Report from the fourth international consensus meeting to harmonize core outcome measures for atopic eczema/dermatitis clinical trials (HOME initiative).

This article is a report of the fourth meeting of the Harmonising Outcome Measures for Eczema (HOME) initiative held in Malmö, Sweden on 23-24 April 2015 (HOME IV). The aim of the meeting was to achieve consensus over the preferred outcome instruments for measuring patient-reported symptoms and quality of life for the HOME core outcome set for atopic eczema (AE). Following presentations, which included data from systematic reviews, consensus discussions were held in a mixture of whole group and small group discussions. Small groups were allocated a priori to ensure representation of different stakeholders and countries. Decisions were voted on using electronic keypads. For the patient-reported symptoms, the group agreed by vote that itch, sleep loss, dryness, redness/inflamed skin and irritated skin were all considered essential aspects of AE symptoms. Many instruments for capturing patient-reported symptoms were discussed [including the Patient-Oriented SCOring Atopic Dermatitis index, Patient-Oriented Eczema Measure (POEM), Self-Administered Eczema Area and Severity Index, Itch Severity Scale, Atopic Dermatitis Quickscore and the Nottingham Eczema Severity Score] and, by consensus, POEM was selected as the preferred instrument to measure patient-reported symptoms. Further work is needed to determine the reliability and measurement error of POEM. Further work is also required to establish the importance of pain/soreness and the importance of collecting information regarding the intensity of symptoms in addition to their frequency. Much of the discussion on quality of life concerned the Dermatology Life Quality Index and Quality of Life Index for Atopic Dermatitis; however, consensus on a preferred instrument for measuring this domain could not be reached. In summary, POEM is recommended as the HOME core outcome instrument for measuring AE symptoms.

On the theory of drainage area for regular and non-regular points.

The drainage area is an important, non-local property of a landscape, which controls surface and subsurface hydrological fluxes. Its role in numerous ecohydrological and geomorphological applications has given rise to several numerical methods for its computation. However, its theoretical analysis has lagged behind. Only recently, an analytical definition for the specific catchment area was proposed (Gallant & Hutchinson. 2011 Water Resour. Res.47, W05535. (doi:10.1029/2009WR008540)), with the derivation of a differential equation whose validity is limited to regular points of the watershed. Here, we show that such a differential equation can be derived from a continuity equation (Chen et al. 2014 Geomorphology219, 68-86. (doi:10.1016/j.geomorph.2014.04.037)) and extend the theory to critical and singular points both by applying Gauss's theorem and by means of a dynamical systems approach to define basins of attraction of local surface minima. Simple analytical examples as well as applications to more complex topographic surfaces are examined. The theoretical description of topographic features and properties, such as the drainage area, channel lines and watershed divides, can be broadly adopted to develop and test the numerical algorithms currently used in digital terrain analysis for the computation of the drainage area, as well as for the theoretical analysis of landscape evolution and stability.

Is the kinetic equation for turbulent gas-particle flows ill posed?

This paper is about the kinetic equation for gas-particle flows, in particular its well-posedness and realizability and its relationship to the generalized Langevin model (GLM) probability density function (PDF) equation. Previous analyses, e.g. [J.-P. Minier and C. Profeta, Phys. Rev. E 92, 053020 (2015)PLEEE81539-375510.1103/PhysRevE.92.053020], have concluded that this kinetic equation is ill posed, that in particular it has the properties of a backward heat equation, and as a consequence, its solution will in the course of time exhibit finite-time singularities. We show that this conclusion is fundamentally flawed because it ignores the coupling between the phase space variables in the kinetic equation and the time and particle inertia dependence of the phase space diffusion tensor. This contributes an extra positive diffusion that always outweighs the negative diffusion associated with the dispersion along one of the principal axes of the phase space diffusion tensor. This is confirmed by a numerical evaluation of analytic solutions of these positive and negative contributions to the particle diffusion coefficient along this principal axis. We also examine other erroneous claims and assumptions made in previous studies that demonstrate the apparent superiority of the GLM PDF approach over the kinetic approach. In so doing, we have drawn attention to the limitations of the GLM approach, which these studies have ignored or not properly considered, to give a more balanced appraisal of the benefits of both PDF approaches.

Differential effect of alpha-syntrophin knockout on aquaporin-4 and Kir4.1 expression in retinal macroglial cells in mice.

Aquaporin-4 water channels and the inwardly rectifying potassium channels Kir4.1 are coexpressed in a highly polarized manner at the perivascular and subvitreal endfeet of retinal Müller cells and astrocytes. The present study was aimed at resolving the anchoring mechanisms responsible for the coexpression of these molecules. Both aquaporin-4 and Kir4.1 contain PDZ-domain binding motifs at their C-termini and it was recently shown that mice with targeted disruption of the dystrophin gene display altered distribution of aquaporin-4 and Kir4.1 in the retina. To test our hypothesis that alpha-syntrophin (a PDZ-domain containing protein of the dystrophin associated protein complex) is involved in aquaporin-4 and Kir4.1 anchoring in retinal cells, we studied the expression pattern of these molecules in alpha-syntrophin null mice. Judged by quantitative immunogold cytochemistry, deletion of the alpha-syntrophin gene causes a partial loss (by 70%) of aquaporin-4 labeling at astrocyte and Müller cell endfeet but no decrease in Kir4.1 labeling at these sites. These findings suggest that alpha-syntrophin is not involved in the anchoring of Kir4.1 and only partly responsible for the anchoring of aquaporin-4 in retinal endfeet membranes. Furthermore we show that wild type and alpha-syntrophin null mice exhibit strong beta1 syntrophin labeling at perivascular and subvitreal Müller cell endfeet, raising the possibility that beta1 syntrophin might be involved in the anchoring of Kir4.1 and the alpha-syntrophin independent pool of aquaporin-4.

