Personalised anti-inflammatory therapy for bronchiectasis and cystic fibrosis:selecting patients for controlled trials of neutrophil elastase inhibition

Background Neutrophil elastase (NE) has been linked to lung neutrophil dysfunction in bronchiectasis and cystic fibrosis (CF), making NE inhibition a potential therapeutic target. NE inhibitor trials have given mixed result perhaps because not all patients have elevated airway NE activity. Methods We tested whether a single baseline sputum NE measurement or a combination of clinical parameters could enrich patient populations with elevated NE activity for “personalised medicine”. Intra- and interindividual variations of total and active NE levels in induced sputum from patients with CF or bronchiectasis were monitored over 14 days. Patients with established CF and bronchiectasis (n=5 per group) were recruited. NE was measured using three different methods: one total and two active NE assays. Subsequently, we analysed the association between clinical parameters and NE from a large bronchiectasis cohort study (n=381). Results All three assays showed a high degree of day-to-day variability (0–233% over 14 days). There were strong correlations found between all assays (p<0.0001). Despite high day-to-day variability, patients could be stratified into “high” or “low” groups based on moderate cut-off levels. In the bronchiectasis cohort study, factors most associated with high sputum NE levels were: Pseudomonas aeruginosa infection (β-estimate 11.5, 95% CI −6.0–29.0), sputum colour (β-estimate 10.4, 95% CI 4.3–16.6), Medical Research Council dyspnoea score (β-estimate 6.4, 95% CI 1.4–11.4) and exacerbation history (β-estimate 3.4, 95% CI 1.4–5.3). Collectively, P. aeruginosa infection, sputum colour and exacerbation frequency provided the greatest specificity for “high” NE (98.7%, 95% CI 7.0–99.6%). Conclusion These results show that patients with bronchiectasis and CF can be effectively divided into “high” or “low” groups, based on sputum NE assays or clinical inclusion criteria

Long-term dietary intervention trials: critical issues and challenges

Background: There are many challenges involved in running randomised controlled dietary intervention trials that investigate health outcomes. The aim of this paper was to evaluate the recruitment process, retention of participants and challenges faced in our dairy intervention trial, and to provide strategies to combat the difficulties of running long-term dietary intervention trials.Methods: A 12-month, randomised, two-way crossover study was conducted in overweight adults with habitually low dairy food consumption to assess the effects of a high dairy intake (4 servings of reduced-fat dairy per day) compared with a low dairy intake (1 serving of reduced-fat dairy per day) on measures of cardiometabolic and cognitive health. On completion of the high dairy intake phase, each participant was interviewed about their experience in the trial and responses were used to evaluate the key issues for study participants.Results: Although the recruitment target was achieved, high rates of attrition (49.3%) and difficulties maintaining participant compliance (reported by 37.8% of participants) were major threats to the viability of the study. Factors that contributed to the high attrition included inability to comply with the dietary requirements of the study protocol (27.0%), health problems or medication changes (24.3%) and time commitment (10.8%).Conclusion: Attrition and adherence to study requirements present challenges to trials requiring longer-term dietary change. Including a run-in period to further assess the motivation, commitment and availability of participants, maintaining regular contact with participants during control phases, minimising time commitment, providing flexibility with dietary requirements, facilitating positive experiences, and stringent monitoring of diet are some key recommendations for future dietary intervention trials.Trial registration: Australia and New Zealand Clinical Trials Registry (ACTRN 12608000538347)

FIRE (facilitating implementation of research evidence) : a study protocol

Research evidence underpins best practice, but is not always used in healthcare. The Promoting Action on Research Implementation in Health Services (PARIHS) framework suggests that the nature of evidence, the context in which it is used, and whether those trying to use evidence are helped (or facilitated) affect the use of evidence. Urinary incontinence has a major effect on quality of life of older people, has a high prevalence, and is a key priority within European health and social care policy. Improving continence care has the potential to improve the quality of life for older people and reduce the costs associated with providing incontinence aids

Effects of control interventions on Clostridium difficile infection in England: an observational study

