Fifteen-minute consultation: Empowering children, young people and families through shared decision-making: a practical guide.

Shared decision-making (SDM) is a collaborative approach to healthcare decision-making that involves patients and healthcare professionals working together to make decisions that are informed by the best available medical evidence, as well as the patient's values, preferences and goals. The importance of SDM and the intricate interplay among parents, children and young people (CYP), and healthcare professionals are increasingly acknowledged as the crucial aspects of delivering high-quality paediatric care. While there is a substantial evidence base for SDM improving knowledge and reducing decisional conflict, the evidence for long-term measures such as improved health outcomes is limited and mainly inconclusive. To support healthcare teams in implementing SDM, the authors offer a practical guide to enhance decision-making processes and empower CYP and their families.

Projecting the impact of triple CFTR modulator therapy on intravenous antibiotic requirements in cystic fibrosis using patient registry data combined with treatment effects from randomised trials.

BACKGROUND: Cystic fibrosis (CF) is a life-threatening genetic disease, affecting around 10 500 people in the UK. Precision medicines have been developed to treat specific CF-gene mutations. The newest, elexacaftor/tezacaftor/ivacaftor (ELEX/TEZ/IVA), has been found to be highly effective in randomised controlled trials (RCTs) and became available to a large proportion of UK CF patients in 2020. Understanding the potential health economic impacts of ELEX/TEZ/IVA is vital to planning service provision. METHODS: We combined observational UK CF Registry data with RCT results to project the impact of ELEX/TEZ/IVA on total days of intravenous (IV) antibiotic treatment at a population level. Registry data from 2015 to 2017 were used to develop prediction models for IV days over a 1-year period using several predictors, and to estimate 1-year population total IV days based on standards of care pre-ELEX/TEZ/IVA. We considered two approaches to imposing the impact of ELEX/TEZ/IVA on projected outcomes using effect estimates from RCTs: approach 1 based on effect estimates on FEV1% and approach 2 based on effect estimates on exacerbation rate. RESULTS: ELEX/TEZ/IVA is expected to result in significant reductions in population-level requirements for IV antibiotics of 16.1% (~17 800 days) using approach 1 and 43.6% (~39 500 days) using approach 2. The two approaches require different assumptions. Increased understanding of the mechanisms through which ELEX/TEZ/IVA acts on these outcomes would enable further refinements to our projections. CONCLUSIONS: This work contributes to increased understanding of the changing healthcare needs of people with CF and illustrates how Registry data can be used in combination with RCT evidence to estimate population-level treatment impacts.

The impact of plasma 25-hydroxyvitamin D on pulmonary function and exercise physiology in cystic fibrosis: A multicentre retrospective study.

BACKGROUND: A 25-hydroxyvitamin D (25OHD) may exert immunomodulatory effects on respiratory health, which may translate to improvements in exercise physiology. Thus, we aimed to investigate whether plasma 25OHD is associated with lung function and aerobic fitness in people with cystic fibrosis (pwCF). METHODS: A multicentre retrospective review of pwCF (> 9 years old) attending the Royal Hospital for Sick Children (Edinburgh) or Wessex CF-Unit (Southampton) was performed between July 2017 and October 2019. Demographic and clinical data were collected. Plasma 25OHD measured closest in time to clinical cardiopulmonary exercise testing and/or spirometry [forced expiratory volume (FEV1 )% predicted] was recorded. Pancreatic insufficiency was diagnosed based on faecal elastase of < 100 µg g-1 . We performed multiple-regression analysis with aerobic fitness outcomes [peak oxygen uptake (VO2 peak )] and FEV1 % predicted as primary outcomes. RESULTS: Ninety pwCF [mean ± SD age: 19.1 ± 8.6 years, 54 (60%) children, 48 (53%) males and 88 (98%) Caucasian] were included. 25OHD deficiency and insufficiency was 15 (17%) and 44 (49%), respectively. 25OHD deficiency and insufficiency was significantly associated with pancreatic insufficiency (χ2  = 4.8, p = 0.02). Plasma 25OHD was not significantly associated with FEV1 % predicted (r2  = 0.06, p = 0.42, 95% CI = -0.09 to 0.19) or VO2 peak (r2  = 0.04, p = 0.07, 95% CI = -011 to 0.005) in all pwCF. However, 25OHD was significantly associated with both FEV1 % (r2  = 0.15, p = 0.02, 95% CI = 1.99-2.64) and VO2 peak (r2  = 0.13, p = 0.05, 95% CI = -0.26 to -0.005) in the paediatric cohort. CONCLUSIONS: We showed that 25OHD is associated with improved lung function and aerobic fitness in children and adolescents with CF. Mechanistic and high-quality prospective studies including both lung function and aerobic fitness as primary outcomes are now warranted.

