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BACKGROUND: Bone disease has become an increasingly recognized complication of cystic fibrosis (CF). Although causes of CF bone disease are multifactorial, there has been recent interest in the role of vitamin K in CF bone disease. AIMS AND METHODS: A questionnaire survey of all UK paediatric CF centre dietitians and centre directors was carried out to ascertain current practice with regard to vitamin K prescribing and bone health surveillance. RESULTS: The survey had a 97% response rate representing 3414 CF children. Twenty-three centre directors and 19 dietitians responded, and at least moderate agreement was noted with kappa scores >0.41 for all but one question assessed. Ninety-three per cent centres report that >90% pancreatic insufficient patients receive vitamins A, D and E, yet only 18% centres routinely supplement vitamin K. The majority (60%) report that <10% of their CF patients receive vitamin K, whilst vitamin K dosage varied from 0.3-0.5 to 10 mg day(-1). Only one centre undertook no bone health surveillance, and vitamin D levels are measured in 89%, calcium intake assessed in 82% and dual-energy X-ray absorptiometry scans performed in 61% centres. DISCUSSION: Heterogeneity in both vitamin K prescribing practices and bone health surveillance in CF across the UK were noted, underlining the need for a national consensus on bone health management, as well as acting as a call for longitudinal research into the clinical effectiveness of vitamin K therapy in CF. [ABSTRACT FROM AUTHOR]

Objective: There is currently no consensus about managing upper airway obstruction (UAO) in infants with Robin sequence (RS), in terms of treatment efficacy or clinical outcomes. This study describes UAO management in UK/Ireland, and explores relationships between patient characteristics, UAO management, and clinical outcomes in the first 2 years of life., Methods: Active surveillance of RS throughout UK/Ireland via the British Paediatric Surveillance Unit and nationally commissioned cleft services. Clinical data were collected at initial notification and 12-month follow-up., Results: 173 infants with RS were identified, of which 47% had additional congenital anomalies or an underlying syndrome (non-isolated RS). Two-thirds (n = 119) required an airway intervention other than prone positioning: non-surgical in 84% and surgical (tracheostomy) in 16%. Nasopharyngeal airway (NPA) was the most common intervention, used in 83% (n = 99) for median 90 days (IQR 136). Surgical UAO management was associated with prolonged hospital admission, higher prevalence of neurodevelopmental delay (NDD), lower weight-for-age z-scores, and delayed oral feeding. These findings were not attributable to a higher prevalence of non-isolated RS in this group. Although more commonly associated with non-isolated RS, growth faltering was also identified in 48%, and NDD in 18%, of cases of isolated RS., Conclusions: In UK/Ireland, most infants with RS are managed with NPA, and tracheostomy is reserved for refractory severe UAO. Clinical outcomes and duration of use indicate that NPA is a safe and feasible first-line approach to UAO. Longitudinal assessment of neurodevelopment and growth is imperative, including in children with isolated RS. Current variations in practice reinforce the need for evidence-based treatment guidelines., (© 2024 The Author(s). Pediatric Pulmonology published by Wiley Periodicals LLC.)

Pulse oximetry is widely used to non-invasively estimate the oxygen saturation of haemoglobin in arterial blood (SpO 2 ). It is used widely throughout healthcare and was used extensively during the Covid-19 pandemic to detect and treat hypoxic patients. Research has suggested that pulse oximetry is less accurate in patients with darker skin. This led the US Food and Drug Administration agency (FDA) to issue a safety statement warning that pulse oximeters may be inaccurate when patients have pigmented skin. Evidence suggests that the oxygen saturation of arterial blood (SaO 2 ) may be being overestimated by measuring SpO 2 in those with pigmented skin. The degree of overestimation increases as SaO 2 decreases especially when SpO 2 reads below 80%. We review how pulse oximetry works and consider the implications for a patient's health when interpreting SpO 2 in individuals with pigmented skin., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Primary ciliary dyskinesia (PCD) is a genetic disorder affecting motile cilia. Most cases are inherited recessively, due to variants in >50 genes that result in abnormal or absent motile cilia. This leads to chronic upper and lower airway disease, subfertility, and laterality defects. Given overlapping clinical features and genetic heterogeneity, diagnosis can be difficult and often occurs late. Of those tested an estimated 30% of genetically screened PCD patients still lack a molecular diagnosis. A molecular diagnosis allows for appropriate clinical management including prediction of phenotypic features correlated to genotype. Here, we aimed to identify how readily a genetic diagnosis could be made using whole genome sequencing (WGS) to facilitate identification of pathogenic variants in known genes as well as novel PCD candidate genes., Methods: WGS was used to screen for pathogenic variants in eight patients with PCD., Results: 7/8 cases had homozygous or biallelic variants in DNAH5, DNAAF4 or DNAH11 classified as pathogenic or likely pathogenic. Three identified variants were deletions, ranging from 3 to 13 kb, for which WGS identified precise breakpoints, permitting confirmation by Sanger sequencing. WGS yielded identification of a de novo variant in a novel PCD gene TUBB4B., Conclusion: Here, WGS uplifted genetic diagnosis of PCD by identifying structural variants and novel modes of inheritance in new candidate genes. WGS could be an important component of the PCD diagnostic toolkit, increasing molecular diagnostic yield from current (70%) levels, and enhancing our understanding of fundamental biology of motile cilia and variants in the noncoding genome., (© 2024 The Author(s). Pediatric Pulmonology published by Wiley Periodicals LLC.)

