Predicting response to holistic breathlessness services: a pooled analysis of trial data

Background: Holistic breathlessness services have been developed for people with advanced disease and chronic breathlessness, leading to improved psychological aspects of breathlessness and health. The extent to which patient characteristics influence outcomes is unclear. Aim: To identify patient characteristics predicting outcomes of mastery and distress around breathlessness following holistic breathlessness services. Design: Secondary analysis of pooled individual patient data from three clinical trials. Our primary analysis assessed predictors of clinically important improvements in Chronic Respiratory Questionnaire mastery scores (+0.5 point), and our secondary analysis predictors of improvements in Numerical Rating Scale distress due to breathlessness (-1 point). Variables significantly related to improvement in univariate models were considered in separate backwards stepwise logistic regression models. Participants: The dataset comprised 259 participants (118 female; mean (standard deviation) age 69.2(10.6) years) with primary diagnoses of chronic obstructive pulmonary disease (49.8%), cancer (34.7%) and interstitial lung disease (10.4%).Results: Controlling for age, sex, and trial, baseline mastery remained the only significant independent predictor of improvement in mastery (odds ratio 0.57, 95% confidence intervals 0.43 to 0.74; p <0001), and baseline distress remained the only significant predictor of improvement in distress (odds ratio 1.64; 95% confidence intervals 1.35 to 2.03; p<001). Baseline lung function, breathlessness severity, health status, mild anxiety and depression, and diagnosis did not predict outcomes. Conclusions: Outcomes of mastery and distress following holistic breathlessness services are influenced by baseline scores for these variables, and not by diagnosis, lung function, or health status. Stratifying patients by levels of mastery and/or distress appears appropriate for clinical trials and services

Atmospheric oxygenation caused by a change in volcanic degassing pressure

International audienceThe Precambrian history of our planet is marked by two major events: a pulse of continental crust formation at the end of the Archaean eon and a weak oxygenation of the atmosphere (the Great Oxidation Event) that followed, at 2.45 billion years ago. This oxygenation has been linked to the emergence of oxygenic cyanobacteria1,2 and to changes in the compositions of volcanic gases3,4, but not to the composition of erupting lavas--geochemical constraints indicate that the oxidation state of basalts and their mantle sources has remained constant since 3.5 billion years ago5,6. Here we propose that a decrease in the average pressure of volcanic degassing changed the oxidation state of sulphur in volcanic gases, initiating themodern biogeochemical sulphur cycle and triggering atmospheric oxygenation. Using thermodynamic calculations simulating gas-melt equilibria in erupting magmas, we suggest that mostly submarine Archaean volcanoes produced gases with SO2/H2S,1 and low sulphur content. Emergence of the continents due to a global decrease in sea level and growth of the continental crust in the late Archaean then led to widespread subaerial volcanism, which in turn yielded gases much richer in sulphur and dominated bySO2. Dissolution of sulphur in sea water and the onset of sulphate reduction processes could then oxidize the atmosphere

Predictors of linkage to care following community-based HIV counseling and testing in rural Kenya

Despite innovations in HIV counseling and testing (HCT), important gaps remain in understanding linkage to care. We followed a cohort diagnosed with HIV through a community-based HCT campaign that trained persons living with HIV/AIDS (PLHA) as navigators. Individual, interpersonal, and institutional predictors of linkage were assessed using survival analysis of self-reported time to enrollment. Of 483 persons consenting to follow-up, 305 (63.2%) enrolled in HIV care within 3 months. Proportions linking to care were similar across sexes, barring a sub-sample of men aged 18–25 years who were highly unlikely to enroll. Men were more likely to enroll if they had disclosed to their spouse, and women if they had disclosed to family. Women who anticipated violence or relationship breakup were less likely to link to care. Enrolment rates were significantly higher among participants receiving a PLHA visit, suggesting that a navigator approach may improve linkage from community-based HCT campaigns.Vestergaard Frandse

Viral Kinetics Suggests a Reconciliation of the Disparate Observations of the Modulation of Claudin-1 Expression on Cells Exposed to Hepatitis C Virus

The tight junction protein claudin-1 (CLDN1) is necessary for hepatitis C virus (HCV) entry into target cells. Recent studies have made disparate observations of the modulation of the expression of CLDN1 on cells following infection by HCV. In one study, the mean CLDN1 expression on cells exposed to HCV declined, whereas in another study HCV infected cells showed increased CLDN1 expression compared to uninfected cells. Consequently, the role of HCV in modulating CLDN1 expression, and hence the frequency of cellular superinfection, remains unclear. Here, we present a possible reconciliation of these disparate observations. We hypothesized that viral kinetics and not necessarily HCV-induced receptor modulation underlies these disparate observations. To test this hypothesis, we constructed a mathematical model of viral kinetics in vitro that mimicked the above experiments. Model predictions provided good fits to the observed evolution of the distribution of CLDN1 expression on cells following exposure to HCV. Cells with higher CLDN1 expression were preferentially infected and outgrown by cells with lower CLDN1 expression, resulting in a decline of the mean CLDN1 expression with time. At the same time, because the susceptibility of cells to infection increased with CLDN1 expression, infected cells tended to have higher CLDN1 expression on average than uninfected cells. Our study thus presents an explanation of the disparate observations of CLDN1 expression following HCV infection and points to the importance of considering viral kinetics in future studies of receptor expression on cells exposed to HCV