Cephalosporin nitric oxide-donor prodrug DEA-C3D disperses biofilms formed by clinical cystic fibrosis isolates of Pseudomonas aeruginosa.

OBJECTIVES: The cephalosporin nitric oxide (NO)-donor prodrug DEA-C3D ('DiEthylAmin-Cephalosporin-3'-Diazeniumdiolate') has been shown to initiate the dispersal of biofilms formed by the Pseudomonas aeruginosa laboratory strain PAO1. In this study, we investigated whether DEA-C3D disperses biofilms formed by clinical cystic fibrosis (CF) isolates of P. aeruginosa and its effect in combination with two antipseudomonal antibiotics, tobramycin and colistin, in vitro. METHODS: ß-Lactamase-triggered release of NO from DEA-C3D was confirmed using a gas-phase chemiluminescence detector. MICs for P. aeruginosa clinical isolates were determined using the broth microdilution method. A crystal violet staining technique and confocal laser scanning microscopy were used to evaluate the effects of DEA-C3D on P. aeruginosa biofilms alone and in combination with tobramycin and colistin. RESULTS: DEA-C3D was confirmed to selectively release NO in response to contact with bacterial ß-lactamase. Despite lacking direct, cephalosporin/ß-lactam-based antibacterial activity, DEA-C3D was able to disperse biofilms formed by three P. aeruginosa clinical isolates. Confocal microscopy revealed that DEA-C3D in combination with tobramycin produces similar reductions in biofilm to DEA-C3D alone, whereas the combination with colistin causes near complete eradication of P. aeruginosa biofilms in vitro. CONCLUSIONS: DEA-C3D is effective in dispersing biofilms formed by multiple clinical isolates of P. aeruginosa and could hold promise as a new adjunctive therapy to patients with CF.

Airway Microbiome and Development of Bronchopulmonary Dysplasia in Preterm Infants: A Systematic Review.

OBJECTIVES: To summarize evidence regarding microbial dysbiosis of the airway associated with bronchopulmonary dysplasia (BPD) and to explore heterogeneity among studies. STUDY DESIGN: We included studies that evaluated the airway microbiome in preterm infants who developed BPD using culture-independent molecular techniques and reported alpha- and beta-diversity metrics and microbial profiles. RESULTS: The 6 included studies had substantial clinical and methodological heterogeneity. Most studies reported the presence of an airway microbiome early after birth and an evolution in the first weeks of life with increasing bacterial loads. The early airway microbiome was dominated by Staphylococcus and Ureaplasma spp. Two studies reported differences in alpha- and beta- diversity indices in preterm infants with BPD compared with those who did not develop BPD. Increased microbial community turnover, changes in the relative abundance of Proteobacteria and Firmicutes, and decreased Lactobacilli were reported with BPD progression. Most included infants were born by cesarean delivery, and a majority were exposed to postnatal antibiotics. No data regarding feeding human milk or correlations with the development of gut microbiota (gut-lung axis) were available. CONCLUSIONS: Microbial dysbiosis may be associated with BPD progression and severity, and further study of microbiome optimization in preterm infants at risk for BPD is warranted.

