bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase 2 Randomized Study of Oral Ibrexafungerp Versus Fluconazole in Vulvovaginal Candidiasis
Authors: Nyirjesy Paul , Schwebke Jane R , Angulo David A , Harriott Itzel A , Azie Nkechi E , Sobel Jack D 
Published: September 2021

Abstract

Background
Vulvovaginal candidiasis affects approximately 75% of women in their lifetime. Approved treatment options are limited to oral or topical azoles. Ibrexafungerp, a novel, first-in-class oral triterpenoid glucan synthase inhibitor, has demonstrated broad fungicidal Candida activity and a favorable tolerability profile. The primary objective of this dose-finding study was to identify the optimal dose of oral ibrexafungerp in patients with acute vulvovaginal candidiasis.

Methods
Patients with vulvovaginal signs and symptoms score ≥7 were randomized equally to 6 treatments groups: 5 treatment doses of oral ibrexafungerp or oral fluconazole 150 mg. The primary endpoint was the percentage of patients with a clinical cure (complete resolution of vulvovaginal signs and symptoms) at the test-of-cure visit (day 10).

Results
Overall, 186 patients were randomized into the 6 treatment groups. Results, using the modified intent-to-treat population (baseline positive culture), are reported for ibrexafungerp 300 mg twice daily (BID) for 1 day (n = 27), which was the dose selected for phase 3 studies, and fluconazole 150 mg for 1 day (n = 24). At day 10, the clinical cure rates for ibrexafungerp and fluconazole were 51.9% and 58.3%, respectively; at day 25, patients with no signs or symptoms were 70.4% and 50.0%, respectively. During the study ibrexafungerp patients required less antifungal rescue medications compared with fluconazole (3.7% vs 29.2%, respectively). Ibrexafungerp was well tolerated, with the most common treatment-related adverse events being mild gastrointestinal events.

Conclusions
Ibrexafungerp is a well-tolerated novel antifungal with comparable efficacy to fluconazole in the treatment of acute vulvovaginal candidiasis.

Clinical Trials Registration
NCT03253094
Silent Inflammatory Bowel Disease
Authors: Coates Matthew D , Binion David G 
Published: September 2021

Abstract
Inflammatory bowel disease (IBD) is frequently associated with a variety of problematic symptoms, including abdominal pain and bowel habit changes, which are associated with poor patient quality of life and significant healthcare expenditure. Interestingly, silent IBD, a condition where patients demonstrate reduced perception and/or reporting of symptoms in the setting of active inflammation, may be as clinically consequential. This condition has been associated with serious complications leading to more costly interventions. It is by its nature an under-recognized phenomenon that affects substantial portions of patients with either Crohn’s disease or ulcerative colitis. At the present time, although there are a variety of theories relating to the underlying causes and contributors, little is known about why this phenomenon occurs. As a result, there is a lack of cost-effective, reliable diagnostic methods to identify and manage “at-risk” patients. However, it is significantly likely that further study and an improved understanding of this condition will lead to improved approaches for the diagnosis and treatment of patients with silent IBD as well as other gastrointestinal disorders associated with alterations in symptomatic perception. In this article, we critically review studies that have investigated silent IBD. Specifically, we discuss the following: (1) the methods for defining silent IBD, (2) the known epidemiology of silent IBD, (3) potential causes of and contributors to this clinical entity, (4) current diagnostic modalities available to identify it, and (5) gaps in our understanding as well as potential novel diagnostic and therapeutic applications that could be developed with further study of this condition.
Cell Type-Specific Membrane Potential Changes in Dorsolateral Striatum Accompanying Reward-Based Sensorimotor Learning
Authors: Sippy Tanya , Chaimowitz Corryn , Crochet Sylvain , Petersen Carl C H 
Published: September 2021

