bluuebunny/crossref_metadata_2025_split huggingface dataset:
Feasibility study of a randomised controlled trial to investigate the treatment of sarcoidosis-associated fatigue with methylphenidate (FaST-MP): a study protocol
Authors: Atkins Christopher , Fordham Richard , Clark Allan B , Stockl Andrea , Jones Andrew P , Wilson Andrew M 
Published: December 2017

IntroductionFatigue is a frequent and troublesome manifestation of chronic sarcoidosis. This symptom can be debilitating and difficult to treat, with poor response to the treatment. Symptomatic management with neurostimulants, such as methylphenidate, is a possible treatment option. The use of such treatment strategies is not without precedent and has been trialled in cancer-related fatigue. Their use in sarcoidosis requires further evaluation before it can be recommended for clinical practice.Methods and analysisThe Fatigue and Sarcoidosis—Treatment with Methylphenidate study is a randomised, controlled, parallel-arm and feasibility trial of methylphenidate for the treatment of sarcoidosis-associated fatigue. Patients are eligible if they have a diagnosis of sarcoidosis, significant fatigue (measured using the Fatigue Assessment Scale) and have stable disease. Up to 30 participants will be randomly assigned to either methylphenidate (20 mg two times per day) or identical placebo in a 3:2 ratio for 24 weeks. The primary objective is to collect data determining the feasibility of a future study powered to determine the clinical efficacy of methylphenidate for sarcoidosis-associated fatigue. The trial is presently open and will continue until July 2018.Ethics and disseminationEthical approval for the study was granted by the Cambridge Central Research Ethics Committee on 21 June 2016 (reference 16/EE/0087) and was approved and sponsored by the Norfolk and Norwich University Hospital (reference 190280). Clinical Trial Authorisation (EudraCT number 2016-000342-60) from the Medicines and Healthcare products Regulatory Agency (MHRA) was granted on 19 April 2016. Results will be presented at relevant conferences and submitted to appropriate journals following trial closure and analysis.Trial registration numberNCT02643732; Pre-results.
Trivial extensions defined by 2-absorbing-like conditions
Authors: Issoual Mohammed , Mahdou Najib 
Published: December 2017

Let [Formula: see text] be a commutative ring with [Formula: see text] The notions of 2-absorbing ideal and 2-absorbing primary ideal are introduced by Ayman Badawi as generalizations of prime ideal and primary ideal, respectively. A proper ideal [Formula: see text] of [Formula: see text] is called a 2-absorbing ideal of [Formula: see text] (respectively, 2-absorbing primary ideal) if whenever [Formula: see text] with [Formula: see text] then [Formula: see text] or [Formula: see text] or [Formula: see text] (respectively, [Formula: see text] or [Formula: see text] or [Formula: see text]). In this paper, we investigate the transfer of 2-absorbing-like properties to trivial ring extensions.
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Nalbuphine ER Tablets for Uremic Pruritus
Authors: Mathur Vandana S. , Kumar Jayant , Crawford Paul W. , Hait Howard , Sciascia Thomas ,   for the TR02 Study Investigators
Published: December 2017

<b><i>Background:</i></b> Pruritus is a distressing hallmark of the uremic condition, affecting approximately 60% of hemodialysis patients. Abnormal endogenous opioid ligand activity at μ and κ-opioid receptors has been postulated as a mechanism in uremic pruritus. Nalbuphine is a μ-opioid antagonist and κ-opioid agonist. <b><i>Methods:</i></b> In this multicenter, randomized, double-blind, placebo-controlled trial, 373 hemodialysis patients with moderate or severe uremic pruritus were randomized in a 1: 1:1 ratio to nalbuphine extended-release tablets 120 mg (NAL 120), 60 mg (NAL 60), or placebo and treated for 8 weeks. Three hundred seventy-one were analyzed for efficacy. The primary endpoint was the change from baseline to treatment weeks 7 and 8 in itching intensity on a Numerical Rating Scale (NRS, 0 [no itching]; 10 [worst possible itching]) using an intent-to-treat approach. The aim was to evaluate the safety and antipruritic efficacy of NAL. <b><i>Results:</i></b> The mean duration of itching was 3.2 years. From a baseline NRS of 6.9 (1.5), the mean NRS declined by 3.5 (2.4) and by 2.8 (2.2) in NAL 120 mg and the placebo groups, respectively (<i>p</i> = 0.017). There was no evidence of tolerance. A trend for less sleep disruption due to itching (<i>p</i> = 0.062, NAL 120 vs. placebo) was also observed. There were no significant differences between NAL 60 vs. placebo. Serious adverse events occurred in 6.7, 12.7, and 15.4% in the NAL 120, NAL 60, and placebo groups respectively. <b><i>Conclusions:</i></b> In this largest-to-date randomized controlled trial in uremic pruritus, NAL 120 durably and significantly reduced the itching intensity among hemodialysis patients.
Renal Function, Time in Therapeutic Range and Outcomes in Warfarin-Treated Atrial Fibrillation Patients: A Retrospective Analysis of Nationwide Registries
Authors: Bonde Anders , Lip Gregory , Kamper Anne-Lise , Staerk Laila , Torp-Pedersen Christian , Gislason Gunnar , Olesen Jonas 
Published: December 2017

