Functional Evidence for Complement-activating Immune Complexes in the Skin of Patients with Bullous Pemphigoid

Previous immunofluorescent studies showing deposits of immunoglobulin and complement at the cutaneous basement membrane zone have provided evidence supporting a role for immune complexes in the pathogenesis of bullous pemphigoid. In this study the functional activity of the deposits has been examined using leukocyte attachment, a method for detecting and quantitating the biological activity of complement-activating immune complexes in tissues. When peripheral blood leukocytes suspended in serum complement were incubated with cryostat sections of lesional and adjacent normal-appearing skin from 9 patients with pemphigoid, skin from 11 normal controls and lesional skin from 14 nonpemphigoid disease controls there was significantly greater attachment of leukocytes to the basement membrane zone of lesional bullous pemphigoid skin compared to normal-appearing pemphigoid skin and skin of both control groups. A significant reduction in attachment in the absence of serum complement suggested the reaction was dependent on activation of complement by tissue-deposited complexes. Although leukocyte attachment was greater in lesional than normal-appearing pemphigoid skin, a comparison of the incidence and intensity of cutaneous IgG and complement immunofluorescence between the 2 groups showed no significant differences. Furthermore, no correlation between leukocyte attachment and serum titers of immunoglobulin G or complement-binding anti-basement membrane zone antibodies was observed. These results suggest that immune reactants in lesional pemphigoid skin are functional complement-activating immune complexes, that differences exist between the activity of complexes in lesional and normal-appearing pemphigoid skin and may explain why lesions develop at some sites and not others

Development and validation of a 5-year mortality prediction model using regularized regression and Medicare data

Purpose: De-implementation of low-value services among patients with limited life expectancy is challenging. Robust mortality prediction models using routinely collected health care data can enhance health care stakeholders' ability to identify populations with limited life expectancy. We developed and validated a claims-based prediction model for 5-year mortality using regularized regression methods. Methods: Medicare beneficiaries age 66 or older with an office visit and at least 12 months of pre-visit continuous Medicare A/B enrollment were identified in 2008. Five-year mortality was assessed through 2013. Secondary outcomes included 30-, 90-, and 180-day and 1-year mortality. Claims-based predictors, including comorbidities and indicators of disability, frailty, and functional impairment, were selected using regularized logistic regression, applying the least absolute shrinkage and selection operator (LASSO) in a random 80% training sample. Model performance was assessed and compared with the Gagne comorbidity score in the 20% validation sample. Results: Overall, 183 204 (24%) individuals died. In addition to demographics, 161 indicators of comorbidity and function were included in the final model. In the validation sample, the c-statistic was 0.825 (0.823-0.828). Median-predicted probability of 5-year mortality was 14%; almost 4% of the cohort had a predicted probability greater than 80%. Compared with the Gagne score, the LASSO model led to improved 5-year mortality classification (net reclassification index = 9.9%; integrated discrimination index = 5.2%). Conclusions: Our claims-based model predicting 5-year mortality showed excellent discrimination and calibration, similar to the Gagne score model, but resulted in improved mortality classification. Regularized regression is a feasible approach for developing prediction tools that could enhance health care research and evaluation of care quality

The Theta+ (1540) as a heptaquark with the overlap of a pion, a kaon and a nucleon

We study the very recently discovered Theta+ (1540) at SPring-8, at ITEP and at CLAS-Thomas Jefferson Lab. We apply the same RGM techniques that already explained with success the repulsive hard core of nucleon-nucleon, kaon-nucleon exotic scattering, and the attractive hard core present in pion-nucleon and pion-pion non-exotic scattering. We find that the K-N repulsion excludes the Theta+ as a K-N s-wave pentaquark. We explore the Theta+ as a heptaquark, equivalent to a N+pi+K borromean bound-state, with positive parity and total isospin I=0. We find that the kaon-nucleon repulsion is cancelled by the attraction existing both in the pion-nucleon and pion-kaon channels. Although we are not yet able to bind the total three body system, we find that the Theta^+ may still be a heptaquark state. We conclude with predictions that can be tested experimentally.Comment: 5 pages, 5 figures, 2 tables, submitted to Phys. Rev. D, rapid communicatio