Abstract
The striatum integrates sensorimotor and motivational signals, likely playing a key role in reward-based learning of goal-directed behavior. However, cell type-specific mechanisms underlying reinforcement learning remain to be precisely determined. Here, we investigated changes in membrane potential dynamics of dorsolateral striatal neurons comparing naïve mice and expert mice trained to lick a reward spout in response to whisker deflection. We recorded from three distinct cell types: (i) direct pathway striatonigral neurons, which express type 1 dopamine receptors; (ii) indirect pathway striatopallidal neurons, which express type 2 dopamine receptors; and (iii) tonically active, putative cholinergic, striatal neurons. Task learning was accompanied by cell type-specific changes in the membrane potential dynamics evoked by the whisker deflection and licking in successfully-performed trials. Both striatonigral and striatopallidal types of striatal projection neurons showed enhanced task-related depolarization across learning. Striatonigral neurons showed a prominent increase in a short latency sensory-evoked depolarization in expert compared to naïve mice. In contrast, the putative cholinergic striatal neurons developed a hyperpolarizing response across learning, driving a pause in their firing. Our results reveal cell type-specific changes in striatal membrane potential dynamics across the learning of a simple goal-directed sensorimotor transformation, helpful for furthering the understanding of the various potential roles of different basal ganglia circuits.
Identification of essential genes in Caenorhabditis elegans through whole-genome sequencing of legacy mutant collections
Authors: Li-Leger Erica , Feichtinger Richard , Flibotte Stephane , Holzkamp Heinke , Schnabel Ralf , Moerman Donald G 
Published: September 2021

Abstract
It has been estimated that 15%–30% of the ∼20,000 genes in C. elegans are essential, yet many of these genes remain to be identified or characterized. With the goal of identifying unknown essential genes, we performed whole-genome sequencing on complementation pairs from legacy collections of maternal-effect lethal and sterile mutants. This approach uncovered maternal genes required for embryonic development and genes with apparent sperm-specific functions. In total, 58 putative essential genes were identified on chromosomes III–V, of which 52 genes are represented by novel alleles in this collection. Of these 52 genes, 19 (40 alleles) were selected for further functional characterization. The terminal phenotypes of embryos were examined, revealing defects in cell division, morphogenesis, and osmotic integrity of the eggshell. Mating assays with wild-type males revealed previously unknown male-expressed genes required for fertilization and embryonic development. The result of this study is a catalog of mutant alleles in essential genes that will serve as a resource to guide further study toward a more complete understanding of this important model organism. As many genes and developmental pathways in C. elegans are conserved and essential genes are often linked to human disease, uncovering the function of these genes may also provide insight to further our understanding of human biology.
MIND Diet and Cognitive Function in Puerto Rican Older Adults
Authors: Boumenna Tahani , Scott Tammy M , Lee Jong-Soo , Zhang Xiyuan , Kriebel David , Tucker Katherine L , Palacios Natalia 
Published: September 2021

AbstractBackgroundHealthy diets have been associated with better cognitive function. Socioeconomic factors including education, poverty, and job complexity may modify the relationship between diet and cognition.MethodsWe used adjusted linear mixed models to examine the association between long-term adherence to the Mediterranean-Dietary Approaches to Stop Hypertension - Intervention for Neurodegenerative Delay (MIND) diet and cognitive function over 8 years of follow-up in Puerto Rican adults residing in the Boston, MA area (aged 45–75 years at baseline). We also examined whether the MIND diet—cognition association was confounded or modified by socioeconomic measures.ResultsIn both cross-sectional and longitudinal analyses the highest, versus lowest, MIND quintile was associated with better cognition function (β = 0.093; 95% CI: 0.035, 0.152; p trend = .0019), but not with cognitive trajectory over 8 years. Education &lt;=8th grade (β = −0.339; 95% CI: 0.394, −0.286; p &lt; .0001) and income-to-poverty ratio &lt;120% (β = −0.049; 95% CI: −0.092, −0.007; p = .024) were significantly associated with lower cognitive function, while higher job complexity (β = 0.008; 95% CI: 0.006, 0.011; p &lt; .0001) was associated with better cognition function. These variables acted as confounders, but not effect modifiers of the MIND-diet—cognitive function relationship.ConclusionAdherence to the MIND diet was associated with better cognitive function at baseline and over 8 years of follow-up; however, MIND diet was not associated with 8-year cognitive trajectory. More studies are needed to better understand whether the MIND diet is protective against long-term cognitive decline.
α-synuclein inhibits Snx3-retromer retrograde trafficking of the conserved membrane-bound proprotein convertase Kex2 in the secretory pathway of Saccharomyces cerevisiae
Authors: Rajasekaran Santhanasabapathy , Peterson Patricia P , Liu Zhengchang , Robinson Lucy C , Witt Stephan N 
Published: September 2021

