Budesonide and Formoterol Reduce Early Innate Anti-Viral Immune Responses In Vitro

Asthma is a chronic inflammatory airways disease in which respiratory viral infections frequently trigger exacerbations. Current treatment of asthma with combinations of inhaled corticosteroids and long acting beta2 agonists improves asthma control and reduces exacerbations but what impact this might have on innate anti-viral immunity is unclear. We investigated the in vitro effects of asthma drugs on innate anti-viral immunity. Peripheral blood mononuclear cells (PBMC) from healthy and asthmatic donors were cultured for 24 hours with the Toll-like receptor 7 agonist, imiquimod, or rhinovirus 16 (RV16) in the presence of budesonide and/or formoterol. Production of proinflammatory cytokines and expression of anti-viral intracellular signalling molecules were measured by ELISA and RT-PCR respectively. In PBMC from healthy donors, budesonide alone inhibited IP-10 and IL-6 production induced by imiquimod in a concentration-dependent manner and the degree of inhibition was amplified when budesonide and formoterol were used in combination. Formoterol alone had little effect on these parameters, except at high concentrations (10−6 M) when IL-6 production increased. In RV16 stimulated PBMC, the combination of budesonide and formoterol inhibited IFNα and IP-10 production in asthmatic as well as healthy donors. Combination of budesonide and formoterol also inhibited RV16-stimulated expression of the type I IFN induced genes myxovirus protein A and 2′, 5′ oligoadenylate synthetise. Notably, RV16 stimulated lower levels of type Myxovirus A and oligoadenylate synthase in PBMC of asthmatics than control donors. These in vitro studies demonstrate that combinations of drugs commonly used in asthma therapy inhibit both early pro-inflammatory cytokines and key aspects of the type I IFN pathway. These findings suggest that budesonide and formoterol curtail excessive inflammation induced by rhinovirus infections in patients with asthma, but whether this inhibits viral clearance in vivo remains to be determined

Rhinovirus Genome Variation during Chronic Upper and Lower Respiratory Tract Infections

Routine screening of lung transplant recipients and hospital patients for respiratory virus infections allowed to identify human rhinovirus (HRV) in the upper and lower respiratory tracts, including immunocompromised hosts chronically infected with the same strain over weeks or months. Phylogenetic analysis of 144 HRV-positive samples showed no apparent correlation between a given viral genotype or species and their ability to invade the lower respiratory tract or lead to protracted infection. By contrast, protracted infections were found almost exclusively in immunocompromised patients, thus suggesting that host factors rather than the virus genotype modulate disease outcome, in particular the immune response. Complete genome sequencing of five chronic cases to study rhinovirus genome adaptation showed that the calculated mutation frequency was in the range observed during acute human infections. Analysis of mutation hot spot regions between specimens collected at different times or in different body sites revealed that non-synonymous changes were mostly concentrated in the viral capsid genes VP1, VP2 and VP3, independent of the HRV type. In an immunosuppressed lung transplant recipient infected with the same HRV strain for more than two years, both classical and ultra-deep sequencing of samples collected at different time points in the upper and lower respiratory tracts showed that these virus populations were phylogenetically indistinguishable over the course of infection, except for the last month. Specific signatures were found in the last two lower respiratory tract populations, including changes in the 5′UTR polypyrimidine tract and the VP2 immunogenic site 2. These results highlight for the first time the ability of a given rhinovirus to evolve in the course of a natural infection in immunocompromised patients and complement data obtained from previous experimental inoculation studies in immunocompetent volunteers

Pre-biologic assessment of adherence in severe asthma and association with biologic continuation: a UK Severe Asthma Registry Study

Background: Biologic therapies are approved for uncontrolled severe asthma despite good adherence to inhaled corticosteroids (ICS) and additional controllers. We examined the adherence assessments used across UK Severe Asthma Centres (SACs) and their relationship with biologic continuation and response. Methods: UK SACs completed a quantitative survey on adherence assessment practices in 2022. We included all adult patients with severe asthma patients on ICS starting biologic therapy from the UK Severe Asthma Registry, which collects pre-biologic adherence data, including medication possession ratio (MPR), fractional exhaled nitric oxide (FeNO) suppression testing and serum prednisolone levels. Biologic continuation and response were defined as continuation on any biologic and the same biologic after 1 year, respectively. Associations were determined using multivariable logistic regression. Results: At 21 SACs, MPR for ICS was assessed at 19 (90%) centres, prednisolone and/or cortisol levels in patients on daily oral corticosteroids at 15 (71%), and FeNO suppression testing at 9 (43%). Of 3307 biologic-initiated patients, 1943 (59%) had MPR for ICS recorded, of which 1802 (93%) demonstrated good adherence (≥75% MPR). Only 110 (9%) and 272 (16%) had FeNO suppression and serum prednisolone results, respectively. Good ICS adherence was associated with 2.65-fold higher odds (95% CI 1.02 to 6.91) of biologic continuation, but not with biologic response (OR 1.37, 95% CI 0.50 to 3.76). Conclusion: Good pre-biologic ICS adherence, measured using MPR, is associated with biologic continuation at 1 year. Further research is needed to determine whether baseline adherence predicts biologic response based on clinical and biologic criteria

