Is COPD a Progressive Disease? A Long Term Bode Cohort Observation

Background: The Global Initiative for Obstructive Lung Diseases (GOLD) defines COPD as a disease that is usually progressive. GOLD also provides a spirometric classification of airflow limitation. However, little is known about the long-term changes of patients in different GOLD grades. Objective: Explore the proportion and characteristics of COPD patients that change their spirometric GOLD grade over long-term follow-up. Methods: Patients alive for at least 8 years since recruitment and those who died with at least 4 years of repeated spirometric measurements were selected from the BODE cohort database. We purposely included the group of non survivors to avoid a “survival selection” bias. The proportion of patients that had a change (improvement or worsening) in their spirometric GOLD grading was calculated and their characteristics compared with those that remained in the same grade. Results: A total of 318 patients were included in the survivor and 217 in the non-survivor groups. Nine percent of survivors and 11% of non survivors had an improvement of at least one GOLD grade. Seventy one percent of survivors and non-survivors remained in the same GOLD grade. Those that improved had a greater degree of airway obstruction at baseline. Conclusions: In this selected population of COPD patients, a high proportion of patients remained in the same spirometric GOLD grade or improved in a long-term follow-up. These findings suggest that once diagnosed, COPD is usually a non-progressive disease

Acoustic surveillance of cough for detecting respiratory disease using artificial intelligence

Research question Can smartphones be used to detect individual and population-level changes in cough frequency that correlate with the incidence of coronavirus disease 2019 (COVID-19) and other respiratory infections? Methods This was a prospective cohort study carried out in Pamplona (Spain) between 2020 and 2021 using artificial intelligence cough detection software. Changes in cough frequency around the time of medical consultation were evaluated using a randomisation routine; significance was tested by comparing the distribution of cough frequencies to that obtained from a model of no difference. The correlation between changes of cough frequency and COVID-19 incidence was studied using an autoregressive moving average analysis, and its strength determined by calculating its autocorrelation function (ACF). Predictors for the regular use of the system were studied using a linear regression. Overall user experience was evaluated using a satisfaction questionnaire and through focused group discussions. Results We followed-up 616 participants and collected >62 000 coughs. Coughs per hour surged around the time cohort subjects sought medical care (difference +0.77 coughs.h(-1); p=0.00001). There was a weak temporal correlation between aggregated coughs and the incidence of COVID-19 in the local population (ACF 0.43). Technical issues affected uptake and regular use of the system. Interpretation Artificial intelligence systems can detect changes in cough frequency that temporarily correlate with the onset of clinical disease at the individual level. A clearer correlation with population-level COVID-19 incidence, or other respiratory conditions, could be achieved with better penetration and compliance with cough monitoring

Epidemiology of foodborne Norovirus outbreaks in Catalonia, Spain

Background: Noroviruses are one of the principal biological agents associated with the consumption of contaminated food. The objective of this study was to analyse the size and epidemiological characteristics of foodborne outbreaks of gastroenteritis in Catalonia, a region in the northeast of Spain. Methods: In all reported outbreaks of gastroenteritis associated with food consumption, faecal samples of persons affected were analysed for bacteria and viruses and selectively for parasites. Study variables included the setting, the number of people exposed, age, sex, clinical signs and hospital admissions. The study was carried out from October 2004 to October 2005. Results: Of the 181 outbreaks reported during the study period, 72 were caused by Salmonella and 30 by norovirus (NoV); the incidence rates were 14.5 and 9.9 per 100,000 person-years, respectively. In 50% of the NoV outbreaks and 27% of the bacterial outbreaks (p = 0.03) the number of persons affected was ¿10; 66.7% of NoV outbreaks occurred in restaurants; no differences in the attack rates were observed according to the etiology. Hospitalizations were more common (p = 0.03) in bacterial outbreaks (8.6%) than in NoV outbreaks (0.15%). Secondary cases accounted for 4% of cases in NoV outbreaks compared with 0.3% of cases in bacterial outbreaks (p < 0.001) Conclusion: Norovirus outbreaks were larger but less frequent than bacterial outbreaks, suggesting that underreporting is greater for NoV outbreaks. Food handlers should receive training on the transmission of infections in diverse situations. Very strict control measures on handwashing and environmental disinfection should be adopted in closed or partially-closed institutions

