public funding,  ANR  and  PHRC , and Scientific advisory board: Increlex (IPSEN),  GNAP  ( Novo Nordisk ),  KIGS France (Pfizer ). K C J Y: Research grants to  Barrow Neurological Institute from Ascendis, Crinetics, Amryt, and Corcept, and Scientific Advisory Boards  for  Novo Nordisk, Ascendis, Amryt, Ipsen, Strongbridge, Recordati , and Corcept.
Reimbursement of travel expenses from  Ipsen  and lecture honoraria from  Pfizer. Supported by the  German Childhood Cancer Foundation ,  Bonn ,  Germany. L S: Personal  fees and non-financial support from  Ascendis, Hexal ,  Merck ,  Novo Nordisk ,  Pfizer , and  Sandoz. P T: Lectures  fees from  Novo Nordisk, Ipsen ,  Pfizer ,  Merck. G J: Consulting  fee from  Novo Nordisk  and unrestricted research grants from  NovoNordisk  and  Pfizer.
Indeed, the regulatory status of phages has not been harmonized worldwide, and no phage product is currently approved for human use by the European Medicines Agency (EMA) or the Food and Drug Administration (FDA). EMA considers phages as medicinal products, but some differences exist within Europe. For example, in Belgium, phages are indicated as Active Product Ingredients (API), and as such a monography is present in the Belgium Pharmacopeia  [16]. Currently, phages are mostly used as compassionate therapy and the therapeutic evaluation is mainly based on clinical reports comporting numerous biases  [14]. Randomized controlled trials are relatively rare, although urgently required. In April 2022, on the clinicaltrials. gov website, 43 clinical trials including the term "bacteriophages" were registered in the interventional study category.
Phage therapy, via an oral administration, could be considered to treat gastrointestinal inflammatory diseases. However, on the Clinicaltrials. gov database, a single clinical trial is registered (in the recruiting phase) for oral phage therapy (NCT03808103) for the treatment of Crohn's disease (Table  1 ), highlighting the interest of studying the phagome in the context of inflammatory intestinal diseases and also confirming the difficulties in using phages via enteral administration. Despite the challenges related to this mode of administration, the oral route is the preferred and most convenient one, as it offers several advantages such as the possibility of self-administration, the high patient compliance, and the avoidance of sterile conditions for product manufacturing thereby reducing production costs.
Finally, wound infections represent a major risk of sepsis due to the proliferation of microorganisms and their progressive invasion of deeper tissues. Therefore, anti-bacterial therapy has to be urgently initiated, especially in burned patients, but their efficacy may be compromised because of the spread of multi-drug resistance. In the particular context of burned patients, a phase-1/2 clinical trial (Phagoburn, NCT02116010) involving a phage therapy has been published  [17]. An alginate template was soaked with a cocktail of 12 natural anti-P. aeruginosa phages and was daily applied for 7 days onto the wounds. This experimental treatment was compared to the standard of care, corresponding to a 1% sulfadiazine silver emulsion cream applied daily for 7 days. This study demonstrated the safety of the application of phages to burned patients.
Acknowledgements The authors are very grateful to the  National Research Agency (ANR)  which supports the PHAG- ONE  project ( ANR 20-PAMR-0009 ). Authors also acknowledge the research directory of  Hospices Civils de Lyon  and the  Hospices Civils de Lyon foundation , which support the development of phagotherapy in the Lyon university hospitals through the  PHAG-EinLYON program. The authors would like to thank the  PHAGEinLYON Study Group :  Tristan Ferry  and  Frédéric Laurent  (coordinators),  Mathieu Medina ,  Camille Kolenda ,  Floriane Laumay ,  Mélanie Bonhomme ,  Leslie Blazere ,  Tiphaine Legendre ,  Eline Terrazzoni ,  Fabrice Pirot ,  Camille Merienne ,  Samira Filali ,  Benjamine Lapras ,  Chloé Marchand ,  Gilles Leboucher  and  Thomas Briot.
