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Objective: Previously, only the HLA–DRB1 alleles have been assessed in rheumatoid arthritis (RA). The aim of the present study was to identify the key major histocompatibility complex (MHC) susceptibility factors showing a significant association with anti–carbamylated protein antibody–positive (anti‐CarP+) RA. Methods: Analyses were restricted to RA patients who were anti–cyclic citrullinated peptide antibody negative (anti‐CCP−), because the anti‐CCP status dominated the results otherwise. Therefore, we studied samples from 1,821 anti‐CCP− RA patients and 6,821 population controls from Spain, Sweden, and the Netherlands. The genotypes for ~8,000 MHC biallelic variants were assessed by dense genotyping and imputation. Their association with the anti‐CarP status in RA patients was tested with logistic regression and combined with inverse‐variance meta‐analysis. Significance of the associations was assessed according to a study‐specific threshold of P < 2.0 × 10−5. Results: The HLA–B*08 allele and its correlated amino acid variant Asp‐9 showed a significant association with anti‐CarP+/anti‐CCP− RA (P < 3.78 × 10−7; I2 = 0). This association was specific when assessed relative to 3 comparator groups: population controls, anti‐CarP−/anti‐CCP− RA patients, and anti‐CCP− RA patients who were positive for other anti–citrullinated protein antibodies. Based on these findings, anti‐CarP+/anti‐CCP− RA patients could be separated from other antibody‐defined subsets of RA patients in whom an association with the HLA–B*08 allele has been previously demonstrated. No other MHC variant remained associated with anti‐CarP+/anti‐CCP− RA after accounting for the presence of the HLA–B*08 allele. Specifically, the reported association of HLA–DRB1*03 was observed at a level comparable to that reported previously, but it was attributable to linkage disequilibrium. Conclusion: These results identify HLA–B*08 carrying Asp‐9 as the MHC locus showing the strongest association with anti‐CarP+/anti‐CCP− RA. This knowledge may help clarify the role of the HLA in susceptibility to specific subsets of RA, by shaping the spectrum of RA autoantibodies. [ABSTRACT FROM AUTHOR]

The initial management of rheumatoid arthritis (RA) has a high impact on disease prognosis. Therefore, we need to select the most appropriate treatment as soon as possible. This goal requires biomarkers of disease severity and prognosis. One such biomarker may be the presence of anti-carbamylated protein antibodies (ACarPA) because it is associated with adverse long term outcomes as radiographic damage and mortality. Here, we have assessed the ACarPA as short-term prognostic biomarkers. The study was conducted in 978 prospective early arthritis (EA) patients that were followed for two years. Our results show the association of ACarPA with increased levels of all the disease activity measures in the first visit after arthritis onset. However, the associations were more significant with the high levels in local measures of inflammation and physician assessment than with the increases in systemic inflammation and patient-reported outcomes. More notably, disease activity was persistently increased in the ACarPA positive patients during the two years of follow-up. These differences were significant even after accounting for the presence of other RA autoantibodies. Therefore, the ACarPA could be considered short-term prognostic biomarkers of increased disease activity in the EA patients. [ABSTRACT FROM AUTHOR]

The major environmental risk factor for rheumatoid arthritis (RA) is smoking, which according to a widely accepted model induces protein citrullination in the lungs, triggering the production of anti-citrullinated protein antibodies (ACPA) and RA development. Nevertheless, some research findings do not fit this model. Therefore, we obtained six independent cohorts with 2253 RA patients for a detailed analysis of the association between smoking and RA autoantibodies. Our results showed a predominant association of smoking with the concurrent presence of the three antibodies: rheumatoid factor (RF), ACPA and anti-carbamylated protein antibodies (ACarPA) (3 Ab vs. 0 Ab: OR = 1.99, p = 2.5 × 10–8). Meta-analysis with previous data (4491 patients) confirmed the predominant association with the concurrent presence of the three antibodies (3 Ab vs. 0 Ab: OR = 2.00, p = 4.4 ×10–16) and revealed that smoking was exclusively associated with the presence of RF in patients with one or two antibodies (RF+1+2vs. RF−0+1+2: OR = 1.32, p = 0.0002). In contrast, no specific association with ACPA or ACarPA was found. Therefore, these results showed the need to understand how smoking favors the concordance of RA specific antibodies and RF triggering, perhaps involving smoking-induced epitope spreading and other hypothesized mechanisms. [ABSTRACT FROM AUTHOR]

