bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis of Infections and All‐Cause Mortality in Phase II, Phase III, and Long‐Term Extension Studies of Tofacitinib in Patients With Rheumatoid Arthritis
Authors: Cohen Stanley , Radominski Sebastião C. , Gomez‐Reino Juan J. , Wang Lisy , Krishnaswami Sriram , Wood Susan P. , Soma Koshika , Nduaka Chudi I. , Kwok Kenneth , Valdez Hernan , Benda Birgitta , Riese Richard 
Published: July 2014

ObjectiveTo determine the rate of infection and all‐cause mortality across tofacitinib phase II, phase III, and long‐term extension (LTE) studies in patients with moderately to severely active rheumatoid arthritis (RA).MethodsPooled data from studies of tofacitinib in patients with RA were analyzed. In these studies, tofacitinib was administered as monotherapy or in combination with methotrexate or other nonbiologic disease‐modifying antirheumatic drugs. The cutoff date for inclusion of data was April 19, 2012.ResultsAcross phase II, phase III, and LTE studies, 4,789 patients received tofacitinib (8,460 patient‐years of exposure). The overall rate of serious infection was 3.09 events per 100 patient‐years (95% confidence interval [95% CI] 2.73–3.49), and rates were stable over time. A Cox proportional hazards model showed that age, corticosteroid dose, diabetes, and tofacitinib dose were independently linked to the risk of serious infection. Lymphocyte counts of <0.5 × 103/mm3 were rare but were associated with an increased risk of treated and/or serious infection. Overall, all‐cause mortality rates were 0.30 events per 100 patient‐years (95% CI 0.20–0.44).ConclusionThe overall risk of infection (including serious infection) and mortality rates in RA patients treated with tofacitinib appear to be similar to those observed in RA patients treated with biologic agents. The rates of serious infection were stable over time.
Prevention of Murine Lupus Nephritis by Targeting Multiple Signaling Axes and Oxidative Stress Using a Synthetic Triterpenoid
Authors: Wu Tianfu , Ye Yujin , Min So‐Youn , Zhu Jiankun , Khobahy Elhaum , Zhou Jason , Yan Mei , Hemachandran Sriram , Pathak Simanta , Zhou Xin J. , Andreeff Michael , Mohan Chandra 
Published: July 2014

ObjectiveCurrent treatment options for lupus are far from optimal. Previously, we reported that phosphatidylinositol 3‐kinase/Akt/mammalian target of rapamycin, MEK‐1/ERK‐1,2, p38, STAT‐3, STAT‐5, NF‐κB, multiple Bcl‐2 family members, and various cell cycle molecules were overexpressed in splenic B cells in an age‐dependent and gene dose–dependent manner in mouse strains with spontaneous lupus. Since the synthetic triterpenoid methyl‐2‐cyano‐3,12‐dioxooleana‐1,9‐dien‐28‐oate (CDDO‐Me) has been shown to inhibit AKT, MEK‐1/2, and NF‐κB, and to induce caspase‐mediated apoptosis, we tested the therapeutic potential of this agent in murine lupus nephritis.MethodsThe synthetic triterpenoid CDDO‐Me or placebo was administered to 2‐month‐old B6.Sle1.Sle3 mice or MRL/lpr mice, which develop spontaneous lupus. All mice were phenotyped for disease.ResultsCDDO‐Me–treated mice exhibited significantly reduced splenic cellularity, with decreased numbers of both CD4+ T cells and activated CD69+/CD4+ T cells compared to the placebo‐treated mice. These mice also exhibited a significant reduction in serum autoantibody levels, including anti–double‐stranded DNA (anti‐dsDNA) and antiglomerular antibodies. Finally, CDDO‐Me treatment attenuated renal disease in mice, as indicated by reduced 24‐hour proteinuria, blood urea nitrogen, and glomerulonephritis. At the mechanistic level, CDDO‐Me treatment dampened MEK‐1/2, ERK, and STAT‐3 signaling within lymphocytes and oxidative stress. Importantly, the NF‐E2–related factor 2 pathway was activated after CDDO‐Me treatment, indicating that CDDO‐Me may modulate renal damage in lupus via the inhibition of oxidative stress.ConclusionThese findings underscore the importance of AKT/MEK‐1/2/NF‐κB signaling in engendering murine lupus. Our findings indicate that the blockade of multiple signaling nodes and oxidative stress may effectively prevent and reverse the hematologic, autoimmune, and pathologic manifestations of lupus.
Oral Bisphosphonate Use and Total Knee/Hip Implant Survival: Validation of Results in an External Population‐Based Cohort
Authors: Prieto‐Alhambra Daniel , Lalmohamed Arief , Abrahamsen Bo , Arden Nigel K. , de Boer Anthonius , Vestergaard Peter , de Vries Frank 
Published: July 2014