Background: Bacteriophage (phage) therapy is a promising alternative antimicrobial approach that has the potential to transform the way we treat bacterial infections. The antibiotic resistance crisis is driving renewed interest in phage therapy. There are currently no licensed phage therapy medicinal products and phage therapy is used in small but growing patient numbers on an unlicensed basis., Objectives: This article provides guidelines on the assessment of patient suitability for unlicensed phage therapy for clinicians in the United Kingdom., Sources: This article builds on Health Improvement Scotland's recommendation for the consideration of phage therapy in difficult-to-treat infections and the experience of the author group, who have collectively assessed the suitability of 30 patients for phage therapy., Content: In the United Kingdom, unlicenced medicines, including phages, may be considered to meet special clinical needs. The use of unlicenced medicines is governed by national legislation and local National Health Service trust policies. Phages can be used in any National Health Service trust and decisions about suitability should be made through existing local clinical management pathways. This article sets out guidelines to support local clinical teams in the assessment of patient suitability for phage therapy. Clinical and microbiological considerations are presented, including allergy and pregnancy., Implications: The assessment of patient suitability for phage therapy is within the scope of local clinical teams. Local assessment through existing clinical management pathways will develop confidence and competence in phage therapy among clinical teams nationally and ensure timely patient care., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Study Objectives: Epilepsy and obstructive sleep apnea syndrome (OSAS) are each relatively common in children. OSAS may affect cognition, such that recognition of OSAS is important for children and young people with epilepsy (CYPWE). Published pilot data reported 55% of CYPWE had symptoms suggestive of OSAS, compared with 7% of typically developing controls. The primary aim of this study was to ascertain OSAS prevalence by polysomnography in CYPWE, with secondary aims being to evaluate the utility of sleep questionnaires in CYPWE., Methods: CYPWE and age- and sex-matched typically developing controls were studied. A single night of level I attended polysomnography was undertaken, along with questionnaires (Sleep-Related Breathing Disorder scale of the Pediatric Sleep Questionnaire, Pittsburgh Sleep Quality Index, and the childhood and adolescent Epworth Sleepiness Scale). OSAS was defined as obstructive apnea-hypopnea index of ≥ 1 event/h., Results: Polysomnography was performed in 72 children including 48 CYPWE (60% male) and 24 controls (54% male). Mean age (11 years) was similar for CYPWE and controls ( P = .42), with slightly higher body mass index z scores (0.7 vs 0.1, P = .03) noted in CYPWE. Mean obstructive apnea-hypopnea index was 0.61 in CYPWE vs 0.42 in controls ( P = .62). Despite higher Sleep-Related Breathing Disorder scale of the Pediatric Sleep Questionnaire scores in CYPWE (0.38 vs 0.12, P < .001), no difference in OSAS prevalence (10% vs 4%, P = .78) was found. CYPWE had higher childhood and adolescent Epworth Sleepiness Scale (6 vs 3.5, P = .01) and Pittsburgh Sleep Quality Index (5 vs 3.3, P = .02) scores, indicating greater levels of daytime sleepiness and poorer sleep quality., Conclusions: The study found no evidence for increased OSAS prevalence in CYPWE, and the utility of the Sleep-Related Breathing Disorder scale of the Pediatric Sleep Questionnaire in predicting OSAS appears limited for CYPWE. CYPWE are, however, demonstrably sleepier and have poorer sleep quality. The cause for these findings remains unclear., Clinical Trial Registration: Registry: ClinicalTrials.gov; Name: Investigation of Sleep Quality and Prevalence of Sleep-disordered Breathing in Children and Young People With Epilepsy; URL: https://www.clinicaltrials.gov/study/NCT03103841; Identifier: NCT03103841., Citation: Urquhart DS, McLellan AE, Hill LE, et al. A case-control study to investigate the prevalence of obstructive sleep apnea and the utility of the Sleep-Related Breathing Disorder scale of the Pediatric Sleep Questionnaire in children and young people with epilepsy. J Clin Sleep Med . 2024;20(7):1039-1047., (© 2024 American Academy of Sleep Medicine.)

Background: Elexacaftor in combination with Tezacaftor and Ivacaftor (ETI) became licensed in the United Kingdom in early 2022 for children aged 6-11 years with cystic fibrosis (CF) and an eligible mutation. Many in this age group have excellent prior lung health making quantitative measurement of benefit challenging. Clinical trials purport that lung clearance index (LCI 2.5 ) measurement is most suitable for this purpose., Objectives: This study aimed to understand the clinical utility of LCI 2.5 in detecting change after commencing ETI in the real world., Patient Selection/methods: Baseline anthropometric data were collected along with spirometry (forced expiratory volume in 1 s [FEV 1 ], forced vital capacityFV and LCI 2.5 measures in children aged 6-11 years with CF before starting ETI. Measures were repeated after a mean (range) of 8.2 (7-14) months of ETI treatment. The primary endpoint was a change in LCI 2.5 , with secondary endpoints including change in FEV 1 and change in body mass index (BMI) also reported., Results: Twelve children were studied (seven male, mean age 9.5 years at baseline). Our study population had a mean (SD) LCI 2.5 of 7.01 (1.14) and FEV 1 of 96 (13) %predicted at baseline. Mean (95% confidence interval) changes in LCI 2.5 [-0.7 (-1.4, 0), p = .06] and BMI [+0.7 (+0.1, +1.3), p = .03] were observed, along with changes in FEV 1 of +3.1 (-1.9, +8.1) %predicted., Conclusions: Real-world changes in LCI 2.5 (-0.7) are different to those reported in clinical trials (-2.29). Lower baseline LCI 2.5 as a result of prior modulator exposure, high baseline lung health, and new LCI 2.5 software analyses all contribute to lower LCI 2.5 values being recorded in the real world of children with CF., (© 2024 Wiley Periodicals LLC.)

