Efficacy of tofacitinib monotherapy in methotrexate-naive patients with early or established rheumatoid arthritis.

IntroductionTofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Tofacitinib monotherapy was previously shown to inhibit structural damage, reduce clinical signs and symptoms of RA, and improve physical functioning over 24 months in methotrexate (MTX)-naive adult patients with RA. In this post hoc analysis, we compared efficacy and safety of tofacitinib in patients with early (disease duration <1 year) versus established (≥1 year) RA.MethodsMTX-naive patients ≥18 years with active RA received tofacitinib monotherapy (5 or 10 mg two times a day, or MTX monotherapy, in a 24-month Phase 3 trial.ResultsOf 956 patients (tofacitinib 5 mg two times a day, n=373; tofacitinib 10 mg two times a day, n=397; MTX, n=186), 54% had early RA. Baseline disease activity and functional disability were similar in both groups; radiographic damage was greater in patients with established RA. At month 24, clinical response rates were significantly greater in patients with early versus established RA in the tofacitinib 5 mg two times a day group. Both tofacitinib doses had greater effects on clinical, functional and radiographic improvements at 1 and 2 years compared with MTX, independent of disease duration. No new safety signals were observed.ConclusionsTreatment response was generally similar in early and established RA; significantly greater improvements were observed at month 24 with tofacitinib 5 mg two times a day in early versus established RA. Tofacitinib 5 and 10 mg two times a day demonstrated greater efficacy versus MTX irrespective of disease duration. No difference in safety profiles was observed between patients with early or established RA.Trial registration numberNCT01039688; Results

Human CD49a+ Lung Natural Killer Cell Cytotoxicity in Response to Influenza A Virus

Influenza A virus (IAV) is a major global public health burden due to its routine evasion of immunization strategies. Natural killer (NK) cells are innate cytotoxic cells with important antiviral activity in the human body, yet the function of these cells in the control of IAV infection is unclear. The aim of this study was to determine the role of lung NK cell cytotoxic responses to IAV. Human lung explants were infected ex vivo with IAV, and lung NK cell activation was analyzed by flow cytometry. Cytotoxic responses of NK cell subsets against IAV-infected macrophages were measured by flow cytometry and ELISA. Despite reports of hypofunctionality in the pulmonary environment, human lung-associated NK cells responded rapidly to ex vivo IAV infection, with upregulation of surface CD107a 24 h post-infection. The lung NK cell phenotype is similar in maturity and differentiation to NK cells of the peripheral blood but a unique CD56brightCD49a+CD103+CD69+ NK cell population was identified in the lung, indicating NK cell residency within this organ. In response to ex vivo IAV infection a greater proportion of resident CD56brightCD49a+ NK cells expressed surface CD107a compared with CD56brightCD49a− NK cells, suggesting a hyperfunctional NK cell population may be present within human lung tissue and could be the result of innate immunological training. Furthermore, NK cells provided significant antiviral, cytotoxic activity following contact with influenza-infected cells, including the production and release of IFN-γ and granzyme-B resulting in macrophage cell death. These results suggest that a resident, trained NK cell population are present in the human lung and may provide early and important control of viral infection. A greater understanding of this resident mucosal population may provide further insight into the role of these cells in controlling viral infection and generating appropriate adaptive immunity to IAV

Tendinous tissue properties after short and long-term functional overload: Differences between controls, 12 weeks and 4 years of resistance training.

