Psoriatic Arthritis and Burden of Disease: Patient Perspectives from the Population-Based Multinational Assessment of Psoriasis and Psoriatic Arthritis (MAPP) Survey

Introduction: Psoriatic arthritis (PsA) is underdiagnosed and has a substantial impact on quality of life, disability, and work productivity. The population-based Multinational Assessment of Psoriasis and Psoriatic Arthritis (MAPP) survey examined the impact of PsA on patients’ activities of daily living and unmet treatment needs. Methods: This large-scale, random digit dialing, telephone survey of patients self-reporting a diagnosis of psoriasis and/or PsA was conducted in North America and Europe. Results: In all, 3426 patients participated in the survey, including 712 (21%) who identified themselves as having PsA. Over half of the patients reported severe PsA involving more than four joints. Eighty-three percent of patients with PsA visited a health-care provider within the past 12 months. Approximately one-quarter saw their primary care provider or dermatologist most often for their disease; 37% responded that their rheumatologist was the health-care provider seen most often for PsA. Patients with PsA reported a substantial impact of disease on physical function. One-third of patients with PsA reported missing work because of their disease and PsA impacted their ability to work full time. Over half of the patients with PsA (58%) reported receiving no treatment or topical therapy only, leaving their joint disease untreated. Factors associated with lack of adherence were perceived lack of efficacy and concerns about long-term safety. Conclusions: The MAPP survey confirms that PsA has a significant impact on physical function and activities of daily living. Undertreatment of PsA suggests a need for improved screening and diagnosis as well as education about treatment options and adherence

Subcellular heterogeneity of ryanodine receptor properties in ventricular myocytes with low T-tubule density

Rationale: In ventricular myocytes of large mammals, not all ryanodine receptor (RyR) clusters are associated with T-tubules (TTs); this fraction increases with cellular remodeling after myocardial infarction (MI). Objective: To characterize RyR functional properties in relation to TT proximity, at baseline and after MI. Methods: Myocytes were isolated from left ventricle of healthy pigs (CTRL) or from the area adjacent to a myocardial infarction (MI). Ca2+ transients were measured under whole-cell voltage clamp during confocal linescan imaging (fluo-3) and segmented according to proximity of TTs (sites of early Ca2+ release, F>F50 within 20 ms) or their absence (delayed areas). Spontaneous Ca2+ release events during diastole, Ca2+ sparks, reflecting RyR activity and properties, were subsequently assigned to either category. Results: In CTRL, spark frequency was higher in proximity of TTs, but spark duration was significantly shorter. Block of Na+/Ca2+ exchanger (NCX) prolonged spark duration selectively near TTs, while block of Ca2+ influx via Ca2+ channels did not affect sparks properties. In MI, total spark mass was increased in line with higher SR Ca2+ content. Extremely long sparks (>47.6 ms) occurred more frequently. The fraction of near-TT sparks was reduced; frequency increased mainly in delayed sites. Increased duration was seen in near-TT sparks only; Ca2+ removal by NCX at the membrane was significantly lower in MI. Conclusion: TT proximity modulates RyR cluster properties resulting in intracellular heterogeneity of diastolic spark activity. Remodeling in the area adjacent to MI differentially affects these RyR subpopulations. Reduction of the number of sparks near TTs and reduced local NCX removal limit cellular Ca2+ loss and raise SR Ca2+ content, but may promote Ca2+ waves

Histone deacetylases as new therapy targets for platinum-resistant epithelial ovarian cancer

Introduction: In developed countries, ovarian cancer is the fourth most common cancer in women. Due to the nonspecific symptomatology associated with the disease many patients with ovarian cancer are diagnosed late, which leads to significantly poorer prognosis. Apart from surgery and radiotherapy, a substantial number of ovarian cancer patients will undergo chemotherapy and platinum based agents are the mainstream first-line therapy for this disease. Despite the initial efficacy of these therapies, many women relapse; therefore, strategies for second-line therapies are required. Regulation of DNA transcription is crucial for tumour progression, metastasis and chemoresistance which offers potential for novel drug targets. Methods: We have reviewed the existing literature on the role of histone deacetylases, nuclear enzymes regulating gene transcription. Results and conclusion: Analysis of available data suggests that a signifant proportion of drug resistance stems from abberant gene expression, therefore HDAC inhibitors are amongst the most promising therapeutic targets for cancer treatment. Together with genetic testing, they may have a potential to serve as base for patient-adapted therapies

Report of the Skin Research Working Groups from the GRAPPA 2017 Annual Meeting.

