bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Crossover Study to Evaluate the Pharmacodynamic Effects of VX-150, a Highly Selective NaV1.8 Inhibitor, in Healthy Male Adults
Authors: Hijma Hemme J , Siebenga Pieter S , de Kam Marieke L , Groeneveld Geert Jan 
Published: January 2021

Abstract

Objective
To evaluate the analgesic potential, safety, tolerability, and pharmacokinetics of VX-150, a pro-drug of a highly selective NaV1.8 inhibitor, in healthy subjects.

Design
This was a randomized, double-blind, placebo-controlled, crossover study in healthy subjects.

Subjects
Twenty healthy male subjects with an age of 18–55 years, inclusive, were enrolled. Eligibility was based on general fitness, absence of current or previous medical conditions that could compromise subject safety, and a training assessment of pain tolerance across pain tests to exclude highly tolerant individuals whose tolerance could compromise the ability to detect analgesic responses. All dosed subjects completed the study.

Methods
Subjects were randomized 1:1 to one of two sequences receiving a single VX-150 dose and subsequently placebo, or vice versa, with at least 7 days between dosing. A battery of pain tests (pressure, electrical stair, [capsaicin-induced] heat, and cold pressor) was administered before dosing and repetitively up to 10 h after dosing, with blood sampling up to 24 h after dosing. Safety was monitored throughout the study. Data were analyzed with a repeated-measures mixed-effects model.

Results
VX-150 induced analgesia in a variety of evoked pain tests, without affecting subject safety. Significant effects were reported for the cold pressor and heat pain thresholds. Maximum median concentration for the active moiety was 4.30 µg/mL at 4 h after dosing.

Conclusion
Results of this proof-of-mechanism study are supportive of the potential of VX-150, a highly selective NaV1.8 channel inhibitor, to treat various pain indications.
Hypnotherapy for Procedural Pain and Distress in Children: A Scoping Review Protocol
Authors: Geagea Daly , Tyack Zephanie , Kimble Roy , Eriksson Lars , Polito Vince , Griffin Bronwyn 
Published: January 2021

Abstract

Objective
Inadequately treated pain and distress elicited by medical procedures can put children at higher risk of acute and chronic biopsychosocial sequelae. Children can benefit from hypnotherapy, a psychologically tailored intervention, as an adjunct to pharmacological agents to address the multiple components of pain and distress. Despite providing evidence on the effectiveness and potential superiority of hypnotherapy to other psychological interventions, research on hypnotherapy for pediatric procedural pain and distress has been predominantly limited to oncology and needle procedures. Plus, there is a lack of reporting of intervention manuals, factors influencing hypnotic responding, pain unpleasantness outcomes, theoretical frameworks, adverse events, as well as barriers and facilitators to the feasibility of delivering the intervention and study procedures. The proposed review aims to map the range and nature of the evidence on hypnotherapy for procedural pain and distress in children to identify gaps in literature and areas requiring further investigation.

Methods
This review will follow the Arksey and O‘Malley (2005) methodology and incorporate additional scoping review recommendations by the Joanna Briggs Institute and Preferred Reporting Items for Systematic reviews and Meta-Analyses. Relevant studies will be identified through searching published literature databases (PubMed, Cochrane Library, PsycINFO, Embase, CINAHL, Scopus and Web of Science) and grey literature in addition to hand-searching of reference lists and key journals. Two authors will independently screen titles and abstracts of search results followed by full-texts review against eligibility criteria.

Conclusion
Findings are anticipated to guide future research and inform the development of tailored hypnotic interventions in children.
Phenotype and treatment of elderly onset compared with younger onset rheumatoid arthritis patients in international daily practice
Authors: Maassen Johanna M , Bergstra Sytske Anne , Chopra Arvind , Govind Nimmisha , Murphy Elizabeth A , Vega-Morales David , Huizinga Tom W J , Allaart Cornelia F 
Published: January 2021

Abstract

Objective
To identify possible differences in baseline characteristics, initial treatment and treatment response between RA patient subgroups based on age at disease onset.

