Discontinuing adalimumab in patients with controlled juvenile idiopathic arthritis-associated uveitis (ADJUST—Adalimumab in Juvenile Idiopathic Arthritis-associated Uveitis Stopping Trial): study protocol for a randomised controlled trial

BACKGROUND: Juvenile idiopathic arthritis (JIA)-associated uveitis is a chronic paediatric ocular inflammatory condition that can result in visual impairment. Adalimumab, a tumour necrosis factor (TNF)-alpha inhibitor, effectively controls joint and eye inflammation; however, its long-term use may increase the risk of adverse health outcomes and place an undue financial burden on the patient and healthcare system given its high cost. There is great interest for patients to stop adalimumab following remission due to these reasons but there is a lack of information on the ability to maintain control after discontinuing adalimumab. METHODS: The Adalimumab in Juvenile Idiopathic Arthritis-associated Uveitis Trial (ADJUST) is a multicentred, international trial that will randomise 118 participants aged 2 years and older with controlled JIA-associated uveitis to either continue adalimumab or discontinue adalimumab and receive a placebo. The trial will compare the time to uveitis recurrence between the two groups over 12 months. All participants will receive the standard weight-based dose of adalimumab or placebo: 20 mg biweekly (if < 30 kg) or 40 mg biweekly (if ≥ 30 kg). DISCUSSION: This is the first randomised controlled trial to assess the efficacy of discontinuing adalimumab after demonstrating control of JIA-associated uveitis for at least 12 months. The results of ADJUST will provide information on clinical outcomes to guide clinicians in their decision-making regarding discontinuation of adalimumab. TRIAL REGISTRATION: ClinicalTrials.gov NCT03816397. Registered on 25 January 2019. EudraCT 2019-000412-29. Registered on 17 January 201

Past water flow beneath Pine Island and Thwaites glaciers, West Antarctica

Abstract. Outburst floods from subglacial lakes beneath the Antarctic Ice Sheet modulate ice-flow velocities over periods of months to years. Although subglacial lake drainage events have been observed from satellite-altimetric data, little is known about their role in the long-term evolution of ice-sheet basal hydrology. Here, we systematically map and model past water flow through an extensive area containing over 1000 subglacial channels and 19 former lake basins exposed on over 19 000 km2 of seafloor by the retreat of Pine Island and Thwaites glaciers, West Antarctica. At 507 m wide and 43 m deep on average, the channels offshore of present-day Pine Island and Thwaites glaciers are approximately twice as deep, 3 times as wide, and cover an area over 400 times larger than the terrestrial meltwater channels comprising the Labyrinth in the Antarctic Dry Valleys. The channels incised into bedrock offshore of contemporary Pine Island and Thwaites glaciers would have been capable of accommodating discharges of up to 8.8×106 m3 s−1. We suggest that the channels were formed by episodic discharges from subglacial lakes trapped during ice-sheet advance and retreat over multiple glacial periods. Our results document the widespread influence of episodic subglacial drainage events during past glacial periods, in particular beneath large ice streams similar to those that continue to dominate contemporary ice-sheet discharge. UK Natural Environment Research Council’s iSTAR programme (grant nos. NE/J005703/1, NE/J005746/1, and NE/J005770/1). James D. Kirkham: Debenham Scholarship from the Scott Polar Research Institute, University of Cambridge, and a UK Natural Environment Research Council Ph.D. studentship awarded through the Cambridge Earth System Science Doctoral Training Partnership (grant no. NE/L002507/1

Linear Estimation of Location and Scale Parameters Using Partial Maxima

Consider an i.i.d. sample X^*_1,X^*_2,...,X^*_n from a location-scale family, and assume that the only available observations consist of the partial maxima (or minima)sequence, X^*_{1:1},X^*_{2:2},...,X^*_{n:n}, where X^*_{j:j}=max{X^*_1,...,X^*_j}. This kind of truncation appears in several circumstances, including best performances in athletics events. In the case of partial maxima, the form of the BLUEs (best linear unbiased estimators) is quite similar to the form of the well-known Lloyd's (1952, Least-squares estimation of location and scale parameters using order statistics, Biometrika, vol. 39, pp. 88-95) BLUEs, based on (the sufficient sample of) order statistics, but, in contrast to the classical case, their consistency is no longer obvious. The present paper is mainly concerned with the scale parameter, showing that the variance of the partial maxima BLUE is at most of order O(1/log n), for a wide class of distributions.Comment: This article is devoted to the memory of my six-years-old, little daughter, Dionyssia, who leaved us on August 25, 2010, at Cephalonia isl. (26 pages, to appear in Metrika

Helium-oxygen reduces the production of carbon dioxide during weaning from mechanical ventilation

<p>Abstract</p> <p>Background</p> <p>Prolonged weaning from mechanical ventilation has a major impact on ICU bed occupancy and patient outcome, and has significant cost implications.</p> <p>There is evidence in patients around the period of extubation that helium-oxygen leads to a reduction in the work of breathing. Therefore breathing helium-oxygen during weaning may be a useful adjunct to facilitate weaning. We hypothesised that breathing helium-oxygen would reduce carbon dioxide production during the weaning phase of mechanical ventilation.</p> <p>Materials/patients and methods</p> <p>We performed a prospective randomised controlled single blinded cross-over trial on 19 adult intensive care patients without significant airways disease who fulfilled criteria for weaning with CPAP. Patients were randomised to helium-oxygen and air-oxygen delivered during a 2 hour period of CPAP ventilation. Carbon dioxide production (VCO₂) was measured using a near patient main stream infrared carbon dioxide sensor and fixed orifice pneumotachograph.</p> <p>Results</p> <p>Compared to air-oxygen, helium-oxygen significantly decreased VCO₂production at the end of the 2 hour period of CPAP ventilation; there was a mean difference in CO₂production of 48.9 ml/min (95% CI 18.7-79.2 p = 0.003) between the groups. There were no significant differences in other respiratory and haemodynamic parameters.</p> <p>Conclusion</p> <p>This study shows that breathing a helium-oxygen mixture during weaning reduces carbon dioxide production. This physiological study supports the need for a clinical trial of helium-oxygen mixture during the weaning phase of mechanical ventilation with duration of weaning as the primary outcome.</p> <p>Trial registration</p> <p>ISRCTN56470948</p

