Infection prevention and control in cystic fibrosis: An update of a systematic review of interventions.

Preventing transmissible infection is a priority in cystic fibrosis (CF) care. This is an update of a systematic review of the evidence for infection prevention and control interventions in CF. Our full protocol can be found on PROSPERO (CRD42018109999). We searched for studies and guidelines which included interventions for infection prevention and control in CF. We included 39 studies and 7 guidelines. Strategies included: cohort or individual segregation, hand hygiene, facemasks, equipment, enhanced adherence or a combination of these. Many studies showed a reduction in transmission with segregation. However, the certainty of evidence (using GRADE) was low or very low. Most guideline recommendations have little evidence to support them, with no updates since our original review. Undertaking RCTs in this area is ethically difficult. Large-scale registry-based studies may be the best pragmatic approach. Benefits of infection control must be balanced against the intrusion in the lives of people with CF.

A grumbling concern: an international survey of gastrointestinal symptoms in cystic fibrosis in the modulator era.

Background: Gastrointestinal symptoms in cystic fibrosis (CF) are common and intrusive to daily life. Relieving gastrointestinal symptoms was identified as an important research priority and previously explored in an international survey in 2018. However, following the widespread introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulators in 2019, the landscape of CF treatment has changed. We repeated an online survey to further describe gastrointestinal symptoms and their effect on quality of life (QoL) in the CFTR modulator era. Methods: An electronic survey consisting of closed questions and free text responses was distributed via social media and professional networks for a period of one month between March - April 2022. People with CF (pwCF), their family and friends, and healthcare professionals (HCPs) were invited to take part. Results: There were 164 respondents: 88 pwCF (54%), 22 (13%) family, and 54 (33%) healthcare professionals (HCPs). A total of 89/110 (81%) pwCF or family members reported CFTR modulator treatment. The most commonly reported symptoms were wind / gas, rumbling stomach noises, loose motions (modulator) and bloating (no modulator). Abdominal pain and bloating had the greatest impact on QoL.For those on a CFTR modulator, the proportion of pwCF reporting "no change" or "worse" for all of the symptoms surveyed was greater than the proportion reporting an improvement. Following modulator introduction, dietary changes were recommended by 28/35 (80%) of HCPs and reported by 38/76 (50%) lay respondents. Changes in medication were recommended by 19/35 (54%) HCPs and reported by 44/76 (58%) of patients and family members. Conclusion: This survey has shown that gastrointestinal symptoms remain prevalent in pwCF in the CFTR modulator era, though the nature of these symptoms may have changed. A better understanding of the underlying pathophysiology of these symptoms is essential. Future clinical studies should focus on improving symptoms and QoL.

WHAT IS ALREADY KNOWN: Gastrointestinal symptoms are common and intrusive to everyday life for people with cystic fibrosis (CF), however the majority of studies reporting gastrointestinal symptoms in CF are published prior to the widespread introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies. These are medications which target the underlying defect in CF rather than the consequences of CFTR failure. WHAT THIS STUDY ADDS: Through this survey, we describe the similarities and differences of gastrointestinal symptoms for people with CF on modulator therapy compared to those not receiving modulators. Comparisons were also made to our previous work which was completed in 2018 prior to the licencing of the newest, and most widely used modulator, Elexacaftor / Tezacaftor / Ivacaftor (ETI). How this study might affect future research: This survey provides a snapshot into gastrointestinal symptoms for people with CF which will be of benefit for researchers as well as clinicians caring for people with CF. These results will inform the development of a CF-specific gastrointestinal patient reported outcome measure for people with CF that can be used in clinical trials.

Antibiotic strategies for eradicating Pseudomonas aeruginosa in people with cystic fibrosis.

