Cystic Fibrosis Group Trials Research Articles

Interventions for the eradication of meticillin-resistant Staphylococcus aureus (MRSA) in people with cystic fibrosis.

Interventions for the eradication of meticillin-resistant Staphylococcus aureus (MRSA) in people with cystic fibrosis.

Appetite stimulants for people with cystic fibrosis.

Chronic loss of appetite in cystic fibrosis concerns both individuals and families. Appetite stimulants have been used to help cystic fibrosis patients with chronic anorexia attain optimal body mass index (BMI) and nutritional status. However, these may have adverse effects on clinical status. This is an updated version of the original review. To systematically search for and evaluate the evidence on the beneficial effects of appetite stimulants in the management of cystic fibrosis-related anorexia and synthesise reports of any side effects. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Cystic Fibrosis Trials Register and online trials registries; handsearched reference lists; and contacted local and international experts to identify relevant trials. Last search of the Cystic Fibrosis Trials Register: 23 May 2022. Last search of online trial registries: 10 May 2022. Randomised and quasi-randomised controlled trials of appetite stimulants compared to placebo, control, no treatment or different appetite stimulants, or to the same appetite stimulants at different doses or regimens for at least one month in adults and children with cystic fibrosis. Review authors independently extracted data and assessed risk of bias of the included trials. We used the GRADE approach to assess the certainty of the evidence and performed meta-analyses. We included four trials (70 participants) comparing appetite stimulants (cyproheptadine hydrochloride and megestrol acetate) to placebo; the numbers of adults or children within each trial were not always reported. We assessed the certainty of evidence as low due to the small number of participants, incomplete or selective outcome reporting, and unclear risk of selection bias. Regarding our primary outcomes, a meta-analysis of two trials (42 participants) showed that appetite stimulants may produce a larger increase in weight (kg) at three months (mean difference (MD) 1.25 kg, 95% confidence interval (Cl) 0.45 to 2.05), and one trial (17 participants) showed a similar result at six months (MD 3.80 kg, 95% CI 1.27 to 6.33) (both low-certainty evidence). Results also showed that weight z score may increase with appetite stimulants compared to placebo at three months (MD 0.61, 95% CI 0.29 to 0.93; 3 studies; 40 participants; P < 0.001) and at six months (MD0.74, 95% CI 0.26 to 1.22; 1 trial; 17 participants). There was no evidence of a difference in effect between cyproheptadine hydrochloride and megestrol acetate for either outcome. Only one trial (25 participants) reported analysable data for body composition (BMI), with results favouring cyproheptadine hydrochloride compared to placebo; a further trial (16 participants) narratively agreed with this result. All four trials reported on lung function at durations ranging from two to nine months. Considering analysable data, two trials (42 participants) found that appetite stimulants may make little or no difference in forced expiratory volume at one second (FEV1) % predicted at three months, and one trial (17 participants) found similar results at six months. Two further three-month trials narratively agreed with these results. Limited information was reported for secondary outcomes. Two trials (23 participants) reported results showing that appetite stimulants may increase appetite compared to placebo at three months (odds ratio 45.25, 95% CI 3.57 to 573.33; low-certainty evidence). Only one study reported on quality of life, finding that cyproheptadine reduced fatigue in two participants compared with none with placebo. One study (25 participants) found no difference in energy intake between appetite stimulant or placebo at three months. Insufficient reporting of adverse effects prevented a full determination of their impact. Two studies (33 participants) narratively reported similar requirements for additional antibiotics between appetite stimulants and placebo at three months. AUTHORS' CONCLUSIONS: At six months in adults and children, appetite stimulants improved only two of the outcomes of this review: weight (or weight z score) and subjectively reported appetite. Insufficient reporting of side effects prevented a full determination of their impact. Whilst the data may suggest the potential use of appetite stimulants in treating anorexia in adults and children with cystic fibrosis, this is based upon low-certainty evidence from a small number of trials, therefore firm conclusions cannot be drawn. Clinicians need to be aware of the potential adverse effects of appetite stimulants and actively monitor any individuals prescribed these medications accordingly. Research is required to determine meaningful surrogate measures for appetite and to define what constitutes quality weight gain. Future trials of appetite stimulants should use a validated measure of symptoms including a disease-specific instrument for measuring poor appetite. This review highlights the need for multicentred, adequately powered, and well-designed trials to evaluate agents to safely increase appetite in people with cystic fibrosis and to establish the optimal mode of treatment.

Inhaled antibiotics for pulmonary exacerbations in cystic fibrosis.

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. 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. 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. 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. 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. 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). 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.

Vitamin E supplementation in people with cystic fibrosis.

