bluuebunny/crossref_metadata_2025_split huggingface dataset:
Repurposing Probenecid for the Treatment of Heart Failure (Re-Prosper-HF): a study protocol for a randomized placebo-controlled clinical trial
Authors: Rubinstein Jack , Robbins Nathan , Evans Karen , Foster Gabrielle , Mcconeghy Kevin , Onadeko Toluwalope , Bunke Julie , Parent Melanie , Luo Xi , Joseph Jacob , Wu Wen-Chih 
Published: April 2022

Abstract
Background
Improving contractility in heart failure with reduced ejection fraction (HFrEF) has resurfaced as a potential treatment goal. Inotropic therapy is now better understood through its underlying mechanism as opposed to the observed effect of increasing contractility. Calcitropes are a subgroup of inotropes that largely depend on the stimulation of adenylyl cyclase to transform ATP into cyclic adenosine monophosphate (cAMP). At least two clinically relevant calcitropes—istaroxime and probenecid—improve contractility through an increase in systolic intracellular calcium without activating cAMP production.
Probenecid, which has been safely used clinically for decades in non-cardiac conditions, has recently been identified as an agonist of the transient receptor potential vanilloid 2 channel. Translational studies have shown that it improves calcium cycling and contractility without activating noxious pathways associated with cAMP-dependent calcitropes and can improve cardiac function in patients with HFrEF.

Methods
The Re-Prosper-HF study (Repurposing Probenecid for the Treatment of Heart Failure with Reduced Ejection Fraction) is a three-site double-blinded randomized-controlled trial that will test the hypothesis that probenecid can improve cardiac function in patients with HFrEF. Up to 120 patients will be randomized in this double-blind, placebo-controlled study that will assess whether oral probenecid administered at 1 g orally twice per day for 180 days in patients with NYHA II-III HFrEF improves systolic function (aim 1), functional status (aim 2), and self-reported health status (aim 3).

Discussion
Findings from this study will provide data informing its use for improving symptomatology in patients with HFrEF as well as exploratory data for outcomes such as hospital admission rates.

Trial tegistration
The Re-Prosper HF Study (Re-Prosper HF) is registered on ClinicalTrials.gov with the identifier as NCT04551222. Registered on 9 September 2020.
Novel allyl-hydrazones including 2,4-dinitrophenyl and 1,2,3-triazole moieties as optical sensor for ammonia and chromium ions in water
Authors: Mohamed Hanan A. , Abdel-Wahab Bakr F. , Yousif Mahmoud N. M. , Abdelhameed Reda M. 
Published: April 2022

AbstractIt is critical to take safety action if carcinogenic heavy metals and ammonia can be detected quickly, cheaply, and selectively in an environmental sample. As a result, compound 4a [4-(1-(2-(2,4-Dinitrophenyl)hydrazineylidene)-3-(naphthalen-2-yl)allyl)-5-methyl-1-phenyl-1 H-1,2,3-triazole] and compound 4b [4-(1-(2-(2,4-Dinitrophenyl)hydrazineylidene)-3-(naphthalen-2-yl)allyl)-1-(4-fluorophenyl)-5-methyl-1 H-1,2,3-triazole] were prepared. The aldol condensation process of 4-acetyl-1,2,3-triazoles 1a,b (Ar = C6H4; 4-FC6H4) with 2-naphthaldehyde yields 1-acetyl-1,2,3-triazoles 1a,b (Ar = C6H4; 4-FC6H4) (5-methyl-1-aryl-1 H-1,2,3-triazol-4-yl) -3-(naphthalen-2-yl)prop-2-en-1-ones 3a,b with a yield of around 95%. The target compounds 4a,b are obtained in around 88% yield by condensation of 3a,b with (2,4-dinitrophenyl)hydrazine in a refluxing acidic medium. Compounds 4a,b exhibited possible colorimetric detection for chromium ion in the range of 0–14 ppm and ammonia in the range of 0–20 ppm. As a result, this research suggests that strong electron-withdraw groups in related probes can improve anion detection ability, while the conjugation effect should also be considered while building structures.
Responses to defoliation of Robinia pseudoacacia L. and Sophora japonica L. are soil water condition dependent
Authors: Li Mingyan , Guo Xiao , Liu Lele , Liu Jian , Du Ning , Guo Weihua 
Published: April 2022