Tubulin, one of the most abundant cytoskeletal building blocks, has numerous isotypes in metazoans encoded by different conserved genes. Whether these distinct isotypes form cell type- and context-specific microtubule structures is poorly understood. Based on a cohort of 12 patients with primary ciliary dyskinesia as well as mouse mutants, we identified and characterized variants in the TUBB4B isotype that specifically perturbed centriole and cilium biogenesis. Distinct TUBB4B variants differentially affected microtubule dynamics and cilia formation in a dominant-negative manner. Structure-function studies revealed that different TUBB4B variants disrupted distinct tubulin interfaces, thereby enabling stratification of patients into three classes of ciliopathic diseases. These findings show that specific tubulin isotypes have distinct and nonredundant subcellular functions and establish a link between tubulinopathies and ciliopathies.

Rationale: Cardiopulmonary exercise testing (CPET) provides prognostic information in cystic fibrosis (CF); however, its prognostic value for patients with advanced CF lung disease is unknown. Objectives: To determine the prognostic value of CPET on the risk of death or lung transplant (LTX) within 2 years. Methods: We retrospectively collected data from 20 CF centers in Asia, Australia, Europe, and North America on patients with a forced expiratory volume in 1 second (FEV 1 ) ⩽ 40% predicted who performed a cycle ergometer CPET between January 2008 and December 2017. Time to death/LTX was analyzed using mixed Cox proportional hazards regression. Conditional inference trees were modeled to identify subgroups with increased risk of death/LTX. Results: In total, 174 patients (FEV 1 , 30.9% ± 5.8% predicted) were included. Forty-four patients (25.5%) died or underwent LTX. Cox regression analysis adjusted for age, sex, and FEV 1 revealed percentage predicted peak oxygen uptake ([Formula: see text]o 2peak ) and peak work rate (W peak ) as significant predictors of death/LTX: adjusted hazard ratios per each additional 10% predicted were 0.60 (95% confidence interval, 0.43-0.90; P  = 0.008) and 0.60 (0.48-0.82; P  < 0.001). Tree-structured regression models, including a set of 11 prognostic factors for survival, identified W peak to be most strongly associated with 2-year risk of death/LTX. Probability of death/LTX was 45.2% for those with a W peak  ⩽ 49.2% predicted versus 10.9% for those with a W peak  > 49.2% predicted ( P  < 0.001). Conclusions: CPET provides prognostic information in advanced CF lung disease, and W peak appears to be a promising marker for LTX referral and candidate selection.

Robin sequence (RS), a congenital disorder of jaw maldevelopment and glossoptosis, poses a substantial healthcare burden and has long-term health implications if airway obstruction is suboptimally treated. This study describes the global birth prevalence of RS and investigates whether prevalence estimates differ by geographical location, ethnicity or study data source (registry versus non-registry data). The protocol was prospectively registered with PROSPERO.Databases were searched using keywords and subject terms for "Robin sequence", "epidemiology", "incidence" and "birth prevalence". Meta-analysis was performed fitting random effects models with arcsine transformation.From 34 eligible studies (n=2722 RS cases), pooled birth prevalence was 9.5 per 100 000 live births (95% CI 7.1-12.1) with statistical heterogeneity. One third of studies provided a case definition for RS and numerous definitions were used. A total of 22 countries were represented, predominantly from European populations (53% of studies). There was a trend towards higher birth prevalence in European populations and lower prevalence from registry-based studies. Only two studies reported ethnicity.This study indicates that RS occurs globally. To investigate geographical differences in prevalence, additional studies from non-European populations and reporting of ethnicity are needed. Heterogeneity of estimates may be due to variable diagnostic criteria and ascertainment methods. Recently published consensus diagnostic criteria may reduce heterogeneity among future studies., Competing Interests: Conflict of interest: All authors have nothing to disclose., (Copyright ©The authors 2023.)

Objective: To investigate the BMI trajectories of children attending a tertiary asthma clinic during the COVID-19 pandemic., Methods: Data were collected retrospectively on children and young people with asthma who attended the Royal Hospital for Children and Young People (RHCYP) before March 2020 (pre-COVID-19) and after August 2021 (the lifting of national restrictions)., Main Outcome Measures: Changes in weight, height, and BMI Z score measured between 13/03/2019 and 13/03/2020 (timepoint 1) and then again during the period 01/08/2021 to 01/10/2022 (timepoint 2); changes in lung function parameters (FEV 1 ) between the timepoints; proportion of study sample classed as obese and overweight at both timepoints; interaction analyses according to deprivation indices (SIMD decile), the use of high dose inhaled corticosteroid (ICS) therapy, and the presence of atopy., Results: Eighty-nine children aged 5-18 years were studied. Weight and height Z scores significantly increased between timepoint 1 and 2 [weight Z score: +0.19 (0.08, +0.30), height Z score: +0.15 (+0.07, +0.23)], such that no significant change was observed in the BMI Z score [+ 0.07 (-0.05, +0.20)] or BMI centile [+0.5 (-3.1, +4.1)]. There was also no change in FEV 1 %predicted [-0.1 (-3.8, +3.6)] between the timepoints., Conclusions: No changes in BMI were observed in children with asthma before and after COVID-19 lockdowns. Improved linear growth was noted, implying an improvement in the overall physical health of our study cohort. This may suggest improved asthma control, which may reflect avoidance of viral triggers and/or improved adherence to treatment.