BACKGROUND: Respiratory tract infections with Pseudomonas aeruginosa occur in most people with cystic fibrosis (CF). Established chronic P aeruginosa infection is virtually impossible to eradicate and is associated with increased mortality and morbidity. Early infection may be easier to eradicate. This is an updated review. OBJECTIVES: Does giving antibiotics for P aeruginosa infection in people with CF at the time of new isolation improve clinical outcomes (e.g. mortality, quality of life and morbidity), eradicate P aeruginosa infection, and delay the onset of chronic infection, but without adverse effects, compared to usual treatment or an alternative antibiotic regimen? We also assessed cost-effectiveness. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and conference proceedings. Latest search: 24 March 2022. We searched ongoing trials registries. Latest search: 6 April 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of people with CF, in whom P aeruginosa had recently been isolated from respiratory secretions. We compared combinations of inhaled, oral or intravenous (IV) antibiotics with placebo, usual treatment or other antibiotic combinations. We excluded non-randomised trials and cross-over trials. DATA COLLECTION AND ANALYSIS: Two authors independently selected trials, assessed risk of bias and extracted data. We assessed the certainty of the evidence using GRADE. MAIN RESULTS: We included 11 trials (1449 participants) lasting between 28 days and 27 months; some had few participants and most had relatively short follow-up periods. Antibiotics in this review are: oral - ciprofloxacin and azithromycin; inhaled - tobramycin nebuliser solution for inhalation (TNS), aztreonam lysine (AZLI) and colistin; IV - ceftazidime and tobramycin. There was generally a low risk of bias from missing data. In most trials it was difficult to blind participants and clinicians to treatment. Two trials were supported by the manufacturers of the antibiotic used. TNS versus placebo TNS may improve eradication; fewer participants were still positive for P aeruginosa at one month (odds ratio (OR) 0.06, 95% confidence interval (CI) 0.02 to 0.18; 3 trials, 89 participants; low-certainty evidence) and two months (OR 0.15, 95% CI 0.03 to 0.65; 2 trials, 38 participants). We are uncertain whether the odds of a positive culture decrease at 12 months (OR 0.02, 95% CI 0.00 to 0.67; 1 trial, 12 participants). TNS (28 days) versus TNS (56 days) One trial (88 participants) comparing 28 days to 56 days TNS treatment found duration of treatment may make little or no difference in time to next isolation (hazard ratio (HR) 0.81, 95% CI 0.37 to 1.76; low-certainty evidence). Cycled TNS versus culture-based TNS One trial (304 children, one to 12 years old) compared cycled TNS to culture-based therapy and also ciprofloxacin to placebo. We found moderate-certainty evidence of an effect favouring cycled TNS therapy (OR 0.51, 95% CI 0.31 to 0.82), although the trial publication reported age-adjusted OR and no difference between groups. Ciprofloxacin versus placebo added to cycled and culture-based TNS therapy One trial (296 participants) examined the effect of adding ciprofloxacin versus placebo to cycled and culture-based TNS therapy. There is probably no difference between ciprofloxacin and placebo in eradicating P aeruginosa (OR 0.89, 95% CI 0.55 to 1.44; moderate-certainty evidence). Ciprofloxacin and colistin versus TNS We are uncertain whether there is any difference between groups in eradication of P aeruginosa at up to six months (OR 0.43, 95% CI 0.15 to 1.23; 1 trial, 58 participants) or up to 24 months (OR 0.76, 95% CI 0.24 to 2.42; 1 trial, 47 participants); there was a low rate of short-term eradication in both groups. Ciprofloxacin plus colistin versus ciprofloxacin plus TNS One trial (223 participants) found there may be no difference in positive respiratory cultures at 16 months between ciprofloxacin with colistin versus TNS with ciprofloxacin (OR 1.28, 95% CI 0.72 to 2.29; low-certainty evidence). TNS plus azithromycin compared to TNS plus oral placebo Adding azithromycin may make no difference to the number of participants eradicating P aeruginosa after a three-month treatment phase (risk ratio (RR) 1.01, 95% CI 0.75 to 1.35; 1 trial, 91 participants; low-certainty evidence); there was also no evidence of any difference in the time to recurrence. Ciprofloxacin and colistin versus no treatment A single trial only reported one of our planned outcomes; there were no adverse effects in either group. AZLI for 14 days plus placebo for 14 days compared to AZLI for 28 days We are uncertain whether giving 14 or 28 days of AZLI makes any difference to the proportion of participants having a negative respiratory culture at 28 days (mean difference (MD) -7.50, 95% CI -24.80 to 9.80; 1 trial, 139 participants; very low-certainty evidence). Ceftazidime with IV tobramycin compared with ciprofloxacin (both regimens in conjunction with three months colistin) IV ceftazidime with tobramycin compared with ciprofloxacin may make little or no difference to eradication of P aeruginosa at three months, sustained to 15 months, provided that inhaled antibiotics are also used (RR 0.84, 95 % CI 0.65 to 1.09; P = 0.18; 1 trial, 255 participants; high-certainty evidence). The results do not support using IV antibiotics over oral therapy to eradicate P aeruginosa, based on both eradication rate and financial cost. AUTHORS' CONCLUSIONS: We found that nebulised antibiotics, alone or with oral antibiotics, were better than no treatment for early infection with P aeruginosa. Eradication may be sustained in the short term. There is insufficient evidence to determine whether these antibiotic strategies decrease mortality or morbidity, improve quality of life, or are associated with adverse effects compared to placebo or standard treatment. Four trials comparing two active treatments have failed to show differences in rates of eradication of P aeruginosa. One large trial showed that intravenous ceftazidime with tobramycin is not superior to oral ciprofloxacin when inhaled antibiotics are also used. There is still insufficient evidence to state which antibiotic strategy should be used for the eradication of early P aeruginosa infection in CF, but there is now evidence that intravenous therapy is not superior to oral antibiotics.

Inhaled anti-pseudomonal antibiotics for long-term therapy in cystic fibrosis.