A short purification process for quantitative isolation of PrP(Sc) from naturally occurring and experimental transmissible spongiform encephalopathies

BACKGROUND: Transmissible spongiform encephalopathies (TSEs) are neurodegenerative diseases affecting both humans and animals. They are associated with post-translational conversion of the normal cellular prion protein (PrP(C)) into a heat- and protease-resistant abnormal isoform (PrP(Sc)). Detection of PrP(Sc) in individuals is widely utilized for the diagnosis of prion diseases. METHODS: TSE brain tissue samples have been processed in order to quantitatively isolate PrP(Sc). The protocol includes an initial homogenization, digestion with proteinase K and salt precipitation. RESULTS: Here we show that over 97 percent of the PrP(Sc) present can be precipitated from infected brain material using this simple salting-out procedure for proteins. No chemically harsh conditions are used during the process in order to conserve the native quality of the isolated protein. CONCLUSION: The resulting PrP(Sc)-enriched preparation should provide a suitable substrate for analyzing the structure of the prion agent and for scavenging for other molecules with which it may associate. In comparison with most methods that exist today, the one described in this study is rapid, cost-effective and does not demand expensive laboratory equipment

Autotaxin-lysophosphatidic acid receptor signalling regulates hepatitis C virus replication

Background & Aims Chronic hepatitis C is a global health problem with an estimated 170 million hepatitis C virus (HCV) infected individuals at risk of progressive liver disease and hepatocellular carcinoma (HCC). Autotaxin (ATX, gene name: ENPP2) is a phospholipase with diverse roles in the physiological and pathological processes including inflammation and oncogenesis. Clinical studies have reported increased ATX expression in chronic hepatitis C, however, the pathways regulating ATX and its role in the viral life cycle are not well understood. Methods In vitro hepatocyte and ex vivo liver culture systems along with chimeric humanized liver mice and HCC tissue enabled us to assess the interplay between ATX and the HCV life cycle. Results HCV infection increased hepatocellular ATX RNA and protein expression. HCV infection stabilizes hypoxia inducible factors (HIFs) and we investigated a role for these transcription factors to regulate ATX. In vitro studies show that low oxygen increases hepatocellular ATX expression and transcriptome analysis showed a positive correlation between ATX mRNA levels and hypoxia gene score in HCC tumour tissue associated with HCV and other aetiologies. Importantly, inhibiting ATX-lysophosphatidic acid (LPA) signalling reduced HCV replication, demonstrating a positive role for this phospholipase in the viral life cycle. LPA activates phosphoinositide-3-kinase that stabilizes HIF-1α and inhibiting the HIF signalling pathway abrogates the pro-viral activity of LPA. Conclusions Our data support a model where HCV infection increases ATX expression which supports viral replication and HCC progression. Lay summary Chronic hepatitis C is a global health problem with infected individuals at risk of developing liver disease that can progress to hepatocellular carcinoma. Autotaxin generates the biologically active lipid lysophosphatidic acid that has been reported to play a tumorigenic role in a wide number of cancers. In this study we show that hepatitis C virus infection increases autotaxin expression via hypoxia inducible transcription factor and provides an environment in the liver that promotes fibrosis and liver injury. Importantly, we show a new role for lysophosphatidic acid in positively regulating hepatitis C virus replication.Research in the McKeating laboratory was funded by the MRC, NIHR Birmingham Liver BRU, EU FP7 PathCO and H2020 grant Hep-CAR. Research in the Wakelam lab is supported by BBSRC and Hep-CAR. Stephanie Roessler was supported by Hep-CAR, DFG grant RO4673, the Olympia-Morata Programme, a Brigitte-Schieben-Lange Fellowship and a Heidelberg School of Oncology Fellowship

Role of the podocyte in proteinuria

In recent years, the podocyte, with its elaborate cytoarchitecture and slit diaphragm, has been the focus of extensive research, yet its precise role in the glomerular filtration barrier is still debated. There are puzzling observations indicating that a comprehensive mechanistic model for glomerular filtration is still necessary. There is no doubt that podocytes are essential for glomerular filtration barrier integrity. However, most albumin never reaches the podocyte because it is prevented from entering the glomerular filter at the endothelium level. Another puzzling observation is that the glomerular filter never clogs despite its high load of several kilograms of plasma proteins per day. Recently, we proposed a novel model in which an electrical potential difference is generated across the glomerular filtration barrier by filtration. The model offers novel potential solutions to some of the riddles regarding the glomerular filter

