Paracrine signalling by cardiac calcitonin controls atrial fibrogenesis and arrhythmia.

Atrial fibrillation, the most common cardiac arrhythmia, is an important contributor to mortality and morbidity, and particularly to the risk of stroke in humans1. Atrial-tissue fibrosis is a central pathophysiological feature of atrial fibrillation that also hampers its treatment; the underlying molecular mechanisms are poorly understood and warrant investigation given the inadequacy of present therapies2. Here we show that calcitonin, a hormone product of the thyroid gland involved in bone metabolism3, is also produced by atrial cardiomyocytes in substantial quantities and acts as a paracrine signal that affects neighbouring collagen-producing fibroblasts to control their proliferation and secretion of extracellular matrix proteins. Global disruption of calcitonin receptor signalling in mice causes atrial fibrosis and increases susceptibility to atrial fibrillation. In mice in which liver kinase B1 is knocked down specifically in the atria, atrial-specific knockdown of calcitonin promotes atrial fibrosis and increases and prolongs spontaneous episodes of atrial fibrillation, whereas atrial-specific overexpression of calcitonin prevents both atrial fibrosis and fibrillation. Human patients with persistent atrial fibrillation show sixfold lower levels of myocardial calcitonin compared to control individuals with normal heart rhythm, with loss of calcitonin receptors in the fibroblast membrane. Although transcriptome analysis of human atrial fibroblasts reveals little change after exposure to calcitonin, proteomic analysis shows extensive alterations in extracellular matrix proteins and pathways related to fibrogenesis, infection and immune responses, and transcriptional regulation. Strategies to restore disrupted myocardial calcitonin signalling thus may offer therapeutic avenues for patients with atrial fibrillation.

Detection of Bronchiolitis Obliterans Syndrome after Pediatric Hematopoietic Stem Cell Transplantation: An Official American Thoracic Society Clinical Practice Guideline.

Background: Many children undergo allogeneic hematopoietic stem cell transplantation (HSCT) for the treatment of malignant and nonmalignant conditions. Unfortunately, pulmonary complications occur frequently post-HSCT, with bronchiolitis obliterans syndrome (BOS) being the most common noninfectious pulmonary complication. Current international guidelines contain conflicting recommendations regarding post-HSCT surveillance for BOS, and a recent NIH workshop highlighted the need for a standardized approach to post-HSCT monitoring. As such, this guideline provides an evidence-based approach to detection of post-HSCT BOS in children. Methods: A multinational, multidisciplinary panel of experts identified six questions regarding surveillance for, and evaluation of, post-HSCT BOS in children. A systematic review of the literature was undertaken to answer each question. The Grading of Recommendations, Assessment, Development, and Evaluation approach was used to rate the quality of evidence and the strength of recommendations. Results: The panel members considered the strength of each recommendation and evaluated the benefits and risks of applying the intervention. In formulating the recommendations, the panel considered patient and caregiver values, the cost of care, and feasibility. Recommendations addressing the role of screening pulmonary function testing and diagnostic tests in children with suspected post-HSCT BOS were made. Following a Delphi process, new diagnostic criteria for pediatric post-HSCT BOS were also proposed. Conclusions: This document provides an evidence-based approach to the detection of post-HSCT BOS in children while also highlighting considerations for the implementation of each recommendation. Further, the document describes important areas for future research.

Garnet secondary ion mass spectrometry oxygen isotopes reveal crucial roles of pulsed magmatic fluid and its mixing with meteoric water in lode gold genesis.

SignificanceThere is a common consensus that lode gold deposits mostly precipitated from metamorphic fluids via fluid boiling and/or fluid-rock interaction, but whether magmatic hydrothermal fluids and the mixing of such fluids with an external component have played a vital role in the formation of lode gold deposits remains elusive. We use garnet secondary ion mass spectrometry oxygen isotope analysis to demonstrate that the world-class Dongping lode gold deposit has been formed by multiple pulses of magmatic hydrothermal fluids and their mixing with large volumes of meteoric water. This study opens an opportunity to tightly constrain the origin of lode gold deposits worldwide and other hydrothermal systems that may have generated giant ore deposits in the Earth's crust.