Background: Birth prevalence of Robin sequence (RS) is commonly reported as 1 case per 8000-14 000 live births. These estimates are based on single-source case ascertainment and may miss infants who did not require hospital admission or those without overt upper airway obstruction at birth., Objectives: To identify the true birth prevalence of RS with cleft palate in the UK and Ireland from a population-based birth cohort with high case ascertainment., Methods: Active surveillance of RS with cleft palate was carried out in the UK/Ireland using dual sources of case ascertainment: British Paediatric Surveillance Unit (BPSU) reporting card and nationally commissioned cleft services. Clinical data were collected from notifying clinicians at two time points., Results: 173 live-born infants met the surveillance case definition, giving a birth prevalence of 1 case per 5250 live births (19.1 per 100 000 (95% CI 16.2 to 21.9)), and 1:2690 in Scotland. 47% had non-isolated RS, with Stickler syndrome the most common genetic diagnosis (12% RS cases). Birth prevalence derived from the combined data sources was significantly higher than from BPSU surveillance alone., Conclusions: Birth prevalence of RS in the UK/Ireland derived from active surveillance is higher than reported by epidemiological studies from several other countries, and from UK-based anomaly registries, but consistent with published retrospective data from Scotland. Dual case ascertainment sources enabled identification of cases with mild or late-onset airway obstruction that were managed without hospital admission. Studies of aetiology and equivalent well-designed epidemiological studies from other populations are needed to investigate the identified geographical variability in birth prevalence., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

We present a challenging case that illustrates how the clinical manifestations in children with CFTR mutations of uncertain significance may change over time. This case highlights the evolution of confirming a diagnosis of CF and emphasises the importance of regular review and monitoring of this patient cohort., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Regular exercise testing is recommended for all people with cystic fibrosis (PwCF). A range of validated tests, which integrate both strength and aerobic function, are available and increasingly being used. Together, these tests offer the ability for comprehensive exercise evaluation. Extensive research and expert consensus over recent years has enabled the adaptation and standardisation of a range of exercise tests to aid the understanding of the pathophysiology related to exercise limitation in PwCF and has led to the development of novel exercise tests which may be applied to PwCF. This article provides expert, opinion-based clinical practice guidance, along with test instructions, for a selection of commonly used valid tests which have documented clinimetric properties for PwCF. Importantly, this document also highlights previously used tests that are no longer suggested for PwCF and areas where research is mandated. This collaboration, on behalf of the European Cystic Fibrosis Society Exercise Working Group, represents expert consensus by a multidisciplinary panel of physiotherapists, exercise scientists and clinicians and aims to improve global standardisation of functional exercise testing of PwCF. In short, the standardised use of a small selection of tests performed to a high standard is advocated., Competing Interests: Conflict of Interest: All authors have nothing to disclose., (Copyright ©The authors 2023.)

Objectives: Regular exercise testing is recommended for people with cystic fibrosis (pwCF), as is the provision and regular review of exercise training programmes. A previous survey on exercise testing and training for pwCF in the UK was conducted over a decade ago. With the landscape of CF changing considerably during this time, this survey aimed to evaluate UK-based exercise testing and training practices for pwCF a decade on., Design: Cross-sectional, online survey., Participants: A survey was distributed electronically to UK CF clinics and completed by the individual primarily responsible for exercise services. Descriptive statistics and qualitative analyses were undertaken., Results: In total, 31 CF centres participated, representing ~50% of UK specialist clinics. Of these, 94% reported using exercise testing, 48% of which primarily use cardiopulmonary exercise testing. Exercise testing mostly occurs at annual review (93%) and is most often conducted by physiotherapists (62%). A wide variation in protocols, exercise modalities, normative reference values and cut-offs for exercise-induced desaturation are currently used. All centres reportedly discuss exercise training with pwCF; 94% at every clinic appointment. However, only 52% of centres reportedly use exercise testing to inform individualised exercise training. Physiotherapists typically lead discussions around exercise training (74%)., Conclusions: These data demonstrate that the majority of respondent centres in the UK now offer some exercise testing and training advice for pwCF, representing a marked improvement over the past decade. However, continued efforts are now needed to standardise exercise practices, particularly regarding field testing practices and the translation of test results into personalised training programmes for pwCF., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Increasing evidence suggests that vitamin D is associated with pulmonary health, which may benefit children and young people diagnosed with Cystic Fibrosis (cypCF). Therefore, the aim of this systematic review was to evaluate primary research to establish associations between 25OHD and pulmonary health in cypCF., Methods: Electronic databases were searched with keywords related to CF, vitamin D, children/young people and pulmonary function. Included studies were cypCF (aged ≤21 years) treated in a paediatric setting. The primary outcome was lung function [forced expiratory volume in 1 s (FEV 1 % predicted)] and secondary outcomes were rate of pulmonary exacerbations, 25OHD status and growth. Evidence was appraised for risk of bias using the CASP tool, and quality using the EPHPP tool. A Meta-analysis was performed., Results: Twenty-one studies were included with mixed quality ratings and heterogeneity of reported outcomes. The Meta-analysis including 5 studies showed a significantly higher FEV 1 % predicted in the 25OHD sufficiency compared to the deficiency group [FEV 1 % predicted mean difference (95% CI) was 7.71 (1.69-13.74) %; p = 0.01]. The mean ± SD FEV 1 % predicted for the sufficient (≥75 nmol/L) vs. deficient (<50 nmol/L) group was 94.7 ± 31.9% vs. 86.9 ± 13.2%; I 2  = 0%; χ 2  = 0.5; df = 4). Five studies (5/21) found significantly higher rate of pulmonary exacerbations in those who were 25OHD deficient when compared to the sufficient group and negative associations between 25OHD and FEV% predicted. The effects of vitamin D supplementation dosages on 25OHD status (10/21) varied across studies and no study (12/21) showed associations between 25OHD concentration and growth., Conclusion: This systematic review suggests that 25OHD concentration is positively associated with lung function and a concentration of >75 nmol/L is associated with reduced frequency of pulmonary exacerbations, which may slow lung function decline in cypCF. Future randomised clinical trials and mechanistic studies are warranted., Competing Interests: Declaration of competing interest There are no conflict of interest to declare., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Previous studies have reported differences in aerobic exercise capacity, expressed as peak oxygen uptake (VO 2peak ), between people with and without cystic fibrosis (CF) related diabetes (CFRD). However, none of the studies controlled for the potential influence of physical activity on VO 2peak . We investigated associations between CFRD and VO 2peak following rigorous control for confounders including objectively measured physical activity., Methods: Baseline data from the international multicenter trial ACTIVATE-CF with participants ≥12 years performing up to 4 h per week of vigorous physical activity were used for this project. Multivariable models were computed to study associations between CFRD and VO 2peak (mL.min -1 ) adjusting for a set of pre-defined covariates: age, sex, weight, forced expiratory volume in 1 s (FEV 1 ), breathing reserve index, Pseudomonas aeruginosa infection, and physical activity (aerobic step counts from pedometry). Variables were selected based on their potential confounding effect on the association between VO 2peak and CFRD., Results: Among 117 randomized individuals, 103 (52% female) had a maximal exercise test and were included in the analysis. Participants with (n = 19) and without (n = 84) CFRD did not differ in FEV 1 , physical activity, nutritional status, and other clinical characteristics. There were also no differences in VO 2peak (mL.min -1 or mL.kg -1 .min -1 or% predicted). In the final multivariable model, all pre-defined covariates were significant predictors of VO 2peak (mL.min -1 ), however CFRD [coefficient 82.1, 95% CI -69.5 to 233.8, p = 0.28] was not., Conclusions: This study suggests no meaningful differences in VO 2peak between people with and without CFRD given comparable levels of physical activity., Competing Interests: Conflict of interest None., (Copyright © 2022. Published by Elsevier B.V.)