aeruginosa Oropharyngeal decontamination Not Recruiting NCT04325685 in patients under invasive applicable mechanical ventilation Oral Suspension Cocktail of anti-K. pneumoniae Healthy volunteers 1 Completed NCT04737876 Oral Suspension Anti-E. Coli Bacteremia 1 Not yet NCT05277350 recruiting Oral (nasogastric Suspension (Faecal Viruses, including bacteriophages Necrotizing enterocolitis 1 Not yet NCT05272579 tube) filtrate transfer) recruiting Intravenous Suspension Cocktail of anti-S. aureus Bacteremia 1 Not yet NCT05184764 2 recruiting Intravenous Suspension Anti-E. coli or K. pneumoniae Urinary tract infections 1 Recruiting NCT04287478 Intravesical (neurogenic bladder and 2 complicated urinary tract infections with risk of recurrence) due to E. coli and K. pneumoniae Intraarticular Suspension Anti-S.
aureus, Staphylococcus Prosthetic joint infections (hip or 1 Not yet NCT05269121 (after DAIR epidermidis, Staphylococcus lugdunensis, knee) 2 recruiting procedure) Streptococcus spp. , Enterococcus faecium, Enterococcus faecalis, E. coli, P. aeruginosa, and/or K. pneumoniae Intraarticular Suspension Anti-S. aureus, S. epidermidis, S. Prosthetic joint infections (hip or 2 Not yet NCT05269134 (after DAIR lugdunensis, Streptococcus spp. , E. knee) 3 recruiting procedure) faecium, E. faecalis, E. coli, P. aeruginosa, and/or K. pneumoniae. Pulmonary Suspension Liquid piobacteriophage complex (anti- Acute tonsillitis 3 Active, not NCT04682964 (nebulized) staphylococcus, enterococcus, recruiting streptococcus, E. coli, Proteus vulgaris, Proteus mirabilis, P. aeruginosa, K. pneumoniae, and Klebsiella oxytoca) Pulmonary Suspension Cocktail of bacteriophages (BX004-A) Cystic fibrosis with chronic 1 Not yet NCT05010577 (nebulized) P.
aeruginosa pulmonary infection 2 recruiting Pulmonary Suspension Cocktail (Anti-P. aeruginosa) Cystic fibrosis with chronic 1 Recruiting NCT04596319 P. aeruginosa pulmonary infection 2 Pulmonary Suspension YPT-01 (Anti-P. aeruginosa) Cystic fibrosis with chronic 1 Recruiting NCT04684641 (nebulized) P. aeruginosa airway infections 2 Topical Sterile compress Anti-Staphylococcus Diabetic foot 1 Not yet NCT02664740 dressings impregnated 2 recruiting with a phage solution Topical Suspension Cocktail: Anti-P. aeruginosa, anti-S. Diabetic foot ulcer 1 Recruiting NCT04803708 aureus anti-Acinetobacter 2 Topical Gauze pads saturated Cocktail of anti-S. aureus Healthy volunteers 1 Completed NCT02757755 with the phage cocktail Topical Gel Cocktail of anti-S. aureus Atopic dermatitis 1 Not yet NCT05240300 2 recruiting Topical (spray) Suspension Anti-Stapylococcus aureus, P.
aeruginosa, Wound infection (burned patients) 1 Not yet NCT04323475 or K. pneumoniae recruiting Topical (spray) Microcapsule (obtained Cocktail of 14 bacteriophages against S. Pressure ulcer 1 Not yet NCT04815798 with an amino acid- aureus, P. aeruginosa, or K. pneumoniae 2 recruiting based biodegradable polymer) Topical (via an Suspension (phosphate ultrasonic buffer) debridement device).
Furthermore, MLSA results obtained by locus amplification and sequencing versus extraction from WGS data (for 15 strains analysed by PCR and sequencing with WGS available in GenBank, Table  1 ) were also identical. The only exception was strain F38, for which a single nucleotide polymorphism (SNP) in the H2 locus differentiated MLSA sequences obtained by the two methods. However, since two different laboratory stocks of this strain were used for PCR and sequencing (CIRAD) and WGS (NCTC 10192 T), this SNP may result from divergent evolution undergone by the two laboratory stocks from the original 1974 isolate  [12]. When the scheme was applied to the remaining 39 "unrelated" strains in Table  1 , 24 sequence types (ST) (9 new) were discriminated based on 68 polymorphic positions (16 new), which are shown in Table  2 , with locus sequences from Mccp type strain F38 serving as reference.