AbstractPatients with severely reduced renal function have been excluded from randomized controlled trials of oral anticoagulation in atrial fibrillation (AF). Warfarin treatment in this population is controversial and data on anticoagulation control and the impact on adverse outcomes are needed. By individual-level linkage of nationwide registries, we identified all patients discharged from hospitals with AF in Denmark between 1997 and 2011. Patients with available serum creatinine tests were categorized according to the estimated glomerular filtration rate (eGFR). Time in therapeutic range (TTR) was calculated using the Rosendaal method. The risk of stroke and bleeding was estimated using multivariable Cox regression analyses with eGFR and TTR estimated time dependently throughout follow-up. We identified 10,423 warfarin-treated AF patients with available international normalized ratio and creatinine tests; 5,527 with eGFR > 60 mL/min/1.73 m2, 4,524 with eGFR 30–60 mL/min/1.73 m2 and 372 with eGFR < 30 mL/min/1.73 m2. Median TTR was 66.7, 61.2 and 49.7% in patients with eGFR > 60, 30–59 and <30 mL/min/1.73 m2, respectively. A TTR < 70% was associated with a higher risk of stroke/thromboembolism (hazard ratio [HR]: 1.39; 95% confidence interval [CI]: 1.20–1.60) and bleeding (HR: 1.22; 95% CI: 1.05–1.42) among patients with eGFR of 30 to 59 and a trend towards higher risk of stroke/thromboembolism (HR: 1.24; 95% CI: 0.86–1.80) and bleeding (HR: 1.17; 95% CI: 0.83–1.65) among patients with eGFR < 30 mL/min/1.73 m2. In conclusion, warfarin-treated AF patients with reduced renal function have suboptimal anticoagulation control which was related to the risk of adverse outcomes.
Low-Dose Aspirin after an Episode of Haemorrhagic Stroke Is Associated with Improved Survival
Authors: González-Pérez Antonio , Gaist David , de Abajo Francisco , Sáez María , García Rodríguez Luis 
Published: December 2017

AbstractWe aimed at investigating how antiplatelet drug use affected mortality in patients with a history of haemorrhagic stroke (HS). Thus, starting 30 days after an HS episode, we followed 1,004 patients with intracerebral haemorrhage (ICH) and 929 patients with subarachnoid haemorrhage (SAH) for a median of 6.4 years. We estimated the effect of time-dependent exposure to antiplatelets after HS on all-cause mortality. Cox proportional hazard models were used to compute adjusted hazard ratios (aHRs) and 95% confidence intervals (CI).We found that current use of low-dose aspirin was associated with a 32% improved survival (aHR = 0.68; 95% CI: 0.53–0.88), with a similar association among ICH (aHR = 0.66; 95% CI: 0.49–0.89) and SAH (aHR = 0.61; 95% CI: 0.36–1.04) patients. A statistically significant improved survival associated with current use of low-dose aspirin during follow-up was only observed among individuals who used antithrombotic drugs in the year before the HS (prior use: aHR = 0.56; 95% CI: 0.39–0.80; non-prior use: aHR = 0.87; 95% CI: 0.61–1.24). Current use of clopidogrel was not associated with survival (aHR = 1.35; 95% CI: 0.88–2.08). Statin use was associated with improved survival (aHR = 0.38; 95% CI: 0.31–0.47). On the other hand, discontinuation of statins (aHR = 1.31; 95% CI: 1.02–1.68) or low-dose aspirin (aHR = 1.54; 95% CI: 1.21–1.97) was associated with decreased survival. In our study, use of low-dose aspirin after an episode of HS to reduce vascular risks is safe, particularly in patients who were on antithrombotic therapy before the episode. Our results suggest an improved survival associated with low-dose aspirin. This finding must be interpreted with care due to the observational nature of the study, and warrants further studies.
Erythrocyte Membrane Fluidity Alterations in Sudden Sensorineural Hearing Loss Patients: The Role of Oxidative Stress
Authors: Becatti Matteo , Marcucci Rossella , Mannucci Amanda , Gori Anna , Giusti Betti , Sofi Francesco , Mannini Lucia , Cellai Anna , Alessandrello Liotta Agatina , Mugnaini Marco , Emmi Giacomo , Prisco Domenico , Taddei Niccolò , Fiorillo Claudia 
Published: December 2017

