Adalimumab plus Methotrexate for Uveitis in Juvenile Idiopathic Arthritis

BACKGROUND Adalimumab, a fully human anti–tumor necrosis factor α monoclonal antibody, is effective in the treatment of juvenile idiopathic arthritis (JIA). We tested the efficacy of adalimumab in the treatment of JIA-associated uveitis. METHODS In this multicenter, double-blind, randomized, placebo-controlled trial, we assessed the efficacy and safety of adalimumab in children and adolescents 2 years of age or older who had active JIA-associated uveitis. Patients who were taking a stable dose of methotrexate were randomly assigned in a 2:1 ratio to receive either adalimumab (at a dose of 20 mg or 40 mg, according to body weight) or placebo, administered subcutaneously every 2 weeks. Patients continued the trial regimen until treatment failure or until 18 months had elapsed. They were followed for up to 2 years after randomization. The primary end point was the time to treatment failure, defined according to a multicomponent intraocular inflammation score that was based on the Standardization of Uveitis Nomenclature criteria. RESULTS The prespecified stopping criteria were met after the enrollment of 90 of 114 patients. We observed 16 treatment failures in 60 patients (27%) in the adalimumab group versus 18 treatment failures in 30 patients (60%) in the placebo group (hazard ratio, 0.25; 95% confidence interval [CI], 0.12 to 0.49; P<0.0001 [the prespecified stopping boundary]). Adverse events were reported more frequently in patients receiving adalimumab than in those receiving placebo (10.07 events per patient-year [95% CI, 9.26 to 10.89] vs. 6.51 events per patient-year [95% CI, 5.26 to 7.77]), as were serious adverse events (0.29 events per patient-year [95% CI, 0.15 to 0.43] vs. 0.19 events per patient-year [95% CI, 0.00 to 0.40]). CONCLUSIONS Adalimumab therapy controlled inflammation and was associated with a lower rate of treatment failure than placebo among children and adolescents with active JIA-associated uveitis who were taking a stable dose of methotrexate. Patients who received adalimumab had a much higher incidence of adverse events and serious adverse events than those who received placebo. (Funded by the NIHR Health Technology Assessment Programme and Arthritis Research UK; SYCAMORE EudraCT number, 2010-021141-41. opens in new tab.

Author Correction: Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

Emmanuelle Souzeau, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this Article. This has now been corrected in both the PDF and HTML versions of the Article

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

European Multicentre Tics in Children Studies (EMTICS): protocol for two cohort studies to assess risk factors for tic onset and exacerbation in children and adolescents

Genetic predisposition, autoimmunity and environmental factors [e.g. pre- and perinatal difficulties, Group A Streptococcal (GAS) and other infections, stress-inducing events] might interact to create a neurobiological vulnerability to the development of tics and associated behaviours. However, the existing evidence for this relies primarily on small prospective or larger retrospective population-based studies, and is therefore still inconclusive. This article describes the design and methodology of the EMTICS study, a longitudinal observational European multicentre study involving 16 clinical centres, with the following objectives: (1) to investigate the association of environmental factors (GAS exposure and psychosocial stress, primarily) with the onset and course of tics and/or obsessive-compulsive symptoms through the prospective observation of at-risk individuals (ONSET cohort: 260 children aged 3-10 years who are tic-free at study entry and have a first-degree relative with a chronic tic disorder) and affected individuals (COURSE cohort: 715 youth aged 3-16 years with a tic disorder); (2) to characterise the immune response to microbial antigens and the host's immune response regulation in association with onset and exacerbations of tics; (3) to increase knowledge of the human gene pathways influencing the pathogenesis of tic disorders; and (4) to develop prediction models for the risk of onset and exacerbations of tic disorders. The EMTICS study is, to our knowledge, the largest prospective cohort assessment of the contribution of different genetic and environmental factors to the risk of developing tics in putatively predisposed individuals and to the risk of exacerbating tics in young individuals with chronic tic disorders

Percutaneous tibial nerve stimulation versus sham electrical stimulation for the treatment of faecal incontinence in adults (CONFIDeNT): a double-blind, multicentre, pragmatic, parallel-group, randomised controlled trial