Methods
Daily practice data from the worldwide METEOR registry were used. Patients (7912) were stratified into three age-groups (age at disease diagnosis &lt;45 years, 45–65 years, &gt;65 years). Initial treatment was compared between the different age-groups. With Cox regression analyses the effect of age-group on time-to-switch from first to second treatment was investigated, and with linear mixed models differences in response to treatment (DAS and HAQ) between the age-groups were assessed, after correction for potential confounders.

Results
The &gt;65 years age-group included more men, and more seronegative RA with somewhat higher inflammatory markers. Initial treatment choices differed only slightly between the age-groups, and the time-to-switch from initial treatment to the next was similar. DAS and HAQ improvement were dependent on the age-group, reflected by a significant interaction between age-group and outcome. The stratified analysis showed a difference of −0.02 and −0.05 DAS points and, −0.01 and 0.02 HAQ points per month in the &lt;45 and 45–65 years age-groups as compared with the &gt;65 year age group, a difference that did not seem clinically relevant.

Conclusion
In this international study on worldwide clinical practice, patients with RA onset &gt;65 years include more men and seronegative arthritis, and were initially treated slightly differently than younger patients. We observed no clinically relevant differences in timing of a next treatment step, or response to treatment measured by DAS and HAQ.
Tethered NOS-3, a nematode Nanos RNA-binding protein, enhances reporter expression and mRNA stability
Authors: Doenier Jonathan , Lynch Tina R , Kimble Judith , Aoki Scott T 
Published: January 2021

AbstractRobust methods are critical for testing thein vivoregulatory mechanism of RNA binding proteins. Here we report improvement of a protein-mRNA tethering assay to probe the function of an RNA binding protein in its natural context within theC. elegansadult germline. The assay relies on a dual reporter expressing two mRNAs from a single promoter and resolved by trans-splicing. Thegfpreporter 3’UTR harbors functional binding elements for λN22 peptide, while themCherryreporter 3’UTR carries mutated nonfunctional elements. This strategy enables internally controlled quantitation of reporter protein by immunofluorescence and mRNA by smFISH. To test the new system, we analyzed aC. elegansNanos protein, NOS-3, which serves as a post-transcriptional regulator of germ cell fate. Unexpectedly, tethered NOS-3 enhanced reporter expression. We confirmed this enhancement activity with a second reporter engineered at an endogenous germline gene. NOS-3 enhancement of reporter expression was associated with its N-terminal intrinsically disordered region, not its C-terminal zinc fingers. RNA quantitation revealed that tethered NOS-3 enhances stability of the reporter mRNA. We suggest that this direct NOS-3 enhancement activity may explain a paradox: classically Nanos proteins are expected to repress RNA, butnos-3had been found to promotegld-1expression, an effect that could be direct. Regardless, the new dual reporter dramatically improvesin situquantitation of reporter expression after RBP tethering to determine its molecular mechanism in a multicellular tissue.
Discernment of Mediator and Outcome Measurement in the PACE trial
Authors: Carr Ewan , Vitoratou Silia , Chalder Trudie , Goldsmith Kimberley 
Published: January 2021

AbstractBackgroundWhen measuring latent traits, such as those used in psychology and psychiatry, it can be unclear whether the instruments used are measuring different concepts. This issue is particularly important in context of mediation analysis, since for a sound mediation hypothesis the mediator and outcome should be distinct. We sought to assess the extent of measurement overlap between mediators and outcomes in the PACE trial (n=640).MethodsPotential measurement overlap was assessed using generalised linear latent variable models where confirmatory factor models quantified the extent to which the addition of cross-loading items resulted in significant improvements in model fit.ResultsOut of 26 mediator-outcome pairs considered, only six showed evidence of cross-loading items, supporting the suggestion that mediator and outcome constructs in the PACE trial were conceptually distinct.ConclusionsThis study highlights the importance of assessing measurement overlap in mediation analyses with latent traits to ensure mediator and outcome instruments are distinct.
Evaluation of the rapidBACpro®II kit for the rapid identification of microorganisms directly from blood cultures using MALDI-TOF MS
Authors: Oviaño Marina , Ingebretsen André , Steffensen Anne K , Croxatto Antony , Prod’hom Guy , Quiroga Lidia , Bou Germán , Greub Gilbert , Rodríguez-Sánchez Belén 
Published: January 2021

