bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evolving patterns in the presentation of coeliac disease over the last 25 years
Authors: Stroud Callan , Almilaji Orouba , Nicholas David , Kirkham Silvia , Surgenor Susan L , Williams Imogen , Snook Jonathon 
Published: June 2019

ObjectiveTo document changes in the clinical features of coeliac disease (CD) at presentation over the last 25 years.DesignObservational study.Patients802 subjects diagnosed between 1993 and 2017 at a single general hospital.Outcome measuresDate of diagnosis, age, sex, postcode, symptoms, haematinic deficiency, smoking status, serology, family history and autoimmune phenomena.ResultsThe incidence of diagnosed CD rose threefold during the course of the study, with a rising prevalence of positive coeliac serology and positive family history of CD, and a falling prevalence of symptoms and haematinic deficiencies. There was little change in the female predominance, age at diagnosis or high prevalence of other autoimmune conditions over the 25 years, and a paucity throughout of cigarette smokers, particularly heavy smokers. A cohort of patients with seronegative CD was identified who shared many of the characteristics of seropositive CD, but with a significantly older age at diagnosis and a higher prevalence of cigarette smokers.ConclusionThere have been major changes in the epidemiology of CD over the last 25 years, of relevance to both our understanding of the aetiopathogenesis of CD and the requirement for service provision. The implications are discussed.
Clinicopathological characteristics of ypT0N0 urothelial carcinoma following neoadjuvant chemotherapy and cystectomy
Authors: Magers Martin J , Kaimakliotis Hristos Z , Barboza Marcelo P , Bandali Elhaam , Adra Nabil , Koch Michael O , Cheng Liang 
Published: June 2019

AimsTo describe a large tertiary care academic centre’s experience with patients who achieve a complete pathological response (ie, ypT0N0) following neoadjuvant chemotherapy (NAC) and radical cystectomy (RC) with emphasis on morphological features present in the RC and clinical outcome.Methods41 patients with ypT0N0 disease following transurethral resection of bladder tumour (TURBT), NAC and RC with available clinical follow-up information were analysed. Slides from all RCs were reviewed to confirm pathological stage and assess for morphological parameters (eg, foreign body giant cell reaction, dystrophic calcification, scar and fat necrosis).ResultsWith median follow-up of 32.8 months, the recurrence-free survival at 1 and 5 years was 97.4% and 93.5%, while the overall survival at 3 and 5 years was 94.2% and 88.6%, respectively. No patients died of urothelial carcinoma. Stage assigned at TURBT was 1 pTa (2%), 1 pT1 (2%), 38 pT2 (93%) and 1 pT3a (2%). 17 TURBTs demonstrated variant histology, with the majority of these being squamous (65%). The most common morphological features present at RC were scar (100%), foreign body giant cell reaction (80%), chronic inflammation within lamina propria (68%) and dystrophic calcifications (39%). Other morphological features were less common or absent.ConclusionypT0N0 disease at RC portends an excellent prognosis, regardless of stage or variant histology in the TURBT; scar, foreign body giant cell reaction, chronic inflammation and dystrophic calcifications are often present.
Measuring plasma C4D to monitor immune complexes in lupus nephritis
Authors: Kraaij Tineke , Nilsson Sara C. , van Kooten Cees , Okrój Marcin , Blom Anna M , Teng YK Onno 
Published: June 2019

ObjectiveBecause currently available assays that measure circulating immune complexes (ICx) are suboptimal, a novel assay was recently developed measuring C4d, a stable product of activation of the classical complement pathway. The present study aimed to establish the value of measuring plasma C4d levels in a longitudinal cohort of patients with severe refractory SLE who were treated with a combination therapy of rituximab with belimumab (RTX+BLM).MethodsFifteen patients with SLE who were treated with RTX+BLM in a phase 2A, open label study were included to sequentially measure plasma C4d levels and correlated to well-established markers of ICx-formation, that is, autoantibodies against double-stranded (ds) DNA, autoantibodies against C1q and proteinuria. The performance of plasma C4d measurements, C4 measurements and the ratio of C4d over C4 (C4d:C4) was evaluated.ResultsAfter establishing that on RTX+BLM treatment kinetics of C4d levels was distinct from traditional C3 and C4 levels, we found strong correlation of C4d:C4 with anti-dsDNA (R=0.76, p<0.001) and anti-C1q (R=0.65, p<0.001) autoantibody levels, which outperformed both stand-alone C4 and C4d levels. Additionally, changes in C4d:C4 over time correlated strongly with changes in proteinuria (R=0.59, p<0.001) as well as anti-dsDNA (R=0.46, p=0.003) and anti-C1q (R=0.47, p=0.002).ConclusionIn patients with severe SLE, plasma C4d levels in relation to C4 levels is useful for longitudinal monitoring after RTX+BLM treatment to reflect amelioration of classical complement activation by ICx as well as proteinuria.
Arthropathy of Down syndrome: an under-diagnosed inflammatory joint disease that warrants a name change
Authors: Foley Charlene M , Deely Derek A , MacDermott Emma Jane , Killeen Orla G 
Published: June 2019

