bluuebunny/crossref_metadata_2025_split huggingface dataset:
American College of Gastroenterology-Canadian Association of Gastroenterology Clinical Practice Guideline: Management of Anticoagulants and Antiplatelets During Acute Gastrointestinal Bleeding and the Periendoscopic Period
Authors: Abraham Neena S , Barkun Alan N , Sauer Bryan G , Douketis James , Laine Loren , Noseworthy Peter A , Telford Jennifer J , Leontiadis Grigorios I 
Published: March 2022

AbstractWe conducted systematic reviews of predefined clinical questions and used the Grading of Recommendations, Assessment, Development and Evaluations approach to develop recommendations for the periendoscopic management of anticoagulant and antiplatelet drugs during acute gastrointestinal (GI) bleeding and the elective endoscopic setting. The following recommendations target patients presenting with acute GI bleeding: For patients on warfarin, we suggest against giving fresh frozen plasma or vitamin K; if needed, we suggest prothrombin complex concentrate (PCC) compared with fresh frozen plasma administration; for patients on direct oral anticoagulants (DOACs), we suggest against PCC administration; if on dabigatran, we suggest against the administration of idarucizumab, and if on rivaroxaban or apixaban, we suggest against andexanet alfa administration; for patients on antiplatelet agents, we suggest against platelet transfusions; and for patients on cardiac acetylsalicylic acid (ASA) for secondary prevention, we suggest against holding it, but if the ASA has been interrupted, we suggest resumption on the day hemostasis is endoscopically confirmed. The following recommendations target patients in the elective (planned) endoscopy setting: For patients on warfarin, we suggest continuation as opposed to temporary interruption (1–7 days), but if it is held for procedures with high risk of GI bleeding, we suggest against bridging anticoagulation unless the patient has a mechanical heart valve; for patients on DOACs, we suggest temporarily interrupting rather than continuing these; for patients on dual antiplatelet therapy for secondary prevention, we suggest temporary interruption of the P2Y12 receptor inhibitor while continuing ASA; and if on cardiac ASA monotherapy for secondary prevention, we suggest against its interruption. Evidence was insufficient in the following settings to permit recommendations. With acute GI bleeding in patients on warfarin, we could not recommend for or against PCC administration when compared with placebo. In the elective periprocedural endoscopy setting, we could not recommend for or against temporary interruption of the P2Y12 receptor inhibitor for patients on a single P2Y12 inhibiting agent. We were also unable to make a recommendation regarding same-day resumption of the drug vs 1–7 days after the procedure among patients prescribed anticoagulants (warfarin or DOACs) or P2Y12 receptor inhibitor drugs because of insufficient evidence.
ZWC complex-mediated SPT5 phosphorylation suppresses divergent antisense RNA transcription at active gene promoters
Authors: Park Kihyun , Zhong Jian , Jang Jin Sung , Kim Jihyun , Kim Hye-Jung , Lee Jeong-Heon , Kim Jaehoon 
Published: March 2022

AbstractThe human genome encodes large numbers of non-coding RNAs, including divergent antisense transcripts at transcription start sites (TSSs). However, molecular mechanisms by which divergent antisense transcription is regulated have not been detailed. Here, we report a novel ZWC complex composed of ZC3H4, WDR82 and CK2 that suppresses divergent antisense transcription. The ZWC complex preferentially localizes at TSSs of active genes through direct interactions of ZC3H4 and WDR82 subunits with the S5p RNAPII C-terminal domain. ZC3H4 depletion leads to increased divergent antisense transcription, especially at genes that naturally produce divergent antisense transcripts. We further demonstrate that the ZWC complex phosphorylates the previously uncharacterized N-terminal acidic domain of SPT5, a subunit of the transcription-elongation factor DSIF, and that this phosphorylation is responsible for suppressing divergent antisense transcription. Our study provides evidence that the newly identified ZWC-DSIF axis regulates the direction of transcription during the transition from early to productive elongation.
Predictive modeling of resistance to SMO inhibition in a patient-derived orthotopic xenograft model of SHH medulloblastoma
Authors: Krausert Sonja , Brabetz Sebastian , Mack Norman L , Schmitt-Hoffner Felix , Schwalm Benjamin , Peterziel Heike , Mangang Aileen , Holland-Letz Tim , Sieber Laura , Korshunov Andrey , Oehme Ina , Jäger Natalie , Witt Olaf , Pfister Stefan M , Kool Marcel 
Published: March 2022

Abstract

Background
Inhibition of the sonic hedgehog (SHH) pathway with Smoothened (SMO) inhibitors is a promising treatment strategy in SHH-activated medulloblastoma, especially in adult patients. However, the problem is that tumors frequently acquire resistance to the treatment. To understand the underlying resistance mechanisms and to find ways to overcome the resistance, preclinical models that became resistant to SMO inhibition are needed.

