The TICOPA protocol (TIght COntrol of Psoriatic Arthritis): a randomised controlled trial to compare intensive management versus standard care in early psoriatic arthritis.

BACKGROUND: Psoriatic arthritis (PsA) is estimated to occur in 10-15% of people with psoriasis and accounts for 13% of people attending early arthritis clinics. With an increasing awareness of the poor outcomes associated with PsA and the availability of new effective, but costly, treatments, there is an urgent need to research the optimal treatment for patients with PsA. The aim of the TICOPA study is to establish whether, in treatment naive early PsA patients, "tight control" intensive management with protocol driven therapies and pre-defined objective targets for treatment can improve clinical outcome compared to standard care alone. METHODS/DESIGN: TICOPA is a UK multicentre, open-label, randomised controlled, parallel group trial of 206 patients with early PsA. Patients will be randomised on a 1:1 basis to receive either standard care (12 weekly review) or intensive management (4 weekly review) for a period of 48 weeks. Patients assigned to the intensive management group will follow a strict treatment protocol whereby dose continuation/escalation is determined through the objective assessment of the minimal disease activity (MDA) criteria. Patients assigned to the standard care group will have treatment prescribed as felt appropriate by the treating clinician, with no set protocol. The primary objective of the trial is to compare intensive management with standard care in terms of the proportion of patients achieving an ACR 20 response at 48 weeks post-randomisation, in order to determine whether intensive management has superior clinical efficacy. Key secondary outcomes include ACR 50 and 70, PASI 75 and X-ray Van der Heijde score at 48 weeks post-randomisation along with cost-effectiveness at 12, 24 and 28 weeks. DISCUSSION: The TICOPA trial will provide direct evidence as to whether the use of early and intensive treatment in PsA in routine clinical care leads to an improvement in patients' disease activity and a reduction in radiological joint damage. TRIAL REGISTRATION: ISRCTN30147736, NCT01106079

Large Proteins Have a Great Tendency to Aggregate but a Low Propensity to Form Amyloid Fibrils

The assembly of soluble proteins into ordered fibrillar aggregates with cross-β structure is an essential event of many human diseases. The polypeptides undergoing aggregation are generally small in size. To explore if the small size is a primary determinant for the formation of amyloids under pathological conditions we have created two databases of proteins, forming amyloid-related and non-amyloid deposits in human diseases, respectively. The size distributions of the two protein populations are well separated, with the systems forming non-amyloid deposits appearing significantly larger. We have then investigated the propensity of the 486-residue hexokinase-B from Saccharomyces cerevisiae (YHKB) to form amyloid-like fibrils in vitro. This size is intermediate between the size distributions of amyloid and non-amyloid forming proteins. Aggregation was induced under conditions known to be most effective for amyloid formation by normally globular proteins: (i) low pH with salts, (ii) pH 5.5 with trifluoroethanol. In both situations YHKB aggregated very rapidly into species with significant β-sheet structure, as detected using circular dichroism and X-ray diffraction, but a weak Thioflavin T and Congo red binding. Moreover, atomic force microscopy indicated a morphology distinct from typical amyloid fibrils. Both types of aggregates were cytotoxic to human neuroblastoma cells, as indicated by the MTT assay. This analysis indicates that large proteins have a high tendency to form toxic aggregates, but low propensity to form regular amyloid in vivo and that such a behavior is intrinsically determined by the size of the protein, as suggested by the in vitro analysis of our sample protein

Discovery of blood transcriptomic markers for depression in animal models and pilot validation in subjects with early-onset major depression

Early-onset major depressive disorder (MDD) is a serious and prevalent psychiatric illness in adolescents and young adults. Current treatments are not optimally effective. Biological markers of early-onset MDD could increase diagnostic specificity, but no such biomarker exists. Our innovative approach to biomarker discovery for early-onset MDD combined results from genome-wide transcriptomic profiles in the blood of two animal models of depression, representing the genetic and the environmental, stress-related, etiology of MDD. We carried out unbiased analyses of this combined set of 26 candidate blood transcriptomic markers in a sample of 15–19-year-old subjects with MDD (N=14) and subjects with no disorder (ND, N=14). A panel of 11 blood markers differentiated participants with early-onset MDD from the ND group. Additionally, a separate but partially overlapping panel of 18 transcripts distinguished subjects with MDD with or without comorbid anxiety. Four transcripts, discovered from the chronic stress animal model, correlated with maltreatment scores in youths. These pilot data suggest that our approach can lead to clinically valid diagnostic panels of blood transcripts for early-onset MDD, which could reduce diagnostic heterogeneity in this population and has the potential to advance individualized treatment strategies