There is an increased incidence and prevalence of arthropathy in children with Down syndrome. However, it is rarely reported or recognised at onset, and remains under-diagnosed. Children with arthropathy of Down syndrome (A-DS) are presenting with significant joint damage and disability at diagnosis.ObjectiveTo identify undiagnosed cases of A-DS and document time to diagnosis. Also to describe clinical, laboratory and radiological features of A-DS at diagnosis.MethodologyChildren with Down syndrome (DS) (0–21 years) were invited to attend a musculoskeletal screening clinic. A second physician at a further clinic confirmed suspected cases of A-DS. Investigations and treatment were instigated as per normal clinical practice for Juvenile idiopathic arthritis (JIA). Data on a convenience sample of 21 newly diagnosed children with JIA was collected to create a comparison group.ResultsOver an 18-month period, 503 children with DS were screened for arthritis and 18 new cases diagnosed. In total, 33 children were identified with A-DS (combining cases attending pre-dating commencement of the study and those referred to our centre during the study period). This suggests prevalence of A-DS is 20/1000. A significant delay in diagnosis of A-DS was observed. The majority of children presented with polyarticular-rheumatoid factor-negative arthritis, with predominance in the small joints of the hands and wrists. Erosive changes were reported on X-ray in a significantly greater proportion (42%) of children with A-DS than JIA (14%). MRI was used to confirm diagnosis in four cases.ConclusionChildren with DS are at increased risk of arthritis. Future research to accurately define disease pathogenesis and identify a biomarker of disease would be of benefit.
Evolving IQOS packaging designs change perceptions of product appeal, uniqueness, quality and safety: a randomised experiment, 2018, USA
Authors: Lee Joseph G L , Blanchflower Tiffany M , O'Brien Kevin F , Averett Paige E , Cofie Leslie E , Gregory Kyle R 
Published: June 2019

BackgroundGlobally, the tobacco industry is promoting heated tobacco products. These products may represent a strategy to promote dual use of tobacco products. One product, IQOS from Philip Morris International, is being proposed in the USA for marketing as a less harmful product. The visual design of tobacco products can influence consumers by implying product characteristics. Thus, we sought to test the impact of IQOS packaging designs on cognitive, affective and behavioural intention responses.MethodsFrom existing IQOS packages used globally, we developed three IQOS packages that decreasingly linked the product to the Marlboro brand. In September to October 2018, we assigned participants randomly to one package in an online experiment. All participants (n=954) were US adults reporting current smoking and no colour blindness. The experiment used quota sampling to ensure diversity by gender, sexual orientation, race, ethnicity and education. Measures were informed by the Context of Consumption Framework. To assess differences in ratings, we conducted non-parametric Kruskal–Wallis tests with post hoc comparisons using Dunn’s test.ResultsWe found significant differences in cognitive indicators including appeal (H=6.87, p=0.03), uniqueness (H=15.68, p<0.01), brand equity–quality (H=122.35, p<0.01) and perceived safety compared with other tobacco products (H=14.27, p<0.01). Participants rated packages similarly on affective and behavioural intention measures. All were rated low for talking to others about the product and high for interest in trying with a coupon.ConclusionLinking or separating IQOS products with a well-established cigarette brand changes how adult smokers respond to the product. Regulators should consider the visual design of packaging.
Genomic characterization of three Vietnamese indigenous chicken varieties using mitochondrial D-loop sequences
Authors: Do Son Quang , Nguyen Lan Thi Phuong , Nguyen Thinh Hoang , Nguyen Trung Quoc 
Published: June 2019

