bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy and safety of add‐on tacrolimus versus leflunomide in rheumatoid arthritis patients with inadequate response to methotrexate
Authors: Shin Kichul , Baek Han Joo , Kang Young Mo , Cha Hoon‐Suk , Kang Seong Wook , Park Sung‐Hwan , Jun Jae‐Bum , Lee Yun Jong , Choi In Ah , Song Yeong Wook 
Published: March 2019

AbstractAimTo investigate the efficacy and safety of tacrolimus (TAC) versus leflunomide (LEF) when combined with methotrexate (MTX) in rheumatoid arthritis (RA) patients.MethodThis was a 24‐week multi‐center, double‐blind, randomized, non‐inferiority study targeting RA patients with moderate to severe Disease Activity Score of 28 joints (DAS28 > 3.2) who showed inadequate response to MTX. Patients were randomized into TAC or LEF (add‐on to MTX) groups. Initial daily doses of TAC and LEF were 1.5 and 10 mg, respectively, for 4 weeks and then doubled until the end of the study. The primary endpoint was DAS28 comparison at 24 weeks.ResultsEighty‐seven patients were screened in 10 centers and 75 patients were randomized into two groups. Baseline demographics were comparable between TAC + MTX and LEF + MTX groups. The TAC + MTX group was non‐inferior to the LEF + MTX group in terms of DAS28 at 24 weeks (mean difference of DAS28: −0.1812, 95% confidence interval: −0.8073, 0.4450). There was a greater number of adverse events in the LEF + MTX group (66 in LEF + MTX and 49 in TAC + MTX). Six patients presented with transaminitis in the LEF + MTX group compared with two patients in the TAC + MTX group.ConclusionThe efficacy of TAC combined with MTX was non‐inferior to LEF + MTX. It had a reasonable safety profile in RA patients with moderate to severe disease activity (http://cris.nih.go.kr; KCT0000781).
Voluntary Ethanol Intake Produces Subregion‐Specific Neuroadaptations in Striatal and Cortical Areas of Wistar Rats
Authors: Lagström Oona , Danielsson Klara , Söderpalm Bo , Ericson Mia , Adermark Louise 
Published: March 2019

BackgroundAddiction has been conceptualized as a shift from controlled recreational use toward compulsive and habitual drug‐taking behavior. Although the brain reward system is vital for alcohol reward and reinforcement, other neuronal circuits may be involved in controlling long‐term alcohol‐seeking and drug‐taking behaviors. The aim of this study was to outline alcohol‐induced neuroplasticity in defined cortical and striatal subregions, previously implicated in alcohol use disorder.MethodsMale Wistar rats were allowed to voluntarily consume ethanol (EtOH) in an intermittent manner for 2 months, after which ex vivo electrophysiological recordings were performed and data compared with isolated water controls housed in parallel.ResultsField potential recordings revealed an increase in field excitatory postsynaptic potentials (fEPSPs) in the dorsomedial striatum (DMS) of rats consuming EtOH, while a depression of evoked potentials was detected in the dorsolateral striatum (DLS). Mean activity in cortical (medial prefrontal cortex, lateral orbitofrontal cortex [OFC]), and accumbal regions (nucleus accumbens [nAc] core/shell) was not significantly altered as compared to water‐drinking controls, but a correlation between the amount of alcohol consumed and evoked potentials could be found in both dorsal striatal subregions, OFC, and nAc core. Removal of EtOH for 1 to 2 days was sufficient to restore neurotransmission in the DLS, while the increase in fEPSP amplitude sustained in the DMS.ConclusionsThese preclinical findings are in line with clinical observations indicating that alcohol produces neurophysiological transformations in dorsal striatal circuits, which in turn may lead to disruptions in decision‐making processes that could further promote alcohol misuse.
Severity of Substance Use Disorder: Utility as an Outcome in Clinical Settings
Authors: Dacosta‐Sánchez Daniel , Fernández‐Calderón Fermín , González‐Ponce Bella , Díaz‐Batanero Carmen , Lozano Óscar M. 
Published: March 2019

