Sputum RNA signature in allergic asthmatics following allergen bronchoprovocation test

Background: Inhaled allergen challenge is a validated disease model of allergic asthma offering useful pharmacodynamic assessment of pharmacotherapeutic effects in a limited number of subjects. Objectives: To evaluate whether an RNA signature can be identified from induced sputum following an inhaled allergen challenge, whether a RNA signature could be modulated by limited doses of inhaled fluticasone, and whether these gene expression profiles would correlate with the clinical endpoints measured in this study. Methods: Thirteen non-smoking, allergic subjects with mild-to-moderate asthma participated in a randomised, placebo-controlled, 2-period cross-over study following a single-blind placebo run-in period. Each period consisted of three consecutive days, separated by a wash-out period of at least 3 weeks. Subjects randomly received inhaled fluticasone ((FP) MDI; 500 mcg BID×5 doses in total) or placebo. On day 2, house dust mite extract was inhaled and airway response was measured by FEV1 at predefined time points until 7 h post-allergen. Sputum was induced by NaCl 4.5%, processed and analysed at 24 h pre-allergen and 7 and 24 h post-allergen. RNA was isolated from eligible sputum cell pellets (<80% squamous of 500 cells), amplified according to NuGEN technology, and profiled on Affymetrix arrays. Gene expression changes from baseline and fluticasone treatment effects were evaluated using a mixed effects ANCOVA model at 7 and at 24 h post-allergen challenge. Results: Inhaled allergen-induced statistically significant gene expression changes in sputum, which were effectively blunted by fluticasone (adjusted p<0.025). Forty-seven RNA signatures were selected from these responses for correlation analyses and further validation. This included Th2 mRNA levels for cytokines, chemokines, high-affinity IgE receptor FCER1A, histamine receptor HRH4, and enzymes and receptors in the arachidonic pathway. Individual messengers from the 47 RNA signatures correlated significantly with lung function and sputum eosinophil counts. Conclusion: Our RNA extraction and profiling protocols allowed reproducible assessments of inflammatory signatures in sputum including quantification of drug effects on this response in allergic asthmatics. This approach offers novel possibilities for the development of pharmacodynamic (PD) biomarkers in asthma

The Alliance for Recovery Research in Music Therapy

The mental health recovery movement recognises the importance of expertise by experience held by service users alongside healthcare practitioners. Recovery has gained attention in music therapy but a situation prevails where practitioners and researchers set research agendas. A group of music therapists recognised the absence of service user voices in music therapy research, and in 2017 they established a network called the Alliance for Recovery Research in Music Therapy (ARRIMT). In 2020, they started to develop a multi-national platform to explore mental health recovery in relation to research. Service users and music therapists were invited from three countries including Ireland, Norway, and the United Kingdom (UK). Local meetings were held to introduce stakeholders from each country, followed by three online meetings. Music was central to each meeting and each built upon content from previous meetings. Our conversations opened up new possibilities for working together. Four priorities for practice and research were identified: Music as a connector; music between sessions; music technology; and, online music therapy. This report will share our process and what we learnt from working together. We contextualise our work within concepts of foregrounding and mattering and view this work as a crucial step towards meaningful co-production. We reflect upon the role of music in building group identity alongside the importance of careful curation. Finally, we present ideas for future music therapy and mental health research. Group DescriptionIn 2018 the Alliance for Recovery Research in Music Therapy (ARRIMT) was founded as an international group of music therapy service users, researchers and practitioners from Australia, Ireland, Norway, and the United Kingdom. Fundamental to this group is the concept of recovery where those who use and those who provide mental health services work together to share knowledge and experiences that can have a positive impact on mental health service delivery. Key to this is listening carefully to the voices of those who use music therapy so that their views and experiences influence how music therapy is offered in mental health services. The founders and coordinators of the group are Tríona McCaffrey, Hans Petter Paulen Solli, and Catherine E. Carr. Other members of the group are Cornelia Bent, Darmuid Boyle, Oda Bjørke Dypvik, Kenneth Dybdahl, Tommy Hayes, Lauren M. Hickling, Jane Fernandez, Anne Malerbakken, Brendan Ruddy, and Torgrim Vågan.</jats:p

Quantifying an aquifer nitrate budget and future nitrate discharge using field data from streambeds and well nests