People with cystic fibrosis are at an increased risk of fat-soluble vitamin deficiency, including vitamin E. Vitamin E deficiency can cause a host of conditions such as haemolytic anaemia, cerebellar ataxia and cognitive difficulties. Vitamin E supplementation is widely recommended for people with cystic fibrosis and aims to ameliorate this deficiency. This is an updated version of the review. To determine the effects of any level of vitamin E supplementation on the frequency of vitamin E deficiency disorders in people with cystic fibrosis. We searched the Cochrane Group's Cystic Fibrosis Trials Register and also searched international online trial registries for any ongoing clinical trials that were not identified during our register search. Date of last search of the Register: 11 August 2020. Date of last search of international online trial registries: 20 July 2020. Randomised controlled trials and quasi-randomised controlled trials comparing any preparation of vitamin E supplementation to placebo or no supplement, regardless of dosage or duration. Two authors extracted outcome data from each study (published information) and assessed the risk of bias of each included study. They assessed the quality of the evidence using GRADE. Four studies with a total of 141 participants were included in the review, two of these were in children (aged six months to 14.5 years), and two did not specify participants' age. All studies used different formulations and doses of vitamin E for various durations of treatment (10 days to six months). Two studies compared the supplementation of fat-soluble as well as water-soluble formulations to no supplementation in different arms of the same study. A third study compared a water-soluble formulation to a placebo; and in the fourth study a fat-soluble formulation of vitamin E was assessed against placebo. There was limited detail about randomisation and blinding in the included studies which compromises the quality of the evidence base for the review. The heterogeneous mix of the formulations with differing biovailabilities among these studies also limits the generalisability of the data to the wider cystic fibrosis population. None of the studies in either comparison report the review's primary outcomes of vitamin E total lipid ratio or the incidence of vitamin E-specific deficiency disorders, or the secondary outcomes lung function or quality of life. Water-soluble vitamin E Water-soluble vitamin E may improve serum vitamin E levels compared with control at six months, one study (45 participants), mean difference (MD) 19.74 umol/L (95% confidence interval (CI) 13.48 to 26.00) (low-quality evidence). Similar results were also seen at one month, two studies (32 participants), MD 17.66 umol/L (95% CI 10.59 to 24.74) and at three months, one study (45 participants), MD 11.61 umol/L (95% CI 4.77 to 18.45). Only one study (45 participants) reported weight (secondary outcome of growth and nutritional status) at one and six months, but showed no difference between treatment and control at either time point. Fat-soluble vitamin E Two studies (36 participants) reported higher levels of serum vitamin E at one month with fat-soluble vitamin E compared with control, MD 13.59 umol/L (95% CI 9.52 to 17.66); however, at three months one study (36 participants) showed no difference between treatment and control. No studies in this comparison reported on growth or nutritional status. Vitamin E supplementation may lead to an improvement in vitamin E levels in people with cystic fibrosis, although evidence we assessed was low quality. No data on other outcomes of interest were available to allow conclusions about any other benefits of this therapy. In future, larger studies are needed, especially in people already being treated with enteric-coated pancreatic enzymes and supplemented with vitamin E, to look at more specific outcome measures such as vitamin E status, lung function and nutritional status. Future studies could also look at the optimal dose of vitamin E required to achieve maximal clinical effectiveness.

Newborn screening for galactosaemia

Classical galactosaemia is an autosomal recessive inborn error of metabolism caused by a deficiency of the enzyme galactose-1-phosphate uridyltransferase. This is a rare and potentially lethal condition that classically presents in the first week of life once milk feeds have commenced. Affected babies may present with any or all of the following: cataracts; fulminant liver failure; prolonged jaundice; or Escherichia coli sepsis. Once the diagnosis is suspected, feeds containing galactose must be stopped immediately and replaced with a soya-based formula. The majority of babies will recover, however a number will not survive. There are long-term complications of galactosaemia, despite treatment, including learning disabilities and female infertility. It has been postulated that galactosaemia could be detected on newborn screening and this would prevent the immediate severe liver dysfunction and sepsis. This is an update of a previously published review. To assess whether there is evidence that newborn screening for galactosaemia prevents or reduces mortality and morbidity and improves clinical outcomes in affected neonates and the quality of life in older children. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from electronic database searches, handsearches of relevant journals and conference abstract books. We also searched online trials registries and the reference lists of relevant articles and reviews. Date of the most recent search of Cochrane Cystic Fibrosis Group's Trials Register: 12 December 2019. Date of the most recent search of additional resources: 02 February 2020. Randomised controlled studies and controlled clinical studies, published or unpublished comparing the use of any newborn screening test to diagnose infants with galactosaemia and presenting a comparison between a screened population versus a non-screened population. No studies of newborn screening for galactosaemia were found. No studies were identified for inclusion in the review. We were unable to identify any eligible studies for inclusion in this review and hence it is not possible to draw any conclusions based on randomised controlled studies. However, we are aware of uncontrolled studies which support the efficacy of newborn screening for galactosaemia. There are a number of reviews and economic analyses of non-trial literature suggesting that screening is appropriate.

Timing of hypertonic saline inhalation for cystic fibrosis.

