Early assisted discharge with generic community nursing for chronic obstructive pulmonary disease exacerbations: Results of a randomised controlled tri

Objectives: To determine the effectiveness of early assisted discharge for chronic obstructive pulmonary disease (COPD) exacerbations, with home care provided by generic community nurses, compared with usual hospital care. Design: Prospective, randomised controlled and multicentre trial with 3-month follow-up. Setting: Five hospitals and three home care organisations in the Netherlands. Participants: Patients admitted to the hospital with an exacerbation of COPD. Patients with no or limited improvement of respiratory symptoms and patients with severe unstable comorbidities, social problems or those unable to visit the toilet independently were excluded. Intervention: Early discharge from hospital after 3 days inpatient treatment. Home visits by generic community nurses. Primary outcome measure was change in health status measured by the Clinical COPD Questionnaire (CCQ). Treatment failures, readmissions, mortality and change in generic health-related quality of life (HRQL) were secondary outcome measures. Results: 139 patients were randomised. No difference between groups was found in change in CCQ score at day 7 (difference in mean change 0.29 (95% CI -0.03 to 0.61)) or at 3 months (difference in mean change 0.04 (95% CI -0.40 to 0.49)). No difference was found in secondary outcomes. At day 7 there was a significant difference in change in generic HRQL, favouring usual hospital care. Conclusions: While patients' disease-specific health status after 7-day treatment tended to be somewhat better in the usual hospital care group, the difference was small and not clinically relevant or statistically significant. After 3 months, the difference had disappeared. A significant difference in generic HRQL at the end of the treatment had disappeared after 3 months and there was no difference in treatment failures, readmissions or mortality. Early assisted discharge with community nursing is feasible and an alternative to usual hospital care for selected patients with an acute COPD exacerbation

Human clade 2.3.4.4 A/H5N6 influenza virus lacks mammalian adaptation markers and does not transmit via the airborne route between ferrets

Since their emergence in 1997, A/H5N1 influenza viruses of the A/goose/ Guangdong/1/96 lineage have diversified in multiple genetic and antigenic clades upon continued circulation in poultry in several countries in Eurasia and Africa. Since 2009, reassortant viruses carrying clade 2.3.4.4 hemagglutinin (HA) and internal and neuraminidase (NA) genes of influenza A viruses of different avian origin have been detected, yielding various HA-NA combinations, such as A/H5N1, A/H5N2, A/H5N3, A/H5N5, A/H5N6, and A/H5N8. Previous studies reported on the low pathogenicity and lack of airborne transmission of A/H5N2 and A/H5N8 viruses in the ferret model. However, although A/H5N6 viruses are the only clade 2.3.4.4 viruses that crossed the species barrier and infected humans, the risk they pose for human health remains poorly characterized. Here, the characterization of A/H5N6 A/Guangzhou/39715/2014 virus in vitro and in ferrets is described. This A/H5N6 virus possessed high polymerase activity, mediated by the E627K substitution in the PB2 protein, which corresponds to only one biological trait out of the three that were previously shown to confer airborne transmissibility to A/H5N1 viruses between ferrets. This might explain its lack of airborne transmission between ferrets. After intranasal inoculation, A/H5N6 virus replicated to high titers in the respiratory tracts of ferrets and was excreted for at least 6 days. Moreover, A/H5N6 virus caused severe pneumonia in ferrets upon intratracheal inoculation. Thus, A/H5N6 virus causes a more severe disease in ferrets than previously investigated clade 2.3.4.4 viruses, but our results demonstrate that the risk from airborne spread is currently low

Functional Swallowing Units (FSUs) as organs-at-risk for radiotherapy. PART 2:Advanced delineation guidelines for FSUs