AIM: The potential for tendinous tissues to adapt to functional overload, especially after several years of exposure to heavy resistance training is largely unexplored. This study compared the morphological and mechanical characteristics of the patellar tendon and knee-extensor tendon-aponeurosis complex between young men exposed to long-term (4 years; n=16), short-term (12 weeks; n=15) and no (untrained controls; n=39) functional overload in the form of heavy resistance training. METHODS: Patellar tendon cross-sectional area, vastus-lateralis aponeurosis area and quadriceps femoris volume, plus patellar tendon stiffness and Young's modulus, and tendon-aponeurosis complex stiffness, were quantified with MRI, dynamometry and ultrasonography. RESULTS: As expected long-term trained had greater muscle strength and volume (+58% and +56% vs untrained, both P<0.001), as well as a greater aponeurosis area (+17% vs untrained, P<0.01), but tendon cross-sectional area (mean and regional) was not different between groups. Only long-term trained had reduced patellar tendon elongation/strain over the whole force/stress range, whilst both short-term and long-term overload groups had similarly greater stiffness/Young's modulus at high force/stress (short-term +25/22%, and long-term +17/23% vs untrained; all P<0.05). Tendon-aponeurosis complex stiffness was not different between groups (ANOVA, P = 0.149). CONCLUSION: Despite large differences in muscle strength and size, years of resistance training did not induce tendon hypertrophy. Both short-term and long-term overload, demonstrated similar increases in high force mechanical and material stiffness, but reduced elongation/strain over the whole force/stress range occurred only after years of overload, indicating a force/strain specific time-course to these adaptations. This article is protected by copyright. All rights reserved

No Detectable Fertility Benefit from a Single Additional Mating in Wild Stalk-Eyed Flies

Background: Multiple mating by female insects is widespread, and the explanation(s) for repeated mating by females has been the subject of much discussion. Females may profit from mating multiply through direct material benefits that increase their own reproductive output, or indirect genetic benefits that increase offspring fitness. One particular direct benefit that has attracted significant attention is that of fertility assurance, as females often need to mate multiply to achieve high fertility. This hypothesis has never been tested in a wild insect population.Methodology/Principal Findings: Female Malaysian stalk-eyed flies (Teleopsis dalmanni) mate repeatedly during their lifetime, and have been shown to be sperm limited under both laboratory and field conditions. Here we ask whether receiving an additional mating alleviates sperm limitation in wild females. In our experiment one group of females received a single additional mating, while a control group received an interrupted, and therefore unsuccessful, mating. Females that received an additional mating did not lay more fertilised eggs in total, nor did they lay proportionately more fertilised eggs. Female fertility declined significantly through time, demonstrating that females were sperm limited. However, receipt of an additional mating did not significantly alter the rate of this decline.Conclusions/Significance: Our data suggest that the fertility consequences of a single additional mating were small. We discuss this effect (or lack thereof), and suggest that it is likely to be attributed to small ejaculate size, a high proportion of failed copulations, and the presence of X-linked meiotic drive in this species

High prevalence of subclinical tuberculosis in HIV-1-infected persons without advanced immunodeficiency: implications for TB screening

Background The prevalence of asymptomatic tuberculosis (TB) in recently diagnosed HIV-1-infected persons attending pre-antiretroviral therapy (ART) clinics is not well described. In addition, it is unclear if the detection of Mycobacterium tuberculosis in these patients clearly represents an early asymptomatic phase leading to progressive disease or transient excretion of bacilli. Objective To describe the prevalence and outcome of subclinical TB disease in HIV-1-infected persons not eligible for ART. Methods The study was conducted in 274 asymptomatic ART-naive HIV-1-infected persons in Khayelitsha Day Hospital, Cape Town, South Africa. All participants were screened for TB using a symptom screen and spoligotyping was performed to determine genotypes. Results The prevalence of subclinical TB disease was 8.5% (95% CI 5.1% to 13.0%) (n = 18; median days to culture positivity 17 days), with 22% of patients being smear-positive. Spoligotyping showed a diverse variety of genotypes with all paired isolates being of the same spoligotype, effectively excluding cross-contamination. 56% of patients followed up developed symptoms 3 days to 2 months later. All were well and still in care 6-12 months after TB diagnosis; 60% were started on ART. A positive tuberculin skin test (OR 4.96, p = 0.064), low CD4 count (OR 0.996, p = 0.06) and number of years since HIV diagnosis (OR 1.006, p = 0.056) showed trends towards predicting TB disease. Conclusion This study found a high prevalence but good outcome (retained in care) of subclinical TB disease in HIV-1-infected persons. The results suggest that, in high HIV/TB endemic settings, a positive HIV-1 test should prompt TB screening by sputum culture irrespective of symptoms, particularly in those with a positive tuberculin skin test, longer history of HIV infection and low CD4 count. Operational difficulties in resource-constrained settings with respect to screening with TB culture highlight the need for rapid and affordable point-of-care tests to identify persons with clinical and subclinical TB disease.Immunogenetics and cellular immunology of bacterial infectious disease