CFTR modulator therapy: transforming the landscape of clinical care in cystic fibrosis.

Following discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in 1989 and subsequent elucidation of the varied CFTR protein abnormalities that result, a new era of cystic fibrosis management has emerged-one in which scientific principles translated from the bench to the bedside have enabled us to potentially treat the basic defect in the majority of children and adults with cystic fibrosis, with a resultant burgeoning adult cystic fibrosis population. However, the long-term effects of these therapies on the multiple manifestations of cystic fibrosis are still under investigation. Understanding the effects of modulators in populations excluded from clinical trials is also crucial. Furthermore, establishing appropriate disease measures to assess efficacy in the youngest potential trial participants and in those whose post-modulator lung function is in the typical range for people without chronic lung disease is essential for continued drug development. Finally, recognising that a health outcome gap has been created for some people and widened for others who are not eligible for, cannot tolerate, or do not have access to modulators is important.

ERS technical standard: Global Lung Function Initiative reference values for multiple breath washout indices.

BACKGROUND: Multiple breath washout is a lung function test based on tidal breathing that assesses lung volume and ventilation distribution. The aim of this analysis was to use the Global Lung Function Initiative methodology to develop all-age reference equations for the multiple breath washout indices lung clearance index (LCI) and functional residual capacity (FRC). METHODS: Multiple breath washout data from healthy individuals were collated from sites. Data were re-analysed using the latest software versions. Reference equations were derived using the lambda-mu-sigma (LMS) method using the generalised additive models of location shape and scale programme in R. The impact of equipment type, inert tracer gas, and equipment dead space volume on the derived reference ranges were investigated. RESULTS: Data from 23 sites (n=3647 test occasions) were submitted. Reference equations were derived from 1581 unique observations from participants between the ages of 2 and 81 years. Equipment type, inert tracer gas, and equipment dead space volume did not significantly affect the prediction equations for either LCI or FRC. Reference equations for LCI include age as the only predictor, whereas sex-specific reference equations for FRC included height and age. CONCLUSIONS: Global Lung Function Initiative reference equations for multiple breath washout variables provide a standard for reporting and interpretation of LCI and FRC.

Detailed characterization and impact of small airway dysfunction in school-age asthma.

BACKGROUND: Small airway dysfunction (SAD) is increasingly recognized as an important feature of pediatric asthma yet typically relies on spirometry-derived FEF25-75 to detect its presence. Multiple breath washout (MBW) and oscillometry potentially offer improved sensitivity for SAD detection, but their utility in comparison to FEF25-75, and correlations with clinical outcomes remains unclear for school-age asthma. We investigated SAD occurrence using these techniques, between-test correlation and links to clinical outcomes in 57 asthmatic children aged 8-18 years. METHODS: MBW and spirometry abnormality were defined as z-scores above/below ± 1.96, generating MBW reference equations from contemporaneous controls (n = 69). Abnormal oscillometry was defined as > 97.5th percentile, also from contemporaneous controls (n = 146). Individuals with abnormal FEF25-75, MBW, or oscillometry were considered to have SAD. RESULTS: Using these limits of normal, SAD was present on oscillometry in 63% (resistance at 5-20 Hz; R5-R20; >97.5th percentile), on MBW in 54% (Scond; z-scores> +1.96) and in spirometry FEF25-75 in 44% of participants (z-scores< -1.96). SAD, defined by oscillometry and/or MBW abnormality, occurred in 77%. Among those with abnormal R5-R20, Scond was abnormal in 71%. Correlations indicated both R5-R20 and Scond were linked to asthma medication burden, baseline FEV1 and reversibility. Additionally, Scond correlated with FENO and magnitude of bronchial hyper-responsiveness. SAD, detected by oscillometry and/or MBW, occurred in almost 80% of school-aged asthmatic children, surpassing FEF25-75 detection rates. CONCLUSIONS: Discordant oscillometry and MBW abnormality suggests they reflect different aspects of SAD, serving as complementary tools. Key asthma clinical features, like reversibility, had stronger correlation with MBW-derived Scond than oscillometry-derived R5-R20.