Background and purpose: In a separate article (PART 1), a rationale and explanation of the physiology-and-anatomy-based concept of Functional Swallowing Units (FSUs) was presented. FSUs are swallowing muscles not included in the set of commonly defined swallowing organs at risk (SWOARs). They are involved in three crucial swallowing components: hyolaryngeal elevation (HLE), tongue base retraction (TBR) and tongue motion. This paper is a continuation of PART 1 and it provides detailed computed tomography (CT)-based delineation guidelines for FSUs, which presumably are also at risk of radiationinduced dysphagia. Material and methods: Following analysis of swallowing physiology and human anatomy, presented in PART 1, CT-based delineation guidelines for defined FSUs were created. Delineation was performed by the first author and revised by a panel of experts. Results and conclusions: Detailed delineation guidelines are presented for seven FSUs involved in HLE, TBR and tongue motion. The guidelines are supplemented by CT and MRI-based exemplary illustrations and complete CT/MRI-based delineation atlases (available online). This paper provides information essential to the implementation of the FSU concept in radiation practice, and supports uniform contouring, data collection and further improvement of swallowing sparing radiation-based strategies. (C) 2018 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Epigenome-wide association study of incident type 2 diabetes:a meta-analysis of five prospective European cohorts

AIMS/HYPOTHESIS: Type 2 diabetes is a complex metabolic disease with increasing prevalence worldwide. Improving the prediction of incident type 2 diabetes using epigenetic markers could help tailor prevention efforts to those at the highest risk. The aim of this study was to identify predictive methylation markers for incident type 2 diabetes by combining epigenome-wide association study (EWAS) results from five prospective European cohorts.METHODS: We conducted a meta-analysis of EWASs in blood collected 7-10 years prior to type 2 diabetes diagnosis. DNA methylation was measured with Illumina Infinium Methylation arrays. A total of 1250 cases and 1950 controls from five longitudinal cohorts were included: Doetinchem, ESTHER, KORA1, KORA2 and EPIC-Norfolk. Associations between DNA methylation and incident type 2 diabetes were examined using robust linear regression with adjustment for potential confounders. Inverse-variance fixed-effects meta-analysis of cohort-level individual CpG EWAS estimates was performed using METAL. The methylGSA R package was used for gene set enrichment analysis. Confirmation of genome-wide significant CpG sites was performed in a cohort of Indian Asians (LOLIPOP, UK).RESULTS: The meta-analysis identified 76 CpG sites that were differentially methylated in individuals with incident type 2 diabetes compared with control individuals (p values &lt;1.1 × 10-7). Sixty-four out of 76 (84.2%) CpG sites were confirmed by directionally consistent effects and p values &lt;0.05 in an independent cohort of Indian Asians. However, on adjustment for baseline BMI only four CpG sites remained genome-wide significant, and addition of the 76 CpG methylation risk score to a prediction model including established predictors of type 2 diabetes (age, sex, BMI and HbA1c) showed no improvement (AUC 0.757 vs 0.753). Gene set enrichment analysis of the full epigenome-wide results clearly showed enrichment of processes linked to insulin signalling, lipid homeostasis and inflammation.CONCLUSIONS/INTERPRETATION: By combining results from five European cohorts, and thus significantly increasing study sample size, we identified 76 CpG sites associated with incident type 2 diabetes. Replication of 64 CpGs in an independent cohort of Indian Asians suggests that the association between DNA methylation levels and incident type 2 diabetes is robust and independent of ethnicity. Our data also indicate that BMI partly explains the association between DNA methylation and incident type 2 diabetes. Further studies are required to elucidate the underlying biological mechanisms and to determine potential causal roles of the differentially methylated CpG sites in type 2 diabetes development.</p

Human Clade 2.3.4.4 A/H5N6 Influenza Virus Lacks Mammalian Adaptation Markers and Does Not Transmit via the Airborne Route between Ferrets