Methods
To induce SMO inhibitor resistant tumors, we have treated a patient-derived xenograft (PDX) model of SHH medulloblastoma, sensitive to SMO inhibition, with 20 mg/kg Sonidegib using an intermitted treatment schedule. Vehicle-treated and resistant models were subjected to whole-genome and RNA sequencing for molecular characterization and target engagement. In vitro drug screens (76 drugs) were performed using Sonidegib-sensitive and -resistant lines to find other drugs to target the resistant lines. One of the top hits was then validated in vivo.

Results
Nine independent Sonidegib-resistant PDX lines were generated. Molecular characterization of the resistant models showed that eight models developed missense mutations in SMO and one gained an inactivating point mutation in MEGF8, which acts downstream of SMO as a repressor in the SHH pathway. The in vitro drug screen with Sonidegib-sensitive and -resistant lines identified good efficacy for Selinexor in the resistant line. Indeed, in vivo treatment with Selinexor revealed that it is more effective in resistant than in sensitive models.

Conclusions
We report the first human SMO inhibitor resistant medulloblastoma PDX models, which can be used for further preclinical experiments to develop the best strategies to overcome the resistance to SMO inhibitors in patients.
Ontogeny of the skeleton of Moenkhausia pittieri (Ostariophysi: Characiformes) with discussion on functional demands and ossification patterns in the Characidae
Authors: Marinho Manoela M F 
Published: March 2022

Abstract
Most fishes must face their environment alone in the early stages of life. The overall sequence of bone appearance is related to functional demands of the early developmental stages. This study offers detailed data on the skeletogenesis of Moenkhausia pittieri, as an example of a "generalized characid". The sequence of ossification is determined and discussed in response to functional demands. Early developmental stages involve the rapid development of bones related to respiration and feeding. The last sets of bones to appear include those of the paired fins and infraorbitals. Patterns in the order of ossification are highlighted, and heterochronies are detected and discussed. Loss of late developmental stages related to miniaturization, a trend in the evolution of Characidae, is discussed in the light of comparative anatomy and ontogenetic data. Furthermore, morphological particularities found in M. pittieri and other characids are discussed in an ontogenetic perspective, offering a background for future phylogenetic studies to understand the homology of certain structures and serving as a further step to elucidate the relationships in ostariophysans.
Quantifying Head and Neck Lymphatic Malformation Volume and Composition During Treatment
Authors: Konuthula Neeraja , Bindschadler Michael , Perez Francisco A. , Shivaram Giri M. , Bly Randall A. , Friedman Seth D. , Perkins Jonathan A. 
Published: March 2022

Objective:
Head and neck lymphatic malformation (HNLM) treatment involves a combination of observation, surgery, sclerotherapy, and targeted medical therapy. Objective comparison of these differing treatments is unstandardized due to heterogeneity of HNLM location, size, and variable components. Our objective was to develop a protocol for standardized assessment of magnetic resonance imaging (MRI) image sets through novel semiautomated algorithms. We aimed to obtain reproducible multimodal tissue level data that can be analyzed for interval HNLM treatment response.

Methods:
Patients who were undergoing therapy for HNLM were queried from an institutional database between 2015 and 2020. MRI sequences were registered in 3D Slicer, and in MATLAB a multimodal tool was developed to quantitate HNLM volume and changes in composition. Volume measures were normalized to normal childhood growth using the nasion-basion distance. Reproducibility studies were conducted to evaluate interrater reliability.

Results:
HNLM undergoing excision (n = 3) had a 92.3%–96.7% decrease malformation volume. HNLM having medical treatment with sirolimus and aspirin had a 7.3%–36.4% decrease in normalized volume, the majority of which was due to a decrease in cystic fluid content (reduced by 27.0%–36.4%). HNLM treated with sclerotherapy had no normalized volume change following treatment. One HNLM first treated with sirolimus had a 27.8% decrease in normalized volume and then combined normalized volume reduction of 75.6% after resection.