Background: Chest physiotherapy is an established cornerstone of care for people with cystic fibrosis (pwCF), but is often burdensome. Guidelines recommend at least one chest physiotherapy session daily, using various airway clearance techniques (ACTs). Exercise (with huffs and coughs) may offer an alternative ACT, however the willingness of pwCF to be randomised into a trial needs testing. The 'ExACT-CF: Exercise as an Airway Clearance Technique in people with Cystic Fibrosis' trial will test the feasibility of recruiting pwCF to be randomised to continue usual care (chest physiotherapy) or replace it with exercise ACT (ExACT) for 28-days. Secondary aims include determining the short-term clinical impact (and safety) of stopping routine chest physiotherapy and replacing it with ExACT, and effects on physical activity, sleep, mood, quality of life and treatment burden, alongside preliminary health economic measures and acceptability., Methods: Multi-centre, two-arm, randomised (1:1 allocation using minimisation), pilot trial at two sites. Fifty pwCF (≥10 years, FEV 1 >40% predicted, stable on Elexacaftor/Tezacaftor/Ivacaftor (ETI)) will be randomised to an individually-customised ExACT programme (≥once daily aerobic exercise of ≥20-minutes duration at an intensity that elicits deep breathing, with huffs and coughs), or usual care. After baseline assessments, secondary outcomes will be assessed after 28-days, with additional home lung function and exacerbation questionnaires at 7, 14 and 21-days, physical activity and sleep monitoring throughout, and embedded qualitative and health-economic components. Feasibility measures include recruitment, retention, measurement completion, adverse events, interviews exploring the acceptability of trial procedures, and a trial satisfaction questionnaire., Discussion: Co-designed with the UK CF community, the ExACT-CF pilot trial is the first multi-centre RCT to test the feasibility of recruiting pwCF stable on ETI into a trial investigating ExACT. This pilot trial will inform the feasibility, design, management, likely external validity for progression to a main phase randomised controlled trial., Registration: Clinicaltrials.gov ( NCT05482048)., Competing Interests: No competing interests were disclosed.There are no conflicts of interests for to declare for this trial., (Copyright: © 2022 Urquhart DS et al.)

Pre-operative respiratory assessment of children with spinal deformity requires an understanding of the deformity, the proposed surgery and most importantly the children themselves. The assessment and the tailoring of investigations will differ according to the age, developmental level and co-morbidities of the child. This review uses a mixture of evidence and case-based practice in order to set out a suggested framework for pre-operative spinal assessment, and suggested recommendations that may be provided to best support children undergoing surgery for spinal deformity., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objectives: The COVID-19 pandemic has resulted in unprecedent changes to clinical practice, and as the impact upon delivery of exercise services for people with cystic fibrosis (CF) in the United Kingdom was unknown, this was characterised via a national survey., Methods: An electronic survey was distributed to healthcare professionals involved in the exercise management of CF via established professional networks., Results: In total, 31 CF centres participated. Findings included significant reductions in exercise testing and widespread adaptation to deliver exercise training using telehealth methods. Promisingly, 71% stated that they would continue using virtual methods of engaging patients in future practice., Conclusion: These findings highlight adaptation to the COVID-19 pandemic and the need to develop sustainable and standardised telehealth services to manage patients moving forwards., (© 2022 The Authors. The Clinical Respiratory Journal published by John Wiley & Sons Ltd.)