Background: The control of Clostridium difficile infections is an international clinical challenge. The incidence of C difficile in England declined by roughly 80% after 2006, following the implementation of national control policies; we tested two hypotheses to investigate their role in this decline. First, if C difficile infection declines in England were driven by reductions in use of particular antibiotics, then incidence of C difficile infections caused by resistant isolates should decline faster than that caused by susceptible isolates across multiple genotypes. Second, if C difficile infection declines were driven by improvements in hospital infection control, then transmitted (secondary) cases should decline regardless of susceptibility. Methods: Regional (Oxfordshire and Leeds, UK) and national data for the incidence of C difficile infections and antimicrobial prescribing data (1998–2014) were combined with whole genome sequences from 4045 national and international C difficile isolates. Genotype (multilocus sequence type) and fluoroquinolone susceptibility were determined from whole genome sequences. The incidence of C difficile infections caused by fluoroquinolone-resistant and fluoroquinolone-susceptible isolates was estimated with negative-binomial regression, overall and per genotype. Selection and transmission were investigated with phylogenetic analyses. Findings: National fluoroquinolone and cephalosporin prescribing correlated highly with incidence of C difficile infections (cross-correlations >0·88), by contrast with total antibiotic prescribing (cross-correlations 0·2). Interpretation: Restricting fluoroquinolone prescribing appears to explain the decline in incidence of C difficile infections, above other measures, in Oxfordshire and Leeds, England. Antimicrobial stewardship should be a central component of C difficile infection control programmes

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

In-person versus online delivery of a behavioral sleep intervention (Sleeping Sound©) for children with ADHD: protocol for a parallel-group, non-inferiority, randomized controlled trial

Abstract Background Children with Attention-Deficit/Hyperactivity Disorder (ADHD) often experience sleep difficulties such as difficulty initiating and maintaining sleep. Problem sleep may impact children’s daily functioning and behaviors and exacerbate ADHD symptoms. Most effective behavioral interventions to improve sleep are conducted in person, limiting accessibility to treatment for individuals in remote or rural communities or those who are unable to attend a clinic. This trial aims to assess the efficacy of delivering an established behavioral intervention online, Sleeping Sound with ADHD©, compared to a face-to-face delivery mode. Methods This parallel group, non-inferiority, randomized controlled trial (RCT) will include at least 68 children, aged 5–12 years old with ADHD. Families of children will be recruited from private developmental and psychological clinics and social media, within the state of Western Australia (WA). Once written informed consent and baseline questionnaires are completed, families are randomized to receive the behavioral intervention either in-person or online via Telehealth services. The intervention targets the assessment and management of reported sleep problems, through two individual consultations and a follow-up phone call with a trained clinician. The sleep outcomes assessed consist of a parent-reported sleep questionnaire and actigraphy. Discussion To the best of our knowledge, this is the first RCT to investigate sleep treatment modality for children with ADHD. If effective, clinicians can provide an evidence-based sleep intervention in an accessible manner. Trial registration ANZCTR, ACTRN12621001681842 . Registered 9 December 2021—Retrospectively registered

Dairy consumption and cardiometabolic health: outcomes of a 12-month crossover trial

<p>Abstract</p> <p>Background</p> <p>A growing body of research suggests that regular consumption of dairy foods may counteract obesity and other components of the metabolic syndrome. However, human intervention trials are lacking. We aimed to determine the cardiometabolic health effects of increasing the consumption of reduced fat dairy foods in adults with habitually low dairy intakes in the absence of energy restriction.</p> <p>Methods</p> <p>An intervention trial was undertaken in 61 overweight or obese adults who were randomly assigned to a high dairy diet (HD, 4 serves of reduced fat dairy/day) or a low dairy control diet (LD, ≤1 serve/day) for 6 months then crossed over to the alternate diet for a further 6 months. A range of anthropometric and cardiometabolic parameters including body composition, metabolic rate, blood lipids, blood pressure and arterial compliance were assessed at the end of each diet phase.</p> <p>Results</p> <p>Total energy intake was 1120 kJ/day higher during the HD phase, resulting in slight weight gain during this period. However, there were no significant differences between HD and LD in absolute measures of waist circumference, body weight, fat mass or any other cardiometabolic parameter.</p> <p>Conclusion</p> <p>Recommended intakes of reduced fat dairy products may be incorporated into the diet of overweight adults without adversely affecting markers of cardiometabolic health.</p> <p>Trial Registration</p> <p>The trial was registered with the Australia and New Zealand Clinical Trials Registry (<a href="http://www.anzctr.org.au/ACTRN12608000538347.aspx">ACTRN12608000538347</a>) on 24th October, 2008.</p