Abstract
Key message
Defoliation significantly affected biomass allocation of Robinia pseudoacacia L. and Sophora japonica L., but leaf physiology readjusted to control levels at the end of the experiment. Considering carbon or sink limitation and relative height growth rate, defoliated R. pseudoacacia grew faster than S. japonica under well-watered conditions, while defoliated S. japonica and R. pseudoacacia had similar performance under drought conditions.

Context
Climate change may result in increases of both drought intensity and insect survival, thereby affecting both exotic and native trees in warm temperate forests.

Aims
In this study, we examined the interaction effects of defoliation and drought on an exotic species Robinia pseudoacacia and a native species Sophora japonica in a warm temperate area, to provide a theoretical basis for predicting the distribution and dynamics of the two species under future climate change.

Methods
In a greenhouse, both species were exposed to three soil moisture (75%, 55%, and 35% of field capacity) and three defoliation treatments (no defoliation, 50% defoliation, and 100% defoliation). Leaf physiology, biomass, and non-structural carbohydrate were determined.

Results
Leaf physiology of defoliated trees did not differ from controls trees, but defoliated seedlings allocated relatively more resources to the leaves at the end of the experiment. In well-watered conditions, defoliated R. pseudoacacia was not carbon or sink limited and defoliated S. japonica was carbon limited, while defoliated individuals of the two species were sink limited under drought. Defoliated R. pseudoacacia grow more rapidly than S. japonica in well-watered conditions. Defoliated R. pseudoacacia had a similar growth rate to S. japonica in drought.

Conclusions
Defoliation clearly affects biomass allocation of the two species, but not leaf physiology. Considering the carbon or sink limitation, the growth of S. japonica and R. pseudoacacia may be limited by future global climate change scenarios.
Knockdown of circ_0003928 ameliorates high glucose-induced dysfunction of human tubular epithelial cells through the miR-506-3p/HDAC4 pathway in diabetic nephropathy
Authors: Liu Qiong , Cui Yuanyuan , Ding Nan , Zhou Changxue 
Published: April 2022

Abstract
Background
Previous data have indicated the importance of circular RNA (circRNA) in the pathogenesis of diabetic nephropathy (DN). The study is designed to investigate the effects of circ_0003928 on oxidative stress and apoptosis of high glucose (HG)-treated human tubular epithelial cells (HK-2) and the underlying mechanism.

Methods
The DN cell model was established by inducing HK-2 cells using 30 mmol/L D-glucose. RNA expression of circ_0003928, miR-506-3p and histone deacetylase 4 (HDAC4) was detected by quantitative real-time polymerase chain reaction. Cell viability and proliferation were investigated by cell counting kit-8 and 5-Ethynyl-29-deoxyuridine (EdU) assays, respectively. Oxidative stress was evaluated by commercial kits. Caspase 3 activity and cell apoptotic rate were assessed by a caspase 3 activity assay and flow cytometry analysis, respectively. Protein expression was detected by Western blotting analysis. The interactions among circ_0003928, miR-506-3p and HDAC4 were identified by dual-luciferase reporter and RNA pull-down assays.

Results
Circ_0003928 and HDAC4 expression were significantly upregulated, while miR-506-3p was downregulated in the serum of DN patients and HG-induced HK-2 cells. HG treatment inhibited HK-2 cell proliferation, but induced oxidative stress and cell apoptosis; however, these effects were reversed after circ_0003928 depletion. Circ_0003928 acted as a miR-506-3p sponge, and HDAC4 was identified as a target gene of miR-506-3p. Moreover, the circ_0003928/miR-506-3p/HDAC4 axis regulated HG-induced HK-2 cell dysfunction.