Supercell tornadoes are much stronger and wider than damage-based ratings indicate.

Tornadoes cause damage, injury, and death when intense winds impact structures. Quantifying the strength and extent of such winds is critical to characterizing tornado hazards. Ratings of intensity and size are based nearly entirely on postevent damage surveys [R. Edwards et al., Bull. Am. Meteorol. Soc. 94, 641-653 (2013)]. It has long been suspected that these suffer low bias [C. A. Doswell, D. W. Burgess, Mon. Weather Rev. 116, 495-501 (1988)]. Here, using mapping of low-level tornado winds in 120 tornadoes, we prove that supercell tornadoes are typically much stronger and wider than damage surveys indicate. Our results permit an accurate assessment of the distribution of tornado intensities and sizes and tornado wind hazards, based on actual wind-speed observations, and meaningful comparisons of the distribution of tornado intensities and sizes with theoretical predictions. We analyze data from Doppler On Wheels (DOW) radar measurements of 120 tornadoes at the time of peak measured intensity. In striking contrast to conventional damage-based climatologies, median tornado peak wind speeds are ∼60 m⋅s-1, capable of causing significant, Enhanced Fujita Scale (EF)-2 to -3, damage, and 20% are capable of the most intense EF-4/EF-5 damage. National Weather Service (NWS) EF/wind speed ratings are 1.2 to 1.5 categories (∼20 m⋅s-1) lower than DOW observations for tornadoes documented by both the NWS and DOWs. Median tornado diameter is 250 to 500 m, with 10 to 15% >1 km. Wind engineering tornado-hazard-model predictions and building wind resistance standards may require upward adjustment due to the increased wind-damage risk documented here.

Autopsy of a failed trial part 2: Outcomes, challenges, and lessons learnt from the DAISIES trial.

OBJECTIVE: The relative merits of inpatient or day-treatment for adults with anorexia nervosa (AN) are unknown. The DAISIES trial aimed to establish the non-inferiority of a stepped-care day patient treatment (DPT) approach versus inpatient treatment as usual (IP-TAU) for improving body mass index (BMI) at 12 months in adults with AN. The trial was terminated due to poor recruitment. This paper presents outcomes and investigates the reasons behind the trial's failure. METHOD: Fifteen patients with AN (of 53 approached) participated and were followed-up to 6 or 12 months. Summary statistics were calculated due to low sample size, and qualitative data concerning treatment experiences were analysed using thematic analysis. RESULTS: At baseline, participants in both trial arms rated stepped-care DPT as more acceptable. At 12 months, participants' BMIs had increased in both trial arms. Qualitative analysis highlighted valued and challenging aspects of care across settings. Only 6/12 sites opened for recruitment. Among patients approached, the most common reason for declining participation was their treatment preference (n = 12/38). CONCLUSIONS: No conclusions can be drawn concerning the effectiveness of IP-TAU and stepped-care DPT, but the latter was perceived more positively. Patient-related, service-related and systemic factors (COVID-19) contributed to the trial's failure. Lessons learnt can inform future studies.

Comparing the effects of chemical Ca2+ dyes and R-GECO on contractility and Ca2+ transients in adult and human iPSC cardiomyocytes.

We compared commonly used BAPTA-derived chemical Ca2+ dyes (fura2, Fluo-4, and Rhod-2) with a newer genetically encoded indicator (R-GECO) in single cell models of the heart. We assessed their performance and effects on cardiomyocyte contractility, determining fluorescent signal-to-noise ratios and sarcomere shortening in primary ventricular myocytes from adult mouse and guinea pig, and in human iPSC-derived cardiomyocytes. Chemical Ca2+ dyes displayed dose-dependent contractile impairment in all cell types, and we observed a negative correlation between contraction and fluorescence signal-to-noise ratio, particularly for fura2 and Fluo-4. R-GECO had no effect on sarcomere shortening. BAPTA-based dyes, but not R-GECO, inhibited in vitro acto-myosin ATPase activity. The presence of fura2 accentuated or diminished changes in contractility and Ca2+ handling caused by small molecule modulators of contractility and intracellular ionic homeostasis (mavacamten, levosimendan, and flecainide), but this was not observed when using R-GECO in adult guinea pig left ventricular cardiomyocytes. Ca2+ handling studies are necessary for cardiotoxicity assessments of small molecules intended for clinical use. Caution should be exercised when interpreting small molecule studies assessing contractile effects and Ca2+ transients derived from BAPTA-like chemical Ca2+ dyes in cellular assays, a common platform for cardiac toxicology testing and mechanistic investigation of cardiac disease physiology and treatment.