Conclusion:
This proof-of-concept use of longitudinal HNLM MRI in pediatric patients undergoing treatment demonstrates that objective information can be obtained through this method. This information can be used to determine treatment efficacy and optimize lesion specific treatment strategies.
Laparoscopic Training for Gastrointestinal Surgery Using Japanese Traditional Papercraft Origami
Authors: Hiraki Masatsugu , Kimura Naoya , Kitagawa Hiroshi , Kohya Naohiko , Samejima Ryuichiro 
Published: March 2022

Purpose:
The aim of this study is to show the experience and results of laparoscopic training using origami, a Japanese traditional papercraft, and to discuss its usefulness in gastrointestinal surgery.

Materials and Methods:
A laparoscopic training dry box was used. An origami paper crane was folded using laparoscopic instruments. The time to complete the origami crane was measured.

Results:
Two trainees participated in this study; the total number of origami cranes folded by these trainees was 2000 and 700, respectively. The learning curve gradually improved. According to our experience, this training strengthened mental faculties and was associated with the improvement of hand-eye and left-right coordination, reduction of tremor, acquisition of delicate technique, the ability to distinguish subtle differences in color, ability to respond to trouble.

Conclusions:
Laparoscopic training for gastrointestinal surgery using origami may have the potential to improve the technical skills in laparoscopic surgery.
Prevention of SARS-CoV-2 airborne transmission in a workplace based on CO2 sensor network
Authors: Yokogawa Shinji , Ishigaki Yo , Kitamura Hiroko , Saito Akira , Kawauchi Yuto , Hiraide Taisei 
Published: March 2022

AbstractWe measured the compartmental air change per hour (ACH) using a CO2 sensor network in an office space where a cluster of COVID-19 infections attributed to aerosol transmission occurred. Generalized linear mixed models and dynamic time warping were used for a time series data analysis, and the results indicated that the ventilation conditions were poor at the time of the cluster outbreak, and that the low ACH in the room likely contributed to the outbreak. In addition, the adverse effects of inappropriate partitions and the effectiveness of ventilation improvements were investigated in detail. ACH of less than 2 /h was considered a main contributor for the formation of the COVID-19 cluster in the studied facility.Practical ImplicationsA systematic method for measuring and evaluating indoor ventilation to prevent the spread of infectious diseases caused by aerosols is presented. Ventilation bias caused by ventilation pathways and inappropriate use of plastic sheeting can be detected by a CO2 sensor network and time series data analysis. Estimated ventilation rate will be a good index to suppress the formation of the COVID-19 cluster.
High-throughput molecular dynamics-based alchemical free energy calculations for predicting the binding free energy change associated with the common mutations in the spike receptor-binding domain of SARS-CoV-2
Authors: Bhadane Rajendra , Salo-Ahen Outi M. H. 
Published: March 2022

AbstractThe ongoing pandemic caused by SARS-CoV-2 has gone through various phases. From the initial outbreak the virus has mutated several times, with some lineages showing even stronger infectivity and faster spread than the original virus. Among all the variants, beta, gamma, delta and the latest (omicron) are currently classified as variants of concern (VOC) while the remaining are labelled either as variants of interest (VOI) or variants under monitoring (VUM). In this work, we have focused on the mutations observed in important variants, particularly at the receptor-binding domain (RBD) of the spike protein that is responsible for the interactions with the host ACE2 receptor and binding of antibodies. Studying these mutations is particularly important for understanding the viral infectivity, spread of the disease and for tracking the escape routes of this virus from antibodies. Molecular dynamics (MD) based alchemical free energy calculations have been shown to be very accurate in predicting the free energy change due to a mutation that could have a deleterious or a stabilising effect on the protein itself or its binding affinity to another protein. Here, we investigated the significance of six commonly observed spike RBD mutations on the stability of the spike protein binding to ACE2 by free energy calculations using high throughput MD simulations. For comparison, we also used other (rigorous and non-rigorous) binding free energy prediction methods and compared our results with the experimental data if available. The alchemical free energy-based method consistently predicted the free-energy changes with an accuracy close to ±1.0 kcal/mol when compared with the available experimental values. As per our simulation data the most significant mutations responsible for stabilising the spike RBD interactions with human ACE2 are N501Y and L452R.
The acid ceramidase/ceramide axis controls parasitemia in Plasmodium yoelii-infected mice by regulating erythropoiesis
Authors: Günther Anne , Hose Matthias , Schumacher Fabian , Kleuser Burkhard , Matuschewski Kai , Lang Karl S. , Gulbins Erich , Buer Jan , Westendorf Astrid M. , Hansen Wiebke 
Published: March 2022