Introduction Sudden sensorineural hearing loss (SSNHL) involves an acute unexplained hearing loss, nearly always unilateral, that occurs over less than a 72-hour period. SSNHL pathogenesis is not yet fully understood. Cochlear vascular occlusion has been proposed as a potential mechanism of hearing damage and cochlear ischaemia has been related to alterations of cochlear microvessels. In addition, some researchers have focused their attention on the rheological alterations and blood hyperviscosity. Erythrocyte deformability plays a key role in determining blood viscosity, and it is critical to cochlear perfusion. It has been shown that oxidative stress-induced erythrocyte membrane fluidity alterations are linked to the progression of cardiovascular diseases.
Methods To determine whether erythrocytes from SSNHL patients show signs of oxidative stress, and whether this condition can modify the haemorheologic profile in these patients, we analysed haemorheologic profile and erythrocyte oxidative stress in 35 SSNHL patients and 35 healthy subjects, matched for age and sex. Fluorescence anisotropy was used to evaluate the fluidity of erythrocyte membranes.
Results Our results show a significant structural and functional involvement of erythrocyte membrane alterations in SSNHL, as well as elevated levels of membrane lipid peroxidation and intracellular reactive oxygen species (ROS) production. In addition, erythrocyte-derived ROS and erythrocyte lipid peroxidation positively correlated with whole blood viscosity and erythrocyte deformability. Moreover, in vitro experiments demonstrated that ROS display a key role in erythrocyte membrane fluidity.
Conclusion These findings indicate that erythrocyte oxidative stress plays a key role in the pathogenesis of SSNHL and pave the way to new therapeutic interventions.
Developmental Stage–Specific Manifestations of Absent TPO/c-MPL Signalling in Newborn Mice
Authors: Lorenz Viola , Ramsey Haley , Liu Zhi-Jian , Italiano Joseph , Hoffmeister Karin , Bihorel Sihem , Mager Donald , Hu Zhongbo , Slayton William , Kile Benjamin , Sola-Visner Martha , Ferrer-Marin Francisca 
Published: December 2017

AbstractCongenital amegakaryocytic thrombocytopaenia (CAMT) is a disorder caused by c-MPL mutations that impair thrombopoietin (TPO) signalling, resulting in a near absence of megakaryocytes (MKs). While this phenotype is consistent in adults, neonates with CAMT can present with severe thrombocytopaenia despite normal MK numbers. To investigate this, we characterized MKs and platelets in newborn c-MPL
–/– mice. Liver MKs in c-MPL
–/– neonates were reduced in number and size compared with wild-type (WT) age-matched MKs, and exhibited ultrastructural abnormalities not found in adult c-MPL
–/– MKs. Platelet counts were lower in c-MPL
–/– compared with WT mice at birth and did not increase over the first 2 weeks of life. In vivo biotinylation revealed a significant reduction in the platelet half-life of c-MPL
–/– newborn mice (P2) compared with age-matched WT pups, which was not associated with ultrastructural abnormalities. Genetic deletion of the pro-apoptotic Bak did not rescue the severely reduced platelet half-life of c-MPL
–/– newborn mice, suggesting that it was due to factors other than platelets entering apoptosis early. Indeed, adult GFP+ (green fluorescent protein transgenic) platelets transfused into thrombocytopenic c-MPL
–/– P2 pups also had a shortened lifespan, indicating the importance of cell-extrinsic factors. In addition, neonatal platelets from WT and c-MPL
–/– mice exhibited reduced P-selectin surface expression following stimulation compared with adult platelets of either genotype, and platelets from c-MPL
–/– neonates exhibited reduced glycoprotein IIb/IIIa (GPIIb/IIIa) activation in response to thrombin compared with age-matched WT platelets. Taken together, our findings indicate that c-MPL deficiency is associated with abnormal maturation of neonatal MKs and developmental stage-specific defects in platelet function.
Thrombus Burden of Deep Vein Thrombosis and Its Association with Thromboprophylaxis and D-Dimer Measurement: Insights from the APEX Trial
Authors: Chi Gerald , Goldhaber Samuel , Hull Russell , Hernandez Adrian , Kerneis Mathieu , Al Khalfan Fahad , Cohen Alexander , Harrington Robert , Gibson C. 
Published: December 2017