Phage Therapy of Mycobacterium Infections: Compassionate Use of Phages in 20 Patients With Drug-Resistant Mycobacterial Disease.

BACKGROUND: Nontuberculous Mycobacterium infections, particularly Mycobacterium abscessus, are increasingly common among patients with cystic fibrosis and chronic bronchiectatic lung diseases. Treatment is challenging due to intrinsic antibiotic resistance. Bacteriophage therapy represents a potentially novel approach. Relatively few active lytic phages are available and there is great variation in phage susceptibilities among M. abscessus isolates, requiring personalized phage identification. METHODS: Mycobacterium isolates from 200 culture-positive patients with symptomatic disease were screened for phage susceptibilities. One or more lytic phages were identified for 55 isolates. Phages were administered intravenously, by aerosolization, or both to 20 patients on a compassionate use basis and patients were monitored for adverse reactions, clinical and microbiologic responses, the emergence of phage resistance, and phage neutralization in serum, sputum, or bronchoalveolar lavage fluid. RESULTS: No adverse reactions attributed to therapy were seen in any patient regardless of the pathogen, phages administered, or the route of delivery. Favorable clinical or microbiological responses were observed in 11 patients. Neutralizing antibodies were identified in serum after initiation of phage delivery intravenously in 8 patients, potentially contributing to lack of treatment response in 4 cases, but were not consistently associated with unfavorable responses in others. Eleven patients were treated with only a single phage, and no phage resistance was observed in any of these. CONCLUSIONS: Phage treatment of Mycobacterium infections is challenging due to the limited repertoire of therapeutically useful phages, but favorable clinical outcomes in patients lacking any other treatment options support continued development of adjunctive phage therapy for some mycobacterial infections.

CalTrack: High-Throughput Automated Calcium Transient Analysis in Cardiomyocytes.

[Figure: see text].

Approaches to the management of haemoptysis in young people with cystic fibrosis.

Haemoptysis occurs in up to 25 % of young people with Cystic fibrosis (CF) [1]. We undertook a literature review and described the management approach to haemoptysis in CF between 2010 and 2020 at an Australian tertiary paediatric centre, The Children's Hospital Westmead, Sydney, New South Wales, using a retrospective review of the medical records which identified 67 episodes. Sixty episodes met inclusion criteria, including 31 patients. Using the US CF Foundation guidelines, episodes were classified as scant (53.3 %), moderate (38.3 %) or massive (8.3 %). Fifty-two percent of patients were female, mean age at presentation was 15.4 years (SD+/- 2.4) and 58 % were homozygous for the Fdel508 genotype. Twelve episodes (9 patients) required bronchial artery embolization (BAE). BAE was used in all cases of massive haemoptysis 5/5 (100 %), 6/23 (22 %) episodes of moderate and 1/32 (3 %) episode of scant haemoptysis as an elective procedure for recurrent haemoptysis. Our literature review and institutional experience highlights the need for up-to-date management guidelines in the management of haemoptysis in Cystic Fibrosis. Based on our experience, we provide a proposed algorithm to help guide the management of haemoptysis in CF.

Asthma and landscape fire smoke: A Thoracic Society of Australia and New Zealand position statement.

Landscape fires are increasing in frequency and severity globally. In Australia, extreme bushfires cause a large and increasing health and socioeconomic burden for communities and governments. People with asthma are particularly vulnerable to the effects of landscape fire smoke (LFS) exposure. Here, we present a position statement from the Thoracic Society of Australia and New Zealand. Within this statement we provide a review of the impact of LFS on adults and children with asthma, highlighting the greater impact of LFS on vulnerable groups, particularly older people, pregnant women and Aboriginal and Torres Strait Islander peoples. We also highlight the development of asthma on the background of risk factors (smoking, occupation and atopy). Within this document we present advice for asthma management, smoke mitigation strategies and access to air quality information, that should be implemented during periods of LFS. We promote clinician awareness, and the implementation of public health messaging and preparation, especially for people with asthma.