This resulted in a Simpson's index of diversity of 0. 970 (0. 953-0. 987), which expresses the probability of two unrelated strains being characterised as the same type  [13, 14]. All the strains could be discriminated individually by WGS analysis  [6]  and all but two of those analysed by Dupuy et al. [5]  provided distinct genotypes (Table  1 ). However, these two isolates were actually discriminated by MLSA, which allowed typing of non-viable strains (n = 6, Table  1 ) with no added difficulty or cost. A robust tree (Figure  1 ) was obtained by distance analysis of MLSA data using  DARwin 6 [15]  as previously described. Seven genotyping groups were identified, distributed in the two lineages previously described. Pre-existing MLSA groups 1-5 were unchanged, with the exception of several additional ST identified in group 1, corresponding to East African and Emirati strains originating from domestic goat and wild ungulates respectively.
While all relational database systems are based on the bag data model, much of theoretical research still views relations as sets. Recent attempts to provide theoretical foundations for modern data management problems under the bag semantics concentrated on applications that need to deal with incomplete relations, i. e. , relations populated by constants and nulls. Our goal is to provide a complete characterization of the complexity of query answering over such relations in fragments of bag relational algebra. The main challenges that we face are twofold. First, bag relational algebra has more operations than its set analog (e. g. , additive union, max-union, min-intersection, duplicate elimination) and the relationship between various fragments is not fully known. Thus we first fill this gap.
Introduction While all relational database management systems (DBMSs) use bags as the basis of their data model, much of relational database theory uses a model based on sets, thus disallowing repetitions of tuples. The presence of duplicates in real-life databases is a very important consideration that is reflected in practically all aspects of data management, such as querying, storing, and accessing data  [2, 3]. Theoretical research has raised this issue several times. By the early 1990s there was agreement on what the standard collection of bag relational algebra operations is  [4] , and in the mid 1990s their expressiveness and complexity were thoroughly studied  [5, 6] , albeit in the context of the model of nested relations, or complex objects, which was the research focus back then  [7, 8].
Around the same time it was noticed that the well developed theory of query optimization, especially for conjunctive queries, does not apply to bag semantics  [9] , and despite many attempts and partial results  [10, 11] , the key problem ✩ Work supported by EPSRC, United Kingdom grants M025268 and N023056. ✩✩ This is the full version of a paper of the same title that appeared in the proceedings of ICDT 2019, the 22nd International Conference on Database Theory  [1]. This work was also presented at AMW 2019, the 13th Alberto Mendelzon International Workshop on Foundations of Data Management, where it was invited to this special issue. and max(ā, q, D) = max D ′ ∈ D # ( ā, q(D ′ ) ). Under set semantics, min(D, q, ā) = 1 means that ā is a certain answer to q on D, and max(D, q, ā) = 1 means that ā is a possible answer.
Complexity of min For fragments in the shaded area, computing min(ā, q, D) is tractable, and it can be done by evaluating the query naively on the incomplete database. For all fragments outside the shaded area, and all fragments with duplicate elimination (from SPC{ε} to the full RA), the complexity is intractable: checking whether min(ā, q, D) θ n is NP-complete when θ is ≤, coNP-complete when θ is ≥, and DP-complete when θ is =. Recall that DP is the class of problems that are the intersection of an NP problem and a coNP problem  [22].
Bag relational algebra We now describe the standard operations of bag relational algebra and provide their semantics  [4] [5] [6] 20]. A bag is a collection of elements with associated multiplicities (numbers of occurrences); if an element b occurs n times in a bag B, we write #(b, B) = n. If #(b, B) = 0, it means that b does not occur in B. Sets are just a special case when #(b, B) ∈ {0, 1}. In a database D, each k-ary relation name R of the schema is associated with a bag R D of k-tuples; we will omit the superscript D whenever it is clear from the context. We assume that the attributes of a k-ary relation are 1,. , k, i. e. , we adopt the unnamed perspective  [18]. The arity of RA expressions is defined as follows: for base relations, it is given by the schema; for σ i=j (e) and ε(e), it is the arity of e; for π α (e), it is the arity of α; for e × e ′ , it is the sum of the arities of e and e ′ ; for e ⋆ e ′ with ⋆ ∈ {∪, ⊎, ∩, -}, it is the arity of e.