BackgroundSome authors have pointed out the usefulness of the levels of substance use disorder (SUD) as a treatment outcome. However, in order to use this variable as an outcome measure, its impact needs to be addressed within a clinical context. The aim of this study was to analyze the sensitivity of SUD levels as a measure for detecting reliable changes and to make a comparison between the changes in SUD levels detected when using the number of criteria fulfilled and when using the reliable change index (RCI).MethodsThe sample consisted of 206 (106 in follow‐up) patients diagnosed with abuse/dependence on alcohol and cocaine, according to DSM‐IV criteria. The Substance Dependence Severity Scale for DSM‐5 was used to determine current alcohol use disorder (AUD) and cocaine use disorder (CUD). Number of DSM‐5 criteria fulfilled and RCI were used to determine the change in SUD levels.ResultsNo association was found between adherence to/abandonment of treatment and AUD severity levels (χ2 = 7.029, p = 0.071) or CUD severity levels (χ2 = 2.044, p = 0.413). Statistical significant differences for levels of AUD (z = −3.870, p = 0.000) and CUD (z = −5.382, p = 0.000) were found between baseline assessment and follow‐up. According to the number of DSM‐5 criteria and RCI, the Kappa coefficient for the change in patient status (improved, worsened, or no change) was k = 0.61 for alcohol patients and k = 0.64 for cocaine patients. The “mild” category showed the greatest inconsistency between both procedures.ConclusionsLevels of SUD are sensitive to the impact of treatment as measured by the difference between the baseline assessment and 3‐month follow‐up. However, conclusions differ according to whether the DSM‐5 criteria or the RCI is applied.
Predictors and Costs of 30‐Day Readmissions After Index Hospitalizations for Alcohol‐Related Disorders in U.S. Adults
Authors: Wani Rajvi J. , Tak Hyo Jung , Watanabe‐Galloway Shinobu , Klepser Donald G. , Wehbi Nizar K. , Chen Li‐Wu , Wilson Fernando A. 
Published: March 2019

BackgroundIn 2015, the Hospital Readmissions Reduction Program mandated financial penalties to hospitals with greater rates of readmissions for certain conditions. Alcohol‐related disorders (ARD) are the fourth leading cause of 30‐day readmissions. Yet, there is a dearth of national‐level research to identify high‐risk patient populations and predictors of 30‐day readmission. This study examined patient‐ and hospital‐level predictors for index hospitalizations with principal diagnosis of ARD and predicted the cost of 30‐day readmissions.MethodsThe 2014 Nationwide Readmissions Database was used to identify ARD‐related index hospitalizations. Multivariable logistic regression was used to estimate patient‐ and hospital‐level predictors for readmissions, and a 2‐part model was used to predict the incremental cost conditional upon readmission.ResultsIn 2014, 285,767 index hospitalizations for ARD were recorded, and 18.9% of ARD‐associated hospitalizations resulted in at least one 30‐day readmission. Patients who were males, aged 45 to 64 years, Medicaid enrollees, living in urban and low‐income areas, or with 1 to 2 comorbidities had high risk of readmission. Index hospitalization costs were higher among readmitted patients ($8,840 vs. $8,036, p < 0.01). Predicted mean costs for readmissions on index stay with ARD were greater among those aged 45 to 64 years ($1,908, p < 0.001), Medicare enrollees ($2,133, p < 0.001), rural residents ($1,841, p < 0.01), living in high‐income areas ($1,876, p < 0.001), with 4 or more comorbidities ($2,415, p < 0.001), or admitted in large metropolitan hospitals ($2,032, p < 0.001), with large number of beds ($1,964, p < 0.001), with government ownership ($2,109, p < 0.001), or with low volume of ARD cases ($2,155, p < 0.001).ConclusionsOne in 5 ARD‐related index hospitalizations resulted in a 30‐day readmission. Overall, costs of index hospitalizations for ARD were $2.3 billion, of which $512 million were spent on hospitalizations that resulted in at least 1 readmission. There is a need to develop patient‐centric health programs to reduce readmission rates and costs among ARD patients.
Concentration‐dependent cytokine responses of silica nanoparticles and role of ROS in human lung epithelial cells
Authors: Refsnes Magne , Skuland Tonje , Lilleaas Edel , Øvrevik Johan , Låg Marit 
Published: March 2019