Psychometric evaluation of a patient-reported outcome measure in pancreatic exocrine insufficiency (PEI).

BACKGROUND/OBJECTIVES: Pancreatic exocrine insufficiency (PEI) is commonly caused by chronic pancreatitis (CP) or cystic fibrosis (CF). There are no PEI-specific patient-reported assessments of symptoms and impacts. The PEI Questionnaire (PEI-Q) was developed through qualitative research with PEI patients and expert clinical input. This study evaluated the psychometric properties of the PEI-Q. METHODS: 162 PEI patients (CF = 71 and CP = 91), 62 diarrhoea-specific irritable bowel syndrome (IBS-D) patients and 60 healthy controls completed the 26-item PEI-Q and the Gastrointestinal Quality of Life Index (GIQLI) at baseline. PEI patients completed the measures again two weeks later to assess the test-retest reliability of the PEI-Q. Analyses supported item reduction and scoring algorithm development, followed by psychometric evaluation. RESULTS: Over 90% of PEI patients completed at least 23 of the 26 items at baseline. Item responses and clinical relevance supported retention of 18 items. Factor analysis supported a three-factor solution (abdominal symptoms, bowel movements, impacts) with adequate model fit. PEI-Q scores had good internal consistency (Cronbach's alpha: 0.77-0.82) and test-retest reliability (ICC: 0.73-0.87). Correlations between PEI-Q and GIQLI supported convergent validity. Known-groups and receiver operating characteristic analyses demonstrated that PEI-Q scores discriminated (p < 0.001) between differing PEI severities, and PEI patients and controls. CONCLUSIONS: The PEI-Q has good validity and reliability. Results indicate that the PEI-Q could be used to aid identification and diagnosis of PEI, assist in the management of patients already diagnosed with PEI, ensuring correct and optimum treatment as well as enhance patient-clinician communication.

Ready, Steady, Go - Achieving successful transition in cystic fibrosis.

Successful transfer to adult services is the paediatric team's anticipated endpoint for the care they provide to their patients. The preceding transition process needs to be well planned and designed to address young peoples' psycho-social, educational and vocational as well as their medical needs. Ready, Steady, Go is a generic programme that has been successfully implemented to make the transition process an integral part of the routine care of young people with cystic fibrosis. Used in combination with other initiatives, the programme helps achieve the more seamless transfer of young people better prepared to meet their ongoing needs.

The use of lumacaftor/ivacaftor to treat acute deterioration in paediatric cystic fibrosis.

Lumacaftor/ivacaftor is a precision medicine targeting the defective cystic fibrosis transmembrane regulator (CFTR) protein in cystic fibrosis (CF) patients homozygous for Phe508del genotype. Whilst there is evidence for efficacy in children aged 6-11 years who are stable with good lung function, there are little data about the use of this medication for children with acute deterioration in this age group. We describe the use of this drug to treat a child with an unusually severe exacerbation of CF lung disease and review the potential of lumacaftor/ivacaftor as a rescue therapy in the paediatric CF population.

Low-Dose Nitric Oxide as Targeted Anti-biofilm Adjunctive Therapy to Treat Chronic Pseudomonas aeruginosa Infection in Cystic Fibrosis.