Syntax We then say that an RA expression is well-formed w. r. t. a schema if: it mentions only relation names from the schema; i and j in σ i=j (e) are less than or equal to the arity of e; the elements of α in π α (e) are less than or equal to the arity of e; the expressions e and e ′ in e ⋆ e ′ , with ⋆ ∈ {∪, ⊎, ∩, -}, have the same arity. In the rest of the paper, we implicitly assume that we are always working with well-formed RA expressions. Semantics. We give the semantics of (well-formed) RA expressions e by inductively defining the quantity #(ā, e, D), which is the number of occurrences of a tuple ā (of appropriate arity) in the result of applying e to a database D. This is done as follows: #(ā, R, D) = # ( ā, R D ) #(ā, σ i=j (e), D) = { #(ā, e, D) if ā. i = ā. j 0 otherwise #(ā, π α (e), D) = ∑ ā′ :πα (ā ′ )=ā #(ā ′ , e, D) # ( āā ′ , e × e ′ , D ) = # ( ā, e, D ) • # ( ā′ , e ′ , D ) #(ā, e ⊎ e ′ , D) = #(ā, e, D) + #(ā, e ′ , D) #(ā, e ∪ e ′ , D) = max { #(ā, e, D), #(ā, e ′ , D) } #(ā, e ∩ e ′ , D) = min { #(ā, e, D), #(ā, e ′ , D) } #(ā, e -e ′ , D) = max { #(ā, e, D) -#(ā, e ′ , D), 0 } #(ā, ε(e), D) = min { #(ā, e, D), 1.
} where ā. i denotes the ith element of ā, π i 1 ,. ,in (ā) is the tuple (ā. i 1 ,. , ā. i n ), and the tuples ā and ā′ in the rule for e × e ′ have the same arity as e and e ′ , respectively. Then, for an expression e and a database D, we define e(D) as the bag of tuples ā of the same arity as e so that # ( ā, e(D) ) = #(ā, e, D). Fragments. The two main fragments of RA we consider are SPC, consisting of selection (σ ), projection (π ) and Cartesian product (×), and RA + , which is SPC extended with additive union (⊎). Given a fragment L of RA, we write L{op 1 ,. , op n } to denote the fragment obtained by adding the RA operations op 1 ,. , op n to L. Thus, for instance, RA + is SPC{⊎}. A query is a mapping q from databases to bags of tuples. We always assume that queries are generic, that is, invariant under permutations of the domain  [18].
A query q is expressible in a fragment L of RA if there is an expression e in that fragment so that e(D) = q(D) for every database D. Then, given two fragments L and L ′ , we say that L ′ is at least as expressive as L, and write L ⊆ L ′ , if every query expressible in L is also expressible in L ′. We say that L ′ is more expressive than L, and write L ⊊ L ′ , if L ′ is at least as expressive as L and there is a query that is expressible in L ′ but not in L. Notice that if L ′ has all the operations of L, then L ′ is at least as expressive as L.
SPC ⊊ SPC{⋆} for ⋆ ∈ {∪, ∩}. We now show that additive union increases the expressive power of SPC{∩} and SPC{∪}. Proposition 2. SPC{⋆} ⊊ RA + {⋆} for ⋆ ∈ {∪, ∩}. The proof of the above result is based on the fact that, on databases consisting of nullary relations of size 1, there are RA + expressions whose results size is greater than 1, whereas every SPC{∪, ∩} expression can only yield a (nullary) relation of size 1, as the following lemma shows. Lemma 1. Let D be a database over a schema consisting only of nullary relation names and such that R D = {()} for every relation name R in the schema. Then, for every SPC{∪, ∩} expression e, it is the case that e(D) = {()}. Proof. Let e be an SPC{∪, ∩} expression over the schema of D. Observe that all subexpressions of e are nullary and, since there are no attributes, none of them can be a selection.
Moreover, projection will be over an empty list of attributes and so it can be discarded. Thus, assuming w. l. o. g. that there is no projection, we proceed by induction on the structure of e to show that e(D) = {()}. {⋆} is at least as expressive as SPC{⋆}, thus we only need to show that there is a query expressible in the former but not in latter. To this end, consider a schema consisting of a nullary relation name R, and suppose that e = R⊎R (which, in particular, is an RA + expression) is expressible in SPC{⋆}, i. e. , there exists an SPC{⋆} expression e ′ equivalent to e. Towards a contradiction of this equivalence, let D be a database where R D = {()}. Then, since e ′ is an SPC{∪, ∩} expression, by Lemma 1 we have that e ′ (D) = {()}, whereas e(D) = {(), ()}. □ In particular, the proof of Proposition 2 also applies to show the following.