Background The aim of this study was to evaluate the effect of betrixaban on the occurrence of deep vein thrombosis (DVT) and also the extent of thrombus and to assess the association of baseline D-dimer with subsequent thrombus burden.
Methods In the APEX trial (ClinicalTrials.gov: NCT01583218), 7,513 acutely ill hospitalized medical patients were randomly assigned to extended-duration betrixaban (35–42 days) or enoxaparin (10 ± 4 days). D-dimer concentration was measured at baseline, and mandatory lower-extremity compression ultrasonography (CUS) was performed at 35 to 42 days. The thrombus burden of DVT was assessed by the number of non-compressible vascular segments in six target proximal veins and compared between treatment groups and D-dimer categories (≥2 × upper limit of normal [ULN] versus <2 × ULN).
Results Compared with enoxaparin, extended-duration betrixaban reduced the DVT risk at 35 to 42 days (any-dose: relative risk [RR] = 0.76 [95% confidence interval: 0.61–0.94]; p = 0.013; full-dose: RR = 0.70 [0.55–0.90]; p = 0.005). Patients who received betrixaban were more likely to have a lower thrombus burden (p = 0.012 for any-dose and p = 0.001 for full-dose). Elevated D-dimer at baseline was independently associated with a 2.12-fold increased risk of developing DVT (p < 0.001). A greater thrombus burden was also observed in those with D-dimer ≥ 2 × ULN compared with <2 × ULN (p < 0.0001).
Conclusion Extended-duration betrixaban reduced the number of venous segments with thrombosis at 35 to 42 days compared with enoxaparin. A positive D-dimer was associated with a greater extent of thrombus burden among acutely ill medical patients who developed DVT despite receiving thromboprophylaxis.
Clinical Trial Registration: URL: http://www.clinicaltrials.gov. ClinicalTrials.gov identifier: NCT01583218.
The Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) Study for Patients on a Direct Oral Anticoagulant Who Need an Elective Surgery or Procedure: Design and Rationale
Authors: Douketis James , Spyropoulos Alex , Anderson Julia , Arnold Donald , Bates Shannon , Blostein Mark , Carrier Marc , Caprini Joseph , Clark Nathan , Coppens Michiel , Dentali Francesco , Duncan Joanne , Gross Peter , Kassis Jeannine , Kowalski Stephen , Lee Agnes , Le Gal Gregoire , Le Templier Geneviève , Li Na , MacKay Elizabeth , Shah Vinay , Shivakumar Sudeep , Solymoss Susan , Spencer Frederick , Syed Summer , Tafur Alfonso , Vanassche Thomas , Thiele Thomas , Wu Cynthia , Yeo Erik , Schulman Sam 
Published: December 2017

Background The perioperative management of patients who take a direct oral anticoagulant (DOAC) for atrial fibrillation and require treatment interruption for an elective surgery/procedure is a common clinical scenario for which best practices are uncertain. The Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) study is designed to address this unmet clinical need. We discuss the rationale for the PAUSE design and analysis plan as well as the rationale supporting the perioperative DOAC protocol.
Methods PAUSE is a prospective study with three parallel cohorts, one for each DOAC, to assess a standardized but patient-specific perioperative management protocol for DOAC-treated patients with atrial fibrillation. The perioperative protocol accounts for DOAC type, patient's renal function and surgery/procedure-related bleeding risk. The primary study aim is to demonstrate the safety of the PAUSE protocol for the perioperative management of each DOAC. The secondary aim is to determine the effect of the pre-procedure interruption on residual anticoagulation when measured by the dilute thrombin time for dabigatran and anti-factor Xa levels for rivaroxaban and apixaban. The study hypothesis is that the perioperative management protocol for each DOAC is safe for patient care, defined by expected risks for major bleeding of 1% (80% power to exclude 2%), and for arterial thromboembolism of 0.5% (80% power to exclude 1.5%) in each DOAC group.
Conclusion The PAUSE study has the potential to establish a standard-of-care approach for the perioperative management of DOAC-treated patients. The PAUSE management protocol is designed to be easily applied in clinical practice, as it is standardized and also patient specific.
Regional Differences in Antithrombotic Treatment for Atrial Fibrillation: Insights from the GLORIA-AF Phase II Registry
Authors: Mazurek Michał , Huisman Menno , Rothman Kenneth , Paquette Miney , Teutsch Christine , Diener Hans-Christoph , Dubner Sergio , Halperin Jonathan , Ma Chang , Zint Kristina , Elsaesser Amelie , Lu Shihai , Lip Gregory ,   on behalf of the GLORIA-AF Investigators
Published: December 2017

