Development of tolerogenic dendritic cells and regulatory T cells favors exponential bacterial growth and survival during early respiratory tularemia

Tularemia is a vector-borne zoonosis caused by Ft, a Gram-negative, facultative intracellular bacterium. Ft exists in two clinically relevant forms, the European biovar B (holarctica), which produces acute, although mild, self-limiting infections, and the more virulent United States biovar A (tularensis), which is often associated with pneumonic tularemia and more severe disease. In a mouse model of tularemia, respiratory infection with the virulence-attenuated Type B (LVS) or highly virulent Type A (SchuS4) strain engenders peribronchiolar and perivascular inflammation. Paradoxically, despite an intense neutrophilic infiltrate and high bacterial burden, T(h)1-type proinflammatory cytokines (e.g., TNF, IL-1β, IL-6, and IL-12) are absent within the first ～72 h of pulmonary infection. It has been suggested that the bacterium has the capacity to actively suppress or block NF-κB signaling, thus causing an initial delay in up-regulation of inflammatory mediators. However, our previously published findings and those presented herein contradict this paradigm and instead, strongly support an alternative hypothesis. Rather than blocking NF-κB, Ft actually triggers TLR2-dependent NF-κB signaling, resulting in the development and activation of tDCs and the release of anti-inflammatory cytokines (e.g., IL-10 and TGF-β). In turn, these cytokines stimulate development and proliferation of T(regs) that may restrain T(h)1-type proinflammatory cytokine release early during tularemic infection. The highly regulated and overall anti-inflammatory milieu established in the lung is permissive for unfettered growth and survival of Ft. The capacity of Ft to evoke such a response represents an important immune-evasive strategy.     

Production of hepatitis B defective particles is dependent on liver status

Defective hepatitis B virus (dHBV) generated from spliced RNA is detected in the sera of HBV-chronic carriers. Our study was designed to determine whether the proportion of dHBV changed during the course of infection, and to investigate whether dHBV might interfere with HBV replication. To achieve this, HBV wild-type and dHBV levels were determined by Q-PCR in sera from 56 untreated chronic patients and 23 acute patients, in sequential samples from 4 treated-patients and from liver-humanized mice after HBV infection. The proportion of dHBV was higher in patients with severe compared to null/moderate liver disease or with acute infection. Follow-up showed that the proportion of dHBV increased during disease progression. By contrast, a low and stable proportion of dHBV was observed in the humanized-mouse model of HBV infection. Our results highlight a regulation of the proportion of dHBV during liver disease progression that is independent of interference with viral replication.     

Salience and Impact of Health Warning Label on Cigarette Packs in Vietnam: Findings From the Global Adult Tobacco Survey 2015

Viet Nam is among the countries having highest rate of male smokers in the world. The country has joined the Global Tobacco Surveillance System since 2010. Under this system, two rounds of Global Adult Tobacco Survey (GATS) were conducted in 2010 and 2015. Those two surveys provide excellent comparable data on tobacco usage and its related aspects in Vietnam. This study using the data from GATS 2015 to examine the salience and impact of cigarette pack health warnings on quitting intention in Vietnam. The Vietnam GATS 2015 was a nationally representative survey in which 9,513 households were selected using two-stage random systematic sampling method. Results of multivariate analysis showed that the strongest predictor for quit intention because of health warnings was “ever made a quit attempt in the past 12 months” followed by “believes that tobacco smoking causes serious illness”. Compared to GATS 2010, GATS 2015 observed the increase in salience of cigarette health warnings. However, the current pictorial health warnings are losing their impact on motivating intention to quit. The results highlight that it is time to start the rotation cycle to refresh the current health warning set. Actions to select a new and more impressive set of pictorial health warnings should be developed as soon as possible.     

Recommendations for next generation sequencing data reanalysis of unsolved cases with suspected Mendelian disorders: A systematic review and meta-analysis

PurposeThe study aimed to determine the diagnostic yield, optimal timing, and methodology of next generation sequencing data reanalysis in suspected Mendelian disorders.MethodsWe conducted a systematic review and meta-analysis of studies that conducted data reanalysis in patients with suspected Mendelian disorders. Random effects model was used to pool the estimated outcome with subgroup analysis stratified by timing, sequencing methodology, sample size, segregation, use of research validation, and artificial intelligence (AI) variant curation tools.ResultsA search of PubMed, Embase, Scopus, and Web of Science between 2007 and 2021 yielded 9327 articles, of which 29 were selected. Significant heterogeneity was noted between studies. Reanalysis had an overall diagnostic yield of 0.10 (95% CI = 0.06-0.13). Literature updates accounted for most new diagnoses. Diagnostic yield was higher after 24 months, although this was not statistically significant. Increased diagnoses were obtained with research validation and data sharing. AI-based tools did not adversely affect reanalysis diagnostic rate.ConclusionNext generation sequencing data reanalysis can improve diagnostic yield. Owing to the heterogeneity of the studies, the optimal time to reanalysis and the impact of AI-based tools could not be determined with confidence. We propose standardized guidelines for future studies to reduce heterogeneity and improve the quality of the conclusions.