Conclusion
Circ_0003928 acted as a sponge for miR-506-3p to regulate HG-induced oxidative stress and apoptosis of HK-2 cells through HDAC4, which suggested that circ_0003928 might be helpful in the therapy of DN.
Circulating Metabolic Biomarkers Are Consistently Associated With Type 2 Diabetes Risk in Asian and European Populations
Authors: Seah Jowy Yi Hoong , Hong Yueheng , Cichońska Anna , Sabanayagam Charumathi , Nusinovici Simon , Wong Tien Yin , Cheng Ching-Yu , Jousilahti Pekka , Lundqvist Annamari , Perola Markus , Salomaa Veikko , Tai E Shyong , Würtz Peter , van Dam Rob M , Sim Xueling 
Published: April 2022

Abstract

Context
While Asians have a higher risk of type 2 diabetes (T2D) than Europeans for a given body mass index (BMI), it remains unclear whether the same markers of metabolic pathways are associated with diabetes.

Objective
We evaluated associations between metabolic biomarkers and incidence of T2D in 3 major Asian ethnic groups (Chinese, Malay, and Indian) and a European population.

Methods
We analyzed data from adult males and females of 2 cohorts from Singapore (n = 6393) consisting of Chinese, Malays, and Indians and 3 cohorts of European-origin participants from Finland (n = 14 558). We used nuclear magnetic resonance to quantify 154 circulating metabolic biomarkers at baseline and performed logistic regression to assess associations with T2D risk adjusted for age, sex, BMI and glycemic markers.

Results
Of the 154 metabolic biomarkers, 59 were associated with higher risk of T2D in both Asians and Europeans (P &lt; 0.0003, Bonferroni-corrected). These included branched chain and aromatic amino acids, the inflammatory marker glycoprotein acetyls, total fatty acids, monounsaturated fatty acids, apolipoprotein B, larger very low-density lipoprotein particle sizes, and triglycerides. In addition, 13 metabolites were associated with a lower T2D risk in both populations, including omega-6 polyunsaturated fatty acids and larger high-density lipoprotein particle sizes. Associations were consistent within the Asian ethnic groups (all Phet ≥ 0.05) and largely consistent for the Asian and European populations (Phet ≥ 0.05 for 128 of 154 metabolic biomarkers).

Conclusion
Metabolic biomarkers across several biological pathways were consistently associated with T2D risk in Asians and Europeans.
Patterns and Persistence of Perioperative Plasma and Cerebrospinal Fluid Neuroinflammatory Protein Biomarkers After Elective Orthopedic Surgery Using SOMAscan
Authors: Dillon Simon T. , Otu Hasan H. , Ngo Long H. , Fong Tamara G. , Vasunilashorn Sarinnapha M. , Xie Zhongcong , Kunze Lisa J. , Vlassakov Kamen V. , Abdeen Ayesha , Lange Jeffrey K. , Earp Brandon E. , Cooper Zara R. , Schmitt Eva M. , Arnold Steven E. , Hshieh Tammy T. , Jones Richard N. , Inouye Sharon K. , Marcantonio Edward R. , Libermann Towia A. ,   RISE Study Group
Published: April 2022

BACKGROUND:
The neuroinflammatory response to surgery can be characterized by peripheral acute plasma protein changes in blood, but corresponding, persisting alterations in cerebrospinal fluid (CSF) proteins remain mostly unknown. Using the SOMAscan assay, we define acute and longer-term proteome changes associated with surgery in plasma and CSF. We hypothesized that biological pathways identified by these proteins would be in the categories of neuroinflammation and neuronal function and define neuroinflammatory proteome changes associated with surgery in older patients.