Systems chemistry aims to mimic the functional behavior of living systems by constructing chemical reaction networks with well‐defined dynamic properties. Enzymes can play a key role in such networks, but there is currently no general and scalable route to the design and construction of enzymatic reaction networks. Here, we introduce reversible, cleavable peptide inhibitors that can link proteolytic enzymatic activity into simple network motifs. As a proof‐of‐principle, we show auto‐activation topologies producing sigmoidal responses in enzymatic activity, explore cross‐talk in minimal systems, design a simple enzymatic cascade, and introduce non‐inhibiting phosphorylated peptides that can be activated using a phosphatase. [ABSTRACT FROM AUTHOR]

Systems chemistry aims to mimic the functional behavior of living systems by constructing chemical reaction networks with well‐defined dynamic properties. Enzymes can play a key role in such networks, but there is currently no general and scalable route to the design and construction of enzymatic reaction networks. Here, we introduce reversible, cleavable peptide inhibitors that can link proteolytic enzymatic activity into simple network motifs. As a proof‐of‐principle, we show auto‐activation topologies producing sigmoidal responses in enzymatic activity, explore cross‐talk in minimal systems, design a simple enzymatic cascade, and introduce non‐inhibiting phosphorylated peptides that can be activated using a phosphatase. [ABSTRACT FROM AUTHOR]

Objective: Recognition of a new type of rheumatoid arthritis (RA)–specific autoantibody, the anti–carbamylated protein antibodies (anti‐CarP), has provided an opportunity to improve the management and understanding of RA. The current study was undertaken to assess the relationship between anti‐CarP antibodies and HLA–DRB1 alleles in RA. Methods: Serum samples were obtained from 3 different collections, comprising a total of 1,126 RA patients. Serum reactivity against in vitro carbamylated fetal calf serum proteins was determined by enzyme‐linked immunosorbent assay. HLA–DRB1 alleles were determined using either hybridization techniques or imputation from HLA‐dense genotypes. Results of these analyses were combined in a meta‐analysis with data from 3 previously reported cohorts. The carrier frequencies of the common HLA–DRB1 alleles were compared between the antibody‐positive RA subgroups and the double‐negative subgroup of RA patients stratified by anti–citrullinated protein antibody (ACPA)/anti‐CarP antibody status, and also between the 4 RA patient strata and healthy controls. Results: Meta‐analysis was conducted with 3,709 RA patients and 2,305 healthy control subjects. Results revealed a significant increase in frequency of HLA–DRB1*03 carriers in the ACPA−/anti‐CarP+ subgroup as compared to ACPA−/anti‐CarP− RA patients and healthy controls; this was consistently found across the 6 sample collections. This association of HLA–DRB1*03 with ACPA−/anti‐CarP+ RA was independent of the presence of the shared allele (SE) and any other confounders analyzed. No other allele was specifically associated with the ACPA−/anti‐CarP+ RA patient subgroup. In contrast, frequency of the SE was significantly increased in the ACPA+/anti‐CarP− and ACPA+/anti‐CarP+ RA patient subgroups, without a significant distinction between them. Furthermore, some alleles (including HLA–DRB1*03) were associated with protection from ACPA+ RA. Conclusion: These findings indicate a specific association of HLA–DRB1*03 with ACPA−/anti‐CarP+ RA, suggesting that preferential presentation of carbamylated peptides could be a new mechanism underlying the contribution of HLA alleles to RA susceptibility. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) has a negative impact on bone that is partly mediated by anti-citrullinated proteins antibodies (ACPA). These antibodies are associated with erosions, and with juxta-articular and systemic bone loss. Other RA autoantibodies, the anti-carbamylated protein antibodies (anti-CarPA), are independently associated with erosions. However, we do not know if they are also associated with juxta-articular and systemic bone loss. Here, we have addressed this question with data from 548 early arthritis (EA) patients. Bone mineral density (BMD) was assessed by dual-energy x-ray absorptiometry at the lumbar spine (LS), total hip (TH) and metacarpophalangeal joints (MCP). The 25.9% anti-CarPA positive patients did not show significant differences in BMD Z-scores with the negative patients. Nevertheless, this result was due to the similarity between negative and low-positive (below the median of the positive) patients, whereas the high-positive patients showed significant decrease of BMD at LS (β = -0.39, p = 0.01) and TH (β = -0.30, p = 0.02); but not at the juxta-articular bone of MCP. Given the overlap between anti-CarPA and ACPA, we included the two autoantibodies in an analysis that showed significantly lower BMD Z-scores at LS and TH (p< 0.01) only in the ACPA positive/anti-CarPA high-positive subgroup. However, the similar coefficients of regression between the ACPA positive/anti-CarPA high-positive and the ACPA negative/anti-CarPA high-positive subgroups (β = -0.50 vs. -0.52 at LS, and β = -0.37 vs. -0.30 at TH) suggested an independent association. Overall, these results support a contribution of anti-CarPA to systemic bone loss in EA patients. [ABSTRACT FROM AUTHOR]

