Phasevarion Mediated Epigenetic Gene Regulation in Helicobacter pylori

Many host-adapted bacterial pathogens contain DNA methyltransferases (mod genes) that are subject to phase-variable expression (high-frequency reversible ON/OFF switching of gene expression). In Haemophilus influenzae and pathogenic Neisseria, the random switching of the modA gene, associated with a phase-variable type III restriction modification (R-M) system, controls expression of a phase-variable regulon of genes (a “phasevarion”), via differential methylation of the genome in the modA ON and OFF states. Phase-variable type III R-M systems are also found in Helicobacter pylori, suggesting that phasevarions may also exist in this key human pathogen. Phylogenetic studies on the phase-variable type III modH gene revealed that there are 17 distinct alleles in H. pylori, which differ only in their DNA recognition domain. One of the most commonly found alleles was modH5 (16% of isolates). Microarray analysis comparing the wild-type P12modH5 ON strain to a P12ΔmodH5 mutant revealed that six genes were either up- or down-regulated, and some were virulence-associated. These included flaA, which encodes a flagella protein important in motility and hopG, an outer membrane protein essential for colonization and associated with gastric cancer. This study provides the first evidence of this epigenetic mechanism of gene expression in H. pylori. Characterisation of H. pylori modH phasevarions to define stable immunological targets will be essential for vaccine development and may also contribute to understanding H. pylori pathogenesis

Asthma hospitalisation trends from 2010 to 2015: variation among rural and metropolitan Australians

Abstract Background Asthma remains a leading cause of illness, where primary care can assist to reduce hospitalisations through prevention, controlling acute episodes, and overall management of asthma. In Victoria, Asthma hospitalisations were as high as 3.1 hospitalisations per 1000 population in 1993–94. The primary aims of this study are to: determine if changes in asthma hospitalisations have occurred between 2010 and 2015; determine the key factors that impact asthma hospitalisation over time; and verify whether rural and urban asthma hospitalisations are disparate. A secondary aim of the study is to compare 2010–2015 results with asthma data prior to 2010. Methods Hospital separation data from 1 July 2010 to 30 June 2015 were obtained through the Victorian Admitted Episodes Dataset and other agencies. Data included sex, age, Local Government Area, private or public patient, length of stay, and type of discharge. Asthma and predictor variables were analysed according to hospital separation rates after adjusting for smoking and sex. Hierarchical multiple regression examined the association between asthma and predictor variables. Results During the study period, 49,529 asthma hospital separations occurred, of which 77.5% were in metropolitan hospitals, 55.4% hospital separations were aged 0–14 years, and 21.7% were privately funded. State-wide hospital separations were 1.85 per 1000 population and were consistently higher in metropolitan compared to rural areas (1.93 vs 1.64 per 1000 population). When data among metropolitan adults aged 15 and over were analysed, an increase in the proportion of smokers in the population was reflected by an increase in the number of hospital separations (Adj OR 1.035). Further, among rural and metropolitan children aged 0–14 the only predictor of asthma hospital separations was sex, where metropolitan male children had higher odds of separation than metropolitan females of the same age (Adj OR 4.297). There was no statistically meaningful difference for separation rates between males and females in rural areas. Conclusions We demonstrated a higher overall hospital separation rate in metropolitan Victoria. For children in metropolitan areas, males were hospitalised at higher rates than females, while the inverse was demonstrated for children residing in rural areas. Therefore, optimising asthma management requires consideration of the patient’s age, gender and residential context. Primary health care may play a leading role in increasing health literacy for patients in order to improve self-management and health-seeking behaviour

Influence of Contact Definitions in Assessment of the Relative Importance of Social Settings in Disease Transmission Risk

BACKGROUND: Realistic models of disease transmission incorporating complex population heterogeneities require input from quantitative population mixing studies. We use contact diaries to assess the relative importance of social settings in respiratory pathogen spread using three measures of person contact hours (PCH) as proxies for transmission risk with an aim to inform bipartite network models of respiratory pathogen transmission. METHODS AND FINDINGS: Our survey examines the contact behaviour for a convenience sample of 65 adults, with each encounter classified as occurring in a work, retail, home, social, travel or "other" setting. The diary design allows for extraction of PCH-interaction (cumulative time in face-face conversational or touch interaction with contacts)--analogous to the contact measure used in several existing surveys--as well as PCH-setting (product of time spent in setting and number of people present) and PCH-reach (product of time spent in setting and number of people in close proximity). Heterogeneities in day-dependent distribution of risk across settings are analysed using partitioning and cluster analyses and compared between days and contact measures. Although home is typically the highest-risk setting when PCH measures isolate two-way interactions, its relative importance compared to social and work settings may reduce when adopting a more inclusive contact measure that considers the number and duration of potential exposure events. CONCLUSIONS: Heterogeneities in location-dependent contact behaviour as measured by contact diary studies depend on the adopted contact definition. We find that contact measures isolating face-face conversational or touch interactions suggest that contact in the home dominates, whereas more inclusive contact measures indicate that home and work settings may be of higher importance. In the absence of definitive knowledge of the contact required to facilitate transmission of various respiratory pathogens, it is important for surveys to consider alternative contact measures