ObjectiveAseptic loosening is the most common cause of revision arthroplasty. Bisphosphonates could minimize this through their antiresorptive effects. This study was undertaken to investigate the association between bisphosphonate use and implant survival.MethodsA retrospective cohort study was conducted within the Danish nationwide registries (5.5 million residents). Using procedure codes of the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, we identified patients age ≥40 years undergoing total joint replacement in 1998–2007. We excluded users of disease‐modifying antirheumatic drugs as well as patients with rheumatoid arthritis, Paget's disease, or hip fracture. Participants were classified as bisphosphonate users if they had been receiving treatment for ≥6 months. A time‐varying exposure was used to avoid immortal time bias. Up to 6 bisphosphonate nonusers undergoing arthroplasty were matched to each bisphosphonate user, using propensity scores. Stratified Cox regression was performed to model implant survival according to bisphosphonate use. Further, we studied the associations of implant survival with duration of use, adherence (medication possession ratio), and timing of therapy initiation (preoperative/postoperative).ResultsOf 95,392 patients with a primary total joint replacement, 80,342 (84.2%) were eligible. We identified 1,590 bisphosphonate users (2.0%), and 1,558 of them (98.0%) were matched to 8,966 bisphosphonate nonusers. Twenty‐seven of the 1,558 bisphosphonate users (1.73%) and 399 of the 8,966 matched nonusers (4.45%) underwent revision surgery during the study followup period (at a median 2.61 years after the first surgery [interquartile range 1.04–5.41 years]). Cox regression showed a reduced risk of revision surgery in bisphosphonate users (hazard ratio 0.41 [95% confidence interval 0.27–0.61]). This association was strongest in patients with the longest duration of treatment and/or the best adherence.ConclusionOral bisphosphonate users have a 59% reduced risk of revision surgery. This association is only present when bisphosphonates are started after arthroplasty surgery. Confirmation in randomized controlled trials is urgently needed.
Fat Metaplasia and Backfill Are Key Intermediaries in the Development of Sacroiliac Joint Ankylosis in Patients With Ankylosing Spondylitis
Authors: Maksymowych Walter P. , Wichuk Stephanie , Chiowchanwisawakit Praveena , Lambert Robert G. , Pedersen Susanne J. 
Published: July 2014

ObjectiveFat metaplasia in bone marrow on T1‐weighted magnetic resonance imaging (MRI) scans may develop after resolution of inflammation in patients with ankylosing spondylitis (AS) and may predict new bone formation in the spine. Similar tissue, termed backfill, may also fill areas of excavated bone in the sacroiliac (SI) joints and may reflect resolution of inflammation and tissue repair at sites of erosions. The purpose of this study was to test our hypothesis that SI joint ankylosis develops following repair of erosions and that tissue characterized by fat metaplasia is a key intermediary step in this pathway.MethodsWe used the Spondyloarthritis Research Consortium of Canada (SPARCC) SI structural lesion score (SSS) method to assess fat metaplasia, erosions, backfill, and ankylosis on MRIs of the SI joints in 147 patients with AS monitored for 2 years. Univariate and multivariate regression analyses focused first on identifying significant MRI predictors of new backfill and fat metaplasia. We then assessed the role of backfill and fat metaplasia in the development of new ankylosis. All analyses were adjusted for demographic features, treatment, and baseline and 2‐year change in SSS values for parameters of inflammation and MRI structural lesions.ResultsResolution of inflammation and reduction of erosions were each independently associated with the development of new backfill and fat metaplasia at 2 years on multivariate analyses. Multivariate regression analysis that included demographic features, baseline and 2‐year change in parameters of inflammation and MRI structural lesion showed that reduction in erosions (P = 0.0005) and increase in fat metaplasia (P = 0.002) at 2 years was each independently associated with the development of new ankylosis.ConclusionOur data support a disease model whereby ankylosis develops following repair of erosions, and fat metaplasia and backfill are key intermediary steps in this pathway.
Whole‐Exome Sequencing Reveals Overlap Between Macrophage Activation Syndrome in Systemic Juvenile Idiopathic Arthritis and Familial Hemophagocytic Lymphohistiocytosis
Authors: Kaufman Kenneth M. , Linghu Bolan , Szustakowski Joseph D. , Husami Ammar , Yang Fan , Zhang Kejian , Filipovich Alexandra H. , Fall Ndate , Harley John B. , Nirmala N. R. , Grom Alexei A. 
Published: July 2014