An overview of research activities and achievement in Geotechnics from the Scottish Universities Geotechnics Network (SUGN)

ABSTRACT: Design of geotechnical systems is often challenging as it requires the understanding of complex soil behaviour and its influence on field-scale performance of geo-structures. To advance the scientific knowledge and the technological development in geotechnical engineering, a Scottish academic community, named Scottish Universities Geotechnics Network (SUGN), was established in 2001, composing of eight higher education institutions. The network gathers geotechnics researchers, including experimentalists as well as centrifuge, constitutive, and numerical modellers, to generate multiple synergies for building larger collaboration and wider research dissemination in and beyond Scotland. The paper will highlight the research excellence and leading work undertaken in SUGN emphasising some of the contribution to the geotechnical research community and some of the significant research outcomes. RÉSUMÉ: Conception de systèmes géotechniques est souvent difficile car elle nécessite la compréhension du comportement des sols complexes et son influence sur la performance échelle du champ de géo-structures. Pour faire avancer la connaissance scientifique et le développement technologique en ingénierie géotechnique, une communauté universitaire écossais, nommé écossais universités Géotechnique réseau (SUGN), a été créé en 2001, la composition des huit établissements d'enseignement supérieur. Le réseau réunit géotechnique chercheurs, y compris les expérimentateurs ainsi que centrifugeuse, constitutif, et les modélisateurs numériques, de générer des synergies multiples pour la construction de plus grande collaboration et une plus large diffusion de la recherche en Ecosse et au-delà. Le document mettra l'accent sur l'excellence de la recherche et de diriger le travail entrepris dans SUGN soulignant certains de la contribution à la communauté de recherche en géotechnique et certains des résultats importants de la recherche

Dialysis initiation, modality choice, access, and prescription: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference

Globally, the number of patients undergoing maintenance dialysis is increasing, yet throughout the world there is significant variability in the practice of initiating dialysis. Factors such as availability of resources, reasons for starting dialysis, timing of dialysis initiation, patient education and preparedness, dialysis modality and access, as well as varied \u201ccountry-specific\u201d factors significantly affect patient experiences and outcomes. As the burden of end-stage kidney disease (ESKD) has increased globally, there has also been a growing recognition of the importance of patient involvement in determining the goals of care and decisions regarding treatment. In January 2018, KDIGO (Kidney Disease: Improving Global Outcomes) convened a Controversies Conference focused on dialysis initiation, including modality choice, access, and prescription. Here we present a summary of the conference discussions, including identified knowledge gaps, areas of controversy, and priorities for research. A major novel theme represented during the conference was the need to move away from a \u201cone-size-fits-all\u201d approach to dialysis and provide more individualized care that incorporates patient goals and preferences while still maintaining best practices for quality and safety. Identifying and including patient-centered goals that can be validated as quality indicators in the context of diverse health care systems to achieve equity of outcomes will require alignment of goals and incentives between patients, providers, regulators, and payers that will vary across health care jurisdictions

Characteristics of the nuclear (18S, 5.8S, 28S and 5S) and mitochondrial (12S and 16S) rRNA genes of Apis mellifera (Insecta: Hymenoptera): structure, organization, and retrotransposable elements