Multiple Geographic Origins of Commensalism and Complex Dispersal History of Black Rats

The Black Rat (Rattus rattus) spread out of Asia to become one of the world's worst agricultural and urban pests, and a reservoir or vector of numerous zoonotic diseases, including the devastating plague. Despite the global scale and inestimable cost of their impacts on both human livelihoods and natural ecosystems, little is known of the global genetic diversity of Black Rats, the timing and directions of their historical dispersals, and the risks associated with contemporary movements. We surveyed mitochondrial DNA of Black Rats collected across their global range as a first step towards obtaining an historical genetic perspective on this socioeconomically important group of rodents. We found a strong phylogeographic pattern with well-differentiated lineages of Black Rats native to South Asia, the Himalayan region, southern Indochina, and northern Indochina to East Asia, and a diversification that probably commenced in the early Middle Pleistocene. We also identified two other currently recognised species of Rattus as potential derivatives of a paraphyletic R. rattus. Three of the four phylogenetic lineage units within R. rattus show clear genetic signatures of major population expansion in prehistoric times, and the distribution of particular haplogroups mirrors archaeologically and historically documented patterns of human dispersal and trade. Commensalism clearly arose multiple times in R. rattus and in widely separated geographic regions, and this may account for apparent regionalism in their associated pathogens. Our findings represent an important step towards deeper understanding the complex and influential relationship that has developed between Black Rats and humans, and invite a thorough re-examination of host-pathogen associations among Black Rats

Interpretative and predictive modelling of Joint European Torus collisionality scans

Transport modelling of Joint European Torus (JET) dimensionless collisionality scaling experiments in various operational scenarios is presented. Interpretative simulations at a fixed radial position are combined with predictive JETTO simulations of temperatures and densities, using the TGLF transport model. The model includes electromagnetic effects and collisions as well as □(→┬E ) X □(→┬B ) shear in Miller geometry. Focus is on particle transport and the role of the neutral beam injection (NBI) particle source for the density peaking. The experimental 3-point collisionality scans include L-mode, and H-mode (D and H and higher beta D plasma) plasmas in a total of 12 discharges. Experimental results presented in (Tala et al 2017 44th EPS Conf.) indicate that for the H-mode scans, the NBI particle source plays an important role for the density peaking, whereas for the L-mode scan, the influence of the particle source is small. In general, both the interpretative and predictive transport simulations support the experimental conclusions on the role of the NBI particle source for the 12 JET discharges

Alveolar Hemorrhage in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: Results of an International Randomized Controlled Trial (PEXIVAS)

Rationale: Diffuse alveolar hemorrhage (DAH) is a life-threatening manifestation of antineutrophil cytoplasmic antibody–associated vasculitis (AAV). The PEXIVAS (Plasma Exchange and Glucocorticoids in Severe Antineutrophil Cytoplasmic Antibody–Associated Vasculitis) (NCT00987389) trial was the largest in AAV and the first to enroll participants with DAH requiring mechanical ventilation. Objectives: Evaluate characteristics, treatment effects, and outcomes for patients with AAV with and without DAH. Methods: PEXIVAS randomized 704 participants to plasma exchange (PLEX) or no-PLEX and reduced or standard-dose glucocorticoids (GC). DAH status was defined at enrollment as no-DAH, nonsevere, or severe (room air oxygen saturation of ⩽ 85% as measured by pulse oximetry, or use of mechanical ventilation). Measurements and Main Results: At enrollment, 191 (27.1%) participants had DAH (61 severe, including 29 ventilated) and were younger, more frequently relapsing, PR3 (proteinase 3)-ANCA positive, and had lower serum creatinine but were more frequently dialyzed than participants without DAH (n = 513; 72.9%). Among those with DAH, 8/95 (8.4%) receiving PLEX died within 1 year versus 15/96 (15.6%) with no-PLEX (hazard ratio, 0.52; confidence interval [CI], 0.21–1.24), whereas 13/96 (13.5%) receiving reduced GC died versus 10/95 (10.5%) with standard GC (hazard ratio, 1.33; CI, 0.57–3.13). When ventilated, ventilator-free days were similar with PLEX versus no-PLEX (medians, 25; interquartile range [IQR], 22–26 vs. 22–27) and fewer with reduced GC (median, 23; IQR, 20–25) versus standard GC (median, 26; IQR, 25–28). Treatment effects on mortality did not vary by presence or severity of DAH. Overall, 23/191 (12.0%) with DAH died within 1 year versus 34/513 (6.6%) without DAH. End-stage kidney disease and serious infections did not differ by DAH status or treatments. Conclusions: Patients with AAV and DAH differ from those without DAH in multiple ways. Further data are required to confirm or refute a benefit of PLEX or GC dosing on mortality.publishedVersio