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 (FEV 1 )% 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 (VO 2 peak )] and FEV 1 % 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 (χ 2  = 4.8, p = 0.02). Plasma 25OHD was not significantly associated with FEV 1 % predicted (r 2  = 0.06, p = 0.42, 95% CI = -0.09 to 0.19) or VO 2 peak (r 2  = 0.04, p = 0.07, 95% CI = -011 to 0.005) in all pwCF. However, 25OHD was significantly associated with both FEV 1 % (r 2  = 0.15, p = 0.02, 95% CI = 1.99-2.64) and VO 2 peak (r 2  = 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., (© 2021 The British Dietetic Association Ltd.)

Sleep-related breathing disorders are a common problem in infancy and childhood. The most common type of sleep-related breathing disorder in this age group is obstructive sleep apnea syndrome (OSAS), generally caused by factors affecting airway patency, such as tonsillar hypertrophy or obesity. However, in adults OSAS can also be caused by processes affecting the brainstem, such as central nervous system tumors. This report describes a 2-year-old girl who presented with symptoms of snoring, restless sleep, repeated night-time waking, and apneic events while asleep. She had no comorbidities, and examination revealed normal-sized tonsils. A sleep study demonstrated severe OSAS with an obstructive apnea/hypopnea index of 34. Her OSAS completely resolved on excision of the tumor. The case highlights the importance of neurological examination as part of evaluation of OSAS, especially in cases where tonsils are not enlarged and there are no other risk factors for OSAS., Citation: Buller F, Kamal MA, Brown SK, et al. Obstructive sleep apnea syndrome as a rare presentation in a young girl with a central nervous system tumor. J Clin Sleep Med . 2022;18(4):1211-1214., (© 2022 American Academy of Sleep Medicine.)

Exercise is considered as an important component of the package of care delivered to people with cystic fibrosis (pwCF). However, despite the well-known short-term physiological and psychological benefits, training effects are heterogenous and the transfer of structured exercise programmes to the daily life of pwCF is challenging. Training concepts and strategies developed over the last decades must be adapted to consider the aging population of pwCF with associated comorbidities, and also a new generation of young pwCF that are healthier than ever. In the present review we propose a new framework for optimising the choice among available exercise training procedures and we provide a theoretical and scientifically justified rationale for considering and testing new exercise training modalities. We propose a multidisciplinary approach, considering various physiological, psychological and logistical factors, with the aim to increase effects of exercise training and build positive long-term exercise behaviour., (Copyright © 2021. Published by Elsevier B.V.)

Rationale: The long-term effects of vigorous physical activity (PA) on lung function in cystic fibrosis are unclear. Objectives: To evaluate effects of a 12-month partially supervised PA intervention using motivational feedback. Methods: In a parallel-arm multicenter randomized controlled trial (ACTIVATE-CF), relatively inactive patients aged at least 12 years were randomly assigned (1:1 ratio) to an intervention group or control group. The intervention group consented to add 3 hours of vigorous PA per week, whereas the control group was asked not to change their PA behavior. Primary endpoint was change in percent predicted FEV 1 (ΔFEV 1 ) at 6 months. Secondary endpoints included PA, exercise capacity, exercise motives, time to first exacerbation and exacerbation rates, quality of life, anxiety, depression, stress, and blood glucose control. Data were analyzed using mixed linear models. Measurements and Main Results: A total of 117 patients (40% of target sample size) were randomized to an intervention (n = 60) or control group (n = 57). After 6 months, ΔFEV 1 was significantly higher in the control group compared with the intervention group (2.70% predicted [95% confidence interval, 0.13-5.26]; P  = 0.04). The intervention group reported increased vigorous PA compared with the control group at each study visit, had higher exercise capacity at 6 and 12 months, and higher PA at 12 months. No effects were seen in other secondary outcomes. Conclusions: ACTIVATE-CF increased vigorous PA and exercise capacity, with effects carried over for the subsequent 6 months, but resulted in better FEV 1 in the control group.

Background: The roles of physical activity (PA) and exercise within the management of cystic fibrosis (CF) are recognised by their inclusion in numerous standards of care and treatment guidelines. However, information is brief, and both PA and exercise as multi-faceted behaviours require extensive stakeholder input when developing and promoting such guidelines., Method: On 30 th June and 1 st July 2021, 39 stakeholders from 11 countries, including researchers, healthcare professionals and patients participated in a virtual conference to agree an evidence-based and informed expert consensus about PA and exercise for people with CF. This consensus presents the agreement across six themes: (i) patient and system centred outcomes, (ii) health benefits, iii) measurement, (iv) prescription, (v) clinical considerations, and (vi) future directions. The consensus was achieved by a stepwise process, involving: (i) written evidence-based synopses; (ii) peer critique of synopses; (iii) oral presentation to consensus group and peer challenge of revised synopses; and (iv) anonymous voting on final proposed synopses for adoption to the consensus statement., Results: The final consensus document includes 24 statements which surpassed the consensus threshold (>80% agreement) out of 30 proposed statements., Conclusion: This consensus can be used to support health promotion by relevant stakeholders for people with CF.