The SR-BI Partner PDZK1 Facilitates Hepatitis C Virus Entry

Entry of hepatitis C virus (HCV) into hepatocytes is a multi-step process that involves a number of different host cell factors. Following initial engagement with glycosaminoglycans and the low-density lipoprotein receptor, it is thought that HCV entry proceeds via interactions with the tetraspanin CD81, scavenger receptor class B type I (SR-BI), and the tight-junction proteins claudin-1 (CLDN1) and occludin (OCLN), culminating in clathrin-dependent endocytosis of HCV particles and their pH-dependent fusion with endosomal membranes. Physiologically, SR-BI is the major receptor for high-density lipoproteins (HDL) in the liver, where its expression is primarily controlled at the post-transcriptional level by its interaction with the scaffold protein PDZK1. However, the importance of interaction with PDZK1 to the involvement of SR-BI in HCV entry is unclear. Here we demonstrate that stable shRNA-knockdown of PDZK1 expression in human hepatoma cells significantly reduces their susceptibility to HCV infection, and that this effect can be reversed by overexpression of full length PDZK1 but not the first PDZ domain of PDZK1 alone. Furthermore, we found that overexpression of a green fluorescent protein chimera of the cytoplasmic carboxy-terminus of SR-BI (amino acids 479–509) in Huh-7 cells resulted in its interaction with PDZK1 and a reduced susceptibility to HCV infection. In contrast a similar chimera lacking the final amino acid of SR-BI (amino acids 479–508) failed to interact with PDZK1 and did not inhibit HCV infection. Taken together these results indicate an indirect involvement of PDZK1 in HCV entry via its ability to interact with SR-BI and enhance its activity as an HCV entry factor

The validation of a new measure quantifying the social quality of life of ethnically diverse older women: two cross-sectional studies

<p>Abstract</p> <p>Background</p> <p>To our knowledge, the available psychometric literature does not include an instrument for the quantification of social quality of life among older women from diverse ethnic backgrounds. To address the need for a tool of this kind, we conducted two studies to assess the initial reliability and validity of a new instrument. The latter was created specifically to quantify the contribution of a) social networks and resources (e.g., family, friends, and community) as well as b) one's perceived power and respect within family and community to subjective well-being in non-clinical, ethnically diverse populations of older women.</p> <p>Methods</p> <p>In Study 1, we recruited a cross-sectional sample of primarily non-European-American older women (<it>N </it>= 220) at a variety of community locations. Participants were administered the following: a short screener for dementia; a demographic list; an initial pool of 50 items from which the final items of the new Older Women's Social Quality of Life Inventory (OWSQLI) were to be chosen (based on a statistical criterion to apply to the factor analysis findings); the Single Item Measure of Social Support (SIMSS); and the Medical Outcome Study 36-item Short-Form Health Survey (MOS SF-36). Study 2 was conducted on a second independent sample of ethnically diverse older women. The same recruitment strategies, procedures, and instruments as those of Study 1 were utilized in Study 2, whose sample was comprised of 241 older women with mostly non-European-American ethnic status.</p> <p>Results</p> <p>In Study 1, exploratory factor analysis of the OWSQLI obtained robust findings: the total variance explained by one single factor with the final selection of 22 items was over 44%. The OWSQLI demonstrated strong internal consistency (<it>α </it>= .92, <it>p </it>< .001), adequate criterion validity with the SIMSS (<it>r </it>= .33; <it>p </it>< .01), and (as expected) moderate concurrent validity with the MOS SF-36 for both physical (<it>r </it>= .21; <it>p </it>< .01) and mental (<it>r </it>= .26; <it>p </it>< .01) quality of life. In order to confirm the validity of the 22-item OWSQLI scale that emerged from Study 1 analyses, we replicated those analyses in Study 2, although using confirmatory factor analysis. The total variance accounted for by one factor was about 42%, again quite high and indicative of a strong single-factor solution. Study 2 data analyses yielded the same strong reliability findings (i.e., <it>α </it>= .92, <it>p </it>< .001). The 22-item OWSQLI was correlated with the SIMSS (<it>r </it>= .27, <it>p </it>< .001) in the expected direction. Finally, correlations with the MOS SF- 36 demonstrated moderate concurrent validity for physical (<it>r </it>= .14; <it>p </it>< .01) and mental (<it>r </it>= .18; <it>p </it>< .01) quality of life, as expected.</p> <p>Conclusions</p> <p>The findings of these two studies highlight the potential for our new tool to provide a valid measure of older women's social quality of life, yet they require duplication in longitudinal research. Interested clinicians should consider using the OWSQLI in their assessment battery to identify older women's areas of lower versus higher social quality of life, and should establish the maximization of patients' social quality of life as an important therapeutic goal, as this variable is significantly related to both physical and mental health.</p