BACKGROUND: Inhaled antibiotics are commonly used to treat persistent airway infection with Pseudomonas aeruginosa that contributes to lung damage in people with cystic fibrosis. Current guidelines recommend inhaled tobramycin for individuals with cystic fibrosis and persistent Pseudomonas aeruginosa infection who are aged six years or older. The aim is to reduce bacterial load in the lungs so as to reduce inflammation and deterioration of lung function. This is an update of a previously published review. OBJECTIVES: To evaluate the effects of long-term inhaled antibiotic therapy in people with cystic fibrosis on clinical outcomes (lung function, frequency of exacerbations and nutrition), quality of life and adverse events (including drug-sensitivity reactions and survival). SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched ongoing trials registries. Date of last search: 28 June 2022. SELECTION CRITERIA: We selected trials where people with cystic fibrosis received inhaled anti-pseudomonal antibiotic treatment for at least three months, treatment allocation was randomised or quasi-randomised, and there was a control group (either placebo, no placebo or another inhaled antibiotic). DATA COLLECTION AND ANALYSIS: Two authors independently selected trials, judged the risk of bias, extracted data from these trials and judged the certainty of the evidence using the GRADE system. MAIN RESULTS: The searches identified 410 citations to 125 trials; 18 trials (3042 participants aged between five and 45 years) met the inclusion criteria. Limited data were available for meta-analyses due to the variability of trial design and reporting of results. A total of 11 trials (1130 participants) compared an inhaled antibiotic to placebo or usual treatment for a duration between three and 33 months. Five trials (1255 participants) compared different antibiotics, two trials (585 participants) compared different regimens of tobramycin and one trial (90 participants) compared intermittent tobramycin with continuous tobramycin alternating with aztreonam. One trial (18 participants) compared an antibiotic to placebo and also to a different antibiotic and so fell into both groups. The most commonly studied antibiotic was tobramycin which was studied in 12 trials. Inhaled antibiotics compared to placebo We found that inhaled antibiotics may improve lung function measured in a variety of ways (4 trials, 814 participants). Compared to placebo, inhaled antibiotics may also reduce the frequency of exacerbations (risk ratio (RR) 0.66, 95% confidence interval (CI) 0.47 to 0.93; 3 trials, 946 participants; low-certainty evidence). Inhaled antibiotics may lead to fewer days off school or work (quality of life measure) (mean difference (MD) -5.30 days, 95% CI -8.59 to -2.01; 1 trial, 245 participants; low-certainty evidence). There were insufficient data for us to be able to report an effect on nutritional outcomes and there was no effect on survival. There was no effect on antibiotic resistance seen in the two trials that were included in meta-analyses. We are uncertain of the effect of the intervention on adverse events (very low-certainty evidence), but tinnitus and voice alteration were the only events occurring more often in the inhaled antibiotics group. The overall certainty of evidence was deemed to be low for most outcomes due to risk of bias within the trials and imprecision due to low event rates. Different antibiotics or regimens compared Of the eight trials comparing different inhaled antibiotics or different antibiotic regimens, there was only one trial for each unique comparison. We found no differences between groups for any outcomes except for the following. Aztreonam lysine for inhalation probably improved forced expiratory volume at one second (FEV1) % predicted compared to tobramycin (MD -3.40%, 95% CI -6.63 to -0.17; 1 trial, 273 participants; moderate-certainty evidence). However, the method of defining the endpoint was different to the remaining trials and the participants were exposed to tobramycin for a long period making interpretation of the results problematic. We found no differences in any measure of lung function in the remaining comparisons. Trials measured pulmonary exacerbations in different ways and showed no differences between groups except for aztreonam lysine probably leading to fewer people needing treatment with additional antibiotics than with tobramycin (RR 0.66, 95% CI 0.51 to 0.86; 1 trial, 273 participants; moderate-certainty evidence); and there were fewer hospitalisations due to respiratory exacerbations with levofloxacin compared to tobramycin (RR 0.62, 95% CI 0.40 to 0.98; 1 trial, 282 participants; high-certainty evidence). Important treatment-related adverse events were not very common across comparisons, but were reported less often in the tobramycin group compared to both aztreonam lysine and colistimethate. We found the certainty of evidence for these comparisons to be directly related to the risk of bias within the individual trials and varied from low to high. AUTHORS' CONCLUSIONS: Long-term treatment with inhaled anti-pseudomonal antibiotics probably improves lung function and reduces exacerbation rates, but pooled estimates of the level of benefit were very limited. The best evidence available is for inhaled tobramycin. More evidence from trials measuring similar outcomes in the same way is needed to determine a better measure of benefit. Longer-term trials are needed to look at the effect of inhaled antibiotics on quality of life, survival and nutritional outcomes.

Industry influence in healthcare harms patients: myth or maxim?

Healthcare is a major global industry accounting for a significant proportion of government spending. Drug and medical device manufacturers are publicly traded companies with a responsibility to their shareholders to maximise profits by increasing sales. In order to achieve this, industry exerts influence over every part of healthcare including academic research, medical education, clinical guideline development, physician prescribing and through direct interactions with patients. In contrast, healthcare services seek to provide effective, safe and evidence-based treatments. This article examines interactions with industry across these domains and seeks to identify mutually beneficial relationships and potential conflict leading to patient harms. Case studies are used to illustrate these interactions. There is no single solution for improving healthcare's relationship with industry, although increased transparency has raised awareness of this issue. We briefly discuss some successful interventions that have been tried at national and regulatory level. While industry influence is widespread in healthcare and this has benefits for shareholders, healthcare practitioners have an ethical obligation to prioritise their patients' best interests. Industry interactions with healthcare professionals have a valid role in product development and distribution, but industry sponsorship of healthcare education and practice, guideline development or regulatory decision-making can have harmful consequences for patients. Healthcare practitioners need to carefully consider these issues when deciding whether to collaborate with industry. Educational aims: To explore the many areas where industry influences healthcare and the subsequent effects on patient care. Case studies are used to illustrate examples of beneficial and harmful effects of this influence.To raise awareness of the effects of industry influence and for readers to consider their own potential conflicts of interest.To suggest potential ways to improve the current system with a focus on solutions which have successfully been trialled already.