AbstractReactive oxygen species (ROS) is regarded as a critical denominator in nanoparticle toxicology and inflammation. Previously, we have shown that silica nanoparticles sized 50 nm (Si50) induce release of CXCL8 and IL‐6 from BEAS‐2B cells, via mechanisms involving NFκB, p38 MAP kinase and TGF‐α‐activated EGF receptor. In the present study, the role of ROS‐mediated mechanisms in the concentration‐dependent Si50 induction of CXCL8 and IL‐6 responses was examined. Si50 (200 µg/mL) induced a time‐dependent ROS formation and a postponed increase in expression of haem oxygenase (HO‐1) mRNA and protein. Pre‐treatment with the ROS inhibitors N‐acetyl cysteine (NAC) and diphenyleneiodonium (DPI) partially attenuated CXCL8 and IL‐6 responses to 200 µg/mL, but not to 100 µg/mL Si50. The release of TGF‐α induced by Si50 (200 µg/mL) was significantly reduced by NAC, but not by DPI nor siRNA against NADPH oxidase DUOX‐1 (siDUOX‐1). Furthermore, siDUOX‐1 reduced Si50‐induced CXCL8, but not IL‐6. Both p38 and p65 phosphorylations were inhibited by siDUOX‐1, but for NAC only p65 phosphorylation reached a significant reduction. Neither NAC nor DPI reduced Si50‐induced CXCL8 and IL‐6 gene expressions. In conclusion, Si50‐induced CXCL8 and IL‐6 involved both ROS‐dependent and ROS‐independent mechanisms. Notably, the role of ROS seemed restricted to effects of higher concentrations of Si50 and not mediated via the gene expression.
Identification of compounds that inhibit the binding of Keap1a/Keap1b Kelch DGR domain with Nrf2 ETGE/DLG motifs in zebrafish
Authors: Raghunath Azhwar , Nagarajan Raju , Sundarraj Kiruthika , Palanisamy Kavipriya , Perumal Ekambaram 
Published: March 2019

AbstractThe Keap1‐Nrf2‐ARE system serves as a premier defence mechanism to curb oxidative stress, which remains as one of the major causes of ageing and pathogenesis in various diseases. Nrf2 is the principal master regulator of the cellular defence system, and its activation remains the prospective therapeutic approach against chronic diseases. One of the recent strategies is to disrupt Keap1‐Nrf2 protein‐protein interaction (PPI) that alters the docking of Keap1 with Nrf2 by compounds occupying a position in the Keap1 blocking the interface with Nrf2. In this study, we made an attempt to identify the compounds with anticancer, antioxidant and anti‐inflammatory properties to disrupt Keap1a/b‐Nrf2 PPI through in silico molecular docking in zebrafish. The phylogenetic analysis of Keap1 proteins revealed the existence of orthologous Keap1‐Nrf2‐ARE system in lower vertebrates that includes zebrafish. The DGR domains of zebrafish Keap1a and Keap1b were modelled with Modeller 9.19 using Keap1 of Mus musculus (PDB ID:5CGJ) as template. Based on the docking calculations, top hit compounds were identified to disrupt both Keap1a and Keap1b interaction with Nrf2 which include quercetin 3,4′‐diglucoside, flavin adenine dinucleotide disodium salt hydrate, salvianolic acid A, tunicamycin and esculin. The LC50 of esculin in 3 dpf zebrafish larvae is 5 mmol/L, and the qRT‐PCR results showed that esculin significantly increased the transcription of Nrf2 target genes—Gstpi, Nqo1, Hmox1a and Prdx1 in 3 dpf zebrafish larvae. These potential hits could serve as safer Nrf2 activators due to their non‐covalent disruption of Keap1‐Nrf2 PPI and be developed into efficacious preventive/therapeutic agents for various diseases.
Immunological and pathological effects of electronic cigarettes
Authors: Chen I‐Ling , Todd Ian , Fairclough Lucy C. 
Published: March 2019