AbstractObjectivesIdentification of microorganisms directly from blood cultures (BCs) using MALDI-TOF MS has shown to be the application with most impact in this methodology. In this study, a novel commercial method, the rapidBACpro®II, was evaluated in four clinical microbiology laboratories.MethodsPositive blood culture samples (n=801) were processed using the rapidBACpro®II kit and then compared with routine gold standard. A subset of monomicrobial BCs (n=560) were analyzed in parallel with the Sepsityper®kit (Bruker Daltonics, Bremen, Germany) and compared with the rapidBACpro®II kit. In addition, the rapidBACpro®II kit was also compared with two different in-house methods.ResultsOverall, 80.0% of the monomicrobial isolates (609/761) were correctly identified by the rapidBACpro®II kit at the species level (92.3% of the Gram negative and 72.4% of the Gram positive bacteria). The comparison with the Sepsityper®kit yielded higher rates of correct species-level identification provided by the rapidBACpro®II kit for all categories (p>0.0001) except for yeasts identified with score values >1.7. It also proved superior to the ammonium chloride method (p>0.0001) but the differential centrifugation method allowed higher rates of correct identification for Gram negative bacteria (p>0.1).ConclusionsThe rapidBACpro®II kit allowed a high rate of microorganisms correctly identified. The percentage of accurate species-level identification of Gram positive bacteria was particularly noteworthy in comparison with other commercial and in-house methods. This fact was especially interesting in the case ofStaphylococcussp. andStreptococcussp. in order to elucidate their clinical impact, for example in device-associated bacteremia.
High-fidelity discrimination of ARDS versus other causes of respiratory failure using natural language processing and iterative machine learning
Authors: Afshin-Pour Babak , Qiu Michael , Hosseini Shahrzad , Stewart Molly , Horsky Jan , Aviv Rachel , Zhang Nasen , Narasimhan Mangala , Chelico John , Musso Gabriel , Hajizadeh Negin 
Published: January 2021

ABSTRACTDespite the high morbidity and mortality associated with Acute Respiratory Distress Syndrome (ARDS), discrimination of ARDS from other causes of acute respiratory failure remains challenging, particularly in the first 24 hours of mechanical ventilation. Delay in ARDS identification prevents lung protective strategies from being initiated and delays clinical trial enrolment and quality improvement interventions. Medical records from 1,263 ICU-admitted, mechanically ventilated patients at Northwell Health were retrospectively examined by a clinical team who assigned each patient a diagnosis of “ARDS” or “non-ARDS” (e.g., pulmonary edema). We then applied an iterative pre-processing and machine learning framework to construct a model that would discriminate ARDS versus non-ARDS, and examined features informative in the patient classification process. Data made available to the model included patient demographics, laboratory test results from before the initiation of mechanical ventilation, and features extracted by natural language processing of radiology reports. The resulting model discriminated well between ARDS and non-ARDS causes of respiratory failure (AUC=0.85, 89% precision at 20% recall), and highlighted features unique among ARDS patients, and among and the subset of ARDS patients who would not recover. Importantly, models built using both clinical notes and laboratory test results out-performed models built using either data source alone, akin to the retrospective clinician-based diagnostic process. This work demonstrates the feasibility of using readily available EHR data to discriminate ARDS patients prospectively in a real-world setting at a critical time in their care and highlights novel patient characteristics indicative of ARDS.
Trajectories of Hypoxemia & Respiratory System Mechanics of COVID-19 ARDS in the NorthCARDS dataset
Authors: Jafari Daniel , Gandomi Amir , Makhnevich Alex , Qiu Michael , Rolston Daniel M , Gottesman Eric P , Tsegaye Adey , Mayo Paul H , Stewart Molly E , Zhang Meng , Hajizadeh Negin 
Published: January 2021