Inhaled antibiotics for pulmonary exacerbations in cystic fibrosis.

BACKGROUND: Cystic fibrosis is a genetic disorder in which abnormal mucus in the lungs is associated with susceptibility to persistent infection. Pulmonary exacerbations are when symptoms of infection become more severe. Antibiotics are an essential part of treatment for exacerbations and inhaled antibiotics may be used alone or in conjunction with oral antibiotics for milder exacerbations or with intravenous antibiotics for more severe infections. Inhaled antibiotics do not cause the same adverse effects as intravenous antibiotics and may prove an alternative in people with poor access to their veins. This is an update of a previously published review. OBJECTIVES: To determine if treatment of pulmonary exacerbations with inhaled antibiotics in people with cystic fibrosis improves their quality of life, reduces time off school or work, and improves their long-term lung function. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Group's Cystic Fibrosis Trials Register. Date of the last search: 7 March 2022. We also searched ClinicalTrials.gov, the Australia and New Zealand Clinical Trials Registry and WHO ICTRP for relevant trials. Date of last search: 3 May 2022. SELECTION CRITERIA: Randomised controlled trials in people with cystic fibrosis with a pulmonary exacerbation in whom treatment with inhaled antibiotics was compared to placebo, standard treatment or another inhaled antibiotic for between one and four weeks. DATA COLLECTION AND ANALYSIS: Two review authors independently selected eligible trials, assessed the risk of bias in each trial and extracted data. They assessed the certainty of the evidence using the GRADE criteria. Authors of the included trials were contacted for more information. MAIN RESULTS: Five trials with 183 participants are included in the review. Two trials (77 participants) compared inhaled antibiotics alone to intravenous antibiotics alone and three trials (106 participants) compared a combination of inhaled and intravenous antibiotics to intravenous antibiotics alone. Trials were heterogenous in design and two were only available in abstract form. Risk of bias was difficult to assess in most trials but, for four out of five trials, we judged there to be a high risk from lack of blinding and an unclear risk with regards to randomisation. Results were not fully reported and only limited data were available for analysis. One trial was a cross-over design and we only included data from the first intervention arm. Inhaled antibiotics alone versus intravenous antibiotics alone Only one trial (18 participants) reported a perceived improvement in lifestyle (quality of life) in both groups (very low-certainty evidence). Neither trial reported on time off work or school. Both trials measured lung function, but there was no difference reported between treatment groups (very low-certainty evidence). With regards to our secondary outcomes, one trial (18 participants) reported no difference in the need for additional antibiotics and the second trial (59 participants) reported on the time to next exacerbation. In neither case was a difference between treatments identified (both very low-certainty evidence). The single trial (18 participants) measuring adverse events and sputum microbiology did not observe any in either treatment group for either outcome (very low-certainty  evidence). Inhaled antibiotics plus intravenous antibiotics versus intravenous antibiotics alone Inhaled antibiotics plus intravenous antibiotics may make little or no difference to quality of life compared to intravenous antibiotics alone. None of the trials reported time off work or school. All three trials measured lung function, but found no difference between groups in forced expiratory volume in one second (two trials; 44 participants; very low-certainty evidence) or vital capacity (one trial; 62 participants). None of the trials reported on the need for additional antibiotics. Inhaled plus intravenous antibiotics may make little difference to the time to next exacerbation; however, one trial (28 participants) reported on hospital admissions and found no difference between groups. There is likely no difference between groups in adverse events (very low-certainty evidence) and one trial (62 participants) reported no difference in the emergence of antibiotic-resistant organisms (very low-certainty evidence). AUTHORS' CONCLUSIONS: We identified only low- or very low-certainty evidence to judge the effectiveness of inhaled antibiotics for the treatment of pulmonary exacerbations in people with cystic fibrosis. The included trials were not sufficiently powered to achieve their goals. Hence, we are unable to demonstrate whether one treatment was superior to the other or not. Further research is needed to establish whether inhaled tobramycin may be used as an alternative to intravenous tobramycin for some pulmonary exacerbations.

Short-acting inhaled bronchodilators for cystic fibrosis.