AbstractElectronic cigarettes (E‐cigarettes) are considered a preferable alternative to conventional cigarettes due to the lack of combustion and the absence of tobacco‐specific toxicants. E‐cigarettes have rapidly gained in popularity in recent years amongst both existing smokers and previous non‐smokers. However, a growing literature demonstrates that E‐cigarettes are not as safe as generally believed. Here, we discuss the immunological, and other, deleterious effects of E‐cigarettes on a variety of cell types and host defence mechanisms in humans and in murine models. We review not only the effects of complete E‐cigarette liquids, but also each of the main components—nicotine, humectants and flavourings. This MiniReview thus highlights the possible role of E‐cigarettes in the pathogenesis of disease and raises awareness of the potential harm that E‐cigarettes may cause.
Accounting for Phenology in the Analysis of Animal Movement
Authors: Scharf Henry R. , Hooten Mevin B. , Wilson Ryan R. , Durner George M. , Atwood Todd C. 
Published: March 2019

Abstract
The analysis of animal tracking data provides important scientific understanding and discovery in ecology. Observations of animal trajectories using telemetry devices provide researchers with information about the way animals interact with their environment and each other. For many species, specific geographical features in the landscape can have a strong effect on behavior. Such features may correspond to a single point (eg, dens or kill sites), or to higher dimensional subspaces (eg, rivers or lakes). Features may be relatively static in time (eg, coastlines or home-range centers), or may be dynamic (eg, sea ice extent or areas of high-quality forage for herbivores). We introduce a novel model for animal movement that incorporates active selection for dynamic features in a landscape. Our approach is motivated by the study of polar bear (Ursus maritimus) movement. During the sea ice melt season, polar bears spend much of their time on sea ice above shallow, biologically productive water where they hunt seals. The changing distribution and characteristics of sea ice throughout the year mean that the location of valuable habitat is constantly shifting. We develop a model for the movement of polar bears that accounts for the effect of this important landscape feature. We introduce a two-stage procedure for approximate Bayesian inference that allows us to analyze over 300 000 observed locations of 186 polar bears from 2012 to 2016. We use our model to estimate a spatial boundary of interest to wildlife managers that separates two subpopulations of polar bears from the Beaufort and Chukchi seas.
“Just a little help”: A qualitative inquiry into the persistent use of uterine fundal pressure in the second stage of labor in Spain
Authors: Rubashkin Nicholas , Torres Cinthia , Escuriet Ramon , Dolores Ruiz‐Berdún Maria 
Published: March 2019

AbstractIntroductionUterine fundal pressure, or the Kristeller maneuver (KM), is a non–evidence‐based procedure used in the second stage of labor to physically force the fetus to delivery. Even though officially banned, the KM is practiced in 25% of vaginal deliveries in Spain.MethodsUsing semi‐structured interviews (N = 10 women, N = 15 midwives, N = 3 obstetricians), we sought to understand how providers justify using the KM, and to describe the current circumstances in which the KM is practiced. Women described their preexisting knowledge of and experiences with the KM; providers described how they learned and practiced the KM. We used framework analysis to analyze the transcripts, and we consensus‐coded across three independent investigators.ResultsProviders reported practicing a new, gentler Kristeller to which official policy did not apply. Providers knew the KM posed risks, but they assumed the risks resulted from poor technical training. Providers did not learn the KM through standard means, and they practiced it in secret. Women knew about the KM before delivery, and many had planned to refuse the procedure. Providers made women's refusal more difficult by offering the KM in coded terms as “just a little help.” Women did not experience the KM as gentle, and the force of the procedure made their refusal nearly impossible.ConclusionsThe normal birth policy has failed to achieve its objectives due to maternity care providers’ unique logic surrounding a new KM technique. Women’s ability to refuse the Kristeller is limited.
Targeting of the unfolded protein response (UPR) as therapy for Parkinson's disease
Authors: Martinez Alexis , Lopez Nelida , Gonzalez Constanza , Hetz Claudio 
Published: March 2019