AbstractRationaleThe preliminary reports of COVID Acute Respiratory Distress Syndrome (COVIDARDS) suggest the existence of a subset of patients with higher lung compliance despite profound hypoxemia. Understanding heterogeneity seen in patients with COVIDARDS and comparing to non-COVIDARDS may inform tailored treatments.ObjectivesTo describe the trajectories of hypoxemia and respiratory compliance in COVIDARDS and associations with outcomes.MethodsA multidisciplinary team of frontline clinicians and data scientists created the Northwell COVIDARDS dataset (NorthCARDS) leveraging over 11,542 COVID-19 hospital admissions. Data was summarized to describe differences based on clinically meaningful categories of lung compliance, and compared to non-COVIDARDS reports. A sophisticated method of extrapolating PaO2 from SpO2, as well estimating FiO2 from non invasive oxygen delivery devices were utilized to create meaningful trends of derived PaO2 to FiO2 (P/F).Measurements and Main ResultsOf the 1595 COVIDARDS patients in the NorthCARDS dataset, there were 538 (34·6%) who had very low lung compliance (<20ml/cmH2O), 982 (63·2%) with low-normal compliance (20-50ml/cmH2O), and 34 (2·2%) with high lung compliance (>50ml/cmH2O). The very low compliance group had double the median time to intubation compared to the low-normal group (107 hours(IQR 26·3, 238·3) vs. 37·9 hours(IQR 4·8, 90·7)). Oxygenation trends have improved in all groups after a nadir immediately post intubation. The P/F ratio improved from a mean of 109 to 155, with the very low compliance group showing a smaller improvement compared to low compliance group. The derived P/F trends closely correlated with blood gas analysis driven P/F trends, except immediately post intubation were the trends diverge as illustrated in the image. Overall, 67·5% (n=1049) of the patients died during the hospitalization. In comparison to non-COVIDARDS reports, there were less patients in the high compliance category (2.2%vs.12%, compliance ≥50mL/cmH20), and more patients with P/F ≤ 150 (57·8% vs. 45.6%). No correlation was apparent between lung compliance and P/F ratio. The Oxygenation Index was similar, (11·12(SD 5·67)vs.12·8(SD 10·8)).ConclusionsHeterogeneity in lung compliance is seen in COVIDARDS, without apparent correlation to degree of hypoxemia. Notably, time to intubation was greater in the very low lung compliance category. Understanding ARDS patient heterogeneity must include consideration of treatment patterns in addition to trajectories of change in patient-level data and demographics.
Resting State Functional Connectivity Predicts Future Changes in Sedentary Behavior
Authors: Morris Timothy P. , Kucyi Aaron , Anteraper Sheeba Arnold , Geddes Maiya Rachel , Nieto-Castañon Alfonso , Burzynska Agnieszka , Gothe Neha , Fanning Jason , Salerno Elizabeth , Whitfield-Gabrieli Susan , Hillman Charles H. , McAuley Edward , Kramer Arthur F. 
Published: January 2021

AbstractInformation about a person’s available energy resources is integrated in daily behavioral choices that weigh motor costs against expected rewards. It has been posited that humans have an innate attraction towards effort minimization and that executive control is required to overcome this prepotent disposition. With sedentary behaviors increasing at the cost of millions of dollars spent in health care and productivity losses due to physical inactivity-related deaths, understanding the predictors of sedentary behaviors will improve future intervention development and precision medicine approaches. In 64 healthy older adults participating in a 6-month aerobic exercise intervention, we use neuroimaging (resting state functional connectivity), baseline measures of executive function and accelerometer measures of time spent sedentary to predict future changes in objectively measured time spent sedentary in daily life. Using cross-validation and bootstrap resampling, our results demonstrate that functional connectivity between 1) the anterior cingulate cortex and the supplementary motor area and 2) the right anterior insula and the left temporoparietal/temporooccipital junction, predict changes in time spent sedentary, whereas baseline cognitive, behavioral and demographic measures do not. Previous research has shown activation in and between the anterior cingulate and supplementary motor area as well as in the right anterior insula during effort avoidance and tasks that integrate motor costs and reward benefits in effort-based decision making. Our results add important knowledge toward understanding mechanistic associations underlying complex sedentary behaviors.
Single-cell transcriptomics defines heterogeneity of epicardial cells and fibroblasts within the infarcted heart
Authors: Hesse Julia , Owenier Christoph , Lautwein Tobias , Zalfen Ria , Weber Jonas F. , Ding Zhaoping , Alter Christina , Lang Alexander , Grandoch Maria , Gerdes Norbert , Fischer Jens W. , Klau Gunnar W. , Dieterich Christoph , Köhrer Karl , Schrader Jürgen 
Published: January 2021