Despite aggressive antibiotic therapy, bronchopulmonary colonization by Pseudomonas aeruginosa causes persistent morbidity and mortality in cystic fibrosis (CF). Chronic P. aeruginosa infection in the CF lung is associated with structured, antibiotic-tolerant bacterial aggregates known as biofilms. We have demonstrated the effects of non-bactericidal, low-dose nitric oxide (NO), a signaling molecule that induces biofilm dispersal, as a novel adjunctive therapy for P. aeruginosa biofilm infection in CF in an ex vivo model and a proof-of-concept double-blind clinical trial. Submicromolar NO concentrations alone caused disruption of biofilms within ex vivo CF sputum and a statistically significant decrease in ex vivo biofilm tolerance to tobramycin and tobramycin combined with ceftazidime. In the 12-patient randomized clinical trial, 10 ppm NO inhalation caused significant reduction in P. aeruginosa biofilm aggregates compared with placebo across 7 days of treatment. Our results suggest a benefit of using low-dose NO as adjunctive therapy to enhance the efficacy of antibiotics used to treat acute P. aeruginosa exacerbations in CF. Strategies to induce the disruption of biofilms have the potential to overcome biofilm-associated antibiotic tolerance in CF and other biofilm-related diseases.

Cephalosporin-3'-Diazeniumdiolate NO Donor Prodrug PYRRO-C3D Enhances Azithromycin Susceptibility of Nontypeable Haemophilus influenzae Biofilms.

PYRRO-C3D is a cephalosporin-3-diazeniumdiolate nitric oxide (NO) donor prodrug designed to selectively deliver NO to bacterial infection sites. The objective of this study was to assess the activity of PYRRO-C3D against nontypeable Haemophilus influenzae (NTHi) biofilms and examine the role of NO in reducing biofilm-associated antibiotic tolerance. The activity of PYRRO-C3D on in vitro NTHi biofilms was assessed through CFU enumeration and confocal microscopy. NO release measurements were performed using an ISO-NO probe. NTHi biofilms grown on primary ciliated respiratory epithelia at an air-liquid interface were used to investigate the effects of PYRRO-C3D in the presence of host tissue. Label-free liquid chromatography-mass spectrometry (LC/MS) proteomic analyses were performed to identify differentially expressed proteins following NO treatment. PYRRO-C3D specifically released NO in the presence of NTHi, while no evidence of spontaneous NO release was observed when the compound was exposed to primary epithelial cells. NTHi lacking ß-lactamase activity failed to trigger NO release. Treatment significantly increased the susceptibility of in vitro NTHi biofilms to azithromycin, causing a log fold reduction (10-fold reduction or 1-log-unit reduction) in viability (P < 0.05) relative to azithromycin alone. The response was more pronounced for biofilms grown on primary respiratory epithelia, where a 2-log-unit reduction was observed (P < 0.01). Label-free proteomics showed that NO increased expression of 16 proteins involved in metabolic and transcriptional/translational functions. NO release from PYRRO-C3D enhances the efficacy of azithromycin against NTHi biofilms, putatively via modulation of NTHi metabolic activity. Adjunctive therapy with NO mediated through PYRRO-C3D represents a promising approach for reducing biofilm-associated antibiotic tolerance.

Contributions of Composition and Interactions to Bacterial Respiration Are Reliant on the Phylogenetic Similarity of the Measured Community.

Bacterial diversity underpins many ecosystem functions; however, the impact of within-species variation on the relationship between diversity and function remains unclear. Processes involving strain differentiation, such as niche radiation, are often overlooked in studies that focus on phylogenetic variation. This study used bacterial isolates assembled in two comparable microcosm experiments to test how species variation affected ecosystem function. We compared the relationship between diversity and activity (CO2 production) in increasingly diverse multispecies microcosms and with multiple ecotypes of a single species. The bacteria used were isolated from a low-diversity environment and are species of potential clinical significance such as Pseudomonas aeruginosa. All isolates were profiled for single carbon source utilisation. These data showed an increased breadth of resource use in the multiple ecotypes when compared to the mixed-species. The study observed significantly increasing respiration in more complex mixed-species assemblages, which was not observed when ecotypes of a single species were combined. We further demonstrate that the variation observed in the bacterial activity was due to the roles of each of the constituent isolates; between different species, the interactions between the isolates drove the variation in activity, whilst in single species, assemblage variation was due to which isolates were present. We conclude that both between- and within-species variations play different roles in community function, although through different mechanisms, and should be included in models of changing diversity and ecosystem functioning.