AbstractParkinson's disease is the second most common neurodegenerative disorder, leading to the progressive decline of motor control due to the loss of dopaminergic neurons in the substantia nigra pars compacta. At the molecular level, Parkinson's disease share common molecular signatures with most neurodegenerative diseases including the accumulation of misfolded proteins in the brain. Alteration in the buffering capacity of the proteostasis network during aging is proposed as one of the triggering steps leading to abnormal protein aggregation in this disease, highlighting disturbances in the function of the endoplasmic reticulum (ER). The ER is the main subcellular compartment involved in protein folding and quality control. ER stress triggers a signalling reaction known as the unfolded protein response (UPR), which aims restoring proteostasis through the induction of adaptive programs or the activation of cell death pathways when damage is chronic and cannot be repaired. Here, we overview most evidence linking ER stress to Parkinson's disease. Strategies to alleviate ER stress by targeting specific components of the UPR using small molecules and gene therapy are highlighted.
Glucose transporter 1 regulates the proliferation and cisplatin sensitivity of esophageal cancer
Authors: Sawayama Hiroshi , Ogata Yoko , Ishimoto Takatsugu , Mima Kosuke , Hiyoshi Yukiharu , Iwatsuki Masaaki , Baba Yoshifumi , Miyamoto Yuji , Yoshida Naoya , Baba Hideo 
Published: March 2019

AbstractGlucose transporter 1 (GLUT1) expression is a prognostic marker for esophageal squamous cell carcinoma (ESCC). Recent work on GLUT1 and development of specific inhibitors supports the feasibility of GLUT1 inhibition as a treatment for various cancers. The anti–proliferative effects of GLUT1‐specific small interfering RNA (siRNA) and a GLUT1 inhibitor were evaluated in ESCC cell lines. Expression of pro–proliferative and anti–proliferative signaling and effector molecules was examined by western blotting and quantitative RT‐PCR. GLUT1 expression in pretreatment clinical biopsy samples was measured by immunohistochemistry and correlated with various clinicopathological parameters and response to chemotherapy. The reduction in standardized uptake value (SUV) of 18F‐fluoro‐deoxyglucose was calculated using the formula: ([pretreatment SUVmax – posttreatment SUVmax]/pretreatment SUVmax) × 100. GLUT1‐specific siRNA expression in ESCC cells inhibited their proliferation, increased expression of p27kip, and decreased expression of cyclin‐dependent kinase 6, pyruvate kinase muscle isozyme M2, lactate dehydrogenase A and phospho‐ERK1/2. Suppression of GLUT1 by siRNA increased low‐dose cisplatin‐induced inhibition of proliferation of TE‐11 ESCC cells, which express high GLUT1 levels. Similarly, BAY‐876, a GLUT1 inhibitor, enhanced cisplatin‐mediated inhibition of ESCC cell proliferation. GLUT1 expression in pretreatment biopsy samples was associated with the response to chemotherapy as well as the pathological tumor stage and histological response grade after esophagectomy. Finally, GLUT1‐negative tumors showed a significantly larger reduction in SUVmax (61.2% ± 4.5%) compared with GLUT1‐positive tumors (46.2% ± 4.4%). GLUT1 expression may be a surrogate marker of response to chemotherapy, and inhibition of GLUT1 may be a potential novel therapy for ESCC patients.
Sharper eyes see shyer lizards: Collaboration with indigenous peoples can alter the outcomes of conservation research
Authors: Ward‐Fear Georgia , Rangers Balanggarra , Pearson David , Bruton Melissa , Shine Rick 
Published: March 2019