BACKGROUND: Respiratory disease is the main cause of morbidity and mortality in cystic fibrosis (CF), and many different therapies are used by people with CF in the management of respiratory problems. Bronchodilator therapy is used to relieve symptoms of shortness of breath and to open the airways to allow clearance of mucus. Despite the widespread use of inhaled bronchodilators in CF, there is little objective evidence of their efficacy. A Cochrane Review looking at both short- and long-acting inhaled bronchodilators for CF was withdrawn from the Cochrane Library in 2016. That review has been replaced by two separate Cochrane Reviews: one on long-acting inhaled bronchodilators for CF, and this review on short-acting inhaled bronchodilators for CF. For this review 'inhaled' includes the use of pressurised metered dose inhalers (MDIs), with or without a spacer, dry powder devices and nebulisers. OBJECTIVES: To evaluate short-acting inhaled bronchodilators in children and adults with CF in terms of clinical outcomes and safety. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books on 28 March 2022 and searched trial registries for any new or ongoing trials on 12 April 2022. We also searched the reference lists of relevant articles and reviews. SELECTION CRITERIA: We searched for randomised controlled trials (RCTs) or quasi-RCTs that looked at the effect of any short-acting inhaled bronchodilator delivered by any device, at any dose, at any frequency and for any duration compared to either placebo or another short-acting inhaled bronchodilator in people with CF. We screened references as per standard Cochrane methodology. DATA COLLECTION AND ANALYSIS: Two review authors extracted data and assessed risk of bias using the Cochrane RoB 1 tool. Where we were not able to enter data into our analyses we reported results directly from the papers. We assessed the certainty of evidence using GRADE. MAIN RESULTS: We included 11 trials from our systematic search, with 191 participants meeting our inclusion criteria; three of these trials had three treatment arms. Eight trials compared short-acting inhaled beta-2 agonists to placebo and four trials compared short-acting inhaled muscarinic antagonists to placebo. Three trials compared short-acting inhaled beta-2 agonists to short-acting inhaled muscarinic antagonists. All were cross-over trials with only small numbers of participants. We were only able to enter data into the analysis from three trials comparing short-acting inhaled beta-2 agonists to placebo. Short-acting inhaled beta-2 agonists versus placebo All eight trials (six single-dose trials and two longer-term trials) reporting on this comparison reported on forced expiratory volume in 1 second (FEV1), either as per cent predicted (% predicted) or L. We were able to combine the data from two trials in a meta-analysis which showed a greater per cent change from baseline in FEV1 L after beta-2 agonists compared to placebo (mean difference (MD) 6.95%, 95% confidence interval (CI) 1.88 to 12.02; 2 trials, 82 participants). Only one of the longer-term trials reported on exacerbations, as measured by hospitalisations and courses of antibiotics. Only the second longer-term trial presented results for participant-reported outcomes. Three trials narratively reported adverse events, and these were all mild. Three single-dose trials and the two longer trials reported on forced vital capacity (FVC), and five trials reported on peak expiratory flow, i.e. forced expiratory flow between 25% and 75% (FEF25-75). One trial reported on airway clearance in terms of sputum weight. We judged the certainty of evidence for each of these outcomes to be very low, meaning we are very uncertain about the effect of short-acting inhaled beta-2 agonists on any of the outcomes we assessed. Short-acting inhaled muscarinic antagonists versus placebo All four trials reporting on this comparison looked at the effects of ipratropium bromide, but in different doses and via different delivery methods. One trial reported FEV1 % predicted; three trials measured this in L. Two trials reported adverse events, but these were few and mild. One trial reported FVC and three trials reported FEF25-75. None of the trials reported on quality of life, exacerbations or airway clearance. We judged the certainty of evidence for each of these outcomes to be very low, meaning we are very uncertain about the effect of short-acting inhaled muscarinic antagonists on any of the outcomes we assessed. Short-acting inhaled beta-2 agonists versus short-acting inhaled muscarinic antagonists  None of the three single-dose trials reporting on this comparison provided data we could analyse. The original papers from three trials report that both treatments lead to an improvement in FEV1 L. Only one trial reported on adverse events; but none were experienced by any participant. No trial reported on any of our other outcomes. We judged the certainty of evidence to be very low, meaning we are very uncertain about the effect of short-acting inhaled beta-2 agonists compared to short-acting inhaled muscarinic antagonists on any of the outcomes we assessed. AUTHORS' CONCLUSIONS: All included trials in this review are small and of a cross-over design. Most trials looked at very short-term effects of inhaled bronchodilators, and therefore did not measure longer-term outcomes. The certainty of evidence across all outcomes was very low, and therefore we have been unable to describe any effects with certainty.

Airway clearance and exercise for people with cystic fibrosis: Balancing longevity with life.

Airway clearance has been an integral part of cystic fibrosis (CF) care for almost as long as CF has been identified as a condition. From diagnosis as a neonate through to end-of-life care, airway clearance is an everyday aspect of life, adding a considerable treatment burden to the lives of people with CF. There are many different techniques used for airway clearance which have evolved over time with an aim to improve effectiveness, support adherence and, more recently, to consider the impact of burden. A popular thought is whether airway clearance could be replaced by exercise. With new precision therapies in the form of CFTR modulators available, the CF landscape is rapidly changing, raising the question of whether certain treatments are needed at all. Depending on factors such as CFTR mutation, age, and pre-existing lung damage before starting a CFTR modulator, individuals with CF may need different levels of intensity and type of maintenance treatment. Precision medicine is likely to lead to the need for increased precision and individualized management around other maintenance therapies such as airway clearance.

What effective ways of motivation, support and technologies help people with cystic fibrosis improve and sustain adherence to treatment?

INTRODUCTION: "What effective ways of motivation, support and technologies help people with cystic fibrosis improve and sustain adherence to treatment?" was identified as one of the James Lind Alliance Priority Setting Partnership's top 10 research questions in cystic fibrosis (CF). Using electronic questionnaires, we aimed to gain a deeper understanding of this research priority. METHOD: The work was led by the steering group representative of the UK CF community consisting of patients, carers and healthcare professionals (HCPs). Electronic questionnaires were completed over a 4-week period and promoted via online forums such as Twitter, the UK CF Trust and US CF Foundation websites and via professional networks. Analysis of the closed questions was completed using Microsoft Excel, with keyword analysis and the final thematic analysis completed using NVivo software. RESULTS: There were 313 respondents; 176/313 (56%) were from people with CF and their families. HCPs comprised of 10 professional groups accounting for 137/313 (44%) of respondents, with global involvement of participants with the majority from the UK. Common themes identified as impacting on adherence included: having no time, treatment burden, competing life demands, fatigue and the patient's general health. Having a routine was identified as the most frequently used motivational strategy, valued by both the patient and professional community. However, some strategies were valued more by HCPs than used in practice by patients; these included the use of short-term goal setting and technology use. CONCLUSION: Adherence to treatment is crucial, however it is often suboptimal and strategies valued by HCPs to promote adherence are not always shared by patients. To promote adherence clinicians and researchers should be mindful that in a condition where treatment burden and time pressures are considerable, any interventions should focus on simplifying care and reducing treatment burden.