AbstractIn the adult heart, the epicardium becomes activated after injury, contributing to cardiac healing by secretion of paracrine factors. Here we analyzed by single-cell RNA sequencing combined with RNA in situ hybridization and lineage tracing of WT1+cells the cellular composition, location, and hierarchy of epicardial stromal cells (EpiSC) in comparison to activated myocardial fibroblasts/stromal cells in infarcted mouse hearts. We identified 11 transcriptionally distinct EpiSC populations, that can be classified in three groups each containing a cluster of proliferating cells. Two groups expressed cardiac specification makers and sarcomeric proteins suggestive of cardiomyogenic potential. Transcripts of HIF-1α and HIF-responsive genes were enriched in EpiSC consistent with an epicardial hypoxic niche. Expression of paracrine factors was not limited to WT1+cells but was a general feature of activated cardiac stromal cells. Our findings provide the cellular framework by which myocardial ischemia may trigger in EpiSC the formation of cardioprotective/regenerative responses.
Sensitivity enhancement and selection are shared mechanisms for spatial and feature-based attention
Authors: Birman Daniel , Gardner Justin L. 
Published: January 2021

AbstractHuman observers use cues to guide visual attention to the most behaviorally relevant parts of the visual world. Cues are often separated into two forms: those that rely on spatial location and those that use features, such as motion or color. These forms of cueing are known to rely on different populations of neurons. Despite these differences in neural implementation, attention may rely on shared computational principles, enhancing and selecting sensory representations in a similar manner for all types of cues. Here we examine whether evidence for shared computational mechanisms can be obtained from how attentional cues enhance performance in estimation tasks. In our tasks, observers were cued either by spatial location or feature to two of four dot patches. They then estimated the color or motion direction of one of the cued patches, or averaged them. In all cases we found that cueing improved performance. We decomposed the effects of the cues on behavior into model parameters that separated sensitivity enhancement from sensory selection and found that both were important to explain improved performance. We found that a model which shared parameters across forms of cueing was favored by our analysis, suggesting that observers have equal sensitivity and likelihood of making selection errors whether cued by location or feature. Our perceptual data support theories in which a shared computational mechanism is re-used by all forms of attention.Significance StatementCues about important features or locations in visual space are similar from the perspective of visual cortex, both allow relevant sensory representations to be enhanced while irrelevant ones can be ignored. Here we studied these attentional cues in an estimation task designed to separate different computational mechanisms of attention. Despite cueing observers in three different ways, to spatial locations, colors, or motion directions, we found that all cues led to similar perceptual improvements. Our results provide behavioral evidence supporting the idea that all forms of attention can be reconciled as a single repeated computational motif, re-implemented by the brain in different neural architectures for many different visual features.
Response time modelling reveals evidence for multiple, distinct sources of moral decision caution
Authors: Andrejević Milan , White Joshua P. , Feuerriegel Daniel , Laham Simon , Bode Stefan 
Published: January 2021

AbstractPeople are often cautious in delivering moral judgments of others’ behaviours, as falsely accusing others of wrongdoing can be costly for social relationships. Caution might further be present when making judgements in information-dynamic environments, as contextual updates can change our minds. This study investigated the processes with which moral valence and context expectancy drive caution in moral judgements. Across two experiments, participants (N= 122) made moral judgements of others’ sharing actions. Prior to judging, participants were informed whether contextual information regarding the deservingness of the recipient would follow. We found that participants slowed their moral judgements when judging negatively valenced actions and when expecting contextual updates. Using a diffusion decision model framework, these changes were explained by shifts in drift rate and decision bias (valence) and boundary setting (context), respectively. These findings demonstrate how moral decision caution can be decomposed into distinct aspects of the unfolding decision process.