AbstractOur ecological studies on large varanid lizards in a remote region of tropical Australia reveal a direct benefit to collaboration with local indigenous people. Although they worked together, in pairs, western scientists and indigenous rangers found lizards with different behavioral phenotypes (“personalities”). The resultant broader sampling of the lizard population enabled us to detect positive effects of a conservation management intervention. Those effects would not have been evident from the subset of animals collected by western scientists, and hence, involvement by researchers from both cultures critically affected our conclusions and paved the way for large‐scale deployment of a novel conservation initiative in Northern Australia.
A single‐center analysis of early readmission after renal transplantation
Authors: Kim Steffan H. , Baird Grayson L. , Bayliss George , Merhi Basma , Osband Adena , Gohh Reginald , Morrissey Paul E. 
Published: March 2019

AbstractBackgroundThirty‐day readmission rates (early hospital readmission, EHR) are an important benchmark for quality improvement. Nationally, patients undergoing renal transplantation incur a 31% EHR rate. While national databases provide useful data, the impact of EHR on individual centers has received little attention. We proposed that an institutional review of EHR after renal transplantation may provide a benchmark for individual transplant programs and identify modifiable program‐specific issues to reduce EHR.MethodsWe reviewed 269 consecutive kidney transplant recipients over a five‐year period (2012‐2016). Early hospital readmission was modeled using generalized linear modeling assuming a binary distribution.ResultsAbout 21% of patients were readmitted within 30 days. Deceased kidney donation (DD), delayed graft functioning (DGF), anti‐thymocyte globulin (ATG) induction, diabetes, public insurance, weekend discharge, and low glomerular filtration rate (eGFR) at discharge were all identified as risk factors for readmission. Early hospital readmission was not correlated with risk of death (5.4% at 44 months: HR 2.2 (95% CI [0.7, 6.6]; P = 0.1473) or graft loss.ConclusionsEHR after renal transplantation is common. Certain factors may predict an increased risk for EHR. A multi‐disciplinary approach to discharge planning may limit some EHR, but most complications and adverse events are unpredictable and require hospital‐level of care.
Characteristics, risks, and outcomes of post‐transplant lymphoproliferative disease >3 years after pediatric heart transplant: A multicenter analysis
Authors: West Shawn C. , Friedland‐Little Josh M. , Schowengerdt Kenneth O. , Naftel David C. , Pruitt Freeze Elizabeth , Smith Kelli S. , Urschel Simon , Michaels Marian G. , Kirklin James K. , Feingold Brian 
Published: March 2019

AbstractPost‐transplant lymphoproliferative disorder (PTLD) is a significant complication after pediatric heart transplantation (HT), occurring in 5%‐15% of patients within 3 years. Data >3 years from HT are limited. We sought to describe the prevalence, risk factors, and outcomes of PTLD occurring late (>3 years) after pediatric HT in the Pediatric Heart Transplant Study from 1993 to 2010. Among 3844 primary HT patients, 110 (3%) developed late, nonrecurrent PTLD. The hazard rate for late PTLD was constant at 0.01 events/year out to 20 years after HT. Risk factors for late PTLD were younger age at HT (HR 1.06, P = 0.003) and Epstein‐Barr virus (EBV) naivety (HR 1.65, P = 0.02). Survival after late PTLD was 86% and 68% at 1 and 5 years, with nonwhite race (HR 2.27, P = 0.03) and earlier year of HT (HR 1.03, P = 0.04) independently associated with mortality. Acute rejection and infection were both common after late PTLD, occurring in 26% and 34% of patients. The constant late hazard and contribution of EBV to late PTLD suggest that vigilance for development of PTLD, including for EBV conversion, should persist indefinitely after pediatric HT. The reasons for elevated risk of death for nonwhites after late PTLD are unclear and warrant further investigation.