At the 2017 annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA), the International Dermatology Outcome Measures (IDEOM) psoriasis working group presented an overview of its cutaneous domain of psoriatic arthritis (PsA) projects. First, the group presented an overview of IDEOM's work to establish psoriasis outcome measures that satisfy the needs of all those involved. Second, the group discussed replacements for the Psoriasis Area and Severity Index (PASI) that can be used in clinical practice, including data that support the use of the physician's global assessment × body surface area measurement score as a PASI surrogate. Third, the group discussed the contribution of skin disease to composite measures of PsA. Last, the group summarized the National Psoriasis Foundation's efforts to establish treat-to-target strategies for psoriasis care

Measurement of the inclusive and dijet cross-sections of b-jets in pp collisions at sqrt(s) = 7 TeV with the ATLAS detector

The inclusive and dijet production cross-sections have been measured for jets containing b-hadrons (b-jets) in proton-proton collisions at a centre-of-mass energy of sqrt(s) = 7 TeV, using the ATLAS detector at the LHC. The measurements use data corresponding to an integrated luminosity of 34 pb^-1. The b-jets are identified using either a lifetime-based method, where secondary decay vertices of b-hadrons in jets are reconstructed using information from the tracking detectors, or a muon-based method where the presence of a muon is used to identify semileptonic decays of b-hadrons inside jets. The inclusive b-jet cross-section is measured as a function of transverse momentum in the range 20 < pT < 400 GeV and rapidity in the range |y| < 2.1. The bbbar-dijet cross-section is measured as a function of the dijet invariant mass in the range 110 < m_jj < 760 GeV, the azimuthal angle difference between the two jets and the angular variable chi in two dijet mass regions. The results are compared with next-to-leading-order QCD predictions. Good agreement is observed between the measured cross-sections and the predictions obtained using POWHEG + Pythia. MC@NLO + Herwig shows good agreement with the measured bbbar-dijet cross-section. However, it does not reproduce the measured inclusive cross-section well, particularly for central b-jets with large transverse momenta.Comment: 10 pages plus author list (21 pages total), 8 figures, 1 table, final version published in European Physical Journal

A comparison of customised and prefabricated insoles to reduce risk factors for neuropathic diabetic foot ulceration: a participant-blinded randomised controlled trial.

UNLABELLED: BACKGROUND: Neuropathic diabetic foot ulceration may be prevented if the mechanical stress transmitted to the plantar tissues is reduced. Insole therapy is one practical method commonly used to reduce plantar loads and ulceration risk. The type of insole best suited to achieve this is unknown. This trial compared custom-made functional insoles with prefabricated insoles to reduce risk factors for ulceration of neuropathic diabetic feet. METHOD: A participant-blinded randomised controlled trial recruited 119 neuropathic participants with diabetes who were randomly allocated to custom-made functional or prefabricated insoles. Data were collected at issue and six month follow-up using the F-scan in-shoe pressure measurement system. Primary outcomes were: peak pressure, forefoot pressure time integral, total contact area, forefoot rate of load, duration of load as a percentage of stance. Secondary outcomes were patient perceived foot health (Bristol Foot Score), quality of life (Audit of Diabetes Dependent Quality of Life). We also assessed cost of supply and fitting. Analysis was by intention-to-treat. RESULTS: There were no differences between insoles in peak pressure, or three of the other four kinetic measures. The custom-made functional insole was slightly more effective than the prefabricated insole in reducing forefoot pressure time integral at issue (27% vs. 22%), remained more effective at six month follow-up (30% vs. 24%, p=0.001), but was more expensive (UK £656 vs. £554, p<0.001). Full compliance (minimum wear 7 hours a day 7 days per week) was reported by 40% of participants and 76% of participants reported a minimum wear of 5 hours a day 5 days per week. There was no difference in patient perception between insoles. CONCLUSION: The custom-made insoles are more expensive than prefabricated insoles evaluated in this trial and no better in reducing peak pressure. We recommend that where clinically appropriate, the more cost effective prefabricated insole should be considered for use by patients with diabetes and neuropathy. TRIAL REGISTRATION: Clinical trials.gov (NCT00999635). Note: this trial was registered on completion