ObjectiveMacrophage activation syndrome (MAS), a life‐threatening complication of systemic juvenile idiopathic arthritis (JIA), resembles familial hemophagocytic lymphohistiocytosis (HLH), a constellation of autosomal‐recessive immune disorders resulting from deficiency in cytolytic pathway proteins. We undertook this study to test our hypothesis that MAS predisposition in systemic JIA could be attributed to rare gene sequence variants affecting the cytotolytic pathway.MethodsWhole‐exome sequencing was used in 14 patients with systemic JIA and MAS and in their parents to identify protein‐altering single‐nucleotide polymorphisms/indels in known HLH‐associated genes. To discover new candidate genes, the entire whole‐exome sequencing data were filtered to identify protein‐altering, rare recessive homozygous, compound heterozygous, and de novo variants with the potential to affect the cytolytic pathway.ResultsHeterozygous protein‐altering rare variants in the known genes (LYST,MUNC13‐4, and STXBP2) were found in 5 of 14 patients with systemic JIA and MAS (35.7%). This was in contrast to only 4 variants in 4 of 29 patients with systemic JIA without MAS (13.8%). Homozygosity and compound heterozygosity analysis applied to the entire whole‐exome sequencing data in systemic JIA/MAS revealed 3 recessive pairs in 3 genes and compound heterozygotes in 73 genes. We also identified 20 heterozygous rare protein‐altering variants that occurred in at least 2 patients. Many of the identified genes encoded proteins with a role in actin and microtubule reorganization and vesicle‐mediated transport. “Cellular assembly and organization” was the top cellular function category based on Ingenuity Pathways Analysis (P < 3.10 × 10−5).ConclusionWhole‐exome sequencing performed in patients with systemic JIA and MAS identified rare protein‐altering variants in known HLH‐associated genes as well as in new candidate genes.
Aqueous two‐phase system‐mediated antibody micropatterning enables multiplexed immunostaining of cell monolayers and tissues
Authors: Frampton John P. , Tsuei Michael , White Joshua B. , Abraham Abin T. , Takayama Shuichi 
Published: July 2014

AbstractConventional immunostaining methods consume large quantities of expensive antibodies and are limited in terms of the number of antigens that can be detected from a single sample. In order to achieve multiplexed immunostaining, we micropatterned antibodies using aqueous two‐phase systems (ATPS) formed from polyethylene glycol (PEG) and dextran. Multiple antigens can be detected on a single fixed sample by incorporating antibodies within dextran solutions, which are then patterned by micropipetting at specific sites on the sample in a solution of PEG. The antibodies are retained within the dextran phase due to biomolecular partitioning, allowing multiple protein markers to be visualized simultaneously by way of chromogenic, chemiluminescent, or immunofluorescent detection. This aqueous two‐phase system‐mediated antibody micropatterning approach allows antibody dilutions to be easily optimized, reduces the consumption of expensive primary antibodies and can prevent antibody cross‐reactions, since the antibodies are retained at separate sites within the dextran microdroplets.
Contribution of cationic amino acids toward the inhibition of Arg‐specific cysteine proteinase (Arg‐gingipain) by the antimicrobial dodecapeptide, CL(14–25), from rice protein
Authors: Taniguchi Masayuki , Matsuhashi Yoshiyasu , Abe Takako K. , Ishiyama Yohei , Saitoh Eiichi , Kato Tetsuo , Ochiai Akihito , Tanaka Takaaki 
Published: July 2014

