BACKGROUND: The objective was to update the 2011 Cochrane systematic review on the effectiveness of workplace interventions for the treatment of occupational asthma. METHODS: A systematic review was conducted with the selection of articles and reports through 2019. The quality of extracted data was evaluated, and meta-analyses were conducted using techniques recommended by the Cochrane Handbook for Systematic Reviews of Interventions. RESULTS: Data were extracted from 26 nonrandomized controlled before-and-after studies. The mean number of participants per study was 62 and the mean follow-up time was 4.5 years. Compared with continued exposure, removal from exposure had an increased likelihood of improved symptoms and change in spirometry. Reduction of exposure also had more favorable results for symptom improvement than continued exposure, but no difference for change in spirometry. Comparing exposure removal to reduction revealed an advantage for removal with both symptom improvement and change in spirometry for the larger group of patients exposed to low-molecular-weight agents. Also, the risk of unemployment was greater for exposure removal versus reduction. CONCLUSIONS: Exposure removal and reduction had better outcomes than continued exposure. Removal from exposure was more likely to improve symptoms and spirometry than reduction among patients exposed to low-molecular-weight agents. The potential benefits associated with exposure removal versus reduction need to be weighed against the potential for unemployment that is more likely with removal from exposure. The findings are based on data graded as very low quality, and additional studies are needed to generate higher quality data.

BACKGROUND: The impact of workplace interventions on the outcome of occupational asthma is not well understood. OBJECTIVES: To evaluate the effectiveness of workplace interventions on occupational asthma. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE (PubMed); EMBASE(Ovid); NIOSHTIC-2; and CISILO (CCOHS) up to July 31, 2019. SELECTION CRITERIA: We included all eligible randomized controlled trials, controlled before and after studies and interrupted time-series of workplace interventions for occupational asthma. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study eligibility and risk of bias, and extracted data. MAIN RESULTS: We included 26 non-randomized controlled before and after studies with 1,695 participants that reported on three comparisons: complete removal from exposure and reduced exposure compared to continued exposure, and complete removal from exposure compared to reduced exposure. Reduction of exposure was achieved by limiting use of the agent, improving ventilation, or using protective equipment in the same job; by changing to another job with intermittent exposure; or by implementing education programs. For continued exposure, 56 per 1000 workers reported absence of symptoms at follow-up, the decrease in forced expiratory volume in one second as a percentage of a reference value (FEV1 %) was 5.4% during follow-up, and the standardized change in non-specific bronchial hyperreactivity (NSBH) was -0.18.In 18 studies, authors compared removal from exposure to continued exposure. Removal may increase the likelihood of reporting absence of asthma symptoms, with risk ratio (RR) 4.80 (95% confidence interval (CI) 1.67 to 13.86), and it may improve asthma symptoms, with RR 2.47 (95% CI 1.26 to 4.84), compared to continued exposure. Change in FEV1 % may be better with removal from exposure, with a mean difference (MD) of 4.23 % (95% CI 1.14 to 7.31) compared to continued exposure. NSBH may improve with removal from exposure, with standardized mean difference (SMD) 0.43 (95% CI 0.03 to 0.82).In seven studies, authors compared reduction of exposure to continued exposure. Reduction of exposure may increase the likelihood of reporting absence of symptoms, with RR 2.65 (95% CI 1.24 to 5.68). There may be no considerable difference in FEV1 % between reduction and continued exposure, with MD 2.76 % (95% CI -1.53 to 7.04) . No studies reported or enabled calculation of change in NSBH.In ten studies, authors compared removal from exposure to reduction of exposure. Following removal from exposure there may be no increase in the likelihood of reporting absence of symptoms, with RR 6.05 (95% CI 0.86 to 42.34), and improvement in symptoms, with RR 1.11 (95% CI 0.84 to 1.47), as well as no considerable change in FEV1 %, with MD 2.58 % (95% CI -3.02 to 8.17). However, with all three outcomes, there may be improved results for removal from exposure in the subset of patients exposed to low molecular weight agents. No studies reported or enabled calculation of change in NSBH.In two studies, authors reported that the risk of unemployment after removal from exposure may increase compared with reduction of exposure, with RR 14.28 (95% CI 2.06 to 99.16). Four studies reported a decrease in income of 20% to 50% after removal from exposure.The quality of the evidence is very low for all outcomes. AUTHORS' CONCLUSIONS: Both removal from exposure and reduction of exposure may improve asthma symptoms compared with continued exposure. Removal from exposure, but not reduction of exposure, may improve lung function compared to continued exposure. When we compared removal from exposure directly to reduction of exposure, the former may improve symptoms and lung function more among patients exposed to low molecular weight agents. Removal from exposure may also increase the risk of unemployment. Care providers should balance the potential clinical benefits of removal from exposure or reduction of exposure with potential detrimental effects of unemployment. Additional high-quality studies are needed to evaluate the effectiveness of workplace interventions for occupational asthma.