Inhalation of hypertonic saline improves sputum rheology, accelerates mucociliary clearance and improves clinical outcomes of people with cystic fibrosis. This is an update of a previously published Cochrane Review. To determine whether the timing of hypertonic saline inhalation (in relation to airway clearance techniques or in relation to time of day) has an impact on its clinical efficacy in people with cystic fibrosis. We identified relevant randomised and quasi-randomised controlled trials from the Cochrane Cystic Fibrosis Trials Register, the Physiotherapy Evidence Database (PEDro), and international cystic fibrosis conference proceedings. Date of the last search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Cystic Fibrosis Trials Register: 28 February 2019. Any trial of hypertonic saline in people with cystic fibrosis where timing of inhalation was the randomised element in the study protocol with either: inhalation up to six hours before airway clearance techniques compared to inhalation during airway clearance techniques compared to inhalation up to six hours after airway clearance techniques; or morning compared to evening inhalation with any definition provided by the author. Both authors independently assessed the trials identified by the search for potential inclusion in the review. The certainty of the evidence was assessed using GRADE. The searches identified 104 trial reports which represented 51 trials, of which three cross-over trials (providing data on 77 participants) met our inclusion criteria. We present three comparisons: inhalation before versus during airway clearance techniques; inhalation before versus after airway clearance techniques; and inhalation during versus after airway clearance techniques. One trial (50 participants), given its three-arm design, was eligible for all three comparisons. No trials compared morning versus evening inhalation of hypertonic saline. The evidence from the three trials was judged to be of low quality downgraded for limitations (high risk of bias due to blinding) and indirectness (all participants are adults, and therefore not applicable to children). Intervention periods ranged from one treatment to three treatments in one day. There were no clinically important differences between the timing regimens of inhaling hypertonic saline before, during or after airway clearance techniques in the mean amount of improvement in lung function or symptom scores (77 participants), with the between-group comparisons being non-significant (low-certainty evidence). While there may be little or no difference in the rating of satisfaction when hypertonic saline was inhaled before versus during the airway clearance techniques (64 participants) (with the 95% confidence interval including the possibility of both a higher and lower rating of satisfaction), satisfaction may be lower on a 100-mm scale when inhaled after the airway clearance techniques compared to before: mean difference (MD) 20.38 mm (95% confidence interval (CI) 12.10 to 28.66) and when compared to during the techniques, MD 14.80 mm (95% CI 5.70 to 23.90). Perceived effectiveness showed similar results: little or no difference for inhalation before versus during airway clearance techniques (64 participants); may be lower when inhaled after the airway clearance techniques compared to before, MD 10.62 (95% CI 2.54 to 18.70); and also when compared to during the techniques, MD 15.60 (95% CI 7.55 to 23.65). There were no quality of life or adverse events reported in any of the trials. Timing of hypertonic saline inhalation makes little or no difference to lung function (low-certainty evidence). However, inhaling hypertonic saline before or during airway clearance techniques may maximise perceived efficacy and satisfaction. The long-term efficacy of hypertonic saline has only been established for twice-daily inhalations; however, if only one dose per day is tolerated, the time of day at which it is inhaled could be based on convenience or tolerability until evidence comparing these regimens is available. The identified trials were all of very short intervention periods, so longer-term research could be conducted to establish the effects arising from regular use, which would incorporate the influence of changes in adherence with long-term use, as well as generating data on any adverse effects that occur with long-term use.

Positive expiratory pressure physiotherapy for airway clearance in people with cystic fibrosis.

Positive expiratory pressure physiotherapy for airway clearance in people with cystic fibrosis.

Antioxidant supplementation for lung disease in cystic fibrosis.

Antioxidant supplementation for lung disease in cystic fibrosis.

Duration of intravenous antibiotic therapy in people with cystic fibrosis.

Progressive lung damage from recurrent exacerbations is the major cause of mortality and morbidity in cystic fibrosis. Life expectancy of people with cystic fibrosis has increased dramatically in the last 40 years. One of the major reasons for this increase is the mounting use of antibiotics to treat chest exacerbations caused by bacterial infections. The optimal duration of intravenous antibiotic therapy is not clearly defined. Individuals usually receive intravenous antibiotics for 14 days, but treatment may range from 10 to 21 days. A shorter duration of antibiotic treatment risks inadequate clearance of infection which could lead to further lung damage. Prolonged courses of intravenous antibiotics are expensive and inconvenient. The risk of systemic side effects such as allergic reactions to antibiotics also increases with prolonged courses and the use of aminoglycosides requires frequent monitoring to minimise some of their side effects. However, some organisms which infect people with cystic fibrosis are known to be multi-resistant to antibiotics, and may require a longer course of treatment. This is an update of previously published reviews. To assess the optimal duration of intravenous antibiotic therapy for treating chest exacerbations in people with cystic fibrosis. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic database searches, handsearches of relevant journals, abstract books and conference proceedings. Most recent search of the Group's Cystic Fibrosis Trials Register: 30 May 2019.We also searched online trials registries. Most recent search of the ClinicalTrials.gov and WHO International Clinical Trials Registry Platform (ICTRP) portal: 06 January 2019. Randomised and quasi-randomised controlled trials comparing different durations of intravenous antibiotic courses for acute respiratory exacerbations in people with CF, either with the same drugs at the same dosage, the same drugs at a different dosage or frequency or different antibiotics altogether, including studies with additional therapeutic agents. No eligible trials were identified for inclusion. A trial looking at the standardised treatment of pulmonary exacerbations is currently ongoing and will be included when the results are published. MAIN RESULTS: No eligible trials were included. There are no clear guidelines on the optimum duration of intravenous antibiotic treatment. Duration of treatment is currently based on unit policies and response to treatment. Shorter duration of treatment should improve quality of life and adherence, result in a reduced incidence of drug reactions and be less costly. However, the shorter duration may not be sufficient to clear a chest infection and may result in an early recurrence of an exacerbation. This systematic review identifies the need for a multicentre, randomised controlled trial comparing different durations of intravenous antibiotic treatment as it has important clinical and financial implications. The currently ongoing STOP2 trial is expected to provide some guidance on these questions when published.

Enteral tube feeding for cystic fibrosis.

