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.

Growth, Body Composition, and Lung Function in Prepubertal Children with Cystic Fibrosis Diagnosed by Newborn Screening.

BACKGROUND: Children with cystic fibrosis (CF) are at risk of altered body composition (BC). Newborn screening (NBS) may lead to improved BC outcomes. We investigated BC and its relationship with lung function in prepubertal children diagnosed with CF by NBS. Secondary aims explored predictors of fat-free mass (FFM) and lung function. METHODS: Thirty-seven screened (non-meconium ileus) children with CF (20 boys) born 2007-2012 had a dual-energy x-ray absorptiometry scan at 5-8 years to determine whole-body (WB) and appendicular BC. Anthropometry was performed and routine spirometry recorded. Results were converted to z-scores, height-adjusted (fat mass index [FMI] and FFM index [FFMI]) and compared with population mean values. Predictors of forced expiratory volume in 1 second (FEV1 ) were assessed using linear regression. RESULTS: Height, body mass index (BMI), and FEV1 were within normal limits, however, weight and BC were significantly low compared with reference data (weight, P = .03; WB FMI, P = .001; WB FFMI, P = .009). Gender differences were detected, with lower appendicular BC in boys and lower weight, BMI, and BC in girls. The association between FEV1 and WB FFMI (r = 0.38; P = .02) was stronger than with BMI (r = 0.29; P = .08). WB FFMI was the only significant predictor of FEV1 in a multivariable model (95% CI, 0.11-0.99; P = .016). CONCLUSION: In this NBS CF population, gender differences in growth and BC were apparent despite preserved lung function. These results support BC assessment in prepubertal children, particularly girls, with an opportunity to direct interventions to optimize FFM.

A novel role for myeloid endothelin-B receptors in hypertension.

AIMS: Hypertension is common. Recent data suggest that macrophages (Mφ) contribute to, and protect from, hypertension. Endothelin-1 (ET-1) is the most potent endogenous vasoconstrictor with additional pro-inflammatory properties. We investigated the role of the ET system in experimental and clinical hypertension by modifying Mφ number and phenotype. METHODS AND RESULTS: In vitro, Mφ ET receptor function was explored using pharmacological, gene silencing, and knockout approaches. Using the CD11b-DTR mouse and novel mice with myeloid cell-specific endothelin-B (ETB) receptor deficiency (LysMETB-/-), we explored the effects of modifying Mφ number and phenotype on the hypertensive effects of ET-1, angiotensin II (ANG II), a model that is ET-1 dependent, and salt. In patients with small vessel vasculitis, the impacts of Mφ depleting and non-depleting therapies on blood pressure (BP) and endothelial function were examined. Mouse and human Mφ expressed both endothelin-A and ETB receptors and displayed chemokinesis to ET-1. However, stimulation of Mφ with exogenous ET-1 did not polarize Mφ phenotype. Interestingly, both mouse and human Mφ cleared ET-1 through ETB receptor mediated, and dynamin-dependent, endocytosis. Mφ depletion resulted in an augmented chronic hypertensive response to both ET-1 and salt. LysMETB-/- mice displayed an exaggerated hypertensive response to both ET-1 and ANG II. Finally, in patients who received Mφ depleting immunotherapy BP was higher and endothelial function worse than in those receiving non-depleting therapies. CONCLUSION: Mφ and ET-1 may play an important role in BP control and potentially have a critical role as a therapeutic target in hypertension.

Hyperbaric oxygen therapy for cerebral air gas embolism following orthotopic heart transplant: case report.

Air gas embolism (AGE) is a rare complication of cardiac surgery, with high morbidity and mortality. We present a case of suspected AGE following orthotopic heart transplant. The patient received hyperbaric oxygen therapy with near-complete resolution of symptoms at follow-up. This case exemplifies the difficulty in diagnosis of AGE, the considerations involved in the treatment of a critical care patient in a hyperbaric chamber, and utility in treating a patient for AGE even after a delay in diagnosis.

An unusual cause for epigastric pain in pregnancy. Spontaneous uterine rupture with herniation of the amniotic sac in a 33-week primigravida.

A 29-year-old in vitro fertilisation patient presented at 33 weeks of gestation with abdominal pain. An abdominal ultrasound revealed a cystic lesion adjacent to the fundus. During caesarean section, a defect at the fundus was identified with herniation of the amniotic sac through this defect. There were no complications postoperatively and the patient made an unremarkable recovery. With at least one maternal death reported in the most recent confidential enquiry into maternal death, uterine rupture is an obstetric emergency and can have catastrophic outcomes. The incidence of uterine rupture as a result of previous perforation is unclear with little published data and few case reports. Cases of uterine rupture after perforation following hysteroscopic resection of fibroids, uterine septum are well published but the authors found no known previous cases related to laparoscopy. Counselling patients post perforation should include discussion regarding the management of future pregnancies and the risk of uterine rupture.

A pilot outreach physiotherapy and dietetic quality improvement initiative reduces IV antibiotic requirements in children with moderate-severe cystic fibrosis.

BACKGROUND: At our hospital the current model of care for children with moderate-severe CF is focused on intensive inpatient intervention, regular outpatient clinic review and specialist outreach care as required. An alternative model providing more regular physiotherapy and dietetic outreach support, in addition to these specialist services, may be more effective. METHODS: 16 children (4 male; 12 female; mean age 10.9±2.93; range 4-15 years) who required >40days of IV antibiotics in the 12-months pre-intervention were enrolled. Physiotherapy included weekly-supervised exercise sessions, alongside regular review of home physiotherapy regimens. Dietetic management included 1-2 monthly monitoring of growth, appetite, intake and absorption, and nutrition education sessions. RESULTS: There was a 23% reduction in inpatient IV antibiotic requirement and 20% reduction in home IV antibiotic requirement during the intervention year. Cost-benefit analyses showed savings of £113,570. VO(2Peak) increased by 4.9 ml·kg·min(-1) (95%CI 1.01 to 8.71; p=0.02), and 10 m-MSWT distance and increment achieved increased by 229 m (95%CI 109 to 350; p<0.001) and 2 levels (95%CI 1 to 3; p<0.002) respectively. No significant differences in physiological and patient reported outcomes were demonstrated, although there was a possible trend towards improvement in outcomes when compared to the pre-intervention year. CONCLUSION: This pilot programme demonstrated a reduction in IV and admission requirements with a cost benefit in a small group of children with moderate-severe CF. A fully powered clinical trial is now warranted.