In this study, partial mitochondrial DNA (mtDNA) D-loop sequences of three Vietnamese indigenous chicken varieties, including Mong Tien Phong, To, and Sau Ngon, were analyzed to access genetic diversity and the maternal lineages of origin. A 525 bp fragment of the mtDNA D-loop region was sequenced from a total of 61 chickens of the three varieties. A neighbor-joining phylogenetic tree was assembled from the haplotypes obtained and reference sequences of mtDNA D-loop sequences of Red Junglefowl and domestic chickens from National Center for Biotechnology Information database. Genetic diversity indices and analysis of molecular variance were performed. Evaluation of genetic relationships between the three varieties was carried out with pairwise fixation index (FST). In total, 16 haplotypes were identified in the chickens studied. These haplotypes were classified in three haplogroups (A, B, and E) with the majority grouped in haplogroup B and haplogroup E. All three chicken varieties studied were distributed into 2–3 haplogroups and all three haplogroups found in this study are also represented by Red Junglefowl. In conclusion, all three Vietnamese indigenous chicken varieties have likely originated from multiple maternal lineages and potentially descended from the Red Junglefowl.
A CMOS low-noise active mixer with enhanced linearity and isolation by exploiting capacitive neutralization technique
Authors: Guo Benqing , Wang Huifen , Chen Jun , Deilamsalehi Mohammad Mehdi 
Published: June 2019

In this paper, a broadband complementary metal–oxide–semiconductor (CMOS) active down-conversion mixer is presented. Specifically, a capacitor cross-coupled (CCC) transconductor serves as the input stage to reduce noise figure of the mixer while providing wideband input matching. Moreover, a capacitive neutralization technique is used to compensate the source-drain parasitic of input stage and boost loop gain of the transconductor, resulting in improved isolation and linearity. The current-reuse technique applied to the developed transconductor by stacked nMOS/pMOS architecture efficiently saves power consumption of the circuit. Implemented in the TSMC 28-nm CMOS process, post-simulations show that the proposed mixer provides a maximal conversion gain of 11.4 dB and an NF of 3.9–4.7 dB across RF input frequency range of 2–9.6 GHz. The average IIP3 of 5 dBm are obtained while the mixer core consumes 6.2 mW from a 1 V supply.
Section problems for configuration spaces of surfaces
Authors: Chen Lei 
Published: June 2019

In this paper, we give a close-to-sharp answer to the basic questions: When is there a continuous way to add a point to a configuration of [Formula: see text] ordered points on a surface [Formula: see text] of finite type so that all the points are still distinct? When this is possible, what are all the ways to do it? More precisely, let PConf[Formula: see text] be the space of ordered [Formula: see text]-tuple of distinct points in [Formula: see text]. Let [Formula: see text] be the map given by [Formula: see text]. We classify all continuous sections of [Formula: see text] up to homotopy by proving the following:(1) If [Formula: see text] and [Formula: see text], any section of [Formula: see text] is either “adding a point at infinity” or “adding a point near [Formula: see text]”. (We define these two terms in Sec. 2.1; whether we can define “adding a point near [Formula: see text]” or “adding a point at infinity” depends in a delicate way on properties of [Formula: see text].) (2) If [Formula: see text] a [Formula: see text]-sphere and [Formula: see text], any section of [Formula: see text] is “adding a point near [Formula: see text]”; if [Formula: see text] and [Formula: see text], the bundle [Formula: see text] does not have a section. (We define this term in Sec. 3.2). (3) If [Formula: see text] a surface of genus [Formula: see text] and for [Formula: see text], we give an easy proof of [D. L. Gonçalves and J. Guaschi, On the structure of surface pure braid groups, J. Pure Appl. Algebra 182 (2003) 33–64, Theorem 2] that the bundle [Formula: see text] does not have a section.
Organization and reorganization of drainage and sediment routing through time: the Mississippi River system
Authors: Blum Mike 
Published: June 2019

Abstract
It has been said that large rivers are the bloodlines of continents, and the Mississippi River system is the most prominent bloodline in North America. The Mississippi drainage stretches from the Rocky Mountains in the western USA to the Appalachian Cordillera in the east, and sediment from this vast area is then routed to the alluvial–deltaic plain of south Louisiana and the basin-floor fan in the deep Gulf of Mexico (GoM). Origins of the Mississippi system can be traced to the Late Cretaceous–Early Paleocene reorganization of North American drainage. However, integration of a continental-scale Mississippi drainage is a Late Neogene phenomenon, and sediment routing to the GoM has changed significantly over multiple timescales in response to a variety of large-scale natural forcing mechanisms and to human activities. This paper reviews large-scale change in drainage, sediment routing and sediment storage for the Mississippi system over timescales of 150 myr, where tectonic and geodynamic processes dominate, the last 150 kyr, where Milankovitch climate and sea-level changes dominate, and the 150 year period of the twentieth and twenty-first centuries when human activities have fundamentally altered the sediment routing and dispersal system.
The Môn–Deemster–Ribblesdale fold–thrust belt, central UK: a concealed Variscan inversion belt located on weak Caledonian crust
Authors: Pharaoh Tim , Haslam Richard , Hough Ed , Kirk Karen , Leslie Graham , Schofield Dave , Heafford Adrian 
Published: June 2019