Observational Study of Pulse Transit Time in Children With Sleep Disordered Breathing.

Background: Pulse transit time (PTT) is a non-invasive measure of arousals and respiratory effort for which we aim to identify threshold values that detect sleep disordered breathing (SDB) in children. We also compare the sensitivity and specificity of oximetry with the findings of a multi-channel study. Methods: We performed a cross-sectional observational study of 521 children with SDB admitted for multi-channel sleep studies (pulse oximetry, ECG, video, sound, movement, PTT) in a secondary care centre. PTT data was available in 368 children. Studies were categorised as normal; primary snoring; upper airway resistance syndrome (UARS); obstructive sleep apnoea (OSA), and "abnormal other." Receiver operator characteristic curves were constructed for different PTT (Respiratory swing; Arousal index) thresholds using a random sample of 50% of children studied (training set); calculated thresholds of interest were validated against the other 50% (test set). Study findings were compared with oximetry categories (normal, inconclusive, abnormal) using data (mean and minimum oxygen saturations; oxygen desaturations > 4%) obtained during the study. Results: Respiratory swing of 17.92 ms identified SDB (OSA/UARS) with sensitivity: 0.80 (C.I. 0.62-0.90) and specificity 0.79 (C.I. 0.49-0.87). PTT arousal index of 16.06/ hour identified SDB (OSA/UARS) with sensitivity: 0.85 (95% C.I. 0.67-0.92) and specificity 0.37 (95% C.I. 0.17-0.48). Oximetry identified SDB (OSA) with sensitivity: 0.38 (C.I. 0.31-0.46) and specificity 0.98 (C.I. 0.97-1.00). Conclusions: PTT is more sensitive but less specific than oximetry at detecting SDB in children. The additional use of video and sound enabled detection of SDB in twice as many children as oximetry alone.

Infection prevention and control in cystic fibrosis: One size fits all The argument against.

As awareness of the risks of cross infection has increased, infection prevention and control measures have become more draconian. Infection control measures can have a profound effect of the organisation and delivery of CF services and on the lives of people with CF outside the hospital. However, the consequences of inadequate infection control measures may be the permanent acquisition of a chronic infection which is virtually untreatable. Recommendations for infection prevention and control therefore must protect patients but should also be evidence-based and proportionate. This article will review the literature, juxtaposing evidence and popular practise.

Characterising burden of treatment in cystic fibrosis to identify priority areas for clinical trials.

In a recent James Lind Alliance Priority Setting Partnership in cystic fibrosis (CF) the top priority clinical research question was: "What are effective ways of simplifying the treatment burden of people with CF?" We aimed to summarise the lived experience of treatment burden and suggest research themes aimed at reducing it. An online questionnaire was co-produced and responses subjected to quantitative and thematic analysis. 941 survey responses were received (641 from lay community). People with CF reported a median of 10 (interquartile range: 6-15) current treatments. Seven main themes relating to simplifying treatment burden were identified. Treatment burden is high, extending beyond time taken to perform routine daily treatments, with impact varying according to person-specific factors. Approaches to communication, support, evaluation of current treatments, service set-up, and treatment logistics (obtaining/administration) contribute to burden, offering scope for evaluation in clinical trials or service improvement.

Infection prevention and control in cystic fibrosis: a systematic review of interventions.

INTRODUCTION: Cystic fibrosis is a life-limiting genetic condition characterized by recurrent pulmonary infection. Acquisition of infection can occur from environmental reservoirs, person-to-person transmission and from the healthcare environment. Primary prevention of infections through infection prevention and control measures is an important strategy in cystic fibrosis care. Areas covered: Here we present a systematic review of the evidence base around infection prevention and control in cystic fibrosis. We found 36 studies and 7 guidelines that met our inclusion criteria. Strategies covered include cohort segregation, individual segregation, hand hygiene, facemasks, combination strategies, equipment strategies, and adherence. Quality of evidence overall was deemed low or very low. Most guideline recommendations have little or no evidence to support them. Expert opinion: Although low quality, there is an abundance of evidence suggesting segregation is beneficial in reducing pathogen spread. Undertaking high-quality studies may, therefore, be ethically challenging. Large-scale registry studies may provide a better strategy for answering questions on the efficacy of infection control policy. With the rise of antibiotic resistance, effective eradication of cystic fibrosis pathogens is becoming more difficult so primary prevention through infection control will become increasingly important over the coming years.

Inhaled antibiotics for pulmonary exacerbations in cystic fibrosis.