AbstractAcid ceramidase (Ac) is part of the sphingolipid metabolism and responsible for the degradation of ceramide. As bioactive molecule, ceramide is involved in the regulation of many cellular processes. However, the impact of cell-intrinsic Ac activity and ceramide on the course of Plasmodium infection remains elusive. Here, we use Ac-deficient mice with ubiquitously increased ceramide levels to elucidate the role of endogenous Ac activity in a murine malaria model. Interestingly, ablation of Ac leads to alleviated parasitemia associated with decreased T cell responses in the early phase of Plasmodium yoelii (P. yoelii) infection. Mechanistically, we identified dysregulated erythropoiesis with reduced numbers of reticulocytes, the preferred host cells of P. yoelii, in Ac-deficient mice. Furthermore, we demonstrate that administration of the Ac inhibitor carmofur to wild type mice has similar effects on P. yoelii infection and erythropoiesis. Notably, therapeutic carmofur treatment after manifestation of P. yoelii infection is efficient in reducing parasitemia. Hence, our results provide evidence for the involvement of Ac and ceramide in controlling P. yoelii infection by regulating red blood cell development.
Pharmacokinetics of favipiravir in adults with mild COVID-19 in Thailand
Authors: Manosuthi Weerawat , Prasanchaimontri Ing-orn , Niyomnaitham Suvimol , Sirijatuphat Rujipas , Charoenpong Lantharita , Copeland Katherine , Cressey Tim R. , Mokmued Phongpan , Chokephaibulkit Kulkanya 
Published: March 2022

AbstractWe assessed the pharmacokinetics of favipiravir (FPV) in adults with symptomatic SARS-CoV-2 infection without pneumonia in Thailand. FPV dosing was 1800 mg twice-daily on day 1, then 800 mg twice-daily for 14 days. Eight subjects (7 female), median (range) age 39 (19-53) years and BMI 27.9 (18.0-33.6) were included. Inter-subject variability was high but all achieved minimum plasma concentrations (Cmin) above EC50(9.7 mg/L). FPV was well tolerated; 1 subject stopped prematurely due to rash.
Possible Role of P-selectin Adhesion in Long-COVID: A Comparative Analysis of a Long-COVID Case Versus an Asymptomatic Post-COVID Case
Authors: Tarasev Michael , Mota Sabrina , Gao Xiufeng , Ferranti Marta , Zaidi Aliya U. , Hannan Bryan , Hines Patrick 
Published: March 2022

AbstractBackgroundLong-term outcomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are now recognized as an emerging public health challenge - a condition termed Long-COVID. The pathophysiology of Long-COVID remains to be established. Functional P-selectin activity, implicated in COVID-19 sequalae, was measured between two convalescent COVID-19 subjects, one with (Long-COVID subject) and another without Long-COVID symptoms.MethodsFlow adhesion of whole blood or isolated white blood cells to P-selectin (FA-WB-Psel and FA-WBC-Psel) was measured using a standardized microfluidics clinical assay; impedance aggregometry with a collagen agonist was measured using model 590 Chrono-Log impedance aggregometer; standard laboratory assays were performed to evaluate changes in blood chemistries.ResultsFor both subjects, hemoglobin, WBC, platelet counts, electrolytes and ferritin were within normal reference ranges, with FA-WB-Psel significantly elevated compared to healthy controls (p< 0.01). In vitro treatment of whole blood samples with crizanlizumab (anti-p-selectin monoclonal antibody) within the clinical dose range (10 μg/ml) mL) inhibited FA-WB-Psel only in samples from asymptomatic post-COVID subject, with the Long-COVID subject sample requiring close to 5-fold elevated dose to achieve a response. Pronounced inhibition of P-selectin adhesion of isolated leukocytes was observed for both subjects in autologous platelet-poor plasma and buffer. Impedance aggregometry showed greater baseline platelet aggregation to collagen in the Long-COVID sample, although both samples responded similarly to aspirin-induced platelet inhibition.ConclusionsPresented results suggest that elevated platelet activation in Long-COVID subject may be associated with increased P-Selectin activity. The results are discussed in terms of possible use on P-selectin inhibition therapies in treating Long-COVID.
Haploinsufficiency underlies the neurodevelopmental consequences ofSLC6A1/GAT-1 variants
Authors: Silva Dina Buitrago , Trinidad Marena , Ljungdahl Alicia , Revalde Jezrael L. , Berguig Geoffrey Y. , Wallace William , Patrick Cory S. , Bomba Lorenzo , Arkin Michelle , Dong Shan , Estrada Karol , Hutchinson Keino , LeBowitz Jonathan H. , Schlessinger Avner , Johannesen Katrine M. , Møller Rikke S. , Giacomini Kathleen M. , Froelich Steven , Sanders Stephan J. , Wuster Arthur 
Published: March 2022