Algorithmic iteration for computational intelligence

Machine awareness is a disputed research topic, in some circles considered a crucial step in realising Artificial General Intelligence. Understanding what that is, under which conditions such feature could arise and how it can be controlled is still a matter of speculation. A more concrete object of theoretical analysis is algorithmic iteration for computational intelligence, intended as the theoretical and practical ability of algorithms to design other algorithms for actions aimed at solving well-specified tasks. We know this ability is already shown by current AIs, and understanding its limits is an essential step in qualifying claims about machine awareness and Super-AI. We propose a formal translation of algorithmic iteration in a fragment of modal logic, formulate principles of transparency and faithfulness across human and machine intelligence, and consider the relevance to theoretical research on (Super)-AI as well as the practical import of our results

Reducing anemia prevalence in Afghanistan: socioeconomic correlates and the particular role of agricultural assets

This research aims to examine the socio-economic correlates of anemia in women, and potential sources of iron in household diets in Afghanistan. It also examines whether ownership of agricultural (particularly livestock) assets and their use in food production has a role in alleviating anaemia, especially where local markets may be inadequate. We analyse data from the 2010/11 Afghanistan Multiple Indicator Cluster Survey, estimating a logistic regression to examine how anemia status of women is associated with socio-economic covariates. A key result found is that sheep ownership has a protective effect in reducing anemia (prevalence odds ratio of sheep ownership on anemia of 0.83, 95% confidence interval (CI): 0.73–0.94) after controlling for wealth and other covariates. This association is found to be robust to alternative model specifications. Given the central role of red meat in heme iron provision and absorption of non-heme iron, we hypothesise that sheep ownership promotes mutton consumption from own-production in a setting where market-sourced provision of nutritious food is a challenge. We then use the 2011/12 National Risk and Vulnerability Assessment household data to understand the Afghan diet from the perspective of dietary iron provision, and to understand interactions between own-production, market sourcing and mutton consumption. Sheep ownership is found to increase the likelihood that a household consumed mutton (odds ratio of 1.27, 95% CI: 1.15–1.42), the number of days in the week that mutton was consumed (prevalence rate ratio of 1.24. 95% CI: 1.12–1.37) and the quantity of mutton consumed (7 grams/person/week). In the subsample of mutton consumers, households sourcing mutton mostly from own production consumed mutton 1.5 days more frequently on average than households relying on market purchase, resulting in 100 grams per person per week higher mutton intake. Thus this analysis lends support to the notion that the linkage between sheep ownership and anemia risk is at least partly due to consumption arising from own-production in the presence of market incompleteness

Autocrine Activation of the MET Receptor Tyrosine Kinase in Acute Myeloid Leukemia

Although the treatment of acute myeloid leukemia (AML) has improved significantly, more than half of all patients develop disease that is refractory to intensive chemotherapy. Functional genomics approaches offer a means to discover specific molecules mediating aberrant growth and survival of cancer cells. Thus, using a loss-of-function RNA interference genomic screen, we identified aberrant expression of the hepatocyte growth factor (HGF) as a critical factor in AML pathogenesis. We found HGF expression leading to autocrine activation of its receptor tyrosine kinase, MET, in nearly half of the AML cell lines and clinical samples studied. Genetic depletion of HGF or MET potently inhibited the growth and survival of HGF-expressing AML cells. However, leukemic cells treated with the specific MET kinase inhibitor crizotinib developed resistance due to compensatory upregulation of HGF expression, leading to restoration of MET signaling. In cases of AML where MET is coactivated with other tyrosine kinases, such as fibroblast growth factor receptor 1 (FGFR1), concomitant inhibition of FGFR1 and MET blocked compensatory HGF upregulation, resulting in sustained logarithmic cell kill both in vitro and in xenograft models in vivo. Our results demonstrate widespread dependence of AML cells on autocrine activation of MET, as well as the importance of compensatory upregulation of HGF expression in maintaining leukemogenic signaling by this receptor. We anticipate that these findings will lead to the design of additional strategies to block adaptive cellular responses that drive compensatory ligand expression as an essential component of the targeted inhibition of oncogenic receptors in human cancers

Social representations of diagnosis in the consultation

Observations of physiotherapy consultations and qualitative interviews with patients were conducted to explore the clinical explanation for sciatic pain. We report three themes which illustrate the contested and negotiated order of the clinical explanation: anchoring, resistance and normalisation. We show using the theory of social representations how the social order in the physiotherapy consultation is maintained, contested and rearticulated. We highlight the importance of agency in patients’ ability to resist the clinical explanation and in turn shape the clinical discourse within the consultation. Social representations offer insights into how the world is viewed by different individuals, in our case physiotherapists and patients with sciatic pain symptoms. The negotiation about the diagnosis reveals the malleable and socially constructed nature of pain and the meaning making process underpinning it. The study has implications for understanding inequalities in the consultation and the key ingredients of consensus