A pragmatic randomised controlled trial of tailored pulmonary rehabilitation in participants with difficult-to-control asthma and elevated body mass index.

BACKGROUND: Difficult-to-control asthma associated with elevated body mass index (BMI) is challenging with limited treatment options. The effects of pulmonary rehabilitation (PR) in this population are uncertain. METHODS: This is a randomised controlled trial of an eight-week asthma-tailored PR programme versus usual care (UC) in participants with difficult-to-control asthma and BMI ≥ 25 kg/m2. PR comprised two hours of education and supervised exercise per week, with encouragement for two individual exercise sessions. Primary outcome was difference in change in Asthma Quality of Life Questionnaire (AQLQ) in PR versus UC groups between visits. Secondary outcomes included difference in change in Asthma Control Questionnaire-6 (ACQ6), and a responder analysis comparing proportion reaching minimum clinically important difference for AQLQ and ACQ6. RESULTS: 95 participants were randomised 1:1 to PR or UC. Median age was 54 years, 60% were female and median BMI was 33.8 kg/m2. Mean  (SD) AQLQ was 3.9 (+/-1.2) and median (IQR) ACQ6 2.8(1.8-3.6). 77 participants attended a second visit and had results analysed. Median (IQR) change in AQLQ was not significantly different: 0.3 (- 0.2 to 0.6) in PR and - 0.1 (- 0.5 to 0.4) in UC, p = 0.139. Mean change in ACQ6 was significantly different: - 0.4 (95% CI - 0.6 to - 0.2) in PR and 0 (- 0.3 to + 0.3) in UC, p = 0.015, but below minimum clinically important difference. In ACQ6 responder analysis, minimum clinically important difference was reached by 18 PR participants (54.5%) versus 10 UC (22.7%), p = 0.009. Dropout rate was 31% between visits in PR group, and time to completion was significantly prolonged in PR group at 94 (70-107) days versus 63 (56-73) in UC, p < 0.001. CONCLUSIONS: PR improved asthma control and reduced perceived breathlessness in participants with difficult-to-control asthma and elevated BMI. However, this format appears to be suboptimal for this population with high drop-out rates and prolonged time to completion. Trial registration Clinicaltrials.gov. ID NCT03630432. Retrospectively registered, submitted May 26th 2017, posted August 14th 2018.

Multi-disciplinary community respiratory team management of patients with chronic respiratory illness during the COVID-19 pandemic.

The Greater Glasgow & Clyde NHS Trust Community Respiratory Response Team was established to manage patients with chronic respiratory disease at home during the COVID-19 pandemic. The team aimed to avert hospital admission while maximally utilising remote consultations. This observational study analysed outcomes of the triage pathway used, use of remote consultations, hospital admissions and mortality among patients managed by the team. Patients' electronic health records were retrospectively reviewed. Rates of emergency department attendance, hospital admission and death within 28 days of referral were compared across triage pathways. Segmented linear regression was carried out for emergency admissions in Greater Glasgow and Clyde pre- and post- Community Respiratory Response Team implementation, using emergency admissions for chronic obstructive pulmonary disease in the rest of Scotland as control and adjusting for all-cause emergency admissions. The triage category correlated with hospital admission and death. The red pathway had the highest proportion attending the emergency department (21%), significantly higher than the amber and green pathways (p = 0.03 and p = 0.004, respectively). The highest number of deaths were in the blue "end-of-life" pathway (p < 0.001). 87% of interactions were undertaken remotely. Triage severity appropriately led to targeted home visits. No nosocomial COVID-19 infections occurred among patients or staff. The Community Respiratory Response Team was associated with a significant decrease in emergency admissions (RR = 0.96 for each additional month under the Poisson model) compared to the counterfactual if the service had not been in place, suggesting a benefit in reducing secondary care pressures. The Community Respiratory Response Team effectively managed patients with chronic respiratory disease in the community, with an associated reduction in secondary care pressures during the COVID-19 pandemic.

Characterization of 4-hydroxyphenylpyruvate dioxygenases, inhibition by herbicides and engineering for herbicide tolerance in crops.