Enteral tube feeding is routinely used in many cystic fibrosis centres when oral dietary and supplement intake has failed to achieve an adequate nutritional status. The use of this method of feeding is assessed on an individual basis taking into consideration the patients age and clinical status. This is a final update of a previously published review. To examine the evidence that in people with cystic fibrosis, supplemental enteral tube feeding improves nutritional status, respiratory function, and quality of life without significant adverse effects. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also contacted the companies that market enteral feeds and reviewed their databases.Date of the most recent search of the Group's Cystic Fibrosis Trials Register: 10 July 2019.Date of the most recent hand search of PubMed: 26 October 2018. All randomised controlled trials comparing supplemental enteral tube feeding for one month or longer with no specific intervention in people with cystic fibrosis. The searches identified 44 trials; however, none were eligible for inclusion in this review. There are no trials included in this review. Supplemental enteral tube feeding is widely used throughout the world to improve nutritional status in people with cystic fibrosis. The methods mostly used, nasogastric or gastrostomy feeding, are expensive and may have a negative effect on self-esteem and body image. Reported use of enteral tube feeding suggests that it results in nutritional and respiratory improvement; but, efficacy has not been fully assessed by randomised controlled trials. It is acknowledged, however, that performing a randomised controlled trial would be difficult due to the ethics of withholding an intervention in a group of people whose nutritional status necessitates it.

Singing as an adjunct therapy for children and adults with cystic fibrosis.

Cystic fibrosis is a genetically inherited, life-threatening condition that affects major organs. The management of cystic fibrosis involves a multi-faceted daily treatment regimen that includes airway clearance techniques, pancreatic enzymes and other medications. Previous studies have found that compliance with this intensive treatment is poor, especially among adolescents. Because of both the nature and consequences of the illness and the relentless demands of the treatment, many individuals with cystic fibrosis have a poor quality of life. Anecdotal reports suggest that singing may provide both appropriate exercise for the whole respiratory system and a means of emotional expression which may enhance quality of life. This is an update of a previously published review. To evaluate the effects of singing as an adjunct therapy to standard treatment on the quality of life, morbidity, respiratory muscle strength and pulmonary function of children and adults with cystic fibrosis. We searched the Group's Cystic Fibrosis Trials Register and the Cochrane Central Register of Controlled Trials. Date of latest search: 07 January 2019.We also searched major allied complementary data bases, and clinical trial registers. Additionally, we handsearched relevant conference proceedings and journals. Date of latest search: 28 March 2019. Randomised controlled trials in which singing (as an adjunct intervention) is compared with either a control intervention (for example, playing computer games or doing craft activities) or no singing in people with cystic fibrosis. Results of searches were reviewed against pre-determined criteria for inclusion. Only one eligible trial was available for analysis. Since only one small study (n = 40) was included, no meta-analysis could be performed. The included randomised controlled study was of parallel design and undertaken at two paediatric hospitals in Australia. The study evaluated the effects of a singing program on the quality of life and respiratory muscle strength of hospitalised children with cystic fibrosis (mean age 11.6 years, 35% male). While the singing group received eight individual singing sessions, the control group participated in preferred recreational activities, such as playing computer games or watching movies. This study was limited by a small sample size (51 participants)anda high drop-out rate (21%).There were no differences between the groups at either post-intervention or follow-up; although by the end of treatment there were some improvements in some of the domains of the quality of life questionnaire Cystic Fibrosis Questionnaire-Revised (e.g. emotional, social and vitality domains) for both singing and control groups. For the respiratory muscle strength indices, maximal expiratory pressure at follow-up (six to eight weeks post-intervention) was higher in the singing group, mean difference 25.80 (95% confidence interval 5.94 to 45.66). There was no difference between groups for any of the other respiratory function parameters (maximal inspiratory pressure, spirometry) at either post-intervention or follow-up. No adverse effects were observed in the singing group; adverse events for the control group were not reported in the paper. There is insufficient evidence to determine the effects of singing on quality of life or on the respiratory parameters in people with cystic fibrosis. However, there is growing interest in non-medical treatments for cystic fibrosis and researchers may wish to investigate the impact of this inexpensive therapy on respiratory function and psychosocial well-being further in the future.

Interventions for promoting participation in shared decision-making for children and adolescents with cystic fibrosis.