Abstract
We tested the ability of alpha-synuclein (α-syn) to inhibit Snx3-retromer-mediated retrograde trafficking of Kex2 and Ste13 between late endosomes and the trans-Golgi network (TGN) using a Saccharomyces cerevisiae model of Parkinson’s disease. Kex2 and Ste13 are a conserved, membrane-bound proprotein convertase and dipeptidyl aminopeptidase, respectively, that process pro-α-factor and pro-killer toxin. Each of these proteins contains a cytosolic tail that binds to sorting nexin Snx3. Using a combination of techniques, including fluorescence microscopy, western blotting and a yeast mating assay, we found that α-syn disrupts Snx3-retromer trafficking of Kex2-GFP and GFP-Ste13 from the late endosome to the TGN, resulting in these two proteins transiting to the vacuole by default. Using three α-syn variants (A53T, A30P, and α-synΔC, which lacks residues 101–140), we further found that A53T and α-synΔC, but not A30P, reduce Snx3-retromer trafficking of Kex2-GFP, which is likely to be due to weaker binding of A30P to membranes. Degradation of Kex2 and Ste13 in the vacuole should result in the secretion of unprocessed, inactive forms of α-factor, which will reduce mating efficiency between MATa and MATα cells. We found that wild-type α-syn but not A30P significantly inhibited the secretion of α-factor. Collectively, our results support a model in which the membrane-binding ability of α-syn is necessary to disrupt Snx3-retromer retrograde recycling of these two conserved endopeptidases.
The utility of Conversation Analysis versus Roter’s Interaction Analysis System for studying communication in pharmacy settings: a scoping review
Authors: Alsubaie Sarah , Grant Daniel , Donyai Parastou 
Published: September 2021

AbstractObjectivesTo compare the usefulness of the Roter Interaction Analysis System with Conversation Analysis (CA) for studying dynamic patient–pharmacist interactions within pharmacy practice. A scoping review was undertaken to identify all studies using Roter’s method or CA to investigate patient–pharmacist interactions. The studies were then compared and contrasted for their methodological advantages and disadvantages.Key findingsIn total, 31 studies met the inclusion criteria. Roter’s method is effective in briefly describing patient–pharmacist interactions and can be used to measure the effect of training courses without consuming too much time. CA, although a time-consuming undertaking, looks at very specific features and the sequence of conversations including the dynamics of two-way interactions and can therefore be used to identify the source of conflict or misunderstandings. A flowchart showing the usefulness of both methods is suggested to help other researchers select the appropriate method(s) for their own research.SummaryAlthough both methods are effective for investigating patient–pharmacist interactions independently, using them sequentially could enable researchers to firstly identify how to make improvements (via CA), design relevant training and then investigate the impact of such training (via Roter’s method) to enrich communications research.
Competition policy’s role in the economic recovery process from the Covid-19 pandemic crisis—insight from UNCTAD
Authors: Moreira Teresa 
Published: September 2021

