The validity and responsiveness of three quality of life measures in the assessment of psoriasis patients: results of a phase II study

BACKGROUND: Patient-reported outcome (PROs) measures are being used more frequently in investigational studies of treatments for moderate to severe plaque psoriasis. The objective of this study was to examine the relationships among the Dermatology Life Quality Index (DLQI), the Short Form 36 (SF-36), and the EuroQOL 5D (EQ-5D) and to assess their validity, responsiveness, and estimates of minimum important differences. METHODS: A Phase II, randomized, double-blind, parallel group, placebo-controlled, multi-center clinical trial assessed the clinical efficacy and safety of two doses of subcutaneously administered adalimumab vs. placebo for 12 weeks in the treatment of 147 patients with moderate to severe plaque psoriasis. This study provided the opportunity to evaluate the validity and responsiveness to change in clinical status of PROs instruments. Patients completed the DLQI, SF-36, and EQ-5D questionnaires at baseline and at 12 weeks. Blinded investigators assessed the Psoriasis Area and Severity Index (PASI) scores and the Physician's Global Assessment (PGA) scores of enrolled patients. The responsiveness of the measures to changes in the clinical endpoints from baseline to Week 12 was assessed. Estimates of minimum important differences (MID) were derived. All analyses were performed with blinded data; findings and conclusions were not biased based on treatment condition. RESULTS: The dermatology-specific DLQI was highly correlated to clinical endpoints at baseline and at Week 12, and was the most responsive PRO to changes in endpoints. Compared with the SF-36, the EQ-5D index score and VAS scores were generally more highly correlated with clinical endpoints, but displayed about the same degree of responsiveness. The most responsive SF-36 scales were the Bodily Pain and Social Functioning scales. Estimates of the MID for the DLQI ranged from 2.3–5.7 and for the SF-36 Physical Component Summary (PCS) score ranged from 2.5–3.9. CONCLUSION: This study provides support for the continued use of the DLQI and SF-36 PCS in the assessment of treatments for psoriasis. On the basis of the results from this trial, the EQ-5D should be considered as a general PRO measure in future clinical trials of patients with moderate to severe plaque psoriasis

Theory of deeply virtual Compton scattering on the nucleon

We compute the cross section for leptoproduction of the real photon off the nucleon, which is sensitive to the deeply virtual Compton scattering amplitude with power accuracy. Our considerations go beyond the leading twist and involve the complete analysis in the twist-three approximation. We discuss consequences of the target and lepton beam polarizations for accessing the generalized parton distributions from experimental measurements of the azimuthal angular dependence of the final state photon or nucleon. We introduce several sets of asymmetries, defined as Fourier moments with respect to the azimuthal angle, which allow for a clear separation of the twist-two and -three sectors. Relying on a simple ansatz for the generalized parton distributions, we give quantitative estimates for azimuthal and spin asymmetries, discuss the uncertainties of these predictions brought in by radiative corrections, and compare them with experimental data as well as other theoretical expectations. Furthermore, we derive a general parametrization of the DVCS amplitudes in the region of small Bjorken variable.Comment: 76 pages, LaTeX, 16 figures, 3 tables, minor correction

Search for fourth generation quarks and leptons at the Fermilab Tevatron and CERN Large Hadron Collider

If next generations of heavy quarks and leptons exist within the standard model (SM), they can manifest themselves in Higgs boson production at the Tevatron and the LHC, before being actually observed. This generation leads to an increase of the Higgs boson production cross section via gluon fusion at hadron colliders by a factor 6-9. So, the study of this process at the Tevatron and LHC can finally fix the number of generations in the SM. Using the $WW^*$ Higgs boson decay channel, the studies at the upgraded Tevatron will answer the question about the next generation for mass values 135 GeV \lsim M_H\lsim 190 GeV. Studying the $\tau\bar{\tau}$ channel we show its large potential for the study of the Higgs boson at the LHC even in the standard case of three generations. At the Tevatron, studies in this channel could explore the mass range 110-140 GeV.Comment: 13 pages, 4 figures, LaTeX/RevTeX, final version accepted for publicatio

Photon and Graviton Mass Limits

Efforts to place limits on deviations from canonical formulations of electromagnetism and gravity have probed length scales increasing dramatically over time.Historically, these studies have passed through three stages: (1) Testing the power in the inverse-square laws of Newton and Coulomb, (2) Seeking a nonzero value for the rest mass of photon or graviton, (3) Considering more degrees of freedom, allowing mass while preserving explicit gauge or general-coordinate invariance. Since our previous review the lower limit on the photon Compton wavelength has improved by four orders of magnitude, to about one astronomical unit, and rapid current progress in astronomy makes further advance likely. For gravity there have been vigorous debates about even the concept of graviton rest mass. Meanwhile there are striking observations of astronomical motions that do not fit Einstein gravity with visible sources. "Cold dark matter" (slow, invisible classical particles) fits well at large scales. "Modified Newtonian dynamics" provides the best phenomenology at galactic scales. Satisfying this phenomenology is a requirement if dark matter, perhaps as invisible classical fields, could be correct here too. "Dark energy" {\it might} be explained by a graviton-mass-like effect, with associated Compton wavelength comparable to the radius of the visible universe. We summarize significant mass limits in a table.Comment: 42 pages Revtex4. This version contains corrections and changes contained in the published version, Rev. Mod. Phys. 82, 939-979 (2010), with a few addition