Shared decision-making is important in child and adolescent healthcare because there is growing international recognition of children and young people's rights to be included in decisions that affect them. In order for young people to participate effectively in shared decision-making they need to develop the skills of engagement with healthcare professionals and confidence in interacting with them. They also need to learn how to manage their condition and treatments on their own when they move into adulthood. Children and young people who participate in shared decision-making in healthcare are likely to be more informed, feel more prepared, and experience less anxiety about the unknown. Significant improvements in cystic fibrosis (CF) survival over recent decades, due to improved therapies and better management of care, means that young people with CF are routinely transitioning to adult healthcare where increasing emphasis on self-management brings greater complexity in decision-making. We need to know what interventions are effective in promoting shared decision-making for young people with CF. To assess the effectiveness of interventions that promote participation in shared decision-making for children and adolescents (aged between four and 18 years) with CF. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearches of journals and conference abstract books. We also searched the reference lists of articles and reviews addressing shared decision-making.Date of most recent search: 12 March 2019.We searched PubMed, CINAHL (EBSCO), Embase (Elsevier), PsycINFO (EBSCO), WHO ICTRP, ASSIA (ProQuest), ERIC (ProQuest), ProQuest Dissertations and Theses, and ClinicalTrials.gov. We contacted study authors with published relevant research in shared decision-making for adults to ask if they were aware of any published or ongoing studies on the promotion of the intervention for children or adolescents (or both) with CF.Date of most recent search: 19 March 2019. We planned to include randomised controlled trials (RCTs) (but not cross-over RCTs) of interventions promoting shared decision-making for children and adolescents with CF aged between four and 18 years, such as information provision, booklets, two-way interaction, checking understanding (by the participant), preparation to participate in a healthcare decision, decision-aids, and training interventions or educational programs. We planned to include interventions aimed at children or adolescents (or both), parents or healthcare professionals or any combination of these groups provided that the focus was aimed at promoting shared decision-making for children and adolescents with CF. Two authors independently reviewed papers identified in the searches. No eligible RCTs were identified for inclusion in this systematic review. We were unable to identify RCTs with evidence which would support healthcare policy-making and practice related to implementation of shared decision-making for children and adolescents (aged between four and 18 years) with CF). We hope that having identified this gap in research, awareness will increase amongst researchers of the need to design high-quality shared decision-making interventions for young people with CF, perhaps adapted from existing models for adults, and to test these interventions and children's preferences in RCTs. It is also important to target health professionals with evidence-based education programmes on shared decision-making and a need for international consensus on addressing the variability in education programmes.

Inhaled antibiotics for pulmonary exacerbations in cystic fibrosis

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. 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. 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. 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. 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. 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). 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.

Nebulised hypertonic saline for cystic fibrosis.

Background Impaired mucociliary clearance characterises lung disease in cystic fibrosis (CF). Hypertonic saline (HS) enhances mucociliary clearance in vitro and may lessen the destructive inflammatory process in the airways. Objectives To investigate the effects of nebulised HS in CF compared to placebo or other treatments for mucociliary clearance. Search methods We searched the Cochrane CF and Genetic Disorders Group Trials Register, comprising references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings. Most recent search: 31 July 2008. Selection criteria Controlled trials assessing HS compared to placebo or other mucolytic therapy, for any duration or dose regimen in people with CF (any age or disease severity). Data collection and analysis Two authors independently reviewed all identified trials and data; and assessed trial quality. Main results Twelve trials (442 participants, aged 6 to 46 years) were included; five excluded and two await classification. In two placebo-controlled trials, HS (3% to 7%, 10 ml twice-a-day) significantly increased forced expiratory volume at one second (FEV1) at four weeks, mean difference (MD) 4.15 (95% CI 1.14 to 7.16); but not significantly after 48 weeks, MD 2.31 (95% CI -2.72 to 7.34). Two trials compared a similar dose of HS to recombinant deoxyribonuclease (RhDNAse). One three-week trial showed a non-significant difference, MD 1.60 (95% CI -7.96 to 11.16). However, in the second trial, after 12 weeks, RhDNAse led to a greater increase in FEV1 than HS (5 ml twice-daily), in participants with moderate to severe lung disease, MD 8.00 (95% CI 2.00 to 14.00). One 48-week placebo-controlled trial showed significant improvements in frequency of antibiotic use and quality of life; also that HS did not increase the concentration of Pseudomonas aeruginosa or Staphylococcus aureus. Authors' conclusions Treatment with 7% HS for 48 weeks showed a small improvement in FEV1 at four weeks; however, this was not sustained at 48 weeks (primary outcome measure of the only long-term trial). Unlike RhDNAse, HS can't, in the long term, be said to improve lung function. However, it did improve quality of life and reduce pulmonary exacerbations. Delivered following a bronchodilator, HS appears inexpensive and safe with no increased infection risk. We believe there is sufficient evidence to recommend using HS in CF; qualifying this we highlight that the only long-term trial failed to demonstrate a significant difference in its primary outcome (lung function) with improvements only in secondary outcomes.

Treatment for chronic methicillin-sensitive Staphylococcus aureus pulmonary infection in people with cystic fibrosis.

Cystic fibrosis is an inherited life-threatening multisystem disorder with lung disease characterized by abnormally thick airway secretions and persistent bacterial infection. Chronic, progressive lung disease is the most important cause of morbidity and mortality in the condition and is therefore the main focus of clinical care and research. Staphylococcus aureus is a major cause of chest infection in people with cystic fibrosis. Early onset, as well as chronic, lung infection with this organism in young children and adults results in worsening lung function, poorer nutrition and increases the airway inflammatory response, thus leading to a poor overall clinical outcome. There are currently no evidence-based guidelines for chronic suppressive therapy for Staphylococcus aureus infection in cystic fibrosis such as those used for Pseudomonas aeruginosa infection. This is an update of a previously published review. To assess the evidence regarding the effectiveness of long-term antibiotic treatment regimens for chronic infection with methicillin-sensitive Staphylococcus aureus (MSSA) infection in people with cystic fibrosis and to determine whether this leads to improved clinical and microbiological outcomes. Trials were identified by searching the Cochrane Cystic Fibrosis and Genetic Disorders Group's Cystic Fibrosis Trials Register, MEDLINE, Embase, handsearching article reference lists and through contact with local and international experts in the field. Date of the last search of the Group's Cystic Fibrosis Trials Register: 09 February 2018.We also searched ongoing trials databases. Date of latest search: 20 May 2018. Randomised or quasi-randomised controlled trials comparing any combinations of topical, inhaled, oral or intravenous antimicrobials used as suppressive therapy for chronic infection with methicillin-sensitive Staphylococcus aureus compared with placebo or no treatment. The authors independently assessed all search results for eligibility. No eligible trials were identified. The searches identified 58 trials, but none were eligible for inclusion in the current version of this review. No randomised controlled trials were identified which met the inclusion criteria for this review. Although methicillin-sensitive Staphylococcus aureus is an important and common cause of lung infection in people with cystic fibrosis, there is no agreement on how best to treat long-term infection. The review highlights the need to organise well-designed trials that can provide evidence to support the best management strategy for chronic methicillin-sensitive Staphylococcus aureus infection in people with cystic fibrosis.