ABSTRACTCL(14–25), a dodecapeptide, exhibits antimicrobial activity against Porphyromonas gingivalis with the 50% growth‐inhibitory concentration (IC50) value of 145 µM, and arginine‐specific gingipain (Rgp)‐inhibitory activity. Kinetic analysis revealed that CL(14–25) is a mixed‐type inhibitor, with inhibition constants (Ki and Ki′ values) of 1.4 × 10−6 M and 4.3 × 10−6 M, respectively. To elucidate the contributions of four cationic amino acid residues at the N‐ and C‐termini of CL(14–25) toward Rgp‐inhibitory activity, we investigated the Rgp‐inhibitory activities of truncated and alanine‐substituted analogs of CL(14–25). Rgp‐inhibitory activities significantly decreased by truncated analogs, CL(15–25) and CL(16–25), whereas those of CL(14–24) and CL(14–23) were almost as high as that of CL(14–25). Rgp‐inhibitory activities of alanine‐substituted analogs, CL(R14A) and CL(R14A, R15A) also significantly decreased, whereas those of CL(K25A) and CL(R24A, K25A) were higher than that of CL(14–25). These results suggest that the arginine residue at position 15 substantially contributes to the Rgp‐inhibitory activity and that the arginine residue at position 14 plays important roles in exerting Rgp‐inhibitory activity. In this study, we demonstrated that CL(K25A) was a potent, dual function, peptide inhibitor candidate, exhibiting Rgp‐inhibitory activity with Ki and Ki′ of 9.6 × 10−7 M and 1.9 × 10−6 M, respectively, and antimicrobial activity against P. gingivalis with an IC50 value of 51 µM. © 2014 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 102: 379–389, 2014.
Optical crossbars on chip, a comparative study based on worst‐case losses
Authors: Le Beux Sébastien , Li Hui , Nicolescu Gabriela , Trajkovic Jelena , O'Connor Ian 
Published: July 2014

SUMMARYThe many‐core design research community has shown high interest in optical crossbar on chip for more than a decade. Key properties of optical crossbars, namely (1) contention‐free data routing, (2) low latency communication, and (3) potential for high bandwidth through the use of wavelength division multiplexing, motivate several implementations of this type of interconnect. These implementations demonstrate very different scalability and power efficiency abilities depending on three key design factors: (1) network topology, (2) considered layout, and (3) insertion losses induced by the fabrication process. In this paper, the worst‐case optical losses of crossbar implementations are compared according to the factors mentioned earlier. The comparison results have the potential to help many‐core system designer to select the most appropriate crossbar implementation according to, for instance, the number of IP cores and the die size. Copyright © 2014 John Wiley & Sons, Ltd.
Developmental antecedents of abnormal eating attitudes and behaviors in adolescence
Authors: Le Grange Daniel , O'Connor Meredith , Hughes Elizabeth K. , Macdonald Jacqui , Little Keriann , Olsson Craig A. 
Published: July 2014

ABSTRACTObjectiveThis study capitalizes on developmental data from an Australian population‐based birth cohort to identify developmental markers of abnormal eating attitudes and behaviors in adolescence. The aims were twofold: (1) to develop a comprehensive path model identifying infant and childhood developmental correlates of Abnormal Eating Attitudes and Behaviors in adolescence, and (2) to explore potential gender differences.MethodData were drawn from a 30‐year longitudinal study that has followed the health and development of a population based cohort across 15 waves of data collection from infancy since 1983: The Australian Temperament Project. Participants in this analysis were the 1,300 youth who completed the 11th survey at 15–16 years (1998) and who completed the eating disorder inventory at this time point.ResultsDevelopmental correlates of Abnormal Eating Attitudes and Behaviors in mid‐adolescence were temperamental persistence, early gestational age, persistent high weight, teen depression, stronger peer relationships, maternal dieting behavior, and pubertal timing. Overall, these factors accounted for 28% of the variance in Abnormal Eating Attitudes and Behaviors at 15–16 years of age. Depressive symptoms, maternal dieting behavior, and early puberty were more important factors for girls. Late puberty was a more important factor for boys.DiscussionFindings address an important gap in our understanding of the etiology of Abnormal Eating Attitudes and Behaviors in adolescence and suggest multiple targets for preventive intervention. © 2014 Wiley Periodicals, Inc. (Int J Eat Disord 2014; 47:813–824)
Association between cardiovascular vs. non‐cardiovascular co‐morbidities and outcomes in heart failure with preserved ejection fraction
Authors: Lund Lars H. , Donal Erwan , Oger Emmanuel , Hage Camilla , Persson Hans , Haugen‐Löfman Ida , Ennezat Pierre‐Vladimir , Sportouch‐Dukhan Catherine , Drouet Elodie , Daubert Jean‐Claude , Linde Cecilia ,   on behalf of the KaRen Investigators
Published: July 2014