The limitations and rigidness of current use of spectrum resources have fostered the design of new power multiplexing techniques to improve frequency efficiency and flexibility. These techniques are based on the simultaneous transmission of different services on the same channel with different power distribution. At the receiver side Log-likelihood ratio (LLR) probability density functions have been so far optimized for single layer systems, so the reception quality of multilayer signals with the existing LLR algorithms is degraded. This paper proposes a new LLR probability density function, including corrections for the multilayer influence, in order to improve reception performance. Simulation results are also included to test the performance improvement in terms of the receiving SNR threshold. [ABSTRACT FROM AUTHOR]

A large fraction of the patients with rheumatoid arthritis (RA) develop specific autoantibodies, which until recently were only of two types, rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA). We aimed to replicate important findings about a recently described third type of specific autoantibodies, anti-carbamylated protein (anti-CarP) antibodies, because they have been described based only in the homemade ELISA from a single laboratory. Our study included 520 patients with established RA and 278 healthy controls of Spanish ancestry and it was done with an independently performed ELISA. The prevalence and pattern of environmental, clinical and genetic associations of the anti-CarP antibodies were similar to the previously described. Notably, the presence and titers of anti-CarP correlated with the presence and titers of ACPA, but the anti-CarP antibodies did not share the known genetic and exposure risk factors of the ACPA. In addition, anti-CarP antibodies were independently associated with a higher (10.5%) prevalence of bone erosions. The reproducibility of these characteristics across laboratories and European subpopulations, indicates the wide validity of the results and suggests that determination of anti-CarP antibodies could contribute to explain RA pathogenesis and identify clinically relevant patient subgroups. [ABSTRACT FROM AUTHOR]

Aims: This study aimed to determine the effect of aging on glucose profiles in a population without diabetes.Methods: We investigated the evolution of glucose profiles in an adult population without diabetes using continuous glucose monitoring (CGM) in two periods separated by 5 years. Anthropometrics, laboratory tests (HbA1c, fasting blood glucose) and CGM data (mean glycemia level, coefficient of variation, time in range) were measured in both periods to study the change in values over time.Results: 125 participants (68% women) mean age 43.1 ± 12.4 years and classified as normoglycemic at baseline were included. Of the total population 15.2% had worsened glycemic status after 5 years, age and baseline glucose values (HbA1c and percentage of values above 175 mg/dL) were the variables related with this change. Related to CGM, we found that after 5 years there was a decrease in the percentage of values between 70 and 99 mg/dl (45.0% to 38.7%, p = 0.002) and an increase in the 100-139 mg/dL range (52.9% to 57.5% p = 0.016).Conclusions: Our results indicate that in an adult population without diabetes there are changes in glucose profiles with aging highlighting the reduction of blood glucose values below 100 mg/dL. [ABSTRACT FROM AUTHOR]

This paper presents the field trials carried out in Bilbao (Spain) for testing and analyzing the performance of the DVB-T2 indoor (fixed and pedestrian) reception. Test services with different DVB-T2 and T2-Lite configuration modes have been broadcasted and indoor measurements have been carried out. As a result, signal to noise ratio threshold values for DVB-T2 indoor reception have been obtained. These values update those provided by previous studies and are also valid for planning tools to be used by broadcasters in the development of DVB-T2 networks. [ABSTRACT FROM AUTHOR]

Patients with rheumatoid arthritis (RA) show autoantibodies against post-translational protein modifications (PTMs), such as anti-citrullinated protein antibodies. However, the range of recognized PTMs is unknown. Here, we addressed four PTMs: chlorination, non-enzymatic glycation, nitration, and homocysteinylation, identified as targets of atypical RA autoantibodies in studies whose protocols we have followed. The modified antigens included collagen type II, an extract of synovial proteins and a selection of peptides. We interpreted the results according to the optical density (OD) obtained in an enzyme-linked immunosorbent assay (ELISA) with the modified antigen and the corrected OD obtained after subtracting the reactivity against the unmodified antigen. The results showed evidence of specific antibodies against glycated collagen type II, as the corrected ODs were higher in the 182 patients with RA than in the 164 healthy controls (p = 0.0003). However, the relevance of these antibodies was doubtful because the magnitude of the specific signal was small (median OD = 0.072 vs. 0.027, respectively). There were no specific antibodies against any of the other three PTMs. Therefore, our results showed that the four PTMs are not inducing a significant autoantibody response in patients with RA. These results indicated that the repertoire of PTM autoantigens in RA is restricted. [ABSTRACT FROM AUTHOR]

