Role of biological agents in treatment of rheumatoid arthritis.

Advances in understanding of the pathophysiology of rheumatoid arthritis with concurrent advances in protein engineering led to the development of biological disease-modifying antirheumatic drugs which have dramatically revolutionized the treatment of this condition. This review article focuses on the role of biological agents currently employed in the treatment of rheumatoid arthritis, as well as novel biological agents in development.

Multiple Imputation for Partial Recording Periodontal Examination Protocols.

AIM: Partial-mouth recording protocols often result in underestimation of population prevalence and extent of periodontitis. We posit that multiple imputation of measures such as clinical attachment loss for nonselected tooth sites in partial-mouth samples can reduce bias in periodontitis estimates. METHODS: Multiple imputation for correlated site-level dichotomous outcomes in a generalized estimating equations framework is used to impute site-level binary indicators for clinical attachment loss exceeding a fixed threshold in partial-mouth samples. Periodontitis case definitions are applied to the imputed "complete" dentitions, enabling estimation of prevalence and other summaries of periodontitis for partial-mouth samples as if for full-mouth examinations. A multiple imputation-bootstrap procedure is described and applied for point and variance estimation of these periodontitis measures. The procedure is evaluated with pseudo-partial-mouth samples based on random site selection protocols of 28 to 84 periodontal sites repeatedly generated from full-mouth periodontal examinations of 3,621 participants in the 2013 to 2014 National Health and Nutrition Examination Survey (NHANES) survey. RESULTS: Multiple imputation applied to partial-mouth samples overestimated periodontitis mean extent, defined as the number of sites with clinical attachment loss 3 mm or greater, by 9.5% in random site selection protocols with 84 sites and overestimated prevalence by 5% to 10% in all the evaluated protocols. CONCLUSIONS: In the 2013 to 2014 NHANES data, multiple imputation of site-level periodontal indicators provides less biased estimates of periodontitis prevalence and extent than has been reported from estimates based on the direct application of full-mouth case definitions to partial-mouth samples. Multiple imputation provides a promising solution to the longstanding, vexing problem of estimation bias in partial-mouth recording, with potential application to a wide array of case definitions, periodontitis measures, and partial recording protocols. KNOWLEDGE TRANSFER STATEMENT: Partial-mouth sampling, while a resource-efficient strategy for obtaining oral disease estimates, often results in underestimation of periodontitis metrics. Multiple imputation for nonselected periodontal sites produces pseudo-full-mouth data sets that may be analyzed and combined to produce estimates with small bias.

Backpropagation With N -D Vector-Valued Neurons Using Arbitrary Bilinear Products.

Vector-valued neural learning has emerged as a promising direction in deep learning recently. Traditionally, training data for neural networks (NNs) are formulated as a vector of scalars; however, its performance may not be optimal since associations among adjacent scalars are not modeled. In this article, we propose a new vector neural architecture called the Arbitrary BIlinear Product NN (ABIPNN), which processes information as vectors in each neuron, and the feedforward projections are defined using arbitrary bilinear products. Such bilinear products can include circular convolution, 7-D vector product, skew circular convolution, reversed-time circular convolution, or other new products that are not seen in the previous work. As a proof-of-concept, we apply our proposed network to multispectral image denoising and singing voice separation. Experimental results show that ABIPNN obtains substantial improvements when compared to conventional NNs, suggesting that associations are learned during training.

Comparison of Ultrasound Features of Major Salivary Glands in Sarcoidosis, Amyloidosis, and Sjögren's Syndrome.

OBJECTIVE: While salivary gland ultrasound (SGU) has gained prominence for evaluating Sjögren's syndrome, little information exists on SGU appearance of sarcoidosis and amyloidosis, potential mimics of Sjögren's syndrome. Our goal in this study was to estimate the diagnostic accuracy of major SGU features in differentiating Sjögren's syndrome from sarcoidosis, amyloidosis, and controls. METHODS: We enrolled consecutive adult ambulatory patients with a clinical diagnosis of Sjögren's syndrome fulfilling the 2016 American College of Rheumatology (ACR) classification criteria; we also enrolled patients with a clinical diagnosis of sarcoidosis or systemic immunoglobulin light chain (AL) amyloidosis, with histologic confirmation from any tissue, and rheumatology outpatients without diagnoses affecting salivary glands. Subjects underwent major SGU using the Hocevar protocol, with resulting video clips reviewed blind to clinical diagnosis. RESULTS: Sjögren's syndrome SGU scores were greater than in patients from the other groups, but there were no distinguishing salivary gland features from AL amyloidosis or sarcoidosis. None of the patients in the control group scored higher than 17, a cutoff previously suggested for Sjögren's syndrome, but 27% of patients with AL amyloidosis and 19% with sarcoidosis scored higher than 17. Adding Hocevar SGU scores of ≥17 to the 2016 ACR/European League Against Rheumatism criteria in a parallel scheme increased the sensitivity for Sjögren's syndrome from 87% to 98%, while combining the 2 criteria in series increased specificity from 81% to 98%. CONCLUSION: Sjögren's syndrome, sarcoidosis, and AL amyloidosis share common SGU features that can help distinguish these conditions from patients without systemic rheumatologic disease. Clinicians should carefully consider these potential mimics when interpreting salivary gland US results.