As an accompanying manuscript to the release of the honey bee genome, we report the entire sequence of the nuclear (18S, 5.8S, 28S and 5S) and mitochondrial (12S and 16S) ribosomal RNA (rRNA)-encoding gene sequences (rDNA) and related internally and externally transcribed spacer regions of Apis mellifera (Insecta: Hymenoptera: Apocrita). Additionally, we predict secondary structures for the mature rRNA molecules based on comparative sequence analyses with other arthropod taxa and reference to recently published crystal structures of the ribosome. In general, the structures of honey bee rRNAs are in agreement with previously predicted rRNA models from other arthropods in core regions of the rRNA, with little additional expansion in non-conserved regions. Our multiple sequence alignments are made available on several public databases and provide a preliminary establishment of a global structural model of all rRNAs from the insects. Additionally, we provide conserved stretches of sequences flanking the rDNA cistrons that comprise the externally transcribed spacer regions (ETS) and part of the intergenic spacer region (IGS), including several repetitive motifs. Finally, we report the occurrence of retrotransposition in the nuclear large subunit rDNA, as R2 elements are present in the usual insertion points found in other arthropods. Interestingly, functional R1 elements usually present in the genomes of insects were not detected in the honey bee rRNA genes. The reverse transcriptase products of the R2 elements are deduced from their putative open reading frames and structurally aligned with those from another hymenopteran insect, the jewel wasp Nasonia (Pteromalidae). Stretches of conserved amino acids shared between Apis and Nasonia are illustrated and serve as potential sites for primer design, as target amplicons within these R2 elements may serve as novel phylogenetic markers for Hymenoptera. Given the impending completion of the sequencing of the Nasonia genome, we expect our report eventually to shed light on the evolution of the hymenopteran genome within higher insects, particularly regarding the relative maintenance of conserved rDNA genes, related variable spacer regions and retrotransposable elements

A novel formulation of inhaled sodium cromoglicate (PA101) in idiopathic pulmonary fibrosis and chronic cough: a randomised, double-blind, proof-of-concept, phase 2 trial

Background Cough can be a debilitating symptom of idiopathic pulmonary fibrosis (IPF) and is difficult to treat. PA101 is a novel formulation of sodium cromoglicate delivered via a high-efficiency eFlow nebuliser that achieves significantly higher drug deposition in the lung compared with the existing formulations. We aimed to test the efficacy and safety of inhaled PA101 in patients with IPF and chronic cough and, to explore the antitussive mechanism of PA101, patients with chronic idiopathic cough (CIC) were also studied. Methods This pilot, proof-of-concept study consisted of a randomised, double-blind, placebo-controlled trial in patients with IPF and chronic cough and a parallel study of similar design in patients with CIC. Participants with IPF and chronic cough recruited from seven centres in the UK and the Netherlands were randomly assigned (1:1, using a computer-generated randomisation schedule) by site staff to receive PA101 (40 mg) or matching placebo three times a day via oral inhalation for 2 weeks, followed by a 2 week washout, and then crossed over to the other arm. Study participants, investigators, study staff, and the sponsor were masked to group assignment until all participants had completed the study. The primary efficacy endpoint was change from baseline in objective daytime cough frequency (from 24 h acoustic recording, Leicester Cough Monitor). The primary efficacy analysis included all participants who received at least one dose of study drug and had at least one post-baseline efficacy measurement. Safety analysis included all those who took at least one dose of study drug. In the second cohort, participants with CIC were randomly assigned in a study across four centres with similar design and endpoints. The study was registered with ClinicalTrials.gov (NCT02412020) and the EU Clinical Trials Register (EudraCT Number 2014-004025-40) and both cohorts are closed to new participants. Findings Between Feb 13, 2015, and Feb 2, 2016, 24 participants with IPF were randomly assigned to treatment groups. 28 participants with CIC were enrolled during the same period and 27 received study treatment. In patients with IPF, PA101 reduced daytime cough frequency by 31·1% at day 14 compared with placebo; daytime cough frequency decreased from a mean 55 (SD 55) coughs per h at baseline to 39 (29) coughs per h at day 14 following treatment with PA101, versus 51 (37) coughs per h at baseline to 52 (40) cough per h following placebo treatment (ratio of least-squares [LS] means 0·67, 95% CI 0·48–0·94, p=0·0241). By contrast, no treatment benefit for PA101 was observed in the CIC cohort; mean reduction of daytime cough frequency at day 14 for PA101 adjusted for placebo was 6·2% (ratio of LS means 1·27, 0·78–2·06, p=0·31). PA101 was well tolerated in both cohorts. The incidence of adverse events was similar between PA101 and placebo treatments, most adverse events were mild in severity, and no severe adverse events or serious adverse events were reported. Interpretation This study suggests that the mechanism of cough in IPF might be disease specific. Inhaled PA101 could be a treatment option for chronic cough in patients with IPF and warrants further investigation