Interventions for the eradication of meticillin-resistant Staphylococcus aureus (MRSA) in people with cystic fibrosis.

Cystic fibrosis is an inherited recessive disorder of chloride transport that is characterised by recurrent and persistent pulmonary infections from resistant organisms that result in lung function deterioration and early mortality in sufferers.Meticillin-resistant Staphylococcus aureus (MRSA) has emerged as, not only an important infection in people who are hospitalised, but also as a potentially harmful pathogen in cystic fibrosis. Chronic pulmonary infection with MRSA is thought to confer people with cystic fibrosis with a worse clinical outcome and result in an increased rate of lung function decline. Clear guidance for MRSA eradication in cystic fibrosis, supported by robust evidence, is urgently needed. This is an update of a previous review. To evaluate the effectiveness of treatment regimens designed to eradicate MRSA and to determine whether the eradication of MRSA confers better clinical and microbiological outcomes for people with cystic fibrosis. To ascertain whether attempts at eradicating MRSA can lead to increased acquisition of other resistant organisms (including P aeruginosa) or increased adverse effects from drugs, or both. Randomised and quasi-randomised controlled trials were identified by searching the Cochrane Cystic Fibrosis and Genetic Disorders Group's Cystic Fibrosis Trials Register, PubMed, MEDLINE, clinical trial registries (Clinicaltrials.gov, WHO ICTRP, ISRCTN Registry), handsearching article reference lists and through contact with experts in the field.Date of the last search of the Group's Cystic Fibrosis Trials Register: 27 July 2017.Ongoing trials registries were last searched: 07 August 2017. Randomised or quasi-randomised controlled trials comparing any combinations of topical, inhaled, oral or intravenous antimicrobials with the primary aim of eradicating MRSA compared with placebo, standard treatment or no treatment. The authors independently assessed all search results for eligibility. They used the GRADE methodology to assess the quality of the evidence. The review includes two trials with a total of 106 participants with MRSA infection. In both trials the active treatment was oral trimethoprim and sulfamethoxazole combined with rifampicin; however, one trial administered this combination for two weeks alongside nasal, skin and oral decontamination and a three-week environmental decontamination, while the second trial administered this drug combination for 21 days with five days intranasal mupirocin. In both trials the control arm was observation only.Both trials reported successful eradication of MRSA in people with CF as an outcome; however, the definition used for MRSA eradication differed. The first trial (n = 45) defined MRSA eradication as negative MRSA respiratory cultures at day 28, and reported that, when compared to control, oral trimethoprim and sulfamethoxazole combined with rifampicin may lead to a higher proportion of negative cultures, odds ratio (OR) 12.6 (95% confidence interval (CI) 2.84 to 55.84; low-certainty evidence); however, by day 168 of follow-up there was no difference in the proportion of participants who remained MRSA-negative in either treatment arm, OR 1.17 (95% CI 0.31 to 4.42) (low-quality evidence). In the second trial, successful eradication was defined as the absence of MRSA following treatment (oral co-trimoxazole and rifampicin with intranasal mupirocin or observation) in at least three cultures over a period of six months. At the time of reporting, 40 out of 61 participants had completed follow-up, but results showed no difference between groups. Eradication was achieved in 12 out 29 participants (41%) receiving active treatment, and in 9 out of 32 participants (28%) on the observation arm, OR 1.80 (95% CI 0.62 to 5.25) (very low-quality evidence).With regards to this review's secondary outcomes, these were reported in the first trial only. The trial reports that no differences were observed between the two arms in terms of pulmonary exacerbations (from screening to day 28), nasal colonisation, lung function, weight or participant-reported outcomes. While not a specific outcome of this review, investigators reported that the rate of hospitalisation from screening through day 168 was lower with oral trimethoprim and sulfamethoxazole combined with rifampicin compared to control, rate ratio 0.22 (95% CI 0.05 to 0.72) (P = 0.0102). Early eradication of MRSA is possible in people with cystic fibrosis, with one trial demonstrating superiority of active MRSA treatment compared with observation only in terms of the proportion of MRSA-negative respiratory cultures at day 28. However, by six months, the proportion of participants who remained MRSA-negative did not differ between treatment arms in either trial. Moreover, the longer-term clinical consequences in terms of lung function, mortality and cost of care, remain unclear.Using GRADE methodology, we judged the quality of the evidence provided by this review to be very low to low, due to potential biases from the open-label design and unclear detail reported in one trial. Based on the available evidence, it is the opinion of the authors that whilst early eradication of respiratory MRSA in people with cystic fibrosis is possible, there is not currently enough evidence regarding the clinical outcomes of eradication to support the use of the interventions studied.