Objectives: To determine the indirect consequences of the COVID-19 pandemic on paediatric healthcare utilisation and severe disease at a national level following lockdown on 23 March 2020., Design: National retrospective cohort study., Setting: Emergency childhood primary and secondary care providers across Scotland; two national paediatric intensive care units (PICUs); statutory death records., Participants: 273 455 unscheduled primary care attendances; 462 437 emergency department attendances; 54 076 emergency hospital admissions; 413 PICU unplanned emergency admissions requiring invasive mechanical ventilation; and 415 deaths during the lockdown study period and equivalent dates in previous years., Main Outcome Measures: Rates of emergency care consultations, attendances and admissions; clinical severity scores on presentation to PICU; rates and causes of childhood death. For all data sets, rates during the lockdown period were compared with mean or aggregated rates for the equivalent dates in 2016-2019., Results: The rates of emergency presentations to primary and secondary care fell during lockdown in comparison to previous years. Emergency PICU admissions for children requiring invasive mechanical ventilation also fell as a proportion of cases for the entire population, with an OR of 0.52 for likelihood of admission during lockdown (95% CI 0.37 to 0.73), compared with the equivalent period in previous years. Clinical severity scores did not suggest children were presenting with more advanced disease. The greatest reduction in PICU admissions was for diseases of the respiratory system; those for injury, poisoning or other external causes were equivalent to previous years. Mortality during lockdown did not change significantly compared with 2016-2019., Conclusions: National lockdown led to a reduction in paediatric emergency care utilisation, without associated evidence of severe harm., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The impact of lumacaftor/ivacaftor on exercise tolerance in people with cystic fibrosis (CF) has not been thoroughly studied., Methods: We conducted a multisite Phase 4 trial comparing the impact of lumacaftor/ivacaftor on exercise tolerance with that of placebo in participants ≥ 12 years of age with CF homozygous for F508del-CFTR. The primary endpoint was relative change from baseline in maximum oxygen consumption (VO 2max ) during cardiopulmonary exercise testing (CPET) at Week 24. The key secondary endpoint was relative change from baseline in exercise duration during CPET at Week 24. Other secondary endpoints included changes in other indices of exercise tolerance and changes in CF assessments; safety and tolerability were assessed as an endpoint., Results: Seventy participants were randomized to receive lumacaftor/ivacaftor (n = 34) or placebo (n = 36). The least-squares mean difference for lumacaftor/ivacaftor versus placebo in relative change in VO 2max from baseline at Week 24 was -3.2% (95% CI: -9.2, 2.9; P=0.3021); the least-squares mean difference in relative change from baseline in exercise duration at Week 24 was -3.2% (95% CI: -8.0, 1.6). Safety results were consistent with the known lumacaftor/ivacaftor safety profile., Conclusions: Definitive conclusions regarding the impact of lumacaftor/ivacaftor on exercise tolerance cannot be drawn from these results; however, multicenter studies using CPETs can be reliably performed with multiple time points and conventional methods, provided that calibration can be achieved. Future studies of exercise tolerance may benefit from lessons learned from this study. NCT02875366., Competing Interests: Declaration of Competing Interest All authors received nonfinancial support (assistance with manuscript preparation) from ArticulateScience LLC, which received funding from Vertex Pharmaceuticals Incorporated. DK: personal fees (core laboratory overreading) from Vertex Pharmaceuticals Incorporated during the conduct of the study and personal fees (speaker fees) from Vertex Pharmaceuticals Incorporated outside the submitted work. DSU, ME, and RAH have nothing further to disclose. JW: grants and personal fees from Vertex Pharmaceuticals Incorporated outside the submitted work. LJ is a former employee of Vertex Pharmaceuticals Incorporated and owns stocks in Vertex Pharmaceuticals Incorporated. MD and ST are employees of Vertex Pharmaceuticals Incorporated and may own stock or stock options in Vertex Pharmaceuticals Incorporated. TK: personal fees (consulting fees) from Vertex Pharmaceuticals Incorporated during the conduct of the study. XY is a former employee of Vertex Pharmaceuticals Incorporated and may own stock or stock options in Vertex Pharmaceuticals Incorporated., (Copyright © 2020. Published by Elsevier B.V.)

Background: Severe scoliosis can affect respiratory function in growing patients and produce cardiopulmonary complications, leading to significant morbidity. The development of spinal deformity may impact on young patients' level of function and reported quality of life (QOL). The aim of this study was to investigate the relationship between lung function, exercise capacity and quality of life in young patients with spinal deformity., Methods: This is a retrospective analysis of 104 patients (31% male, 69% female with mean age 14.9yrs). 77% of patients had an adolescent idiopathic scoliosis, with the remainder having other scoliosis diagnoses or Scheuermann's kyphosis. Principal outcomes included Spirometry [FEV 1 , FVC], Whole Body Plethysmography, Cardiopulmonary Exercise Testing [CPET] and patient outcome questionnaires (with SRS-22). CPET measures included maximal exercise capacity [VO 2peak ] as well as VO 2 at ventilatory threshold [VT] expressed as %predicted VO 2max -a measure of physical conditioning, and minute ventilation [V E ] from which breathing reserve [BR] could be calculated., Results: Mean (±SD) main thoracic scoliosis was 59.9⁰ (±15.2⁰), and mean kyphosis in those with Scheuermann's condition was 95.3⁰ (±11.5⁰). No correlation was elicited between FEV 1 or FVC (%predicted) and VO 2peak (%predicted) in this patient cohort. Greater thoracic curves were associated with lower FEV 1 (%predicted), r = -0.343, p = 0.001, FVC (%predicted), r = -0.307, p = 0.003 and BR (%) at the end of exercise (r = -0.-0.459, p < 0.001). The patient cohort had a mean (sd) VO 2 peak of 98(17) %predicted, with greater VO 2 peak levels recorded in female subjects, those of younger age and those with higher scoliosis angles. Those with better lung function [FEV 1 (%predicted)] had better BR (%) at the end of exercise (r = 0.483, p < 0.001). SRS-22 scores correlated significantly with VO 2peak (%predicted) (total SRS-22 versus VO 2peak (%predicted), r = 0.336, p = 0.002)., Conclusion: Larger thoracic scoliotic curves are associated with poorer lung function but better exercise capacity, likely related to higher levels of physical conditioning. Higher QOL scores were recorded in patients who had greater VO 2peak levels, suggesting that exercise capacity may be a protective factor for emotional well-being in patients with spinal deformity., Competing Interests: None to declare., (© 2020 Delhi Orthopedic Association. All rights reserved.)