Physics of B_c mesons

In the framework of potential models for heavy quarkonium the mass spectrum for the system ($\bar b c$) is considered. Spin-dependent splittings, taking into account a change of a constant for effective coulomb interaction between the quarks, and widths of radiative transitions between the ($\bar b c$) levels are calculated. In the framework of QCD sum rules, masses of the lightest vector $B_c^*$ and pseudoscalar $B_c$ states are estimated, scaling relation for leptonic constants of heavy quarkonia is derived, and the leptonic constant $f_{B_c}$ is evaluated. The $B_c$ decays are considered in the framework of both the potential models and the QCD sum rules, where the significance of Coulomb-like corrections is shown. The relations, following from the approximate spin symmetry for the heavy quarks in the heavy quarkonium, are analysed for the form factors of the semileptonic weak exclusive decays of $B_c$. The $B_c$ lifetime is evaluated with the account of the corrections to the spectator mechanism of the decay, because of the quark binding into the meson. The total and differential cross sections of the $B_c$ production in different interactions are calculated. The analytic expressions for the fragmentational production cross sections of $B_c$ are derived. The possibility of the practical $B_c$ search in the current and future experiments at electron-positron and hadron colliders is analysed.Comment: 81 page, latex, ihep.sty is required and attached in the end of the file after \end{document}, figures are not availabl

SEARCHING FOR COLD DARK MATTER

The differential cross-section for the elastic scattering of the lightest supersymmetric particle (LSP) with nuclear targets is calculated in the context of currently fashionable supersymmetric theories (SUSY). An effective four fermion interaction is constructed by considering i) $Z^0$ exchange ii)s-quark exchange and iii) Higgs exchange. It is expressed in terms of the form factors $f^0_V,f^0_A, f^0_S$ (isoscalar) and $f^1_V,f^1_A$ and $f^1_S$ (isovector) which contain all the information of the underlining theory. Numerical values were obtained using representative input parameters in the constrained parameter space of SUSY phenomenology. Both the coherent and for odd-A nuclei the incoherent (spin) nuclear matrix elements were evaluated for nuclei of experimental interest. The spin matrix elements tend to dominate for odd nuclei but the coherent matrix elements become more important in all other cases. For the coherent part the Higgs contribution competes with the Z- and s-quark contributions. Cross-sections as high as $10^{-37} cm^2$ have been obtained.Comment: Latex file, 25 pages , 2 figures (available by fax

Recommendations for diagnosing and managing individuals with glutaric aciduria type 1: Third revision

Glutaric aciduria type 1 is a rare inherited neurometabolic disorder of lysine metabolism caused by pathogenic gene variations in GCDH (cytogenic location: 19p13.13), resulting in deficiency of mitochondrial glutaryl-CoA dehydrogenase (GCDH) and, consequently, accumulation of glutaric acid, 3-hydroxyglutaric acid, glutaconic acid and glutarylcarnitine detectable by gas chromatography/mass spectrometry (organic acids) and tandem mass spectrometry (acylcarnitines). Depending on residual GCDH activity, biochemical high and low excreting phenotypes have been defined. Most untreated individuals present with acute onset of striatal damage before age 3 (to 6) years, precipitated by infectious diseases, fever or surgery, resulting in irreversible, mostly dystonic movement disorder with limited life expectancy. In some patients, striatal damage develops insidiously. In recent years, the clinical phenotype has been extended by the finding of extrastriatal abnormalities and cognitive dysfunction, preferably in the high excreter group, as well as chronic kidney failure. Newborn screening is the prerequisite for pre-symptomatic start of metabolic treatment with low lysine diet, carnitine supplementation and intensified emergency treatment during catabolic episodes, which, in combination, have substantially improved neurologic outcome. In contrast, start of treatment after onset of symptoms cannot reverse existing motor dysfunction caused by striatal damage. Dietary treatment can be relaxed after the vulnerable period for striatal damage, that is, age 6 years. However, impact of dietary relaxation on long-term outcomes is still unclear. This third revision of evidence-based recommendations aims to re-evaluate previous recommendations (Boy et al., J Inherit Metab Dis, 2017;40(1):75-101; Kolker et al., J Inherit Metab Dis 2011;34(3):677-694; Kolker et al., J Inherit Metab Dis, 2007;30(1):5-22) and to implement new research findings on the evolving phenotypic diversity as well as the impact of non-interventional variables and treatment quality on clinical outcomes