Tendinous tissue adaptation to explosive- vs. sustained-contraction strength training

© 2018 Massey, Balshaw, Maden-Wilkinson, Tillin and Folland. The effect of different strength training regimes, and in particular training utilizing brief explosive contractions, on tendinous tissue properties is poorly understood. This study compared the efficacy of 12 weeks of knee extensor explosive-contraction (ECT; n = 14) vs. sustained-contraction (SCT; n = 15) strength training vs. a non-training control (n = 13) to induce changes in patellar tendon and knee extensor tendon-aponeurosis stiffness and size (patellar tendon, vastus-lateralis aponeurosis, quadriceps femoris muscle) in healthy young men. Training involved 40 isometric knee extension contractions (three times/week): gradually increasing to 75% of maximum voluntary torque (MVT) before holding for 3 s (SCT), or briefly contracting as fast as possible to ~80% MVT (ECT). Changes in patellar tendon stiffness and Young's modulus, tendon-aponeurosis complex stiffness, as well as quadriceps femoris muscle volume, vastus-lateralis aponeurosis area and patellar tendon cross-sectional area were quantified with ultrasonography, dynamometry, and magnetic resonance imaging. ECT and SCT similarly increased patellar tendon stiffness (20% vs. 16%, both p < 0.05 vs. control) and Young's modulus (22% vs. 16%, both p < 0.05 vs. control). Tendon-aponeurosis complex high-force stiffness increased only after SCT (21%; p < 0.02), while ECT resulted in greater overall elongation of the tendon-aponeurosis complex. Quadriceps muscle volume only increased after sustained-contraction training (8%; p = 0.001), with unclear effects of strength training on aponeurosis area. The changes in patellar tendon cross-sectional area after strength training were not appreciably different to control. Our results suggest brief high force muscle contractions can induce increased free tendon stiffness, though SCT is needed to increase tendon-aponeurosis complex stiffness and muscle hypertrophy

Towards an Understanding of Changing-Look Quasars: An Archival Spectroscopic Search in SDSS

The uncertain origin of the recently-discovered `changing-looking' quasar phenomenon -- in which a luminous quasar dims significantly to a quiescent state in repeat spectroscopy over ~10 year timescales -- may present unexpected challenges to our understanding of quasar accretion. To better understand this phenomenon, we take a first step to building a sample of changing-look quasars with a systematic but simple archival search for these objects in the Sloan Digital Sky Survey Data Release 12. By leveraging the >10 year baselines for objects with repeat spectroscopy, we uncover two new changing-look quasars, and a third discovered previously. Decomposition of the multi-epoch spectra and analysis of the broad emission lines suggest that the quasar accretion disk emission dims due to rapidly decreasing accretion rates (by factors of >2.5), while disfavoring changes in intrinsic dust extinction for the two objects where these analyses are possible. Broad emission line energetics also support intrinsic dimming of quasar emission as the origin for this phenomenon rather than transient tidal disruption events or supernovae. Although our search criteria included quasars at all redshifts and transitions from either quasar-like to galaxy-like states or the reverse, all of the clear cases of changing-look quasars discovered were at relatively low-redshift (z ~ 0.2 - 0.3) and only exhibit quasar-like to galaxy-like transitions.Comment: 15 pages, 8 figures. Updated to accepted versio