Signaling to the epithelium is not sufficient to mediate all of the effects of transforming growth factor beta and bone morphogenetic protein 4 on murine embryonic lung development.

Many studies have suggested that transforming growth factor beta (TGF-beta) and bone morphogenetic protein 4 (Bmp4) regulate early development of the lung. In this study, administration of growth factors directly into the lumen of lungs grown in organ culture was used to limit their activity to the epithelium and test the hypothesis that signaling to the epithelium is sufficient to mediate the known effects of TGF-beta and BMP-4 on early lung development. Addition of TGF-beta1, beta2, or beta3 to the medium surrounding lungs grown in organ culture resulted in decreased branching, reduced cell proliferation, accumulation of alpha-smooth muscle actin protein (alpha-SMA) in the mesenchyme, and decreased expression of a marker for respiratory epithelium, surfactant protein-C (Sp-C). When TGF-beta1 was restricted to the epithelium, accumulation of alpha-SMA and inhibition of Sp-C expression were not observed but branching and proliferation were inhibited. In contrast, branching was not inhibited in lungs where TGF-beta2 or TGF-beta3 were restricted to the epithelium suggesting differences in the mechanism of signaling by TGF-beta1, TGF-beta2 or TGF -beta3 in lung. Addition of Bmp4 to the medium surrounding lungs grown in organ culture stimulated cell proliferation and branching morphogenesis; however, direct injection of Bmp4 into the lung lumen had no effect on proliferation or branching. Based on these data and data from mesenchyme-free cultures, we propose that the mesenchyme influences growth factor signaling in the lung.

Quality of life and patient preference for sequential versus continuous combined HRT: the UK Kliofem multicenter study experience. UK Continuous Combined HRT Study Investigators.

Hormone replacement therapy (HRT) must be taken for many years to attain the long-term benefits on osteoporosis and cardiovascular disease. However, this level of compliance with HRT is rarely achieved. This analysis documents the effect of continuous combined HRT with Kliogest on the relief of menopausal symptoms, and the patient preference for HRT over a 9-month treatment period. A total of 2151 postmenopausal women, of whom 1435 were currently on sequential therapy and 716 had not been previously treated, were enrolled from 55 centers in the UK. Women received a daily tablet of Kliogest for 9 months. Quality of life was assessed using the Greene Climacteric Scale, and the women completed patient preference questionnaires. Treatment with continuous combined therapy was at least as effective as previous sequential regimens in alleviating menopausal symptoms. By the study conclusion, patient preference was strongly in favor of Kliogest with 91% of completers preferring it to their previous sequential therapy. Improved quality of life and patient preference for continuous combined therapy may encourage long-term compliance with treatment, allowing more women to experience the long-term beneficial effects of HRT on osteoporosis and cardiovascular disease.

Trace element distribution in the hair of some sickle cell anemia patients and controls.

Hair samples of some young sickle cell anemia (SCA) and control patients in Nigeria were analyzed for 12 elements, viz, Se, Hg, Cr, Fe, Zn, Co, Cu, Br, As, Sb, Na, and Sc, using Instrumental Neutron Activation Analysis (INAA). With the exception of Cu, which was found to be significantly higher in the hair of SCA patients (at the 0.05 level of the t-test), there were generally no significant differences in elemental concentrations within the two groups. A preliminary study of the elemental contents of the fingernails of the same subjects showed a higher abundance of most of the elements in nail than in hair. These preliminary results were compared with similar studies from some other parts of the world.

Drift-free kinetic equations for turbulent dispersion.

The dispersion of passive scalars and inertial particles in a turbulent flow can be described in terms of probability density functions (PDFs) defining the statistical distribution of relevant scalar or particle variables. The construction of transport equations governing the evolution of such PDFs has been the subject of numerous studies, and various authors have presented formulations for this type of equation, usually referred to as a kinetic equation. In the literature it is often stated, and widely assumed, that these PDF kinetic equation formulations are equivalent. In this paper it is shown that this is not the case, and the significance of differences among the various forms is considered. In particular, consideration is given to which form of equation is most appropriate for modeling dispersion in inhomogeneous turbulence and most consistent with the underlying particle equation of motion. In this regard the PDF equations for inertial particles are considered in the limit of zero particle Stokes number and assessed against the fully mixed (zero-drift) condition for fluid points. A long-standing question regarding the validity of kinetic equations in the fluid-point limit is answered; it is demonstrated formally that one version of the kinetic equation (derived using the Furutsu-Novikov method) provides a model that satisfies this zero-drift condition exactly in both homogeneous and inhomogeneous systems. In contrast, other forms of the kinetic equation do not satisfy this limit or apply only in a limited regime.