METHODS:
SOMAscan analyzed 1305 proteins in blood plasma (n = 14) and CSF (n = 15) samples from older patients enrolled in the Role of Inflammation after Surgery for Elders (RISE) study undergoing elective hip and knee replacement surgery with spinal anesthesia. Systems biology analysis identified biological pathways enriched among the surgery-associated differentially expressed proteins in plasma and CSF.

RESULTS:
Comparison of postoperative day 1 (POD1) to preoperative (PREOP) plasma protein levels identified 343 proteins with postsurgical changes (P < .05; absolute value of the fold change [|FC|] > 1.2). Comparing postoperative 1-month (PO1MO) plasma and CSF with PREOP identified 67 proteins in plasma and 79 proteins in CSF with altered levels (P < .05; |FC| > 1.2). In plasma, 21 proteins, primarily linked to immune response and inflammation, were similarly changed at POD1 and PO1MO. Comparison of plasma to CSF at PO1MO identified 8 shared proteins. Comparison of plasma at POD1 to CSF at PO1MO identified a larger number, 15 proteins in common, most of which are regulated by interleukin-6 (IL-6) or transforming growth factor beta-1 (TGFB1) and linked to the inflammatory response. Of the 79 CSF PO1MO-specific proteins, many are involved in neuronal function and neuroinflammation.

CONCLUSIONS:
SOMAscan can characterize both short- and long-term surgery-induced protein alterations in plasma and CSF. Acute plasma protein changes at POD1 parallel changes in PO1MO CSF and suggest 15 potential biomarkers for longer-term neuroinflammation that warrant further investigation.
Urinary Catheterization Induces Delirium-Like Behavior Through Glucose Metabolism Impairment in Mice
Authors: Jiang Zhangjie , Liang Feng , Zhang Yida , Dong Yuanlin , Song Annie , Zhu Xiaoping , Zhang Yiying , Xie Zhongcong 
Published: April 2022

BACKGROUND:
Delirium, an acute confusion status, is associated with adverse effects, including the development of Alzheimer’s disease. However, the etiology and underlying mechanisms of delirium remain largely to be determined. Many patients have urinary catheterization (UC), and UC is associated with delirium. However, the cause effects of UC-associated delirium and the underlying mechanisms remain largely unknown. We, therefore, established an animal model of UC, without urinary tract infection, in mice and determined whether UC could induce delirium-like behavior in the mice and the underlying mechanism of these effects.

METHODS:
Adult female mice (16 weeks old) had UC placement under brief isoflurane anesthesia. The delirium-like behavior was determined using our established mice model at 3, 6, 9, and 24 hours after UC placement. We measured the amounts of glucose in both blood and brain interstitial fluid, adenosine triphosphate (ATP) concentration in the cortex, and glucose transporter 1 in the cortex of mice using western blot, immunohistochemistry imaging, reverse transcriptase-polymerase chain reaction (RT-PCR), and fluorescence at 6 hours after the UC placement. Finally, we used vascular endothelial growth factor (VEGF) in the interaction studies.

RESULTS:
We found that UC induced delirium-like behavior in mice at 3, 6, 9, but not 24 hours after the UC placement. UC decreased glucose amounts in brain interstitial fluid (86.38% ± 4.99% vs 100% ± 6.26%, P = .003), but not blood of mice and reduced ATP amounts (84.49% ± 8.85% vs 100% ± 10.64%, P = .031) in the cortex of mice. Finally, UC reduced both protein amount (85.49% ± 6.83% vs 100% ± 11.93%, P = .040) and messenger ribonucleic acid (mRNA) expression (41.95% ± 6.48% vs 100% ± 19.80%, P = .017) of glucose transporter 1 in the cortex of mice. VEGF attenuated these UC-induced changes.