Efficacy and Safety of Elexacaftor/Tezacaftor/Ivacaftor in Children 6 Through 11 Years of Age with Cystic Fibrosis Heterozygous for F508del and a Minimal Function Mutation: A Phase 3b, Randomized, Placebo-controlled Study.

Rationale: The triple-combination regimen elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be safe and efficacious in children aged 6 through 11 years with cystic fibrosis and at least one F508del-CFTR allele in a phase 3, open-label, single-arm study. Objectives: To further evaluate the efficacy and safety of ELX/TEZ/IVA in children 6 through 11 years of age with cystic fibrosis heterozygous for F508del and a minimal function CFTR mutation (F/MF genotypes) in a randomized, double-blind, placebo-controlled phase 3b trial. Methods: Children were randomized to receive either ELX/TEZ/IVA (n = 60) or placebo (n = 61) during a 24-week treatment period. The dose of ELX/TEZ/IVA administered was based on weight at screening, with children <30 kg receiving ELX 100 mg once daily, TEZ 50 mg once daily, and IVA 75 mg every 12 hours, and children ⩾30 kg receiving ELX 200 mg once daily, TEZ 100 mg once daily, and IVA 150 mg every 12 hours (adult dose). Measurements and Main Results: The primary endpoint was absolute change in lung clearance index2.5 from baseline through Week 24. Children given ELX/TEZ/IVA had a mean decrease in lung clearance index2.5 of 2.29 units (95% confidence interval [CI], 1.97-2.60) compared with 0.02 units (95% CI, -0.29 to 0.34) in children given placebo (between-group treatment difference, -2.26 units; 95% CI, -2.71 to -1.81; P < 0.0001). ELX/TEZ/IVA treatment also led to improvements in the secondary endpoint of sweat chloride concentration (between-group treatment difference, -51.2 mmol/L; 95% CI, -55.3 to -47.1) and in the other endpoints of percent predicted FEV1 (between-group treatment difference, 11.0 percentage points; 95% CI, 6.9-15.1) and Cystic Fibrosis Questionnaire-Revised Respiratory domain score (between-group treatment difference, 5.5 points; 95% CI, 1.0-10.0) compared with placebo from baseline through Week 24. The most common adverse events in children receiving ELX/TEZ/IVA were headache and cough (30.0% and 23.3%, respectively); most adverse events were mild or moderate in severity. Conclusions: In this first randomized, controlled study of a cystic fibrosis transmembrane conductance regulator modulator conducted in children 6 through 11 years of age with F/MF genotypes, ELX/TEZ/IVA treatment led to significant improvements in lung function, as well as robust improvements in respiratory symptoms and cystic fibrosis transmembrane conductance regulator function. ELX/TEZ/IVA was generally safe and well tolerated in this pediatric population with no new safety findings.

Model analysis of multiple breath nitrogen washout data: robustness to variations in breathing pattern.

We recently developed a model-based method for analyzing multiple breath nitrogen washout data that does not require identification of Phase-III. In the present study, we assessed the effect of irregular breathing patterns on the intra-subject variabilities of the model parameters. Nitrogen fraction at the mouth was measured in 18 healthy and 20 asthmatic subjects during triplicate performances of multiple breath nitrogen washout, during controlled (target tidal volume 1 L at 8-12 breaths per minute) and free (unrestricted) breathing. The parameters Scond, Sacin and functional residual capacity (FRC) were obtained by conventional analysis of the slope of Phase-III. Fitting the model to the washout data provided functional residual capacity (FRCM), dead space volume (VD), the coefficient of variation of regional specific ventilation ([Formula: see text]), and the model equivalent of Sacin (Sacin-M). Intra-participant coefficients of variation for the model parameters for both health and asthma were FRCM < 5.2%, VD < 5.4%, [Formula: see text] < 9.0%, and Sacin-M < 45.6% for controlled breathing, and FRCM < 4.6%, VD < 5.3%, [Formula: see text] < 13.2%, and Sacin-M < 103.2% for free breathing. The coefficients of variation limits for conventional parameters were FRC < 6.1%, with Scond < 73.6% and Sacin < 49.2% for controlled breathing and Scond < 35.0% and Sacin < 74.4% for free breathing. The model-fitting approach to multiple breath nitrogen washout analysis provides a measure of regional ventilation heterogeneity in [Formula: see text] that is less affected by irregularities in the breathing pattern than its corresponding Phase-III slope analysis parameter Scond.