In the cytoplasm, the retinoic acid-inducible gene I (RIG-I) senses the RNA genomes of several RNA viruses. RIG-I binds to viral RNA, eliciting an antiviral response via the cellular adaptor MAVS. Crimean-Congo hemorrhagic fever virus (CCHFV), a negative sense RNA virus with a 5' -monophosphorylated genome, is a highly pathogenic zoonotic agent with significant public health and clinical implications. We found that, during CCHFV infection, RIG-I mediated a type-I interferon (IFN) response via MAVS. Interfering with RIG-I signaling reduced IFN production and IFN-stimulated gene expression, and increased viral replication. Immunostimulatory RNA was isolated from CCHFV-infected cells and from virion preparations, and RIG-I co-immunoprecipitation of infected cell lysates isolated immunostimulatory CCHFV RNA. This report serves as the first description of a pattern recognition receptor for CCHFV and highlights a critical signaling pathway in the antiviral response to CCHFV. IMPORTANCE: Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne virus with significant public health and clinical impact. In order for cells to respond to virus infection, they must recognize the virus as foreign and initiate antiviral signaling. To date, the receptors involved in recognition of CCHFV are not known. Herein we investigate and identify retinoic acid-inducible gene I (RIG-I) as a receptor involved in initiating an antiviral response to CCHFV. This receptor was initially not expected to play a role in CCHFV recognition because of characteristics of the viral genome. These findings are important in understanding the antiviral response to CCHFV and support continued investigation into the spectrum of potential viruses recognized by RIG-I.

Influenza A virus (IAV), similar to other viruses, exploits the machinery of human host cells for its survival and replication. We identified alpha-actinin-4, a host cytoskeletal protein, as an interacting partner of IAV nucleoprotein (NP). We confirmed this interaction using co-immunoprecipitation studies, first in a coupled in vitro transcription-translation assay and then in cells either transiently co-expressing the two proteins or infected with whole IAV. Importantly, the NP-actinin-4 interaction was observed in several IAV subtypes, including the 2009 H1N1 pandemic virus. Moreover, immunofluorescence studies revealed that both NP and actinin-4 co-localized largely around the nucleus and also in the cytoplasmic region of virus-infected A549 cells. Silencing of actinin-4 expression resulted in not only a significant decrease in NP, M2 and NS1 viral protein expression, but also a reduction of both NP mRNA and viral RNA levels, as well as viral titers, 24 h post-infection with IAV, suggesting that actinin-4 was critical for viral replication. Furthermore, actinin-4 depletion reduced the amount of NP localized in the nucleus. Treatment of infected cells with wortmannin, a known inhibitor of actinin-4, led to a decrease in NP mRNA levels and also caused the nuclear retention of NP, further strengthening our previous observations. Taken together, the results of the present study indicate that actinin-4, a novel interacting partner of IAV NP, plays a crucial role in viral replication and this interaction may participate in nuclear localization of NP and/or viral ribonucleoproteins.