CONCLUSIONS:
These data demonstrated that UC decreased brain glucose and energy amounts via impairing the glucose transport from blood to brain, leading to delirium-like behavior in mice. These findings will promote more research to identify the etiologies and underlying mechanisms of delirium.
Rivaroxaban Reduces the Dabigatran Dose Required for Anticoagulation During Simulated Cardiopulmonary Bypass
Authors: Nadtochiy Sergiy M. , Stefanos Tatsiana , Angona Ronald E. , Lebedko Natalie , Baldzizhar Aksana , Feng Changyong , Eaton Michael P. 
Published: April 2022

BACKGROUND:
Heparin is the standard anticoagulant for cardiopulmonary bypass (CPB); however, there are problems with its use that make the development of suitable alternatives desirable. Currently, no ideal alternative exists. We have previously reported that the direct thrombin inhibitor dabigatran can prevent coagulation in simulated CPB at high concentrations. These high concentrations may cause difficulties in achieving the reversal of dabigatran with idarucizumab, given the markedly different pharmacokinetics of the 2 drugs. Herein, we test the hypothesis that the addition of the anti-Xa drug rivaroxaban would provide suitable anticoagulation at a lower concentration of dabigatran given likely synergy between the 2 classes of drugs. The primary goal of the study was to investigate whether the addition of rivaroxaban reduces the concentration of dabigatran necessary to allow 2 hours of simulated CPB.

METHODS:
The study was performed in sequential steps. Blood collected from consenting healthy donors was used throughout. First, we added graded concentrations of dabigatran and rivaroxaban alone and in combination and assessed inhibition of anticoagulation using thromboelastometry. Using results from this step, combinations of dabigatran and rivaroxaban were tested in both Chandler loop and simulated CPB circuits. Dabigatran and rivaroxaban were added before recalcification, and the circuits were run for 120 minutes. In both models of CPB, 120 minutes of circulation without visible thrombus was considered successful. In the Chandler loop system, idarucizumab was added to reverse anticoagulant effects. In the CPB circuits, the arterial line filters were examined using scanning electron microscope (SEM) to qualitatively assess for fibrin deposition.

RESULTS:
In vitro analysis of blood samples treated with dabigatran and rivaroxaban showed that dabigatran and rivaroxaban individually prolonged clotting time (CT) in a dose-dependent manner. However, when combined, the drugs behaved synergistically. In the Chandler loop system, dabigatran 2400 and 4800 ng/mL plus rivaroxaban (150 ng/mL) effectively prevented clot formation and reduced the dynamics of clot propagation for 120 minutes. Idarucizumab (250–1000 µg/mL) effectively reversed anticoagulation. In the CPB circuits, dabigatran (2500 ng/mL) and rivaroxaban (200 ng/mL) were successful in allowing 120 minutes of simulated CPB and prevented fibrin deposition. Biomarkers of coagulation activation did not increase during simulated CPB. Heparin controls performed similarly to dabigatran and rivaroxaban.

CONCLUSIONS:
The dual administration of oral anticoagulant drugs (dabigatran and Rivaroxaban) with different pharmacologic mechanisms of action produced synergistic inhibition of coagulation in vitro and successfully prevented clotting during simulated CPB.
Higher 24-h Total Movement Activity Percentile Is Associated with Better Cognitive Performance in U.S. Older Adults
Authors: DOOLEY ERIN E. , PALTA PRIYA , WOLFF-HUGHES DANA L. , MARTINEZ-AMEZCUA PABLO , STAUDENMAYER JOHN , TROIANO RICHARD P. , PETTEE GABRIEL KELLEY 
Published: April 2022

ABSTRACT

Purpose
This study aimed to assess the association of a wrist-worn, device-based metric of 24-h movement with cognitive function and subjective cognitive complaints among older adults, 60 yr and older.