The objective of this document was to standardise published cardiopulmonary exercise testing (CPET) protocols for improved interpretation in clinical settings and multicentre research projects. This document: 1) summarises the protocols and procedures used in published studies focusing on incremental CPET in chronic lung conditions; 2) presents standard incremental protocols for CPET on a stationary cycle ergometer and a treadmill; and 3) provides patients' perspectives on CPET obtained through an online survey supported by the European Lung Foundation. We systematically reviewed published studies obtained from EMBASE, Medline, Scopus, Web of Science and the Cochrane Library from inception to January 2017. Of 7914 identified studies, 595 studies with 26 523 subjects were included. The literature supports a test protocol with a resting phase lasting at least 3 min, a 3-min unloaded phase, and an 8- to 12-min incremental phase with work rate increased linearly at least every minute, followed by a recovery phase of at least 2-3 min. Patients responding to the survey (n=295) perceived CPET as highly beneficial for their diagnostic assessment and informed the Task Force consensus. Future research should focus on the individualised estimation of optimal work rate increments across different lung diseases, and the collection of robust normative data., Competing Interests: Conflict of interest: T. Radtke reports personal fees for registration and travel/accomodation for conferences from Vifor Pharma, outside of the submitted work. Conflict of interest: S. Crook has nothing to disclose. Conflict of interest: G. Kaltsakas has nothing to disclose. Conflict of interest: G. Louvaris has nothing to disclose. Conflict of interest: D. Berton has nothing to disclose. Conflict of interest: D.S. Urquhart has nothing to disclose. Conflict of interest: A. Kampouras has nothing to disclose. Conflict of interest: R.A. Rabinovich has nothing to disclose. Conflict of interest: S. Verges has nothing to disclose. Conflict of interest: D. Kontopidis is President of the Hellenic Cystic Fibrosis Association. Conflict of interest: J. Boyd reports is an employee of the European Lung Foundation. Conflict of interest: T. Tonia reports acting as ERS Methodologist. Conflict of interest: D. Langer has nothing to disclose. Conflict of interest: J. De Brandt has nothing to disclose. Conflict of interest: Y.M.J. Goërtz has nothing to disclose. Conflict of interest: C. Burton has nothing to disclose. Conflict of interest: M.A. Spruit reports grants and personal fees from Boehringer-Ingelheim and AstraZeneca, personal fees from GSK and Novartis, congress travel support from TEVA, and grants from the Netherlands Lung Foundation, outside the submitted work. Conflict of interest: D.C.W. Braeken has nothing to disclose. Conflict of interest: S. Dacha has nothing to disclose. Conflict of interest: F.M.E. Franssen reports personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline and TEVA, and grants and personal fees from Novartis, outside the submitted work. Conflict of interest: P. Laveneziana reports personal fees from Novartis France and Boehringer France, outside the submitted work. Conflict of interest: E. Eber has nothing to disclose. Conflict of interest: T. Troosters has nothing to disclose. Conflict of interest: J.A Neder has nothing to disclose. Conflict of interest: M.A. Puhan has nothing to disclose. Conflict of interest: R. Casaburi reports that he shares patent US 7927251 B1, relating to a linear treadmill testing protocol, issued to Los Angeles Biomedical Research Institute. Conflict of interest: I. Vogiatzis has nothing to disclose. Conflict of interest: H. Hebestreit reports grants and personal fees from Vertex Pharmaceuticals, grants from Mukoviszidose e.V. (German CF Organization), outside the submitted work; and is the Coordinator of the European Cystic Fibrosis Society Exercise Working Group who discuss exercise testing and organise respective symposia., (Copyright ©ERS 2019.)

Rationale: The prognostic value of cardiopulmonary exercise testing (CPET) for survival in cystic fibrosis (CF) in the context of current clinical management, when controlling for other known prognostic factors, is unclear., Objectives: To determine the prognostic value of CPET-derived measures beyond peak oxygen uptake ( V . o 2 peak) following rigorous adjustment for other predictors., Methods: Data from 10 CF centers in Australia, Europe, and North America were collected retrospectively. A total of 510 patients completed a cycle CPET between January 2000 and December 2007, of which 433 fulfilled the criteria for a maximal effort. Time to death/lung transplantation was analyzed using Cox proportional hazards regression. In addition, phenotyping using hierarchical Ward clustering was performed to characterize high-risk subgroups., Measurements and Main Results: Cox regression showed, even after adjustment for sex, FEV 1 % predicted, body mass index (z-score), age at CPET, Pseudomonas aeruginosa status, and CF-related diabetes as covariates in the model, that V . o 2 peak in % predicted (hazard ratio [HR], 0.964; 95% confidence interval [CI], 0.944-0.986), peak work rate (% predicted; HR, 0.969; 95% CI, 0.951-0.988), ventilatory equivalent for oxygen (HR, 1.085; 95% CI, 1.041-1.132), and carbon dioxide (HR, 1.060; 95% CI, 1.007-1.115) (all P < 0.05) were significant predictors of death or lung transplantation at 10-year follow-up. Phenotyping revealed that CPET-derived measures were important for clustering. We identified a high-risk cluster characterized by poor lung function, nutritional status, and exercise capacity., Conclusions: CPET provides additional prognostic information to established predictors of death/lung transplantation in CF. High-risk patients may especially benefit from regular monitoring of exercise capacity and exercise counseling.