Abstract
The Ribblesdale fold belt, representing the Variscan inversion of the Bowland Basin, is a well-known geological feature of northern England. It represents a crustal strain discontinuity between the granite-underpinned basement highs of the northern Pennines and Lake District in the north, and the Central Lancashire High/southern Pennines, in the south. Recent seismic interpretation and mapping have demonstrated that the Ribblesdale fold belt continues offshore towards Anglesey via the Deemster Platform, beneath the Permo-Triassic sedimentary cover of the southern part of the East Irish Sea Basin. The Môn–Deemster fold–thrust belt (FTB) affects strata of Mississippian to late Pennsylvanian age. Variscan thrusts extend down into the pre-Carboniferous basement but apparently terminate at a low-angle detachment deeper in the crust, here correlated with the strongly sheared Penmynydd Zone exposed in the adjacent onshore. Up to 15% shortening is observed on seismic sections across the FTB offshore, but is greater in the strongly inverted onshore segment. Pre-Carboniferous thrusting post-dates formation of the Penmynydd Zone, and is probably of Acadian age, when basement structures such as the southward-vergent Carmel Head Thrust formed. Extensional reactivation of the Acadian structures in early Mississippian time defined the northern edge of the offshore Bowland Basin. The relatively late brittle structures of the Menai Strait fault system locally exhume the Penmynydd Zone and define the southern edge of the basin. The longer seismic records from the offshore provide insights to the tectonic evolution of the more poorly imaged FTB onshore.
A Model System for Studying the DNMT3A Hotspot Mutation (DNMT3AR882) Demonstrates a Causal Relationship between Its Dominant-Negative Effect and Leukemogenesis
Authors: Lu Rui , Wang Jun , Ren Zhihong , Yin Jiekai , Wang Yinsheng , Cai Ling , Wang Gang Greg 
Published: June 2019

Abstract

Mutation of DNA methyltransferase 3A at arginine 882 (DNMT3AR882mut) is prevalent in hematologic cancers and disorders. Recently, DNMT3AR882mut has been shown to have hypomorphic, dominant-negative, and/or gain-of-function effects on DNA methylation under different biological contexts. However, the causal role for such a multifaceted effect of DNMT3AR882mut in leukemogenesis remains undetermined. Here, we report TF-1 leukemia cells as a robust system useful for modeling the DNMT3AR882mut-dependent transformation and for dissecting the cause–effect relationship between multifaceted activities of DNMT3AR882mut and leukemic transformation. Ectopic expression of DNMT3AR882mut and not wild-type DNMT3A promoted TF-1 cell transformation characterized by cytokine-independent growth, and induces CpG hypomethylation predominantly at enhancers. This effect was dose dependent, acted synergistically with the isocitrate dehydrogenase 1 (IDH1) mutation, and resembled what was seen in human leukemia patients carrying DNMT3AR882mut. The transformation- and hypomethylation-inducing capacities of DNMT3AR882mut relied on a motif involved in heterodimerization, whereas its various chromatin-binding domains were dispensable. Mutation of the heterodimerization motif that interferes with DNMT3AR882mut binding to endogenous wild-type DNMT proteins partially reversed the CpG hypomethylation phenotype caused by DNMT3AR882mut, thus supporting a dominant-negative mechanism in cells. In mice, bromodomain inhibition repressed gene-activation events downstream of DNMT3AR882mut-induced CpG hypomethylation, thereby suppressing leukemogenesis mediated by DNMT3AR882mut. Collectively, this study reports a model system useful for studying DNMT3AR882mut, shows a requirement of the dominant-negative effect by DNMT3AR882mut for leukemogenesis, and describes an attractive strategy for the treatment of leukemias carrying DNMT3AR882mut.