Autopsy of a failed trial part 1: A qualitative investigation of clinician's views on and experiences of the implementation of the DAISIES trial in UK-based intensive eating disorder services.

OBJECTIVE: The DAISIES trial, comparing inpatient and stepped-care day patient treatment for adults with severe anorexia nervosa was prematurely terminated in March 2022 due to poor recruitment. This qualitative study seeks to understand the difficulties faced during the trial by investigating stakeholders' views on and experiences of its implementation. METHOD: Semi-structured interview and focus group transcripts, and trial management and oversight group meeting minutes from May 2020-June 2022 were analysed using thematic analysis. Participants were 47 clinicians and co-investigators involved with the DAISIES trial. The Non-Adoption, Abandonment, Scale-up, Spread, and Sustainability (NASSS) framework was applied to the interpretive themes to classify barriers and facilitators to implementation. RESULTS: Five themes were identified: incompatible participation interests; changing standard practice; concerns around clinical management; systemic capacity and capability issues; and Covid-19 disrupting implementation. Applying the NASSS framework indicated the greatest implementation challenges to arise with the adopters (e.g. patients, clinicians), the organisational systems (e.g. service capacity), and the wider socio-political context (e.g. Covid-19 closing services). CONCLUSIONS: Our findings emphasise the top-down impact of systemic-level research implementation challenges. The impact of the Covid-19 pandemic accentuated pre-existing organisational barriers to trial implementation within intensive eating disorder services, further limiting the capacity for research.

Higher exhaled nitric oxide at 6 weeks of age is associated with less bronchiolitis and wheeze in the first 12 months of age.

BACKGROUND: Nitric oxide in exhaled air (eNO) is used as a marker of type 2 immune response-induced airway inflammation. We aimed to investigate the association between eNO and bronchiolitis incidence and respiratory symptoms in infancy, and its correlation with eosinophil protein X (EPX). METHODS: We followed up infants at 6 weeks of age born to mothers with asthma in pregnancy and measured eNO during natural sleep using a rapid response chemiluminescense analyser (CLD88; EcoMedics), collecting at least 100 breaths, interpolated for an expiratory flow of 50 mL/s. EPX normalised to creatinine was measured in urine samples (uEPX/c). A standardised questionnaire was used to measure symptoms in first year of life. Associations were investigated using multiple linear regression and robust Poisson regression models. RESULTS: eNO levels were obtained in 184 infants, of whom 125/184 (68%) had 12 months questionnaire data available and 51/184 (28%) had uEPX/c measured. Higher eNO was associated with less respiratory symptoms during the first 6 weeks of life (n=184, ß-coefficient: -0.49, 95% CI -0.95 to -0.04, p=0.035). eNO was negatively associated with uEPX/c (ß-coefficient: -0.004, 95% CI -0.008 to -0.001, p=0.021). Risk incidence of bronchiolitis, wheeze, cold or influenza illness and short-acting beta-agonist use significantly decreased by 18%-24% for every unit increase in eNO ppb. CONCLUSION: Higher eNO levels at 6 weeks of age may be a surrogate for an altered immune response that is associated with less respiratory symptoms in the first year of life.

Personalized tobramycin dosing in children with cystic fibrosis: a comparative clinical evaluation of log-linear and Bayesian methods.