Cystic Fibrosis Nutrition--Chewing the Fat.

Survival data for successive birth cohorts of cystic fibrosis infants born in the twentieth century have shown consistent improvements. More recent UK and US data suggest a plateau in improvements for clinically relevant outcomes. Better treatment of malnutrition has arguably been the most important advance in CF care, but despite this nearly a half of the UK CF population has a sub-optimal BMI. Nutritional decline typically occurs in late childhood and early adult life. Addressing poor adherence and more targeted multi-disciplinary interventions to prevent or reverse this pattern are key to achieving better outcomes for CF patients in the future.

Routine use of daily oral vitamin K to treat infants with cystic fibrosis.

Vitamin K is routinely administered after birth in the UK to prevent haemorrhagic disease of the newborn. Despite this, vitamin K-deficient coagulopathy still occurs in infants with high morbidity and mortality. Up to 50% of late onset bleeding presents with intracranial haemorrhage. The risk of developing vitamin K coagulopathy is higher in infants with cystic fibrosis (CF) and those that are exclusively breast fed due to low vitamin K levels in breast milk and intestinal changes in bacterial flora. Oral vitamin K supplementation is a simple addition to routine CF treatment during infancy to prevent complications from significant coagulopathy.

Nutritional outcomes in cystic fibrosis - are we doing enough?

Although outcome data for individuals with cystic fibrosis (CF) have shown consistent improvements throughout the twentieth century, more recent national registry data suggests that outcomes have reached a plateau. Median values for nutritional outcomes in CF currently cluster around the fiftieth centile for the normal population. These data suggest that up to half of CF patients have sub-optimal body mass index (BMI) which might have a significant adverse impact on their respiratory status. BMI might be underestimating the extent to which more important lean body mass might also be reduced. Nutritional decline is a particular problem during adolescence and commonly persists into early adult life. Current treatment strategies to optimize nutrition include the use of high energy diets, proton pump inhibitors and optimal use of enzyme preparations including higher strength preparations to decrease pill burden. Whilst these are all of potential benefit, poor adherence to nutritional care recommendations is probably the greatest impediment to future health improvement. More effective strategies to impact on treatment adherence are needed.

Asthma, classical conditioning, and the autonomic nervous system - a hypothesis for why children wheeze.

Paediatric asthma is an increasing global healthcare problem for which current treatments are not always effective. This review explores how abnormal triggering of the autonomic diving reflex might be important in explaining research findings and the real-world experience of asthma. It hypothesises that the way in which stress during pregnancy is associated with childhood asthma could be through effects on the developing nervous system. This results in increased parasympathetic responsiveness and specifically, excessive triggering of the diving reflex in response to wetting and cooling of the face and nose as occurs with upper airway infections and allergic rhinitis. In aquatic mammals the reflex importantly includes the contraction of airway smooth muscle to minimise lung volume and prevent nitrogen narcosis from diving at depth. Misfiring of this reflex in humans could result in the pathological airway narrowing that occurs in asthma. The diving reflex, and possibly also smooth muscle, is a vestigial remnant of our aquatic past. The hypothesis further suggests that classically conditioned reflex responses to neutral cues and contexts that were present at the same time as the stimuli that initially caused symptoms, become of themselves ongoing triggers of recurrent wheeze. Symptoms occurring in this way, irrespective of the presence of allergens and ongoing airway sensitisation, explain why allergen avoidance is poorly effective in alleviating wheeze and why asthma is made worse by stress. Interventions to suppress the diving reflex and to prevent reflex conditioned wheezing could result in more effective asthma management.

Hospital discharge using salbutamol as required after acute attacks of wheeze in children: a service evaluation.