Cost-effectiveness of tight control of inflammation in early psoriatic arthritis: economic analysis of a multicenter randomized controlled trial

Objective: Treat‐to‐target approaches have proved to be effective in rheumatoid arthritis, but have not been studied in psoriatic arthritis (PsA). This study was undertaken to examine the cost‐effectiveness of tight control (TC) of inflammation in early PsA compared to standard care. Methods: Cost‐effectiveness analyses were undertaken alongside a UK‐based, open‐label, multicenter, randomized controlled trial. Taking the perspective of the health care sector, effectiveness was measured using the 3‐level EuroQol 5‐domain, which allows for the calculation of quality‐adjusted life‐years (QALYs). Incremental cost‐effectiveness ratios (ICERs) are presented, which represent the additional cost per QALY gained over a 48‐week time horizon. Sensitivity analyses are presented assessing the impact of variations in the analytical approach and assumptions on the cost‐effectiveness estimates. Results: The mean cost and QALYs were higher in the TC group: £4,198 versus £2,000 and 0.602 versus 0.561. These values yielded an ICER of £53,948 per QALY. Bootstrapped uncertainty analysis suggests that the TC has a 0.07 probability of being cost‐effective at a £20,000 threshold. Stratified analysis suggests that with certain costs being controlled, an ICER of £24,639 can be calculated for patients with a higher degree of disease severity. Conclusion: A tight control strategy to treat PsA is an effective intervention in the treatment pathway; however, this study does not find tight control to be cost‐effective in most analyses. Lower drug prices, targeting polyarthritis patients, or reducing the frequency of rheumatology visits may improve value for money metrics in future studies.</p

River Piracy and Drainage Basin Reorganization Led by Climate-Driven Glacier Retreat

River piracy - the diversion of the headwaters of one stream into another one - can dramatically change the routing of water and sediment, with a profound effect on landscape evolution. Stream piracy has been investigated in glacial environments, but so far it has mainly been studied over Quaternary or longer timescales. Here we document how retreat of Kaskawulsh Glacier - one of Canada\u27s largest glaciers - abruptly and radically altered the regional drainage pattern in spring 2016. We use a combination of hydrological measurements and drone-generated digital elevation models to show that in late May 2016, meltwater from the glacier was re-routed from discharge in a northward direction into the Bering Sea, to southward into the Pacific Ocean. Based on satellite image analysis and a signal-to-noise ratio as a metric of glacier retreat, we conclude that this instance of river piracy was due to post-industrial climate change. Rapid regional drainage reorganizations of this type can have profound downstream impacts on ecosystems, sediment and carbon budgets, and downstream communities that rely on a stable and sustained discharge. We suggest that the planforms of Slims and Kaskawulsh rivers will adjust in response to altered flows, and the future Kaskawulsh watershed will extend into the now-abandoned headwaters of Slims River and eventually capture the Kluane Lake drainage. © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved

The cytoplasmic 60 kDa progesterone receptor isoform predominates in the human amniochorion and placenta at term

<p>Abstract</p> <p>Background</p> <p>The mechanism that initiates human parturition has been proposed to be 'functional progesterone withdrawal' whereby the 116 kDa B-isoform of the progesterone receptor (PR-B) switches in favour of the 94 kDa A-isoform (PR-A) in reproductive tissues. Recently, other PR isoforms, PR-S, PR-C and PR-M generated from the same gene have been identified and partially characterised.</p> <p>Methods and Results</p> <p>Using immunohistochemical, western blotting and RT-PCR techniques, evidence is provided that indicates the major PR isoform present in human term fetal membranes (amnion and chorion) and syncytiotrophoblast of the placenta is neither of the classical nuclear PR-B or PR-A isoforms but is the N-terminally truncated 60 kDa PR-C isoform. Evidence is also provided that this 60 kDa isoform resides in the cytoplasm of the expressing cell types. Data are also presented to show that PR-B, PR-A and PR-S isoforms are essentially absent from the amnion and chorion, whereas PR isoforms A, B, C and S are all present in the decidua, with PR-A being the major isoform. The syncytiotrophoblast of the placenta contains the cytoplasmic 60 kDa isoform, but not isoforms PR-A, PR-B or PR-S.</p> <p>Conclusion</p> <p>The major PR isoform in the amnion, chorion and placenta is a 60 kDa protein that could be PR-C, suggesting that the cytoplasmic isoform has a specific role in extra-embryonic tissues and may be involved in the regulation of human parturition.</p