Epidemiology of foodborne Norovirus outbreaks in Catalonia, Spain

Background: Noroviruses are one of the principal biological agents associated with the consumption of contaminated food. The objective of this study was to analyse the size and epidemiological characteristics of foodborne outbreaks of gastroenteritis in Catalonia, a region in the northeast of Spain. Methods: In all reported outbreaks of gastroenteritis associated with food consumption, faecal samples of persons affected were analysed for bacteria and viruses and selectively for parasites. Study variables included the setting, the number of people exposed, age, sex, clinical signs and hospital admissions. The study was carried out from October 2004 to October 2005. Results: Of the 181 outbreaks reported during the study period, 72 were caused by Salmonella and 30 by norovirus (NoV); the incidence rates were 14.5 and 9.9 per 100,000 person-years, respectively. In 50% of the NoV outbreaks and 27% of the bacterial outbreaks (p = 0.03) the number of persons affected was ¿10; 66.7% of NoV outbreaks occurred in restaurants; no differences in the attack rates were observed according to the etiology. Hospitalizations were more common (p = 0.03) in bacterial outbreaks (8.6%) than in NoV outbreaks (0.15%). Secondary cases accounted for 4% of cases in NoV outbreaks compared with 0.3% of cases in bacterial outbreaks (p < 0.001) Conclusion: Norovirus outbreaks were larger but less frequent than bacterial outbreaks, suggesting that underreporting is greater for NoV outbreaks. Food handlers should receive training on the transmission of infections in diverse situations. Very strict control measures on handwashing and environmental disinfection should be adopted in closed or partially-closed institutions

Evolutionary Dynamics of the Ty3/Gypsy LTR Retrotransposons in the Genome of Anopheles gambiae

Ty3/gypsy elements represent one of the most abundant and diverse LTR-retrotransposon (LTRr) groups in the Anopheles gambiae genome, but their evolutionary dynamics have not been explored in detail. Here, we conduct an in silico analysis of the distribution and abundance of the full complement of 1045 copies in the updated AgamP3 assembly. Chromosomal distribution of Ty3/gypsy elements is inversely related to arm length, with densities being greatest on the X, and greater on the short versus long arms of both autosomes. Taking into account the different heterochromatic and euchromatic compartments of the genome, our data suggest that the relative abundance of Ty3/gypsy LTRrs along each chromosome arm is determined mainly by the different proportions of heterochromatin, particularly pericentric heterochromatin, relative to total arm length. Additionally, the breakpoint regions of chromosomal inversion 2La appears to be a haven for LTRrs. These elements are underrepresented more than 7-fold in euchromatin, where 33% of the Ty3/gypsy copies are associated with genes. The euchromatin on chromosome 3R shows a faster turnover rate of Ty3/gypsy elements, characterized by a deficit of proviral sequences and the lowest average sequence divergence of any autosomal region analyzed in this study. This probably reflects a principal role of purifying selection against insertion for the preservation of longer conserved syntenyc blocks with adaptive importance located in 3R. Although some Ty3/gypsy LTRrs show evidence of recent activity, an important fraction are inactive remnants of relatively ancient insertions apparently subject to genetic drift. Consistent with these computational predictions, an analysis of the occupancy rate of putatively older insertions in natural populations suggested that the degenerate copies have been fixed across the species range in this mosquito, and also are shared with the sibling species Anopheles arabiensis

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

The Toxicity of Silver Nanoparticles Depends on Their Uptake by Cells and Thus on Their Surface Chemistry