Since their emergence in 1997, A/H5N1 influenza viruses of the A/goose/Guangdong/1/96 lineage have diversified in multiple genetic and antigenic clades upon continued circulation in poultry in several countries in Eurasia and Africa. Since 2009, reassortant viruses carrying clade 2.3.4.4 hemagglutinin (HA) and internal and neuraminidase (NA) genes of influenza A viruses of different avian origin have been detected, yielding various HA-NA combinations, such as A/H5N1, A/H5N2, A/H5N3, A/H5N5, A/H5N6, and A/H5N8. Previous studies reported on the low pathogenicity and lack of airborne transmission of A/H5N2 and A/H5N8 viruses in the ferret model. However, although A/H5N6 viruses are the only clade 2.3.4.4 viruses that crossed the species barrier and infected humans, the risk they pose for human health remains poorly characterized. Here, the characterization of A/H5N6 A/Guangzhou/39715/2014 virus in vitro and in ferrets is described. This A/H5N6 virus possessed high polymerase activity, mediated by the E627K substitution in the PB2 protein, which corresponds to only one biological trait out of the three that were previously shown to confer airborne transmissibility to A/H5N1 viruses between ferrets. This might explain its lack of airborne transmission between ferrets. After intranasal inoculation, A/H5N6 virus replicated to high titers in the respiratory tracts of ferrets and was excreted for at least 6 days. Moreover, A/H5N6 virus caused severe pneumonia in ferrets upon intratracheal inoculation. Thus, A/H5N6 virus causes a more severe disease in ferrets than previously investigated clade 2.3.4.4 viruses, but our results demonstrate that the risk from airborne spread is currently low. IMPORTANCE Avian influenza A viruses are a threat to human health, as they cross the species barrier and infect humans occasionally, often with severe outcome. The antigenic and genetic diversity of A/H5 viruses from the A/goose/Guangdong/1/96 lineage is increasing, due to continued circulation and reassortment in poultry, posing a constant risk for public health and requiring regular risk assessments. Here we performed an in-depth characterization of the properties of the newly emerged zoonotic A/H5N6 virus in vitro and in ferrets. The lack of airborne transmission in the ferret model indicates that A/H5N6 virus does not pose a direct public health threat, despite the fact that it can replicate to high titers throughout the respiratory tracts of ferrets and cause more severe disease than other clade 2.3.4.4 viruses.published_or_final_versio

Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus

Elevated serum urate levels, a complex trait and major risk factor for incident gout, are correlated with cardiometabolic traits via incompletely understood mechanisms. DNA methylation in whole blood captures genetic and environmental influences and is assessed in transethnic meta-analysis of epigenome-wide association studies (EWAS) of serum urate (discovery, n = 12,474, replication, n = 5522). The 100 replicated, epigenome-wide significant (p &lt; 1.1E–7) CpGs explain 11.6% of the serum urate variance. At SLC2A9, the serum urate locus with the largest effect in genome-wide association studies (GWAS), five CpGs are associated with SLC2A9 gene expression. Four CpGs at SLC2A9 have significant causal effects on serum urate levels and/or gout, and two of these partly mediate the effects of urate-associated GWAS variants. In other genes, including SLC7A11 and PHGDH, 17 urate-associated CpGs are associated with conditions defining metabolic syndrome, suggesting that these CpGs may represent a blood DNA methylation signature of cardiometabolic risk factors. This study demonstrates that EWAS can provide new insights into GWAS loci and the correlation of serum urate with other complex traits

Meta-analyses identify DNA methylation associated with kidney function and damage

Chronic kidney disease is a major public health burden. Elevated urinary albumin-to-creatinine ratio is a measure of kidney damage, and used to diagnose and stage chronic kidney disease. To extend the knowledge on regulatory mechanisms related to kidney function and disease, we conducted a blood-based epigenome-wide association study for estimated glomerular filtration rate (n = 33,605) and urinary albumin-to-creatinine ratio (n = 15,068) and detected 69 and seven CpG sites where DNA methylation was associated with the respective trait. The majority of these findings showed directionally consistent associations with the respective clinical outcomes chronic kidney disease and moderately increased albuminuria. Associations of DNA methylation with kidney function, such as CpGs at JAZF1, PELI1 and CHD2 were validated in kidney tissue. Methylation at PHRF1, LDB2, CSRNP1 and IRF5 indicated causal effects on kidney function. Enrichment analyses revealed pathways related to hemostasis and blood cell migration for estimated glomerular filtration rate, and immune cell activation and response for urinary albumin-to-creatinineratio-associated CpGs

Understanding the relevance of in-mouth food processing. A review of in vitro techniques