A hepatoprotective Lindera obtusiloba extract suppresses growth and attenuates insulin like growth factor-1 receptor signaling and NF-kappaB activity in human liver cancer cell lines

<p>Abstract</p> <p>Background</p> <p>In traditional Chinese and Korean medicine, an aqueous extract derived from wood and bark of the Japanese spice bush <it>Lindera obtusiloba </it>(<it>L.obtusiloba</it>) is applied to treat inflammations and chronic liver diseases including hepatocellular carcinoma. We previously demonstrated anti-fibrotic effects of <it>L.obtusiloba </it>extract in hepatic stellate cells. Thus, we here consequently examine anti-neoplastic effects of <it>L.obtusiloba </it>extract on human hepatocellular carcinoma (HCC) cell lines and the signaling pathways involved.</p> <p>Methods</p> <p>Four human HCC cell lines representing diverse stages of differentiation were treated with <it>L.obtusiloba </it>extract, standardized according to its known suppressive effects on proliferation and TGF-β-expression. Beside measurement of proliferation, invasion and apoptosis, effects on signal transduction and NF-κB-activity were determined.</p> <p>Results</p> <p><it>L.obtusiloba </it>extract inhibited proliferation and induced apoptosis in all HCC cell lines and provoked a reduced basal and IGF-1-induced activation of the IGF-1R signaling cascade and a reduced transcriptional NF-κB-activity, particularly in the poorly differentiated SK-Hep1 cells. Pointing to anti-angiogenic effects, <it>L.obtusiloba </it>extract attenuated the basal and IGF-1-induced expression of hypoxia inducible factor-1α, vascular endothelial growth factor, peroxisome proliferator-activated receptor-γ, cyclooxygenase-2 and inducible nitric oxide synthase.</p> <p>Conclusions</p> <p>The traditional application of the extract is confirmed by our experimental data. Due to its potential to inhibit critical receptor tyrosine kinases involved in HCC progression via the IGF-1 signaling pathway and NF-κB, the standardized <it>L.obtusiloba </it>extract should be further analysed for its active compounds and explored as (complementary) treatment option for HCC.</p

Adalimumab medium-term dosing strategy in moderate-to-severe hidradenitis suppurativa: integrated results from the phase III randomized placebo-controlled PIONEER trials

Background: Weekly adalimumab (Humira®) is approved for the treatment of hidradenitis suppurativa (HS) based on the 12-week placebo-controlled periods of the two phase III PIONEER trials. Objectives: Using PIONEER integrated trial results, we aimed to evaluate the optimal medium-term adalimumab maintenance dosing strategy for moderate-to-severe HS. Methods: Each trial had two double-blind periods; 12-week Period A and 24-week Period B. Patients randomized to adalimumab 40 mg every week (ADAew) (Period A), were rerandomized in Period B to ADAew (ADAew/ew), ADA every other week (ADAew/eow), or placebo (ADAew/pbo). Placebo-randomized patients were reassigned in Period B to ADAew (PIONEER I) or placebo (PIONEER II). The primary outcome was HS Clinical Response (HiSCR). Patients who lost response during Period B were discontinued from the study and offered an option to enter the open-label extension (OLE) to receive ADAew. Results are reported across the two study periods, and data were combined from the two study periods and the OLE. Results: For week-12 HiSCR achievers, the HiSCR week-36 rate was 48·1% (ADAew/ew) vs. 46·2% (ADAew/eow) and 32·1% (ADAew/pbo). Combining (post hoc) these patients with week-12 partial responders further differentiated outcomes in Period B (ADAew/ew 55·7% vs. ADAew/eow 40·0% and ADAew/pbo 30·1%). Period-B adverse-event rates were ADAew/ew 59·6% vs. ADAew/eow 57·4% and ADAew/pbo 65·0%. One patient (ADAew/ew) reported a serious infection. Conclusions: Weekly adalimumab treatment, effective throughout 36 weeks, was the optimal maintenance medium-term dosing regimen for this population. At least partial response after 12 weeks with continued weekly dosing had better outcomes than dose reduction or interruption. Patients who do not show at least a partial response to weekly adalimumab by week 12 are unlikely to benefit from continued therapy. No new safety risks were identified. What's already known about this topic?. Hidradenitis suppurativa (HS) is a chronic inflammatory disease, commonly misinterpreted as an infection and treated with long-term antibiotic regimens or surgical incisions. Based on the chronicity of HS and the lack of evidence for efficacious and safe long-term HS treatments, it is important to evaluate medium- to long-term therapies for HS. Weekly adalimumab (Humira®) is approved for the treatment of moderate-to-severe HS based on the two phase III PIONEER trials. What does this study add?. This study pooled data from the two PIONEER trials, providing a more robust assessment of outcomes. After at least partial treatment success with weekly adalimumab short-term therapy (12 weeks), continuing weekly dosing during the subsequent 24 weeks had better outcomes than dose reduction or treatment interruption. Patients who do not show at least a partial response to weekly adalimumab by week 12 are unlikely to benefit from continued therapy