A set of three types of silver nanoparticles (Ag NPs) are prepared, which have the same Ag cores, but different surface chemistry. Ag cores are stabilized with mercaptoundecanoic acid (MUA) or with a polymer shell [poly(isobutylene-alt-maleic anhydride) (PMA)]. In order to reduce cellular uptake, the polymer-coated Ag NPs are additionally modifi ed with polyethylene glycol (PEG). Corrosion (oxidation) of the NPs is quantifi ed and their colloidal stability is investigated. MUA-coated NPs have a much lower colloidal stability than PMA-coated NPs and are largely agglomerated. All Ag NPs corrode faster in an acidic environment and thus more Ag(I) ions are released inside endosomal/lysosomal compartments. PMA coating does not reduce leaching of Ag(I) ions compared with MUA coating. PEGylation reduces NP cellular uptake and also the toxicity. PMA-coated NPs have reduced toxicity compared with MUA-coated NPs. All studied Ag NPs were less toxic than free Ag(I) ions. All in all, the cytotoxicity of Ag NPs is correlated on their uptake by cells and agglomeration behavior

Molecular Mechanism of Action of Plant DRM De Novo DNA Methyltransferases

DNA methylation is a conserved epigenetic gene-regulation mechanism. DOMAINS REARRANGED METHYLTRANSFERASE (DRM) is a key de novo methyltransferase in plants, but how DRM acts mechanistically is poorly understood. Here, we report the crystal structure of the methyltransferase domain of tobacco DRM (NtDRM) and reveal a molecular basis for its rearranged structure. NtDRM forms a functional homodimer critical for catalytic activity. We also show that Arabidopsis DRM2 exists in complex with the small interfering RNA (siRNA) effector ARGONAUTE4 (AGO4) and preferentially methylates one DNA strand, likely the strand acting as the template for RNA polymerase V-mediated noncoding RNA transcripts. This strand-biased DNA methylation is also positively correlated with strand-biased siRNA accumulation. These data suggest a model in which DRM2 is guided to target loci by AGO4-siRNA and involves base-pairing of associated siRNAs with nascent RNA transcripts

Mechanism of DNA Methylation-Directed Histone Methylation by KRYPTONITE

In Arabidopsis, CHG DNA methylation is controlled by the H3K9 methylation mark through a self-reinforcing loop between DNA methyltransferase CHROMOMETHYLASE3 (CMT3) and H3K9 histone methyltransferase KRYPTONITE/SUVH4 (KYP). We report on the structure of KYP in complex with methylated DNA, substrate H3 peptide, and cofactor SAH, thereby defining the spatial positioning of the SRA domain relative to the SET domain. The methylated DNA is bound by the SRA domain with the 5mC flipped out of the DNA, while the H3(1-15) peptide substrate binds between the SET and post-SET domains, with the ε-ammonium of K9 positioned adjacent to bound SAH. These structural insights, complemented by functional data on key mutants of residues lining the 5mC and H3K9-binding pockets within KYP, establish how methylated DNA recruits KYP to the histone substrate. Together, the structures of KYP and previously reported CMT3 complexes provide insights into molecular mechanisms linking DNA and histone methylation

Occult Hepatitis C Virus Infection in Patients with Diabetic Nephropathy: Epidemiological and Clinical Implications

Background:A high prevalence of hepatitis C virus (HCV) infection in patients with diabetic kidney disease (DKD) has been reported. However, the epidemiology and relationship between DKD and occult HCV infection (OCI)are unknown.Objetives: To determine the prevalence of OCI in a population without conventional markers of HCV infection diagnosed with DKD, and to study its possible clinical implications.Study design: This prospective study included 125 anti-HCV and serum HCV-RNA-negative patients with DKD for the presence of OCI. HCV-RNA was tested by real-time reverse transcription PCR in peripheral blood mononuclear cells and in plasma after ultracentrifugation. Results: OCI was positive in 10 patients (8%). The patients with OCI had significantly higher ferritin levels (p=.002) and monoclonal gammopathy (30% [3/10] vs. 0.87% [1/115] than the patients without OCI [p=.003]). We found similar plasma ALT and GGT levels and HbA1C in both groups. At the end of the follow-up, the progression rate of renal disease tended to be faster in the group with OCI relative to the negative one, but without a significant difference. We did not find an association between OCI and cardiovascular morbidity. nbspConclusions: There was an 8% prevalence of OCI in patients with chronic renal failure secondary to DKD, higher than in the general population. This occult infection does not appear to play a role in the control of diabetes, cardiovascular risk or steatosis. However, the progression rate of renal disease tended to be faster, and the incidence of associated monoclonal gammopathy was significant.nbs