SB4 in the Era of Biosimilars: Clinical Data and Real-World Experience.

A biosimilar is a biological medicinal product that is highly similar to an already authorized original biological medicinal product. The introduction of biosimilars may allow for a reduction in health care costs, due to discount pricing. Current clinical studies and real-world data suggest that the biosimilar SB4 is equivalent to etanercept with respect to efficacy and safety. Additional real-world safety data for SB4 via pharmacovigilance studies are needed to draw conclusions regarding the risks of rare adverse events such as serious infections and malignancy. Clinical trial design of biosimilars should be standardised to improve consistency, increase confidence and facilitate interpretation of data. Where there are health economic advantages of switching from originator to biosimilar, patients should be appropriately informed, and, ideally, in order to minimise nocebo responses and maximise benefit, switching should be undertaken by shared decision-making between the physician and patient on a case-by-case basis.

When the first visit to the rheumatologist is established rheumatoid arthritis.

The outlook for people living with rheumatoid arthritis (RA) has improved tremendously in a generation. Major contributions to this include recognition of the importance of early treatment initiation, improved understanding of the pathobiology, the identification of therapeutic targets and their subsequent validation in clinic trials and the realisation of the importance of 'tight control' of inflammatory responses. Despite these advances, many patients meeting classification criteria present for the first time to a rheumatologist with longstanding symptoms. There is no definition as to when RA becomes 'established'. But there is evidence that a 'window of opportunity' exists over about 12-16 weeks symptom duration, during which treatment intervention gives rise to the most optimal outcomes. This review addresses issues regarding the management of patients presenting outside the window of opportunity in terms of heterogeneity of presentation, assessment, therapeutic goals and treatment options as well as the importance of a multidisciplinary approach to holistic care.

Total synthesis of (+)-quassin.

A total synthesis of (+)-quassin from naturally occurring (S)-(+)-carvone is described. The total number of steps was 28, and the overall yield was about 2.6%. The synthetic strategy for the construction of the tetracyclic carbon framework was based on a C-->ABC-->ABCD ring annulation sequence, involving an aldol reaction, an intramolecular Diels-Alder reaction, and an intramolecular acylation as the key steps. Subsequent functionalization of ring A and ring C then afforded the target (+)-quassin.

Antitumor effect of chemically synthesized (+)-goniopypyrone.

Chemically synthesized (+)-goniopypyrone was found to suppress the growth of cultured Ehrlich ascites tumor cells as well as PU5-1.8 cells. The ED50 values were found to be 35 and 30 micrograms/ml for the two cell lines used. An LD50 of 193 micrograms/ml was observed in the brine shrimp bioassay.

Kinetic studies on cyclophellitol analogues--mechanism-based inactivators.

The (1R,6S)- and (1R,2S,6S)-diastereoisomers of cyclophellitol were found to be effective irreversible inactivators of alpha-D-glucosidase and alpha-D-mannosidase, respectively. The (1R,6S)-diastereoisomer inactivates brewers yeast alpha-D-glucosidase according to pseudo-first order kinetics with inactivation constants of Ki = 26.9 microM, ki = 0.401 min-1 while the (1R,2S,6S)-diastereoisomer inactivates jack beans alpha-D-mannosidase in a similar manner with Ki = 120 microM, ki = 2.85 min-1. The irreversibility of these compounds was evidenced by the lack of reactivation upon dialysis of the inactivated enzyme.

Synthesis and cytotoxicity of shikimate analogues. Structure:activity studies based on 1-crotonyloxymethyl-3R,4R,5R-trihydroxycyclohex-2-enone.

Syntheses are described for and structure:activity studies undertaken of the anti-tumour activity of (2-crotonyloxymethyl-(4R,5R,6R)-4,5,6-trihydroxycyclohex-2-+ ++enone) (1) and its analogues 1-crotonyloxymethyl-(3R,4S,5R)-3,4,5-trihydroxycyclohex-1-en e (3), 1-crotonyloxymethyl-(3R,4S,5S)-3,4,5-trihydroxycyclohexene (4) and 2-crotonyloxymethyl-2-cyclohexenone (5), which differ from 1 in the presence/absence of the cyclic keto group and/or the stereochemistry at one of the -OH bearing carbon atoms. None of the above compounds, including 1, directly inhibited glyoxalase I, isolated for the first time to homogeneity from rat Yoshida sarcomas and for which a purification protocol was developed. The apparent inhibition of glyoxalase I by 1 and 5 (but not detected for 4 or 3) could be explained by reaction of 1 and 5 with the glutathione present in the assay buffer and the consequent depletion of substrate. 1 and 5 were found to react readily with glutathione whereas 4 and 3 did not react. In vitro chemosensitivity studies against a panel of tumour cell lines of both mouse and human origin showed that in parallel with their thiol reactivity, 1 and 5 exhibited significant in vitro cytotoxicity whereas 4 and 3 did not. Concentrations of drug required to cause 50% cell kill (ID50 values) were in the range 0.5-19 microM (0.1-2.8 micrograms/ml) for 5, and 3-44 microM (0.7-10 micrograms/ml) for 1. The structural features causing the differences in antitumour effects were localized on this basis to the alpha,beta-unsaturated ketone linkage as opposed to the stereochemistry of the (trihydroxy) alcoholic sites.