Methods
This is a cross-sectional analysis of the 2011–2012 and 2013–2014 National Health and Nutrition Examination Survey (NHANES) cycles. A wrist-worn ActiGraph GT3X+ accelerometer captured total 24-h movement activity, analyzed as Monitor-Independent Movement Summary units (MIMS-units), and quantified into placement based on an age- and sex-standardized percentile. Cognitive tests in the domains of memory, language/verbal fluency, and executive performance were administered. Test-specific cognitive z-scores were generated. Subjective cognitive complaints included perceived difficulty remembering and confusion/memory loss.

Results
The analytical sample included 2708 U.S. older adults (69.5 ± 0.2 yr, 55% female, 20.9% non-White). Multivariable linear regressions revealed those in quartiles 3 (50th–74th percentile) and 4 (≥75th percentile) for their age and sex had higher cognitive function z-scores across all domains compared with those in quartile 1. Logistic regressions demonstrated those in quartiles 3 and 4 also had lower odds of reporting difficulty remembering (adjusted odds ratio [AOR] = 0.52, 95% confidence interval [CI] = 0.31–0.89; AOR = 0.57, 95% CI = 0.37–0.88) and confusion/memory loss (AOR = 0.49, 95% CI = 0.27–0.91; AOR = 0.49, 95% CI = 0.27–0.98), respectively, compared with those in quartile 1.

Conclusions
In a representative sample of U.S. older adults, higher cognitive functioning occurs among those that perform total 24-h movement activity at or above the 50th percentile for their age and sex. Future studies should consider movement behaviors across a 24-h period on cognitive health outcomes in older adults. More research exploring prospective associations of MIMS-units and time-use behaviors across midlife and older adulthood that may affect cognitive functioning across diverse populations is needed.
Validation and clinical application of a method to quantify efavirenz in cervicovaginal secretions from flocked swabs using liquid chromatography tandem mass spectrometry
Authors: Olagunju Adeniyi , Nwogu Jacinta , Eniayewu Oluwasegun , Atoyebi Shakir , Amara Alieu , Kpamor John , Bolaji Oluseye , Adejuyigbe Ebunoluwa , Owen Andrew , Khoo Saye 
Published: April 2022

Background : A liquid chromatography tandem mass spectrometry method to quantify drugs in dried cervicovaginal secretions from flocked swabs was developed and validated using the antiretroviral efavirenz as an example. Methods: Cervicovaginal swabs (CVS) were prepared by submerging flocked swabs in efavirenz-spiked plasma matrix. Time to full saturation, weight uniformity, recovery and room temperature stability were evaluated. Chromatographic separation was on a reverse-phase C18 column by gradient elution using 1mM ammonium acetate in water/acetonitrile at 400 µL/min. Detection and quantification were on a TSQ Quantum Access triple quadrupole mass spectrometer operated in negative ionisation mode. The method was used to quantify efavirenz in CVS samples from human immunodeficiency virus (HIV)-positive women in the VADICT study (NCT03284645). A total of 98 samples (35 paired intensive CVS and DBS pharmacokinetic samples, 14 paired sparse CVS and DBS samples) from 19 participants were available for this analysis. Results: Swabs were fully saturated within 15 seconds, absorbing 128 µL of plasma matrix with coefficient of variation (%CV) below 1.3%. The method was linear with a weighting factor (1/X) in the range of 25-10000 ng/mL with inter- and intra-day precision (% CV) of 7.69-14.9%, and accuracy (% bias) of 99.1-105.3%. Mean recovery of efavirenz from CVS was 83.8% (%CV, 11.2) with no significant matrix effect. Efavirenz remained stable in swabs for at least 35 days after drying and storage at room temperature. Median (range) CVS efavirenz AUC 0-24h was 16370 ng*h/mL (5803-22088), C max was 1618 ng/mL (610-2438) at a T max of 8.0 h (8.0-12), and C min was 399 ng/mL (110-981). Efavirenz CVS:plasma AUC 0-24h ratio was 0.41 (0.20-0.59). Conclusions: Further application of this method will improve our understanding of the pharmacology of other therapeutics in the female genital tract, including in low- and middle-income countries.