Introduction Although guideline-adherent antithrombotic therapy (ATT) for stroke prevention in atrial fibrillation (AF) is associated with lower mortality and thromboembolism, ATT uptake shows geographic variation worldwide. We aimed to assess thromboembolic risk and baseline ATT by geographic region and identify factors associated with prescription of ATT in a large, truly global registry of patients with recently diagnosed AF.
Methods and Results Our analysis comprises 15,092 patients newly diagnosed with non-valvular AF at risk for stroke, enrolled in Phase II of Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF). Global oral anticoagulation (OAC) use was 79.9%, being highest in Europe (90.1%), followed by Africa/Middle East (87.4%) and Latin America (85.3%), North America (78.3%) and Asia (55.2%). Among OAC users, vitamin K antagonists (VKAs) have been replaced by non-VKA OACs (NOACs) as the more prevalent OAC option in all regions, with highest use in North America (66.5%) and lowest in Asia (50.2%). In Asia, OAC was 80.4% in community hospitals but only 49.8% in university hospitals and 42.6% in specialist offices, and varied from 21.0% in China to 89.7% in Japan (NOACs at 5.8% in China and 83.3% in Japan). Globally, 76.5% of low-risk patients were prescribed ATT (46.1% OAC), whereas 17.7% high-risk patients were not anticoagulated (Europe 8.8%; North America 18.9%; Asia 42.4%).
Conclusion Substantial inter- and intra-regional differences in ATT for stroke prevention in AF are evident in this global registry. While guideline-adherent ATT can be further improved, NOACs are the main contributor to high OAC use worldwide.
Inhibition of JAK-STAT Signaling Suppresses Pathogenic Immune Responses in Medium and Large Vessel Vasculitis
Authors: Zhang Hui , Watanabe Ryu , Berry Gerald J. , Tian Lu , Goronzy Jörg J. , Weyand Cornelia M. 
Published: December 2017

Background:

Giant cell arteritis, a chronic autoimmune disease of the aorta and its large branches, is complicated by aneurysm formation, dissection, and arterial occlusions. Arterial wall dendritic cells attract CD4
+
T cells and macrophages to form prototypic granulomatous infiltrates. Vasculitic lesions contain a diverse array of effector T cells that persist despite corticosteroid therapy and sustain chronic, smoldering vasculitis. Transmural inflammation induces microvascular neoangiogenesis and results in lumen-occlusive intimal hyperplasia. We have examined whether persistent vessel wall inflammation is maintained by lesional T cells, including the newly identified tissue-resident memory T cells, and whether such T cells are sensitive to the cytokine-signaling inhibitor tofacitinib, a Janus kinase (JAK) inhibitor targeting JAK3 and JAK1.

Methods:
Vascular inflammation was induced in human arteries engrafted into immunodeficient mice that were reconstituted with T cells and monocytes from patients with giant cell arteritis. Mice carrying inflamed human arteries were treated with tofacitinib or vehicle. Vasculitic arteries were examined for gene expression (reverse transcription polymerase chain reaction), protein expression (immunohistochemistry), and infiltrating cell populations (flow cytometry).

Results:

Tofacitinib effectively suppressed innate and adaptive immunity in the vessel wall. Lesional T cells responded to tofacitinib with reduced proliferation rates (<10%) and minimal production of the effector molecules interferon-γ, interleukin-17, and interleukin-21. Tofacitinib disrupted adventitial microvascular angiogenesis, reduced outgrowth of hyperplastic intima, and minimized CD4
+
CD103
+
tissue-resident memory T cells.

Conclusions:
Cytokine signaling dependent on JAK3 and JAK1 is critically important in chronic inflammation of medium and large arteries. The JAK inhibitor tofacitinib effectively suppresses tissue-resident memory T cells and inhibits core vasculitogenic effector pathways.