Standard (head-down tilt) versus modified (without head-down tilt) postural drainage in infants and young children with cystic fibrosis.

Postural drainage is used primarily in infants with cystic fibrosis from diagnosis up to the moment when they are mature enough to actively participate in self-administered treatments. However, there is a risk of gastroesophageal reflux associated with this technique.This is an update of a review published in 2015. To compare the effects of standard postural drainage (15º to 45º head-down tilt) with modified postural drainage (15º to 30º head-up tilt) with regard to gastroesophageal reflux in infants and young children up to six years old with cystic fibrosis in terms of safety and efficacy. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Cystic Fibrosis Trials Register. We also searched the reference lists of relevant articles and reviews. Additional searches were conducted on ClinicalTrials.gov and on the WHO International Clinical Trials Registry Platform for any planned, ongoing and unpublished studies.The date of the most recent literature searches: 19 June 2017. We included randomised controlled studies that compared two postural drainage regimens (standard and modified postural drainage) with regard to gastroesophageal reflux in infants and young children (up to and including six years old) with cystic fibrosis. We used standard methodological procedures expected by Cochrane. Two review authors independently identified studies for inclusion, extracted outcome data and assessed risk of bias. We resolved disagreements by consensus or by involving a third review author. We contacted study authors to obtain missing or additional information. The quality of the evidence was assessed using GRADE. Two studies, involving a total of 40 participants, were eligible for inclusion in the review. We included no new studies in the 2018 update. The included studies were different in terms of the age of participants, the angle of tilt, the reported outcomes, the number of sessions and the study duration. The following outcomes were measured: appearance or exacerbation of gastroesophageal reflux episodes; percentage of peripheral oxygen saturation; number of exacerbations of upper respiratory tract symptoms; number of days on antibiotics for acute exacerbations; chest X-ray scores; and pulmonary function tests. One study reported that postural drainage with a 20° head-down position did not appear to exacerbate gastroesophageal reflux. However, the majority of the reflux episodes in this study reached the upper oesophagus (moderate-quality evidence). The second included study reported that modified postural drainage (30° head-up tilt) was associated with fewer number of gastroesophageal reflux episodes and fewer respiratory complications than standard postural drainage (30° head-down tilt) (moderate-quality evidence). The included studies had an overall low risk of bias. One included study was funded by the Sydney Children's Hospital Foundation and the other by the Royal Children's Hospital Research Foundation and Physiotherapy Research Foundation of Australia. Data were not able to be pooled by meta-analysis due to differences in the statistical presentation of the data. The limited evidence regarding the comparison between the two regimens of postural drainage is still weak due to the small number of included studies, the small number of participants assessed, the inability to perform any meta-analyses and some methodological issues with the studies. However, it may be inferred that the use of a postural regimen with a 30° head-up tilt is associated with a lower number of gastroesophageal reflux episodes and fewer respiratory complications in the long term. The 20° head-down postural drainage position was not found to be significantly different from the 20° head-up tilt modified position. Nevertheless, the fact that the majority of reflux episodes reached the upper oesophagus should make physiotherapists carefully consider their treatment strategy. We do not envisage that there will be any new trials undertaken that will affect the conclusions of this review; therefore, we do not plan to update this review.

Newborn screening for galactosaemia.

Classical galactosaemia is an autosomal recessive inborn error of metabolism caused by a deficiency of the enzyme galactose-1-phosphate uridyltransferase. This is a rare and potentially lethal condition that classically presents in the first week of life once milk feeds have commenced. Affected babies may present with any or all of the following: cataracts; fulminant liver failure; prolonged jaundice; or Escherichia coli sepsis. Once the diagnosis is suspected, feeds containing galactose must be stopped immediately and replaced with a soya-based formula. The majority of babies will recover, however a number will not survive. There are long-term complications of galactosaemia, despite treatment, including learning disabilities and female infertility. It has been postulated that galactosaemia could be detected on newborn screening and this would prevent the immediate severe liver dysfunction and sepsis. To assess whether there is evidence that newborn screening for galactosaemia prevents or reduces mortality and morbidity and improves clinical outcomes in affected neonates and the quality of life in older children. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from electronic database searches, handsearches of relevant journals and conference abstract books. We also searched online trials registries and the reference lists of relevant articles and reviews.Date of the most recent search of Cochrane Cystic Fibrosis Group's Trials Register: 18 December 2017.Date of the most recent search of additional resources: 11 October 2017. Randomised controlled studies and controlled clinical studies, published or unpublished comparing the use of any newborn screening test to diagnose infants with galactosaemia and presenting a comparison between a screened population versus a non-screened population. No studies of newborn screening for galactosaemia were found. No studies were identified for inclusion in the review. We were unable to identify any eligible studies for inclusion in this review and hence it is not possible to draw any conclusions based on randomised controlled studies. However, we are aware of uncontrolled studies which support the efficacy of newborn screening for galactosaemia. There are a number of reviews and economic analyses of non-trial literature suggesting that screening is appropriate.

Combination antimicrobial susceptibility testing for acute exacerbations in chronic infection of Pseudomonas aeruginosa in cystic fibrosis.