Apoptosis induction is an antiviral host response, however, influenza A virus (IAV) infection promotes host cell death. The nucleoprotein (NP) of IAV is known to contribute to viral pathogenesis, but its role in virus-induced host cell death was hitherto unknown. We observed that NP contributes to IAV infection induced cell death and heterologous expression of NP alone can induce apoptosis in human airway epithelial cells. The apoptotic effect of IAV NP was significant when compared with other known proapoptotic proteins of IAV. The cell death induced by IAV NP was executed through the intrinsic apoptosis pathway. We screened host cellular factors for those that may be targeted by NP for inducing apoptosis and identified human antiapoptotic protein Clusterin (CLU) as a novel interacting partner. The interaction between IAV NP and CLU was highly conserved and mediated through beta-chain of the CLU protein. Also CLU was found to interact specifically with IAV NP and not with any other known apoptosis modulatory protein of IAV. CLU prevents induction of the intrinsic apoptosis pathway by binding to Bax and inhibiting its movement into the mitochondria. We found that the expression of IAV NP reduced the association between CLU and Bax in mammalian cells. Further, we observed that CLU overexpression attenuated NP-induced cell death and had a negative effect on IAV replication. Collectively, these findings indicate a new function for IAV NP in inducing host cell death and suggest a role for the host antiapoptotic protein CLU in this process.

The influenza virus neuraminidase (NA) protein primarily aids in the release of progeny virions from infected cells. Here, we demonstrate a novel role for NA in enhancing host cell survival by activating the Src/Akt signaling axis via an interaction with carcinoembryonic antigen-related cell adhesion molecule 6/cluster of differentiation 66c (C6). NA/C6 interaction leads to increased tyrosyl phosphorylation of Src, FAK, Akt, GSK3beta, and Bcl-2, which affects cell survival, proliferation, migration, differentiation, and apoptosis. siRNA-mediated suppression of C6 resulted in a down-regulation of activated Src, FAK, and Akt, increased apoptosis, and reduced expression of viral proteins and viral titers in influenza virus-infected human lung adenocarcinoma epithelial and normal human bronchial epithelial cells. These findings indicate that influenza NA not only aids in the release of progeny virions, but also cell survival during viral replication.

Toll-like receptors (TLRs) play an important role in the induction of innate and adaptive immune response against influenza A virus (IAV) infection; however, the role of Toll-like receptor 7 (TLR7) during the innate immune response to IAV infection and the cell types affected by the absence of TLR7 are not clearly understood. In this study, we show that myeloid derived suppressor cells (MDSC) accumulate in the lungs of TLR7 deficient mice more so than in wild-type C57Bl/6 mice, and display increased cytokine expression. Furthermore, there is an increase in production of Th2 cytokines by TLR7(-/-) compared with wildtype CD4+ T-cells in vivo, leading to a Th2 polarized humoral response. Our findings indicate that TLR7 modulates the accumulation of MDSCs during an IAV infection in mice, and that lack of TLR7 signaling leads to a Th2-biased response.

To better understand the early virus-host interactions of the pandemic 2009 A(H1N1) viruses in humans, we examined early host responses following infection of human epithelial cell cultures with three 2009 A(H1N1) viruses (A/California/08/2009, A/Mexico/4108/2009, and A/Texas/15/2009), or a seasonal H1N1 vaccine strain (A/Solomon Islands/3/2006). We report here that infection with pandemic A/California/08/2009 and A/Mexico/4108/2009 viruses resulted in differences in virus infectivity compared to either pandemic A/Texas/15/2009 or the seasonal H1N1 vaccine strain. In addition, IFN-beta levels were decreased in cell cultures infected with either the A/California/08/2009 or the A/Mexico/4108/2009 virus. Furthermore, infection with A/California/08/2009 and A/Mexico/4108/2009 viruses resulted in lower expression of four key proinflammatory markers (IL-6, RANTES, IP-10, and MIP-1beta) compared with infection with either A/Texas/15/2009 or A/Solomon Islands/3/2006. Taken together, our results demonstrate that 2009 A(H1N1) viruses isolated during the Spring wave induced varying degrees of early host antiviral and inflammatory responses in human respiratory epithelial cells, highlighting the strain-specific nature of these responses, which play a role in clinical disease.