Optical detection of single non-absorbing molecules using the surface plasmon of a gold nanorod

Current optical detection schemes for single molecules require light absorption, either to produce fluorescence or direct absorption signals. This severely limits the range of molecules that can be detected, because most molecules are purely refractive. Metal nanoparticles or dielectric resonators detect non-absorbing molecules by a resonance shift in response to a local perturbation of the refractive index, but neither has reached single-protein sensitivity. The most sensitive plasmon sensors to date detect single molecules only when the plasmon shift is amplified by a highly polarizable label or by a localized precipitation reaction on the particle's surface. Without amplification, the sensitivity only allows for the statistical detection of single molecules. Here we demonstrate plasmonic detection of single molecules in realtime, without the need for labeling or amplification. We monitor the plasmon resonance of a single gold nanorod with a sensitive photothermal assay and achieve a ~ 700-fold increase in sensitivity compared to state-of-the-art plasmon sensors. We find that the sensitivity of the sensor is intrinsically limited due to spectral diffusion of the SPR. We believe this is the first optical technique that detects single molecules purely by their refractive index, without any need for photon absorption by the molecule. The small size, bio-compatibility and straightforward surface chemistry of gold nanorods may open the way to the selective and local detection of purely refractive proteins in live cells

Hybridization in parasites: consequences for adaptive evolution, pathogenesis and public health in a changing world

[No abstract available

Accumulation of Rhodopsin in Late Endosomes Triggers Photoreceptor Cell Degeneration

Progressive retinal degeneration is the underlying feature of many human retinal dystrophies. Previous work using Drosophila as a model system and analysis of specific mutations in human rhodopsin have uncovered a connection between rhodopsin endocytosis and retinal degeneration. In these mutants, rhodopsin and its regulatory protein arrestin form stable complexes, and endocytosis of these complexes causes photoreceptor cell death. In this study we show that the internalized rhodopsin is not degraded in the lysosome but instead accumulates in the late endosomes. Using mutants that are defective in late endosome to lysosome trafficking, we were able to show that rhodopsin accumulates in endosomal compartments in these mutants and leads to light-dependent retinal degeneration. Moreover, we also show that in dying photoreceptors the internalized rhodopsin is not degraded but instead shows characteristics of insoluble proteins. Together these data implicate buildup of rhodopsin in the late endosomal system as a novel trigger of death of photoreceptor neurons

Evolution of ligand specificity in vertebrate corticosteroid receptors

<p>Abstract</p> <p>Background</p> <p>Corticosteroid receptors include mineralocorticoid (MR) and glucocorticoid (GR) receptors. Teleost fishes have a single MR and duplicate GRs that show variable sensitivities to mineralocorticoids and glucocorticoids. How these receptors compare functionally to tetrapod MR and GR, and the evolutionary significance of maintaining two GRs, remains unclear.</p> <p>Results</p> <p>We used up to seven steroids (including aldosterone, cortisol and 11-deoxycorticosterone [DOC]) to compare the ligand specificity of the ligand binding domains of corticosteroid receptors between a mammal (<it>Mus musculus</it>) and the midshipman fish (<it>Porichthys notatus</it>), a teleost model for steroid regulation of neural and behavioral plasticity. Variation in mineralocorticoid sensitivity was considered in a broader phylogenetic context by examining the aldosterone sensitivity of MR and GRs from the distantly related daffodil cichlid (<it>Neolamprologus pulcher</it>), another teleost model for neurobehavioral plasticity. Both teleost species had a single MR and duplicate GRs. All MRs were sensitive to DOC, consistent with the hypothesis that DOC was the initial ligand of the ancestral MR. Variation in GR steroid-specificity corresponds to nine identified amino acid residue substitutions rather than phylogenetic relationships based on receptor sequences.</p> <p>Conclusion</p> <p>The mineralocorticoid sensitivity of duplicate GRs in teleosts is highly labile in the context of their evolutionary phylogeny, a property that likely led to neo-functionalization and maintenance of two GRs.</p

On conditional skewness with applications to environmental data

The statistical literature contains many univariate and multivariate skewness measures that allow two datasets to be compared, some of which are defined in terms of quantile values. In most situations, the comparison between two random vectors focuses on univariate comparisons of conditional random variables truncated in quantiles; this kind of comparison is of particular interest in the environmental sciences. In this work, we describe a new approach to comparing skewness in terms of the univariate convex transform ordering proposed by van Zwet (Convex transformations of random variables. Mathematical Centre Tracts, Amsterdam, 1964), associated with skewness as well as concentration. The key to these comparisons is the underlying dependence structure of the random vectors. Below we describe graphical tools and use several examples to illustrate these comparisons.The research of Félix Belzunce, Julio Mulero and José María Ruíz is partially funded by the Ministerio de Economía y Competitividad (Spain) under Grant MTM2012-34023-FEDER. Alfonso Suárez-Llorens acknowledges support received from the Ministerio de Economía y Competitividad (Spain) under Grant MTM2014-57559-P