Living systems use enzymatic reaction networks to process biochemical information and make decisions in response to external or internal stimuli. Herein, we present a modular and reusable platform for molecular information processing using enzymes immobilised in hydrogel beads and compartmentalised in a continuous stirred tank reactor. We demonstrate how this setup allows us to perform simple arithmetic operations, such as addition, subtraction and multiplication, using various concentrations of substrates or inhibitors as inputs and the production of a fluorescent molecule as the readout. [ABSTRACT FROM AUTHOR]

Living systems use enzymatic reaction networks to process biochemical information and make decisions in response to external or internal stimuli. Herein, we present a modular and reusable platform for molecular information processing using enzymes immobilised in hydrogel beads and compartmentalised in a continuous stirred tank reactor. We demonstrate how this setup allows us to perform simple arithmetic operations, such as addition, subtraction and multiplication, using various concentrations of substrates or inhibitors as inputs and the production of a fluorescent molecule as the readout. [ABSTRACT FROM AUTHOR]

Audit logs are a critical component in today's enterprise business systems as they provide several benefits such as records transparency and integrity and security of sensitive information by creating a layer of evidential support. However, current implementations are vulnerable to attacks on data integrity or availability. This paper presents a Blockchain-based audit trail mechanism that leverages the security features of Blockchain to enable secure and reliable audit trails and to address the aforementioned vulnerabilities. The architecture design and specific implementation are described in detail, resulting in a real prototype of a reliable, secure, and user-friendly audit trail mechanism. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) screening programs have been implemented to reduce the burden of the disease. When an advanced colonic lesion is detected, clinical practice guidelines recommend endoscopic surveillance with different intervals between explorations. Endoscopic surveillance is producing a considerable increase in the number of colonoscopies, with a limited effect on the CRC incidence. Instead, participation in CRC screening programs based on the fecal immunochemical test (FIT) could be a non-inferior alternative to endoscopic surveillance to reduce 10-year CRC incidence. Based on this hypothesis, we have designed a multicenter and randomized clinical trial within the Spanish population CRC screening programs to compare FIT surveillance with endoscopic surveillance. We will include individuals aged from 50 to 65 years with complete colonoscopy and advanced lesions resected within the CRC screening programs. Patients will be randomly allocated to perform an annual FIT and colonoscopy if fecal hemoglobin concentration is ≥10 µg/g, or to perform endoscopic surveillance. On the basis of the non-superior CRC incidence, we will recruit 1894 patients in each arm. The main endpoint is 10-year CRC incidence and the secondary endpoints are diagnostic yield, participation, adverse effects, mortality and cost-effectiveness. Our results may modify the clinical practice after advanced colonic resection in CRC screening programs. [ABSTRACT FROM AUTHOR]

This paper presents a generic methodology to optimize constellations based on their geometrical shaping for bit-interleaved coded modulation (BICM) systems. While the method can be applicable to any wireless standard design it has been tailored to two delivery scenarios typical of broadcast systems: 1) robust multimedia delivery and 2) UHDTV quality bitrate services. The design process is based on maximizing the BICM channel capacity for a given power constraint. The major contribution of this paper is a low complexity optimization algorithm for the design of optimal constellation schemes. The proposal consists of a set of initial conditions for a particle swarm optimization algorithm, and afterward, a customized post processing procedure for further improving the constellation alphabet. According to the broadcast application cases, the sizes of the constellations proposed range from 16 to 4096 symbols. The BICM channel capacities and performance of the designed constellations are compared to conventional quadrature amplitude modulation constellations for different application scenarios. The results show a significant improvement in terms of system performance and BICM channel capacities under additive white Gaussian noise and Rayleigh independently and identically distributed channel conditions. [ABSTRACT FROM PUBLISHER]