AbstractHeterozygous variants in the GAT-1 GABA transporter encoded bySLC6A1are associated with seizures, developmental delay, and autism. The majority of affected individuals carry missense variants, many of which are recurrent germlinede novomutations, raising the possibility of gain-of-function effects. To understand the functional consequences, we performed anin vitroGABA uptake assay for 213 unique variants, including 24 control variants.De novovariants consistently resulted in a decrease in GABA uptake, in keeping with haploinsufficiency underlying all neurodevelopmental phenotypes. Where present, ClinVar pathogenicity reports correlated well with GABA uptake data; the functional data can inform future reports for the remaining 72% of unscored variants. Surface expression was assessed for 86 variants; two-thirds of loss-of-function missense variants prevented GAT-1 from being present on the membrane while GAT-1 was on the surface but with reduced activity for the remaining third. Surprisingly, recurrentde novomissense variants showed moderate loss-of-function effects that reduced GABA uptake with no evidence for dominant negative or gain-of-function effects. Using linear regression across multiple missense severity scores to extrapolate the functional data to all potentialSLC6A1missense variants, we observe an abundance of GAT-1 residues that are sensitive to substitution. The extent of this missense vulnerability accounts for the clinically observed missense enrichment; overlap with hypermutable CpG sites accounts for the recurrent missense variants. Strategies to increase the expression of the wildtypeSLC6A1allele are likely to be beneficial across neurodevelopmental disorders, though the developmental stage and extent of required rescue remain unknown.
Using remotely delivered Spring Forest Qigong™ to reduce neuropathic pain in adults with spinal cord injury: Protocol of a quasi-experimental clinical trial
Authors: Van de Winckel Ann , Carpentier Sydney , Deng Wei , Zhang Lin , Battaglino Ricardo , Morse Leslie 
Published: March 2022

AbstractBackgroundAbout 69% of Americans living with spinal cord injury (SCI) suffer from long-term debilitating neuropathic pain, interfering with the quality of daily life. Neuropathic pain is refractory to many available treatments –some carrying a risk for opioid addiction– highlighting an urgent need for new treatments. In this study, we will test our hypothesis that Spring Forest QigongTMwill reduce SCI-related neuropathic pain by improving body awareness. We will determine whether remotely delivered Qigong isfeasibleand we will collect data on neuropathic pain, and other reported associations with pain such as spasms frequency and/or severity, functional performance, mood, or body awareness.MethodsIn this quasi-experimental pilot clinical trial study, adults with SCI will practice Qigong at home with a 45min video, at least 3x/week for 12 weeks. The Qigong practice includes movements with guided breathing and is individualized based on functional abilities, i.e., the participants follow along with the Qigong movements to the level of their ability, with guided breathing, and perform kinesthetic imagery by focusing on the feeling in the whole body as if doing the whole-body Qigong movement while standing. The highest, average, and lowest neuropathic pain ratings perceived in the prior week will be recorded weekly until the 6-week follow-up. The other outcomes will be collected at 5 time points: at baseline, midway during the Qigong intervention (6 weeks), after the Qigong intervention (12 weeks), after a 6-week and 1-year follow-up. Rate parameters for the feasibility markers will be estimated based on the participants who achieved each benchmark.DiscussionThe University of Minnesota (UMN)’s Institutional Review Board (IRB) approved the study (IRB #STUDY00011997). All participants will sign electronic informed consent on the secure UMN REDCap platform. The results will be presented at academic conferences and published in peer-reviewed publications.Trial registrationClinicalTrial.govregistration number:NCT04917107, first registered 6/8/2021,https://clinicaltrials.gov/ct2/show/NCT04917107.