Antibiotic therapy for acute pulmonary exacerbations in people with cystic fibrosis is usually chosen based on the results of antimicrobial susceptibility testing of individual drugs. Combination antimicrobial susceptibility testing assesses the efficacy of drug combinations including two or three antibiotics in vitro and can often demonstrate antimicrobial efficacy against bacterial isolates even when individual antibiotics have little or no effect. Therefore, choosing antibiotics based on combination antimicrobial susceptibility testing could potentially improve response to treatment in people with cystic fibrosis with acute exacerbations. This is an updated version of a previously published review. To compare antibiotic therapy based on conventional antimicrobial susceptibility testing to antibiotic therapy based on combination antimicrobial susceptibility testing in the treatment of acute pulmonary exacerbations in people with cystic fibrosis and chronic infection with Pseudomonas aeruginosa. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Cystic Fibrosis Trials Register which comprises of references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Date of latest search: 19 December 2016.We also searched ongoing trials registries. Date of latest search: 08 March 2017. Randomised and quasi-randomised controlled studies of antibiotic therapy based on conventional antimicrobial susceptibility testing compared to antibiotic therapy based on combination antimicrobial susceptibility testing in the treatment of acute pulmonary exacerbations in cystic fibrosis due to chronic infection with Pseudomonas aeruginosa. Both authors independently selected studies, assessed their quality and extracted data from eligible studies. Additionally, the authors contacted the study investigators to obtain further information. The search identified one multicentre study eligible for inclusion in the review. This study prospectively assessed whether the use of multiple combination bactericidal antibiotic testing improved clinical outcomes in participants with acute pulmonary exacerbations of cystic fibrosis who were infected with multiresistant bacteria. A total of 132 participants were randomised in the study. The study investigators provided data specific to the 82 participants who were only infected with Pseudomonas aeruginosa for their primary outcome of time until next pulmonary exacerbation. For participants specifically infected with only Pseudomonas aeruginosa, the hazard ratio of a subsequent exacerbation was 0.82, favouring the control group (95% confidence interval 0.44 to 1.51) (P = 0.52). No further data for any of this review's outcomes specific to participants infected with Pseudomonas aeruginosa were available. The risk of bias for the included study was deemed to be low. The quality of the evidence was moderate for the only outcome providing data solely for individuals with infection due to Pseudomonas aeruginosa. For other outcomes, we were unable to judge the quality of the evidence as no data were available for the relevant subset of participants. The current evidence, limited to one study, shows that there is insufficient evidence to determine effect of choosing antibiotics based on combination antimicrobial susceptibility testing compared to choosing antibiotics based on conventional antimicrobial susceptibility testing in the treatment of acute pulmonary exacerbations in people with cystic fibrosis with chronic Pseudomonas aeruginosa infection. A large international and multicentre study is needed to further investigate this issue.The only study included in the review was published in 2005, and we have not identified any further relevant studies up to March 2017. We therefore do not plan to update this review until new studies are published.

Interventions for promoting participation in shared decision-making for children and adolescents with cystic fibrosis

Background Shared decision-making is important in child and adolescent healthcare because there is growing international recognition of children and young people's rights to be included in decisions that affect them. In order for young people to participate effectively in shared decision-making they need to develop the skills of engagement with healthcare professionals and confidence in interacting with them. They also need to learn how to manage their condition and treatments on their own when they move into adulthood. Children and young people who participate in shared decision-making in healthcare are likely to be more informed, feel more prepared, and experience less anxiety about the unknown. Significant improvements in cystic fibrosis (CF) survival over recent decades, due to improved therapies and better management of care, means that young people with CF are routinely transitioning to adult healthcare where increasing emphasis on self-management brings greater complexity in decision-making. We need to know what interventions are effective in promoting shared decision-making for young people with CF. Objectives To assess the effectiveness of interventions that promote participation in shared decision-making for children and adolescents (aged between four and 18 years) with CF. Search methods We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearches of journals and conference abstract books. We also searched the reference lists of articles and reviews addressing shared decision-making.Date of most recent search: 12 March 2019.We searched PubMed, CINAHL (EBSCO), Embase (Elsevier), PsycINFO (EBSCO), WHO ICTRP, ASSIA (ProQuest), ERIC (ProQuest), ProQuest Dissertations and Theses, and ClinicalTrials.gov. We contacted study authors with published relevant research in shared decision-making for adults to ask if they were aware of any published or ongoing studies on the promotion of the intervention for children or adolescents (or both) with CF.Date of most recent search: 19 March 2019. Selection criteria We planned to include randomised controlled trials (RCTs) (but not cross-over RCTs) of interventions promoting shared decision-making for children and adolescents with CF aged between four and 18 years, such as information provision, booklets, two-way interaction, checking understanding (by the participant), preparation to participate in a healthcare decision, decision-aids, and training interventions or educational programs. We planned to include interventions aimed at children or adolescents (or both), parents or healthcare professionals or any combination of these groups provided that the focus was aimed at promoting shared decision-making for children and adolescents with CF. Data collection and analysis Two authors independently reviewed papers identified in the searches. Main results No eligible RCTs were identified for inclusion in this systematic review. Authors' conclusions We were unable to identify RCTs with evidence which would support healthcare policy-making and practice related to implementation of shared decision-making for children and adolescents (aged between four and 18 years) with CF). We hope that having identified this gap in research, awareness will increase amongst researchers of the need to design high-quality shared decision-making interventions for young people with CF, perhaps adapted from existing models for adults, and to test these interventions and children's preferences in RCTs. It is also important to target health professionals with evidence-based education programmes on shared decision-making and a need for international consensus on addressing the variability in education programmes.