Patients with rheumatoid arthritis (RA) have an increased mortality rate that is associated with the presence of RA-specific autoantibodies in many studies. However, the relative role of rheumatoid factor (RF), anti-CCP antibodies and the most recently established RA-autoantibodies, directed against carbamylated proteins (anti-CarP antibodies), is unclear. Here, we have assessed the role of these three antibodies in 331 patients with established RA recruited from 2001 to 2009 and followed until November 2015. During this time, 124 patients died (37.5%). This death rate corresponds to a mortality rate 1.53 (95% CI 1.26 to 1.80) folds the observed in the reference population. We used for analysis of all-cause mortality the Cox proportional hazard regression model with adjustment for age, sex and smoking. It showed a trend for association with increased mortality of each of the three RA autoantibodies in antibody-specific analysis (hazards ratio (HR) from 1.37 to 1.79), but only the HR of the anti-CarP antibodies was significant (HR = 1.79, 95% CI 1.23 to 2.61, p = 0.002). In addition, the multivariate analysis that included all autoantibodies showed a marked decrease in the HR of RF and of anti-CCP antibodies, whereas the HR of anti-CarP remained significant. This increase was specific of respiratory system causes of death (HR = 3.19, 95% CI 1.52 to 6.69, p = 0.002). Therefore, our results suggest a specific relation of anti-CarP antibodies with the increased mortality in RA, and drive attention to their possible connection with respiratory diseases. [ABSTRACT FROM AUTHOR]

Two of the main drawbacks of the current broadcasting services are, on the one hand, the lack of flexibility to adapt to the new generation systems requirements, and on the other hand, the incapability of taking a piece of the current mobile services market. In this paper, layered division multiplexing (LDM), which grew out of the concept of Cloud Txn, is presented as a very promising technique for answering those challenges and enhancing the capacity of broadcasting systems. The major contribution of this paper is to present the first comprehensive study of the LDM performance behavior. In particular, in this paper, the theoretical considerations of the LDM implementation are completed with the first computer based simulations and laboratory tests, covering a wide range of stationary channels and the mobile TU-6 channel. The results will support LDM as a strong candidate for multiplexing different services in the next generation broadcasting systems, increasing both flexibility and performance. [ABSTRACT FROM PUBLISHER]

The presence of rheumatoid factor (RF) or anti-cyclic citrullinated peptide (anti-CCP) autoantibodies contributes to the current rheumatoid arthritis (RA) classification criteria. These criteria involve stratification on antibody levels, which limits reproducibility, and underperform in the RA patients without RF and anti-CCP. Here, we have explored if two anti-acetylated peptide antibodies (AAPA), anti-acetylated lysine (AcLys) and anti-acetylated ornithine (AcOrn), could improve the performance of the current criteria. The analysis was done in 1062 prospectively-followed early arthritis (EA) patients. The anti-AcOrn were more informative than the anti-AcLys, the conventional RA antibodies and the anti-carbamylated protein antibodies. The anti-AcOrn produced a classification that did not require antibody levels and showed improved specificity (77.6% vs. 72.6%, p = 0.003) and accuracy (79.0% vs. 75.8%, p = 0.002) over the current criteria. These improvements were obtained with a scoring system that values concordance between anti-AcOrn, RF and anti-CCP. No significant gain was obtained in sensitivity (80.2% vs. 78.8%, p = 0.25) or in improving the classification of the RA patients lacking RF and anti-CCP, although the anti-AcOrn ranked first among the analysed new antibodies. Therefore, the anti-AcOrn antibodies could contribute to the improvement of RA classification criteria by exploiting antibody concordance. [ABSTRACT FROM AUTHOR]

In addition to the traditional TDM/FDM, the advanced television systems committee (ATSC) 3.0 next generation digital TV standard has adopted state-of-the-art coding and modulation, as well as the new layered division multiplexing (LDM) technology. The ATSC 3.0 system is able to provide higher data throughput, more robust reception, better spectrum efficiency, and flexible service combinations in one RF channel with different robustness and reception conditions. Due to the adoption of a two-layer LDM, the coverage for ATSC 3.0 is very different from the legacy one-transmitter-one-coverage ATSC 1.0 system. With the new enabling technologies, the ATSC 3.0 can greatly increase the coverage/service areas, reduce the distance between co-channel assignments, and introduce local program insertion and targeted advertisement. This paper addresses the ATSC 3.0 coverage and co-channel interference issues, by using the two-layer LDM technology with different operating parameters. Simulations demonstrate that, similar to the 4G long term evolution, the ATSC 3.0 co-channel assignment could be reduced to two times the service coverage radius. This means an improvement of the spectrum efficiency by up to four times in comparison with today’s system. It is also proved through simulations that significant TV program gains can be obtained with this new system. The deployment of single frequency networks can further improve the coverage and reduce the interference. [ABSTRACT FROM AUTHOR]