Background: Percutaneous tibial nerve stimulation (PTNS) is a new ambulatory therapy for faecal incontinence. Data from case series suggest it has beneficial outcomes in 50–80% patients; however its effectiveness against sham electrical stimulation has not been investigated. We therefore aimed to assess the short-term efficacy of PTNS against sham electrical stimulation in adults with faecal incontinence. Methods: We did a double-blind, multicentre, pragmatic, parallel-group, randomised controlled trial (CONtrol of Faecal Incontinence using Distal NeuromodulaTion [CONFIDeNT]) in 17 specialist hospital units in the UK that had the skills to manage patients with faecal incontinence. Eligible participants aged 18 years or older with substantial faecal incontinence for whom conservative treatments (such as dietary changes and pelvic floor exercises) had not worked, were randomly assigned (1:1) to receive either PTNS (via the Urgent PC neuromodulation system) or sham stimulation (via a transcutaneous electrical nerve stimulation machine to the lateral forefoot) once per week for 12 weeks. Randomisation was done with permuted block sizes of two, four, and six, and was stratified by sex and then by centre for women. Patients and outcome assessors were both masked to treatment allocation for the 14-week duration of the trial (but investigators giving the treatment were not masked). The primary outcome was a clinical response to treatment, which we defined as a 50% or greater reduction in episodes of faecal incontinence per week. We assessed this outcome after 12 treatment sessions, using data from patients' bowel diaries. Analysis was by intention to treat, and missing data were multiply imputed. This trial is registered with the ISRCTN registry, number 88559475, and is closed to new participants. Findings: Between Jan 23, 2012, and Oct 31, 2013, we randomly assigned 227 eligible patients (of 373 screened) to receive either PTNS (n=115) or sham stimulation (n=112). 12 patients withdrew from the trial: seven from the PTNS group and five from the sham group (mainly because they could not commit to receiving treatment every week). Two patients (one in each group) withdrew because of an adverse event that was unrelated to treatment (exacerbation of fibromyalgia and rectal bleeding). 39 (38%) of 103 patients with full data from bowel diaries in the PTNS group had a 50% or greater reduction in the number of episodes of faecal incontinence per week compared with 32 (31%) of 102 patients in the sham group (adjusted odds ratio 1·28, 95% CI 0·72–2·28; p=0·396). No serious adverse events related to treatment were reported in the trial. Seven mild, related adverse events were reported in each treatment group, mainly pain at the needle site (four in PTNS, three in sham). Interpretation: PTNS given for 12 weeks did not confer significant clinical benefit over sham electrical stimulation in the treatment of adults with faecal incontinence. Further studies are warranted to determine its efficacy in the long term, and in patient subgroups (ie, those with urgency)

Does progesterone prophylaxis to prevent preterm labour improve outcome? A randomised double-blind placebo-controlled trial (OPPTIMUM) Introduction

Background Progesterone prophylaxis is widely used to prevent preterm birth but is not licensed and there is little information on long-term outcome. Objective To determine the effect of progesterone prophylaxis in women at high risk of preterm birth on obstetric, neonatal and childhood outcomes. Design Double-blind, randomised placebo-controlled trial. Setting Obstetric units in the UK and Europe between February 2009 and April 2013. Participants Women with a singleton pregnancy who are at high risk of preterm birth because of either a positive fibronectin test or a negative fibronectin test, and either previous spontaneous birth at ≤ 34 weeks+0 of gestation or a cervical length of ≤ 25 mm. Interventions Fibronectin test at 18+0 to 23+0 weeks of pregnancy to determine risk of preterm birth. Eligible women were allocated (using a web-based randomisation portal) to 200 mg of progesterone or placebo, taken vaginally daily from 22+0 to 24+0 until 34+0 weeks’ gestation. Participants, caregivers and those assessing the outcomes were blinded to group assignment until data collection was complete. Main outcome measures There were three primary outcomes, as follows: (1) obstetric – fetal death or delivery before 34+0 weeks’ gestation; (2) neonatal – a composite of death, brain injury on ultrasound scan (according to specific criteria in the protocol) and bronchopulmonary dysplasia; and (3) childhood – the Bayley-III cognitive composite score at 22–26 months of age. Results In total, 96 out of 600 (16%) women in the progesterone group and 108 out of 597 (18%) women in the placebo group had the primary obstetric outcome [odds ratio (OR) 0.86, 95% confidence interval (CI) 0.61 to 1.22]. Thirty-nine out of 589 (7%) babies of women in the progesterone group and 60 out of 587 (10%) babies of women in the placebo group experienced the primary neonatal outcome [OR 0.62, 95% CI 0.38 to 1.03]. The mean Bayley-III cognitive composite score of the children at 2 years of age was 97.3 points [standard deviation (SD) 17.9 points; n = 430] in the progesterone group and 97.7 points (SD 17.5 points; n = 439) in the placebo group (difference in means –0.48, 95% CI –2.77 to 1.81). Limitations Overall compliance with the intervention was 69%. Harms There were no major harms, although there was a trend of more deaths from trial entry to 2 years in the progesterone group (20/600) than in the placebo group (16/598) (OR 1.26, 95% CI 0.65 to 2.42). Conclusions In this study, progesterone had no significant beneficial or harmful effects on the primary obstetric, neonatal or childhood outcomes.The OPPTIMUM trial is now complete. We intend to participate in a comprehensive individual patient-level data meta-analysis examining women with a singleton pregnancy with a variety of risk factors for preterm birth

Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study): a multicentre, randomised, double-blind trial

This paper is devoted to a further generalisation of the main results in [5] including the representation of the weak super-replication price (cf. equation (1.6)). In addition to the already established weakening of the technical assumptions in [5] (cf. [24] and [25]), the main results in [5] can be still generalised by considering the geometric structure of the underlying problem (based on the properties of Riesz spaces and polar wedges therein). In Section 5 we show under which geometric conditions of the relevant sets the results still hold (cf. Theorem 5.3 and Corollary 5.5). In particular, we can completely remove the restrictive admissibility assumption and carry forward equation (1.4) to a larger class of wedges K \subseteq L^{0} (cf. Corollary 5.5)