Abstract
The COVID-19 pandemic outbreak disrupted markets and had a serious negative impact in economies across the world. Competition Authorities were at the forefront of initial public response measures through strong law enforcement and active market monitoring actions, temporary exemptions from competition provisions, merger control procedural adjustments and advocacy, an increasingly important function vis-à-vis Governments and all relevant stakeholders. Competition law and policy have therefore remained highly relevant during this period in both developed and developing countries. Current common challenges faced are raised by the increased digitalization of the economy and the dominance of digital platforms, especially considering the number and market share of micro and Small and Medium Sized enterprises (SMEs), the most seriously affected by the pandemic lockdown measures. Several jurisdictions and international organizations are equipping themselves with new legislation and instruments to address these challenges, namely supporting SMEs fair access to digital markets and promoting competitive public procurement, but less experienced and resource-constrained authorities of developing countries must prioritize otherwise. Competition advocacy is now more than ever a priority for them so that the economic recovery packages preserver open, fair, and equitable markets. International cooperation, bringing together developed and developing countries authorities, provides a crucial framework of support especially at this time. UNCTAD is particularly well placed to support developing countries’ Competition Authorities contributions to “building back better” in times of crisis.
Epigenetic Profiling and Response to CD19 Chimeric Antigen Receptor T-Cell Therapy in B-Cell Malignancies
Authors: Garcia-Prieto Carlos A , Villanueva Lorea , Bueno-Costa Alberto , Davalos Veronica , González-Navarro Europa Azucena , Juan Manel , Urbano-Ispizua Álvaro , Delgado Julio , Ortiz-Maldonado Valentín , del Bufalo Francesca , Locatelli Franco , Quintarelli Concetta , Sinibaldi Matilde , Soler Marta , Castro de Moura Manuel , Ferrer Gerardo , Urdinguio Rocio G , Fernandez Agustin F , Fraga Mario F , Bar Diana , Meir Amilia , Itzhaki Orit , Besser Michal J , Avigdor Abraham , Jacoby Elad , Esteller Manel 
Published: September 2021

Abstract

Background
Chimeric antigen receptor (CAR) T cells directed against CD19 (CART19) are effective in B-cell malignancies, but little is known about the molecular factors predicting clinical outcome of CART19 therapy. The increasingly recognized relevance of epigenetic changes in cancer immunology prompted us to determine the impact of the DNA methylation profiles of CART19 cells on the clinical course.

Methods
We recruited 114 patients with B-cell malignancies, comprising 77 patients with acute lymphoblastic leukemia and 37 patients with non-Hodgkin lymphoma who were treated with CART19 cells. Using a comprehensive DNA methylation microarray, we determined the epigenomic changes that occur in the patient T cells upon transduction of the CAR vector. The effects of the identified DNA methylation sites on clinical response, cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, event-free survival, and overall survival were assessed. All statistical tests were 2-sided.

Results
We identified 984 genomic sites with differential DNA methylation between CAR-untransduced and CAR-transduced T cells before infusion into the patient. Eighteen of these distinct epigenetic loci were associated with complete response (CR), adjusting by multiple testing. Using the sites linked to CR, an epigenetic signature, referred to hereafter as the EPICART signature, was established in the initial discovery cohort (n = 79), which was associated with CR (Fisher exact test, P &lt; .001) and enhanced event-free survival (hazard ratio [HR] = 0.36; 95% confidence interval [CI] = 0.19 to 0.70; P = .002; log-rank P = .003) and overall survival (HR = 0.45; 95% CI = 0.20 to 0.99; P = .047; log-rank P = .04;). Most important, the EPICART profile maintained its clinical course predictive value in the validation cohort (n = 35), where it was associated with CR (Fisher exact test, P &lt; .001) and enhanced overall survival (HR = 0.31; 95% CI = 0.11 to 0.84; P = .02; log-rank P = .02).

Conclusions
We show that the DNA methylation landscape of patient CART19 cells influences the efficacy of the cellular immunotherapy treatment in patients with B-cell malignancy.
State Compliance and the Track Record of International Security Institutions: Evidence from the Nuclear Nonproliferation Regime
Authors: Kaplow Jeffrey M 
Published: September 2021

AbstractWhy do states choose to comply with international security institutions, and what factors drive changes in compliance behavior over time? This article argues that these institutions are based on a fundamental bargain among members—each is willing to comply only so long as others do—but there is often uncertainty about the compliance of others. The track record of the institution provides information that helps to resolve this uncertainty. As time passes with few violations, states will be more likely to comply themselves; evidence of increasing noncompliance, on the other hand, will make states more likely to cheat. Analysis of data on nuclear weapons programs from 1968 to 2010 finds that members of the nuclear nonproliferation regime are more likely to pursue nuclear weapons when there have been a greater number of recent violations of the regime. These findings point to a more dynamic view of international security institutions than has generally been recognized in the literature.
Ion acceleration to 100 keV by the ExB wave mechanism in collision-less shocks
Authors: Stasiewicz Krzysztof , Eliasson Bengt 
Published: September 2021