Implications for the Education Department of trends in the use of emergency teachers by Victorian government schools

Thesis (M.Ed.) -- University of Melbourne, 1983The Victorian Education Department emergency teacher system has been depicted as inequitable, extravagant, inefficient and failing to provide for accountability. The purpose of this study was to investigate trends in the use of emergency teachers by schools in Central Metropolitan Region during 1981 in order to: (i) assess the accuracy of these observations for Central Metropolitan Region, (ii) ascertain the impact of the perceived problems on individual schools, (iii) develop recommendations for overcoming the perceived problems. Statistics on levels of staffing, leave and emergency teacher use for regional primary, secondary and technical schools were collated and analysed. It was found that levels and rates of emergency teacher use varied significantly from school to school and appeared to have only a limited relationship to staffing and teacher absence levels. Some schools were observed to be employing emergency teachers at a level which could not be justified by levels of teacher absence. Some schools were observed to automatically employ emergency teachers to cover all teacher absence. Some schools used emergency teachers at a relatively low level either because of limited availability or a preference to absorb teacher absence by other means. Lack of accountability, waste of resources, inequity and administrative inefficiency were seen to be serious problems in the emergency teacher programme operating in Central Metropolitan Region in 1981. Factors other than need as quantified by teacher absence levels appeared to affect levels of emergency teacher use by Central Metropolitan Region schools. It was shown that socio-economic status of schools, percentage of migrant pupils, school size, school type and availability of emergency teachers had a discernable impact on general levels of emergency teacher use. It was not found possible however to gauge the extent of influence of each of the factors on individual schools. The above findings were used in developing a proposal for overcoming the perceived problems of inequity, waste, lack of account-. ability and inefficiency. This involved the allocation of quotas of emergency teacher days to schools, calculated according to specific needs. It involved schools having responsibility for administering their own emergency teacher funds, including the right to direct funds . to alternative personnel areas. The final part of this study proposed formulae for the equitable distribution of emergency teacher funds to schools. Evaluation of the relative effectiveness of these formulae remains as an important area for future investigation

Book Review Essays and Reviews

Book Review EssaysMuseum Activism. Robert R. Janes and Richard Sandell, eds. New York: Routledge, 2019.New Conversations about Safeguarding the Future: A Review of Four Books. - A Future in Ruins: UNESCO, World Heritage, and the Dream of Peace. Lynn Meskell. New York: Oxford University Press, 2018. - Keeping Their Marbles: How the Treasures of the Past Ended Up in Museums—And Why They Should Stay There. Tiffany Jenkins. Oxford: Oxford University Press, 2016. - World Heritage and Sustainable Development: New Directions in World Heritage Management. Peter Bille Larsen and William Logan, eds. New York: Routledge, 2018. - Safeguarding Intangible Heritage: Practices and Politics. Natsuko Akagawa and Laurajane Smith, eds. New York: Routledge, 2019. Book ReviewsThe Filipino Primitive: Accumulation and Resistance in the American Museum. Sarita Echavez See. New York: New York University Press, 2017.The Art of Being a World Culture Museum: Futures and Lifeways of Ethnographic Museums in Contemporary Europe. Barbara Plankensteiner, ed. Berlin: Kerber Verlag, 2018.China in Australasia: Cultural Diplomacy and Chinese Arts since the Cold War. James Beattie, Richard Bullen, and Maria Galikowski. London: Routledge, 2019.Women and Museums, 1850–1914: Modernity and the Gendering of Knowledge. Kate Hill. Manchester: Manchester University Press, 2016.Rethinking Research in the Art Museum. Emily Pringle. New York: Routledge, 2019.A Natural History of Beer. Rob DeSalle and Ian Tattersall. New Haven, CT: Yale University Press, 2019.Fabricating Power with Balinese Textiles: An Anthropological Evaluation of Balinese Textiles in the Mead-Bateson Collection. Urmila Mohan. Chicago: University of Chicago Press, 2018.</jats:p