Comment on "Characterization of excess electrons in water-cluster anions by quantum simulations".

The conclusion by Turi et al. (Reports, 5 August 2005, p. 914) that all experimental spectral and energetic data on water-cluster anions point toward surface-bound electrons is overstated. Comparison of experimental vertical detachment energies with their calculated values for (H2O)n- clusters with surface-bound and internalized electrons supports previous arguments that both types of clusters exist.

Observation of large water-cluster anions with surface-bound excess electrons.

Anionic water clusters have long been studied to infer properties of the bulk hydrated electron. We used photoelectron imaging to characterize a class of (H2O)n- and (D2O)n- cluster anions (n

Addiction Severity Index: experience in the field.

Since its introduction in 1979, the Addiction Severity Index (ASI) has become one of the world's most widely used instruments in substance abuse treatment and research. Its wide acceptance suggests that enhancements of the ASI based upon users' experience would be of considerable value to clinicians and researchers. ASI users are the best source of information regarding the strengths and weaknesses of the instrument, adequacy of the ASI manual, requirements for training ASI interviewers, etc. This paper reports findings from a survey of 25 ASI users in the United States. Topics covered include reasons for selecting the ASI, modifications to the instrument made in response to site-specific requirements, and suggestions regarding enhancements which would promote its appropriate use by well-trained interviewers.

Curability of melanoma: a 25-year retrospective study.

On the basis of a study of 193 patients with localized melanoma followed for 25 years, it appears that such tumors are curable, in about 75% of the cases, by surgical removal alone. Of the 41 patients who died from this tumor, 92% succumbed during the first decade and the rest during the next five years. There were no deaths due to melanoma after 15 years of observation. Prophylactic lymph node dissection on these localized cases improved the survival statistics, but this may have been due to the elimination from this series of those with microscopic nodal metastases. A hopeless prognosis is unjustified in patients with primary melanoma because approximately only 25% of the patients in this series succumbed to this tumor during the 25 years of observation. Therapy in such individuals should be conservative until the diagnosis has been established by histopathologic examination. This policy minimizes unnecessary multilation and morbidity in benign lesions. The diagnosis should be suspected early and established or eliminated at the earliest possible time.

Hydrated electron dynamics: from clusters to bulk.

The electronic relaxation dynamics of size-selected (H2O)n-/(D2O)n[25 eaq-(s(dagger)) internal conversion lifetime.

The endometrial response to sequential and continuous combined oestrogen-progestogen replacement therapy.

OBJECTIVES: 1. To determine the prevalence of endometrial hyperplasia in postmenopausal women taking standard proprietary regimens of sequential oestrogen/progestogen; 2. to determine the effects of nine months treatment with an oral continuous combined regimen of 2 mg 17beta-oestradiol and 1 mg norethisterone acetate (Kliofem [Kliogest outside the UK]; Novo Nordisk, Denmark) on endometrial histology in postmenopausal women. DESIGN: An open, prospective study in postmenopausal women. SETTING: Fifty-four menopause clinics in the UK. PARTICIPANTS: 2028 postmenopausal women: 1312 (Group A) taking sequential oestrogen-progestogen hormone replacement therapy (HRT), and 716 (Group B) not taking HRT, were recruited. In Group A, 388 women took preparations containing 10 days of progestogen, 921 had 12 days, and 3 had 13 days per cycle. METHODS: Endometrial aspiration biopsies were taken towards the end of a three-month run-in period (Group A) or at study entry (Group B), before administration of the continuous combined HRT regimen. Biopsies were repeated at the end of the nine month treatment period. MAIN OUTCOME MEASURE: Endometrial histology. RESULTS: Initial endometrial biopsy data were available for 1106 women in Group A, who by the time of endometrial investigation had been taking HRT for a median duration of 2.56 years (5th to 95th centiles: 0.77 to 8.49 years). Data were available for 661 untreated women, who had no bleeding and had not taken HRT within the last year (Group B). Complex hyperplasia was found in 59 women (5.3%), and atypical hyperplasia in a further eight (0.7%) in Group A. In Group B there were no cases with complex hyperplasia, but one woman showed atypical hyperplasia (0.2%). At the end of the nine months of continuous combined therapy there was no case of hyperplasia among 1196 biopsies (upper 95% confidence limit of risk 0.31%) in women completing the study. Within this Group all of the women with complex hyperplasia arising during previous sequential HRT and who completed the study (n = 38) reverted to normal endometrial patterns. There was no case of endometrial carcinoma during the study. CONCLUSIONS: Despite taking standard regimens of sequential HRT containing at least 10 days of progestogen, there was a 5.3% prevalence of complex endometrial hyperplasia, and a 0.7% prevalence of atypical hyperplasia. However, continuous combined HRT (Kliofem) containing daily progestogen is not associated with an increased risk of hyperplasia and will convert the endometrium to normal in those with complex hyperplasia arising during previous sequential HRT.