AimsThe prevalence of cardiovascular and non‐cardiovascular co‐morbidities and their relative importance for outcomes in heart failure with preserved ejection fraction (HFPEF) remain poorly characterized. This study aimed to investigate this.Methods and resultsThe Karolinska–Rennes (KaRen) Study was a multinational prospective observational study designed to characterize HFPEF. Inclusion required acute HF, defined by the Framingham criteria, LVEF ≥45%, and NT‐pro‐BNP ≥300 ng/L or BNP ≥100 ng/L. Detailed clinical data were collected at baseline and patients were followed prospectively for 18 months. Predictors of the primary (HF hospitalization or all‐cause mortality) and secondary (all‐cause mortality) outcomes were assessed with multivariable Cox regression. A total of 539 patients [56% women; median (interquartile range) age 79 (72–84) years; NT‐pro‐BNP/BNP 2448 (1290–4790)/429 (229–805) ng/L] were included. Known history of HF was present in 40%. Co‐morbidities included hypertension (78%), atrial fibrillation/flutter (65%), anaemia (51%), renal dysfunction (46%), CAD (33%), diabetes (30%), lung disease (25%), and cancer (16%). The primary outcome occurred in 268 patients [50%; 106 deaths (20%) and 162 HF hospitalizations (30%)]. Important independent predictors of the primary and/or secondary outcomes were age, history of non‐cardiovascular syncope, valve disease, anaemia, lower sodium, and higher potassium, but no cardiovascular co‐morbidities. Renin–angiotensin system antagonist and mineralocorticoid receptor antagonist use predicted improved prognosis.ConclusionHFPEF was associated with higher age, female gender, hypertension, atrial fibrillation/flutter, and numerous non‐cardiovascular co‐morbidities. Prognosis was determined by non‐cardiovascular co‐morbidities, but use of conventional heart failure medications may still be associated with improved outcomes.
Kinetics and Mechanism of the Reaction of Hydrogen Sulfide with Diaquacobinamide in Aqueous Solution
Authors: Salnikov Denis S. , Makarov Sergei V. , van Eldik Rudi , Kucherenko Polina N. , Boss Gerry R. 
Published: July 2014

AbstractWe conducted a detailed kinetic study of the reaction of the vitamin B12 analog diaquacobinamide [(H2O)2Cbi(III)] with hydrogen sulfide in water from pH 3 to 11. The reaction proceeds in three steps: (1) the formation of three different complexes between cobinamide and hydrogen sulfide, viz., (HO–)(HS–)Cbi(III), (H2O)(HS–)Cbi(III), and (HS–)2Cbi(III); (2) inner‐sphere electron transfer (ISET) in the two complexes with one coordinated HS– ligand to form the reduced cobinamide complex [(H)S]Cbi(II); and (3) the addition of a second molecule of hydrogen sulfide to the reduced cobinamide. ISET does not proceed in the (HS–)2Cbi(III) complex. The final products of the reaction between cobinamide and hydrogen sulfide were found to be independent of pH, and the main product is a complex of cobinamide(II) with the anion radical SSH2–.
Numerical simulation of transpiration cooling through porous material
Authors: Dahmen W. , Gotzen T. , Müller S. , Rom M. 
Published: July 2014

SUMMARYTranspiration cooling using ceramic matrix composite materials is an innovative concept for cooling rocket thrust chambers. The coolant (air) is driven through the porous material by a pressure difference between the coolant reservoir and the turbulent hot gas flow. The effectiveness of such cooling strategies relies on a proper choice of the involved process parameters such as injection pressure, blowing ratios, and material structure parameters, to name only a few. In view of the limited experimental access to the subtle processes occurring at the interface between hot gas flow and porous medium, reliable and accurate simulations become an increasingly important design tool. In order to facilitate such numerical simulations for a carbon/carbon material mounted in the side wall of a hot gas channel that are able to capture a spatially varying interplay between the hot gas flow and the coolant at the interface, we formulate a model for the porous medium flow of Darcy–Forchheimer type. A finite‐element solver for the corresponding porous medium flow is presented and coupled with a finite‐volume solver for the compressible Reynolds‐averaged Navier–Stokes equations. The two‐dimensional and three‐dimensional results at Mach numberMa= 0.5 and hot gas temperatureTHG=540 K for different blowing ratios are compared with experimental data. Copyright © 2014 John Wiley & Sons, Ltd.
Blackmail is against the Law
Authors: McCallum Peter , Lang Moshe 
Published: July 2014

An annotated transcript of a first interview with a family where mother and daugher have attempted suicide.A 14 year old girl took an overdose of her mother's tablets. Her mother was already seeing a psychiatrist, having herself taken an overdose months earlier. The psychiatrist referred the family because he decided that a family approach was needed.What follows is an annotated verbatim transcript of the first meeting of the family with Moshe Lang, interposed with comments. A conclusion and invited commentaries are included.