OBJECTIVE: Most UK hospitals discharge children after acute wheeze with advice to give regular salbutamol using a fixed dose weaning regime. We have introduced and evaluated the safety and efficacy of changing practice to using bronchodilators only as needed after 4 hourly assessments. DESIGN: A multidisciplinary team of healthcare professionals worked with eight families of children who had needed hospital treatment with acute wheeze to develop guidance for the use of salbutamol on an as required basis after 4 hourly assessments. Data on salbutamol used with this approach were compared with a similar period in the previous year. RESULTS: Data from 103 families showed a 73% reduction in salbutamol on day 1, 69% on day 2 and 50% on day 3 compared with what would have been used according to previous advice. Families found the advice easy to follow. There was a trend towards lower reattendance rates within 1 week compared with those recorded in the previous year. Those who had previously attended preferred this change in practice. CONCLUSIONS: These data suggest that with information to support the use of salbutamol on an as required basis after hospital attendance, children can be safely managed by their parents/guardians with much lower doses of salbutamol than those recommended in commonly used fixed dose weaning regimes.

Case report: Open water swimming as a possible treatment for asthma.

Asthma is a complex medical problem for which currently available treatment can be incompletely effective. This case report describes a 49 year old woman who had suffered from asthma since her teenage years that resolved after she took up regular open water swimming. After sharing this case report with an international open water swimming community on social media, over one hundred people with asthma commented that their symptoms had also improved after taking up this activity. The mechanism whereby open water swimming might alleviate asthma has not been established. Possibilities include benefits to mental health, anti-inflammatory effects, being more fit, improved immune function and suppression of the bronchoconstrictive component of the diving reflex. Further research might usefully confirm or refute these clinical observations.

Standards of care for CFTR variant-specific therapy (including modulators) for people with cystic fibrosis.

Cystic fibrosis (CF) has entered the era of variant-specific therapy, tailored to the genetic variants in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. CFTR modulators, the first variant-specific therapy available, have transformed the management of CF. The latest standards of care from the European CF Society (2018) did not include guidance on variant-specific therapy, as CFTR modulators were becoming established as a novel therapy. We have produced interim standards to guide healthcare professionals in the provision of variant-specific therapy for people with CF. Here we provide evidence-based guidance covering the spectrum of care, established using evidence from systematic reviews and expert opinion. Statements were reviewed by key stakeholders using Delphi methodology, with agreement (≥80%) achieved for all statements after one round of consultation. Issues around accessibility are discussed and there is clear consensus that all eligible people with CF should have access to variant-specific therapy.

A quantitative analysis of Ureaplasma urealyticum and Ureaplasma parvum compared with host immune response in preterm neonates at risk of developing bronchopulmonary dysplasia.

Multiplex, real-time PCR for the identification of Ureaplasma urealyticum and Ureaplasma parvum was performed on nucleic acids extracted from sequential endotracheal aspirates obtained from preterm neonates born at <29 weeks of gestation and ventilated for more than 48 h admitted to two level 3 neonatal intensive care units. Specimens were obtained shortly after birth and sequentially up until extubation. One hundred fifty-two specimens (93.8%) contained material suitable for analysis. Ureaplasma spp. were identified in 5 of 13 neonates studied. In most cases, the DNA load of the detected Ureaplasma species was low and decreased over time. In addition, changes in detectable Ureaplasma species DNA did not relate to changes in the inflammatory marker C-reactive protein (CRP) or respiratory status. All but two blood samples obtained at times of suspected sepsis were culture positive for other microorganisms; the species cultured were typically coagulase-negative staphylococci and were associated with increased levels of CRP (>10 mg/liter). This study was limited by the small number of patients examined and does not have the power to support or contradict the hypothesis that postnatal lung infection with Ureaplasma parvum is causally related to bronchopulmonary dysplasia (BPD) or adverse respiratory outcomes after preterm birth. However, in this study, increases in CRP levels were not associated with patients in whom Ureaplasma parvum was detected, in contrast to the detection of other bacterial species.