[EN] Oral processing of food is the first step in the eating process. Although the food undergoes a number of changes during mastication that influence the subsequent steps, this stage has very often been neglected in studies of digestion, bioavailability, flavor release, satiety potential, glycemic index determination, etc. The present review draws on different sources such as nutrition, medicine, phoniatry and dentistry to explain some in vitro oral processing methods and techniques that could be transferred to food technology studies to mimic in vivo comminution, insalivation, and bolus formation, describing, as a necessary reference, the respective in vivo physiological processes they attempt to imitate. Developing a deeper understanding of all the aspects of in-mouth process will help food technologists to give this crucial step the necessary attention its due importance and to consider better ways to incorporate it into their studies.The authors wish to acknowledge the financial support of the Spanish Government (project AGL2012-36753-C02) and gratefully acknowledge the financial support of EU FEDER funds. Mary Georgina Hardinge assisted with the translation and corrected the English text.Morell Esteve, P.; Hernando Hernando, MI.; Fiszman, SM. (2014). Understanding the relevance of in-mouth food processing. A review of in vitro techniques. Trends in Food Science and Technology. 35(1):18-31. https://doi.org/10.1016/j.tifs.2013.10.005S183135

Fine mapping the CETP region reveals a common intronic insertion associated to HDL-C

Background: Individuals with exceptional longevity and their offspring have significantly larger high-density lipoprotein concentrations (HDL-C) particle sizes due to the increased homozygosity for the I405V variant in the cholesteryl ester transfer protein (CETP) gene. In this study, we investigate the association of CETP and HDL-C further to identify novel, independent CETP variants associated with HDL-C in humans. Methods: We performed a meta-analysis of HDL-C within the CETP region using 59,432 individuals imputed with 1000 Genomes data. We performed replication in an independent sample of 47,866 individuals and validation was done by Sanger sequencing. Results: The meta-analysis of HDL-C within the CETP region identified five independent variants, including an exonic variant and a common intronic insertion. We replicated these 5 variants significantly in an independent sample of 47,866 individuals. Sanger sequencing of the insertion within a single family confirmed segregation of this variant. The strongest reported association between HDL-C and CETP variants, was rs3764261; however, after conditioning on the five novel variants we identified the support for rs3764261 was highly reduced (βunadjusted=3.179 mg/dl (P value=5.25×10−509), βadjusted=0.859 mg/dl (P value=9.51×10−25)), and this finding suggests that these five novel variants may partly explain the association of CETP with HDL-C. Indeed, three of the five novel variants (rs34065661, rs5817082, rs7499892) are independent of rs3764261. Conclusions: The causal variants in CETP that account for the association with HDL-C remain unknown. We used studies imputed to the 1000 Genomes reference panel for fine mapping of the CETP region. We identified and validated five variants within this region that may partly account for the association of the known variant (rs3764261), as well as other sources of genetic contribution to HDL-C

Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus

Serum urate concentration can be studied in large datasets to find genetic and epigenetic loci that may be related to cardiometabolic traits. Here the authors identify and replicate 100 urate-associated CpGs, which provide insights into urate GWAS loci and shared CpGs of urate and cardiometabolic traits.Elevated serum urate levels, a complex trait and major risk factor for incident gout, are correlated with cardiometabolic traits via incompletely understood mechanisms. DNA methylation in whole blood captures genetic and environmental influences and is assessed in transethnic meta-analysis of epigenome-wide association studies (EWAS) of serum urate (discovery, n = 12,474, replication, n = 5522). The 100 replicated, epigenome-wide significant (p < 1.1E-7) CpGs explain 11.6% of the serum urate variance. At SLC2A9, the serum urate locus with the largest effect in genome-wide association studies (GWAS), five CpGs are associated with SLC2A9 gene expression. Four CpGs at SLC2A9 have significant causal effects on serum urate levels and/or gout, and two of these partly mediate the effects of urate-associated GWAS variants. In other genes, including SLC7A11 and PHGDH, 17 urate-associated CpGs are associated with conditions defining metabolic syndrome, suggesting that these CpGs may represent a blood DNA methylation signature of cardiometabolic risk factors. This study demonstrates that EWAS can provide new insights into GWAS loci and the correlation of serum urate with other complex traits.</p