ABSTRACTIt is shown that ions can be accelerated to about 100 keV in the direction perpendicular to the magnetic field by the ExB mechanism of electrostatic waves. The acceleration occurs in discrete steps of duration being a small fraction of the gyroperiod and can explain observations of ion energization to 10 keV at quasi-perpendicular shocks and to hundreds keV at quasi-parallel shocks. A general expression is provided for the maximum energy of ions accelerated in shocks of arbitrary configuration. The waves involved in the acceleration are related to three cross-field current-driven instabilities: the lower hybrid drift (LHD) instability induced by the density gradients in shocks and shocklets, followed by the modified two-stream (MTS) and electron cyclotron drift (ECD) instabilities, induced by the ExB drift of electrons in the strong LHD wave electric field. The ExB wave mechanism accelerates heavy ions to energies proportional to the atomic mass number, which is consistent with satellite observations upstream of the bow shock and also with observations of post-shocks in supernovae remnants. The results are compared with other acceleration mechanisms traditionally discussed in the literature.
A slim disc approach to external photoevaporation of discs
Authors: Owen James E , Altaf Noumahn 
Published: September 2021

ABSTRACT
The photoevaporation of protoplanetary discs by nearby massive stars present in their birth cluster plays a vital role in their evolution. Previous modelling assumes that the disc behaves like a classical Keplerian accretion disc out to a radius where the photoevaporative outflow is launched. There is then an abrupt change in the angular velocity profile, and the outflow is modelled by forcing the fluid parcels to conserve their specific angular momenta. Instead, we model externally photoevaporating discs using the slim disc formalism. The slim disc approach self-consistently includes the advection of radial and angular momentum as well as angular momentum redistribution by internal viscous torques. Our resulting models produce a smooth transition from a rotationally supported Keplerian disc to a photoevaporative driven outflow, where this transition typically occurs over ∼4–5 scale heights. The penetration of ultraviolet photons predominately sets the radius of the transition and the viscosity’s strength plays a minor role. By studying the entrainment of dust particles in the outflow, we find a rapid change in the dust size and surface density distribution in the transition region due to the steep gas density gradients present. This rapid change in the dust properties leaves a potentially observable signature in the continuum spectral index of the disc at mm wavelengths. Using the slim disc formalism in future evolutionary calculations will reveal how both the gas and dust evolve in their outer regions and the observable imprints of the external photoevaporation process.
TYGS and LPSN: a database tandem for fast and reliable genome-based classification and nomenclature of prokaryotes
Authors: Meier-Kolthoff Jan P , Carbasse Joaquim Sardà , Peinado-Olarte Rosa L , Göker Markus 
Published: September 2021

Abstract
Microbial systematics is heavily influenced by genome-based methods and challenged by an ever increasing number of taxon names and associated sequences in public data repositories. This poses a challenge for database systems, particularly since it is obviously advantageous if such data are based on a globally recognized approach to manage names, such as the International Code of Nomenclature of Prokaryotes. The amount of data can only be handled if accurate and reliable high-throughput platforms are available that are able to both comply with this demand and to keep track of all changes in an efficient and flexible way. The List of Prokaryotic names with Standing in Nomenclature (LPSN) is an expert-curated authoritative resource for prokaryotic nomenclature and is available at https://lpsn.dsmz.de. The Type (Strain) Genome Server (TYGS) is a high-throughput platform for accurate genome-based taxonomy and is available at https://tygs.dsmz.de. We here present important updates of these two previously introduced, heavily interconnected platforms for taxonomic nomenclature and classification, including new high-level facilities providing access to bioinformatic algorithms, a considerable expansion of the database content, and new ways to easily access the data.