BACKGROUND: Cystic fibrosis is a genetic disorder in which abnormal mucus in the lungs is associated with susceptibility to persistent infection. Pulmonary exacerbations are when symptoms of infection become more severe. Antibiotics are an essential part of treatment for exacerbations and inhaled antibiotics may be used alone or in conjunction with oral antibiotics for milder exacerbations or with intravenous antibiotics for more severe infections. Inhaled antibiotics do not cause the same adverse effects as intravenous antibiotics and may prove an alternative in people with poor access to their veins. This is an update of a previously published review. OBJECTIVES: To determine if treatment of pulmonary exacerbations with inhaled antibiotics in people with cystic fibrosis improves their quality of life, reduces time off school or work and improves their long-term survival. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Group's Cystic Fibrosis Trials Register. Date of the last search: 03 October 2018.We searched ClinicalTrials.gov, the Australia and New Zealand Clinical Trials Registry and WHO ICTRP for relevant trials. Date of last search: 09 October 2018. SELECTION CRITERIA: Randomised controlled trials in people with cystic fibrosis with a pulmonary exacerbation in whom treatment with inhaled antibiotics was compared to placebo, standard treatment or another inhaled antibiotic for between one and four weeks. DATA COLLECTION AND ANALYSIS: Two review authors independently selected eligible trials, assessed the risk of bias in each trial and extracted data. They assessed the quality of the evidence using the GRADE criteria. Authors of the included trials were contacted for more information. MAIN RESULTS: Four trials with 167 participants are included in the review. Two trials (77 participants) compared inhaled antibiotics alone to intravenous antibiotics alone and two trials (90 participants) compared a combination of inhaled and intravenous antibiotics to intravenous antibiotics alone. Trials were heterogenous in design and two were only available in abstract form. Risk of bias was difficult to assess in most trials, but for all trials we judged there to be a high risk from lack of blinding and an unclear risk with regards to randomisation. Results were not fully reported and only limited data were available for analysis.Inhaled antibiotics alone versus intravenous antibiotics aloneOnly one trial (n = 18) reported a perceived improvement in lifestyle (quality of life) in both groups (very low-quality of evidence). Neither trial reported on time off work or school. Both trials measured lung function, but there was no difference reported between treatment groups (very low-quality evidence). With regards to our secondary outcomes, one trial (n = 18) reported no difference in the need for additional antibiotics and the second trial (n = 59) reported on the time to next exacerbation. In neither case was a difference between treatments identified (both very low-quality evidence). The single trial (n = 18) measuring adverse events and sputum microbiology did not observe any in either treatment group for either outcome (very low-quality evidence).Inhaled antibiotics plus intravenous antibiotics versus intravenous antibiotics aloneNeither trial reported on quality of life or time off work or school. Both trials measured lung function, but found no difference between groups in forced expiratory volume in one second (one trial, n = 28, very low-quality evidence) or vital capacity (one trial, n = 62). Neither trial reported on the need for additional antibiotics or the time to the next exacerbation; however, one trial (n = 28) reported on hospital admissions and found no difference between groups. Both trials reported no difference between groups in adverse events (very low-quality evidence) and one trial (n = 62) reported no difference in the emergence of antibiotic-resistant organisms (very low-quality evidence). AUTHORS' CONCLUSIONS: There is little useful high-level evidence to judge the effectiveness of inhaled antibiotics for the treatment of pulmonary exacerbations in people with cystic fibrosis. The included trials were not sufficiently powered to achieve their goals. Hence, we are unable to demonstrate whether one treatment was superior to the other or not. Further research is needed to establish whether inhaled tobramycin may be used as an alternative to intravenous tobramycin for some pulmonary exacerbations.

Inhaled anti-pseudomonal antibiotics for long-term therapy in cystic fibrosis.