BACKGROUND: Children with cystic fibrosis (CF) pulmonary exacerbations receive IV tobramycin therapy, with dosing guided by either log-linear regression (LLR) or Bayesian forecasting (BF). OBJECTIVES: To compare clinical and performance outcomes for LLR and BF. PATIENTS AND METHODS: A quasi-experimental intervention study was conducted at a tertiary children's hospital. Electronic medical records were extracted (from January 2015 to September 2021) to establish a database consisting of pre-intervention (LLR) and post-intervention (BF) patient admissions and relevant outcomes. All consecutive patients treated with IV tobramycin for CF pulmonary exacerbations guided by either LLR or BF were eligible. RESULTS: A total of 376 hospital admissions (LLR = 248, BF = 128) for CF pulmonary exacerbations were included. Patient demographics were similar between cohorts. There were no significant differences found in overall hospital length of stay, rates of re-admission within 1 month of discharge or change in forced expiratory volume in the first second (Δ FEV1) at the end of tobramycin treatment. Patients treated with LLR on average had twice the number of therapeutic drug monitoring (TDM) blood samples collected during a single hospital admission. The timeframe for blood sampling was more flexible with BF, with TDM samples collected up to 16 h post-tobramycin dose compared with 10 h for LLR. The tobramycin AUC0-24 target of ≥100 mg/L·h was more frequently attained using BF (72%; 92/128) compared with LLR (50%; 124/248) (P < 0.001). Incidence of acute kidney injury was rare in both groups. CONCLUSIONS: LLR and BF result in comparable clinical outcomes. However, BF can significantly reduce the number of blood collections required during each admission, improve dosing accuracy, and provide more reliable target concentration attainment in CF children.

Issues affecting young people with asthma through the transition period to adult care.

Asthma is among the most common medical conditions affecting children and young people, with adolescence a recognised period of increased risk, overrepresented in analyses examining recent increasing asthma mortality rates. Asthma may change significantly during this period and management also occurs in the context of patients seeking increased autonomy and self-governance whilst navigating increasing academic and social demands. A number of disease factors can destabilise asthma during adolescence including: increased rates of anaphylaxis, anxiety, depression, obesity, and, in females, an emerging resistance to corticosteroids and the pro-inflammatory effects of oestrogen. Patient factors such as smoking, vaping, poor symptom recognition, treatment non-adherence and variable engagement with health services contribute to difficult to treat asthma. Significant deficiencies in the current approach to transition have been identified by a recent EAACI task force, and subsequent asthma-specific recommendations, published in 2020 provide an important framework moving forward. As with other chronic conditions, effective transition programmes plan ahead, engage with adolescents and their families to identify the patients' management priorities and the current challenges they are experiencing with treatment. Transition needs may vary significantly across asthma patients and for more complex asthma may include dedicated transition clinics involving multidisciplinary care requiring input including, amongst others, allergy and immunology, psychological medicine, respiratory physicians and scientists and nurse specialists. Across different global regions, barriers to treatment may vary but need to be elicited and an individualised approach taken to optimising asthma care which is sustainable within the local adult healthcare system.

Update in management of paediatric primary spontaneous pneumothorax.

Paediatric spontaneous pneumothorax (PSP) management continues to lack paediatric-specific guideline recommendations. There have been increasing reports of paediatric retrospective case studies supplemented by important well designed RCT (predominantly) adult studies. Taken together, these suggest that conservative management may have an increasing role to play in the management of PSP and that aspiration may have limited utility as a first line intervention. Our local experience, as part of a multicentre retrospective analysis and subsequent audit of management since, corroborates recent published data: it highlights an increasing trend towards conservative management in spontaneous pneumothorax with similar rates of recurrence, compared to intervention, and low use of aspiration with similarly low success rates. We have therefore updated our local practice guidelines and share these with readers. Specifically, we have removed aspiration in the management of primary spontaneous pneumothorax and reserved intervention for children who are clinically unstable or show evidence of increasing air leak irrespective of pneumothorax size. Whilst the success of this change in clinical practice will need to be reviewed in the next 5-10 years, the overall low incidence of the condition, demands a multicentre, and probably multinational, collaborative approach to allow the best chance of obtaining definitive evidence to guide clinical paediatric management.