Novel groundwater sampling (age, flux, and nitrate) carried out beneath a streambed and in wells was used to estimate (1) the current rate of change of nitrate storage, dSNO3 /dt, in a contaminated unconfined aquifer, and (2) future [NO3–]FWM (the flow-weighted mean nitrate concentration in groundwater discharge) and fNO3 (the nitrate flux from aquifer to stream). Estimates of dSNO3 /dt suggested that at the time of sampling (2013) the nitrate storage in the aquifer was decreasing at an annual rate (mean = –9 mmol/m2yr) equal to about one-tenth the rate of nitrate input by recharge. This is consistent with data showing a slow decrease in the [NO3–] of groundwater recharge in recent years. Regarding future [NO3–]FWM and fNO3 , predictions based on well data show an immediate decrease that becomes more rapid after ~5 years before leveling out in the early 2040s. Predictions based on streambed data generally show an increase in future [NO3–]FWM and fNO3 until the late 2020s, followed by a decrease before leveling out in the 2040s. Differences show the potential value of using information directly from the groundwater—surface water interface to quantify the future impact of groundwater nitrate on surface water quality. The choice of denitrification kinetics was similarly important; compared to zero-order kinetics, a first-order rate law levels out estimates of future [NO3–]FWM and fNO3 (lower peak, higher minimum) as legacy nitrate is flushed from the aquifer. Major fundamental questions about nonpoint-source aquifer contamination can be answered without a complex numerical model or long-term monitoring program

A Geographically-Restricted but Prevalent Mycobacterium tuberculosis Strain Identified in the West Midlands Region of the UK between 1995 and 2008

Background: We describe the identification of, and risk factors for, the single most prevalent Mycobacterium tuberculosis strain in the West Midlands region of the UK.Methodology/Principal Findings: Prospective 15-locus MIRU-VNTR genotyping of all M. tuberculosis isolates in the West Midlands between 2004 and 2008 was undertaken. Two retrospective epidemiological investigations were also undertaken using univariable and multivariable logistic regression analysis. The first study of all TB patients in the West Midlands between 2004 and 2008 identified a single prevalent strain in each of the study years (total 155/3,056 (5%) isolates). This prevalent MIRU-VNTR profile (32333 2432515314 434443183) remained clustered after typing with an additional 9-loci MIRU-VNTR and spoligotyping. The majority of these patients (122/155, 79%) resided in three major cities located within a 40 km radius. From the apparent geographical restriction, we have named this the "Mercian" strain. A multivariate analysis of all TB patients in the West Midlands identified that infection with a Mercian strain was significantly associated with being UK-born (OR = 9.03, 95% CI = 4.56-17.87, p 65 years old (OR = 0.25, 95% CI = 0.09-0.67, p < 0.01). A second more detailed investigation analyzed a cohort of 82 patients resident in Wolverhampton between 2003 and 2006. A significant association with being born in the UK remained after a multivariate analysis (OR = 9.68, 95% CI = 2.00-46.78, p < 0.01) and excess alcohol intake and cannabis use (OR = 6.26, 95% CI = 1.45-27.02, p = .01) were observed as social risk factors for infection.Conclusions/Significance: The continued consistent presence of the Mercian strain suggests ongoing community transmission. Whilst significant associations have been found, there may be other common risk factors yet to be identified. Future investigations should focus on targeting the relevant risk groups and elucidating the biological factors that mediate continued transmission of this strain

Persistence, adherence, and toxicity with oral CMF in older women with early-stage breast cancer (Adherence Companion Study 60104 for CALGB 49907)

Cyclophosphamide-methotrexate-5-fluorouracil (CMF) is often selected as adjuvant chemotherapy for older patients with early-stage breast cancer due to perceived superior tolerability. We sought to measure persistence with CMF, adherence to oral cyclophosphamide, and the association of these with toxic effects

Loss-of-function of triacylglycerol lipases are associated with low flour rancidity in pearl millet [Pennisetum glaucum (L.) R. Br.]

Pearl millet is an important cereal crop of semi-arid regions since it is highly nutritious and climate resilient. However, pearl millet is underutilized commercially due to the rapid onset of hydrolytic rancidity of seed lipids post-milling. We investigated the underlying biochemical and molecular mechanisms of rancidity development in the flour from contrasting inbred lines under accelerated aging conditions. The breakdown of storage lipids (triacylglycerols; TAG) was accompanied by free fatty acid accumulation over the time course for all lines. The high rancidity lines had the highest amount of FFA by day 21, suggesting that TAG lipases may be the cause of rancidity. Additionally, the high rancidity lines manifested substantial amounts of volatile aldehyde compounds, which are characteristic products of lipid oxidation. Lipases with expression in seed post-milling were sequenced from low and high rancidity lines. Polymorphisms were identified in two TAG lipase genes (PgTAGLip1 and PgTAGLip2) from the low rancidity line. Expression in a yeast model system confirmed these mutants were non-functional. We provide a direct mechanism to alleviate rancidity in pearl millet flour by identifying mutations in key TAG lipase genes that are associated with low rancidity. These genetic variations can be exploited through molecular breeding or precision genome technologies to develop elite pearl millet cultivars with improved flour shelf life