4-Hydroxyphenylpyruvate dioxgenase (HPPD) enzymes from rat and from several plants contained only about a single inhibitor-binding active site per dimer which matched the content of iron in the purified Arabidopsis thaliana and Avena sativa enzymes. The dimeric HPPDs were about 10 fold more catalytically active than the tetrameric P. fluorescens enzyme with kcat/KmHPP values ranging from 0.8 to 2.5 s-1 µM-1. Most were also highly sensitive to herbicides with, for example, Ki values for mesotrione ranging from 25 to 100 pM. Curiously HPPDs from cool climate grasses were much less herbicide-sensitive. When likewise expressed in Nicotinia tabacum, Avena sativa HPPD, Ki value of 11 nM for mesotrione, conferred far greater tolerance to mesotrione (CallistoTM) than did any of the more sensitive HPPDs. Targeted mutagenesis of the Avena HPPD led to the discovery of 4 mutations imparting improved inherent tolerance, defined as the ratio of Ki to KmHPP, by about 16 fold without any loss of catalytic activity. The Nicotinia line with the highest expression of this quadruple mutant exhibited substantial resistance even up to a 3 kg/ha post-emergence application of mesotrione. The maximum observed expression level of heterologous plant HPPDs in tobacco was ca. 0.35% of the total soluble protein whereas the endogenous tobacco HPPD constituted only ca. 0.00075%. At such high expression even HPPDs with impaired catalytic activity could be effective. A quintuple mutant Avena sativa HPPD conferred substantial tolerance across a broad range of HPPD herbicide chemistries despite being only ca. 5 % as catalytically active as the wild type enzyme. Testing various wild type and mutant HPPDs in tobacco revealed that tolerance to field rates of herbicide generally requires about two order of magnitude increases in both inherent herbicide tolerance and expression relative to endogenous levels. This double hurdle may explain why target-site based resistance to HPPD-inhibiting herbicides has been slow to evolve in weeds.

A prospective qualitative exploration of views about attending pulmonary rehabilitation.

BACKGROUND AND PURPOSE: Pulmonary rehabilitation has been found to be an effective strategy for managing chronic obstructive pulmonary disease (COPD). However, attendance at such programmes is not optimal, therefore, this study aimed to develop an in-depth understanding of views regarding attendance at pulmonary rehabilitation and experiences which may have shaped these views. METHODS: An inductive qualitative study was carried out within the framework of Interpretative Phenomenological Analysis. Five female and four male individuals with COPD who had been referred for pulmonary rehabilitation participated in semi-structured interviews. Interviews were conducted prior to participation in pulmonary rehabilitation. RESULTS: Three main themes were identified that related to views about attending pulmonary rehabilitation. The first is entitled 'Desired benefits of attending pulmonary rehabilitation', which described realistic hopes about impact on daily life. The second theme was called 'Evaluating the threat of exercise', and it encompassed both positive and negative evaluations; some interviewees described fear and avoidance of exercise, while others were determined to overcome symptoms. These attitudes extended to views about pulmonary rehabilitation. The third theme was called 'Attributing value to pulmonary rehabilitation'. Contrasting opinions about the value of attending pulmonary rehabilitation appeared to be influenced by the nature of prior interactions with health personnel and systems as well as information about the programme provided at referral. The referrer's attitude towards pulmonary rehabilitation appeared to be particularly influential. CONCLUSION: In summary, when considering rehabilitation attendance, potential participants are able to identify possible benefits, but previous experiences of symptoms and attitudes towards their condition can influence views both positively and negatively. Information and enthusiasm conveyed by the referring clinician, as well as previous interactions with health professionals can have powerful impact on views about attending. Referral practices should be informative and enthusiastic to increase the likelihood of uptake.

The metal-binding features of the recombinant mussel Mytilus edulis MT-10-IV metallothionein.

In contrast with the paradigmatic mammalian metallothioneins (MTs), mollusc MT systems consist at least of a high-cadmium induced form, possibly involved in detoxification, and another isoform either constitutive or regulated by essential metals and probably associated with housekeeping metabolism. With the aim of providing a deeper characterization of the coordination features of a molluscan MT peptide of the latter kind, we have analyzed here the metal-binding abilities of the recombinant MeMT-10-IV isoform of Mytilus edulis (MeMT). Also, comparison with other MTs of this type has been undertaken. A synthetic complementary DNA was constructed, cloned and expressed into two Escherichia coli systems. Upon zinc coordination, MeMT folds in vivo into highly chiral and stable Zn(7) complexes, with an exceptional reluctance to fully substitute cadmium(II) and/or copper(I) for zinc(II). In vivo cadmium binding leads to homometallic Cd(7) complexes that structurally differ from any of the in vitro prepared Cd(7) complexes. Homometallic Cu-MeMT can only be obtained in vitro from Zn(7)-MeMT after a great molar excess of copper(I) has been added. In vivo, two different heterometallic Zn,Cu-MeMT complexes are recovered, which nicely correspond to two distinct stages of the in vitro zinc/copper replacement. These MeMT metal-binding features are consistent with a physiological role related to basal/housekeeping metal, mainly zinc, metabolism, and confirm the correspondence between the MeMT gene response pattern and the functional properties of the encoded protein.