BACKGROUND: Inhaled antibiotics are commonly used to treat persistent airway infection with Pseudomonas aeruginosa that contributes to lung damage in people with cystic fibrosis. Current guidelines recommend inhaled tobramycin for individuals with cystic fibrosis and persistent Pseudomonas aeruginosa infection who are aged six years or older. The aim is to reduce bacterial load in the lungs so as to reduce inflammation and deterioration of lung function. This is an update of a previously published review. OBJECTIVES: To evaluate the effects long-term inhaled antibiotic therapy in people with cystic fibrosis on clinical outcomes (lung function, frequency of exacerbations and nutrition), quality of life and adverse events (including drug sensitivity reactions and survival). SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched ongoing trials registries.Date of last search: 13 February 2018. SELECTION CRITERIA: We selected trials if inhaled anti-pseudomonal antibiotic treatment was used for at least three months in people with cystic fibrosis, treatment allocation was randomised or quasi-randomised, and there was a control group (either placebo, no placebo or another inhaled antibiotic). DATA COLLECTION AND ANALYSIS: Two authors independently selected trials, judged the risk of bias, extracted data from these trials and judged the quality of the evidence using the GRADE system. MAIN RESULTS: The searches identified 333 citations to 98 trials; 18 trials (3042 participants aged between five and 56 years) met the inclusion criteria. Limited data were available for meta-analyses due to the variability of trial design and reporting of results. A total of 11 trials (1130 participants) compared an inhaled antibiotic to placebo or usual treatment for a duration between three and 33 months. Five trials (1255 participants) compared different antibiotics, two trials (585 participants) compared different regimens of tobramycin and one trial (90 participants) compared intermittent tobramycin with continuous tobramycin alternating with aztreonam. One of the trials (18 participants) compared to placebo and a different antibiotic and so fell into both groups. The most commonly studied antibiotic was tobramycin which was studied in 12 trials.We found limited evidence that inhaled antibiotics improved lung function (four of the 11 placebo-controlled trials, n = 814). Compared to placebo, inhaled antibiotics also reduced the frequency of exacerbations (three trials, n = 946), risk ratio 0.66 (95% confidence interval (CI) 0.47 to 0.93). There were insufficient data for us to be able to report an effect on nutritional outcomes or survival and there were insufficient data for us to ascertain the effect on quality of life. There was no significant effect on antibiotic resistance seen in the two trials that were included in meta-analyses. Tinnitus and voice alteration were the only adverse events significantly more common in the inhaled antibiotics group. The overall quality of evidence was deemed to be low for most outcomes due to risk of bias within the trials and imprecision due to low event rates.Of the eight trials that compared different inhaled antibiotics or different antibiotic regimens, there was only one trial in each comparison. Forced expiratory volume at one second (FEV1) % predicted was only found to be significantly improved with aztreonam lysine for inhalation compared to tobramycin (n = 273), mean difference -3.40% (95% CI -6.63 to -0.17). However, the method of defining the endpoint was different to the remaining trials and the participants were exposed to tobramycin for a long period making interpretation of the results problematic. No significant differences were found in the remaining comparisons with regard to lung function. Pulmonary exacerbations were measured in different ways, but one trial (n = 273) found that the number of people treated with antibiotics was lower in those receiving aztreonam than tobramycin, risk ratio 0.66 (95% CI 0.51 to 0.86). We found the quality of evidence for these comparisons to be directly related to the risk of bias within the individual trials and varied from low to high. AUTHORS' CONCLUSIONS: Inhaled anti-pseudomonal antibiotic treatment probably improves lung function and reduces exacerbation rate, but pooled estimates of the level of benefit were very limited. The best evidence is for inhaled tobramycin. More evidence from trials measuring similar outcomes in the same way is needed to determine a better measure of benefit. Longer-term trials are needed to look at the effect of inhaled antibiotics on quality of life, survival and nutritional outcomes.

The top 10 research priorities in cystic fibrosis developed by a partnership between people with CF and healthcare providers.

There remain many treatment uncertainties in cystic fibrosis (CF). With limited resources, research should focus on questions which are most important to the CF community. We conducted a James Lind Alliance Priority Setting Partnership in CF. Research questions were elicited and then prioritised in successive surveys. A workshop agreed the final top 10. Online methods avoided cross infection and widened participation. The elicitation survey had 482 respondents (1080 questions) and prioritisation survey 677 respondents. Participants were drawn equally from the patient and clinical communities globally. We have achieved a consensus on 10 research priorities which will be attractive to funders.

Role of Hedgehog signalling at the transition from double-positive to single-positive thymocyte.

In the thymus, developing T cells receive signals that determine lineage choice, specificity, MHC restriction and tolerance to self-antigen. One way in which thymocytes receive instruction is by secretion of Sonic hedgehog (Shh) from thymic epithelial cells. We have previously shown that Hedgehog (Hh) signalling in the thymus decreases the CD4:CD8 single-positive (SP) thymocyte ratio. Here, we present data indicating that double-positive (DP) thymocytes are Hh-responsive and that thymocyte-intrinsic Hh signalling plays a role in modulating the production of CD4(+) (SP4), CD8(+) (SP8) and unconventional T-cell subsets. Repression of physiological Hh signalling in thymocytes altered the proportions of DP and SP4 cells. Thymocyte-intrinsic Hh-dependent transcription also attenuated both the production of mature SP4 and SP8 cells, and the establishment of peripheral T-cell compartments in TCR-transgenic mice. Additionally, stimulation or withdrawal of Hh signals in the WT foetal thymus impaired or enhanced upregulation of the CD4 lineage-specific transcription factor Gata3 respectively. These data together suggest that Hh signalling may play a role in influencing the later stages of thymocyte development.

Non-redundant role for the transcription factor Gli1 at multiple stages of thymocyte development.

The Hedgehog (Hh) signaling pathway influences multiple stages of murine T-cell development. Hh signaling mediates transcriptional changes by the activity of the Gli family of transcription factors, Gli1, Gli2 and Gli3. Both Gli2 and Gli3 are essential for mouse development and can be processed to function as transcriptional repressors or transcriptional activators, whereas Gli1, itself a transcriptional target of Hh pathway activation, can only function as a transcriptional activator and is not essential for mouse development. Gli1-deficient mice are healthy and appear normal and nonredundant functions for Gli1 have been difficult to identify. Here we show that Gli1 is non-redundant in the regulation of T-cell development in the thymus, at multiple developmental stages. Analysis of Gli1-deficient embryonic mouse thymus shows a role for Gli1 to promote the differentiation of CD4⁻CD8⁻ double negative (DN) thymocytes before pre- TCR signal transduction, and a negative regulatory function after pre-TCR signaling. In addition, introduction of a Class I-restricted transgenic TCR into the adult Gli1-deficient and embryonic Gli2-deficient thymus showed that both Gli1 and Gli2 influence its selection to the CD8 lineage.