Significance:
These findings highlight a model system to study the functional impact of a hotspot mutation of DNMT3A at R882 in leukemia.
Plasma Metabolomic Signatures Associated with Long-term Breast Cancer Risk in the SU.VI.MAX Prospective Cohort
Authors: Lécuyer Lucie , Dalle Céline , Lyan Bernard , Demidem Aicha , Rossary Adrien , Vasson Marie-Paule , Petera Mélanie , Lagree Marie , Ferreira Thomas , Centeno Delphine , Galan Pilar , Hercberg Serge , Deschasaux Mélanie , Partula Valentin , Srour Bernard , Latino-Martel Paule , Kesse-Guyot Emmanuelle , Druesne-Pecollo Nathalie , Durand Stéphanie , Pujos-Guillot Estelle , Touvier Mathilde 
Published: June 2019

AbstractBackground:Breast cancer is a major cause of death in occidental women. The role of metabolism in breast cancer etiology remains unclear. Metabolomics may help to elucidate novel biological pathways and identify new biomarkers to predict breast cancer long before symptoms appear. The aim of this study was to investigate whether untargeted metabolomic signatures from blood draws of healthy women could contribute to better understand and predict the long-term risk of developing breast cancer.Methods:A nested case–control study was conducted within the SU.VI.MAX prospective cohort (13 years of follow-up) to analyze baseline plasma samples of 211 incident breast cancer cases and 211 matched controls by LC/MS. Multivariable conditional logistic regression models were computed.Results:A total of 3,565 ions were detected and 1,221 were retained for statistical analysis. A total of 73 ions were associated with breast cancer risk (P &lt; 0.01; FDR ≤ 0.2). Notably, we observed that a lower plasma level of O-succinyl-homoserine (OR = 0.70, 95%CI = [0.55-0.89]) and higher plasma levels of valine/norvaline [1.45 (1.15–1.83)], glutamine/isoglutamine [1.33 (1.07–1.66)], 5-aminovaleric acid [1.46 (1.14–1.87)], phenylalanine [1.43 (1.14–1.78)], tryptophan [1.40 (1.10–1.79)], γ-glutamyl-threonine [1.39 (1.09–1.77)], ATBC [1.41 (1.10–1.79)], and pregnene-triol sulfate [1.38 (1.08–1.77)] were associated with an increased risk of developing breast cancer during follow-up.Conclusion: Several prediagnostic plasmatic metabolites were associated with long-term breast cancer risk and suggested a role of microbiota metabolism and environmental exposure.Impact:After confirmation in other independent cohort studies, these results could help to identify healthy women at higher risk of developing breast cancer in the subsequent decade and to propose a better understanding of the complex mechanisms involved in its etiology.
Clinical Efficacy and Safety of Nivolumab: Results of a

M

ulticenter, Op

e

n-label, Single-a

r

m, Japanese Phase II study in Mal

i

gnant Pleural Meso

t

helioma (MERIT)
Authors: Okada Morihito , Kijima Takashi , Aoe Keisuke , Kato Terufumi , Fujimoto Nobukazu , Nakagawa Kazuhiko , Takeda Yuichiro , Hida Toyoaki , Kanai Kuninobu , Imamura Fumio , Oizumi Satoshi , Takahashi Toshiaki , Takenoyama Mitsuhiro , Tanaka Hiroshi , Hirano Jun , Namba Yoshinobu , Ohe Yuichiro 
Published: June 2019

Abstract

Purpose:
Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy with poor prognosis. Patients with MPM who do not respond to standard first-line chemotherapy have limited treatment options. We evaluated the efficacy and safety of nivolumab, an immune checkpoint inhibitor, for the treatment of advanced or metastatic MPM.

Patients and Methods:
Japanese patients with unresectable, advanced, or metastatic MPM resistant or intolerant to ≤2 regimens of chemotherapy and ≥1 measurable lesion(s) were enrolled. Patients received nivolumab 240 mg intravenously every 2 weeks until progressive disease or unacceptable toxicity. The primary endpoint was objective response rate by central assessment according to the Modified Response Evaluation Criteria in Solid Tumors. Adverse events (AEs) and treatment-related AEs (TRAEs) were evaluated.

Results:
Thirty-four patients were enrolled between July 2016 and October 2016. Median follow-up was 16.8 (range: 1.8–20.2) months. Ten (29%, 95% confidence interval, 16.8–46.2) patients showed a centrally assessed objective response. The objective response rates were 26% (7/27), 67% (2/3), and 25% (1/4) patients for epithelioid, sarcomatoid, and biphasic histologic subtypes, respectively. Median duration of response was 11.1 months with a 68% disease control rate. Median overall survival and progression-free survival were 17.3 and 6.1 months, respectively. The objective response rate was 40% with programmed death-ligand 1 expression ≥1% and 8% with &lt;1%. Thirty-two patients (94%) experienced AEs and 26 (76%) experienced TRAEs.

Conclusions:
Nivolumab met the primary endpoint as second- or third-line treatment for patients with MPM and showed promising efficacy with manageable toxicity.
See related commentary by Mansfield and Zauderer, p. 5438