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Background: Elexacaftor–tezacaftor–ivacaftor has been shown to be safe and efficacious in people with cystic fibrosis and at least one F508del allele. Our aim was to identify a novel cystic fibrosis transmembrane conductance regulator (CFTR) modulator combination capable of further increasing CFTR-mediated chloride transport, with the potential for once-daily dosing. Methods: We conducted two phase 2 clinical trials to assess the safety and efficacy of a once-daily combination of vanzacaftor–tezacaftor–deutivacaftor in participants with cystic fibrosis who were aged 18 years or older. A phase 2 randomised, double-blind, active-controlled study (VX18-561-101; April 17, 2019, to Aug 20, 2020) was carried out to compare deutivacaftor monotherapy with ivacaftor monotherapy in participants with CFTR gating mutations, following a 4-week ivacaftor monotherapy run-in period. Participants were randomly assigned to receive either ivacaftor 150 mg every 12 h, deutivacaftor 25 mg once daily, deutivacaftor 50 mg once daily, deutivacaftor 150 mg once daily, or deutivacaftor 250 mg once daily in a 1:1:2:2:2 ratio. The primary endpoint was absolute change in ppFEV1 from baseline at week 12. A phase 2 randomised, double-blind, controlled, proof-of-concept study of vanzacaftor–tezacaftor–deutivacaftor (VX18-121-101; April 30, 2019, to Dec 10, 2019) was conducted in participants with cystic fibrosis and heterozygous for F508del and a minimal function mutation (F/MF genotypes) or homozygous for F508del (F/F genotype). Participants with F/MF genotypes were randomly assigned 1:2:2:1 to receive either 5 mg, 10 mg, or 20 mg of vanzacaftor in combination with tezacaftor–deutivacaftor or a triple placebo for 4 weeks, and participants with the F/F genotype were randomly assigned 2:1 to receive either vanzacaftor (20 mg)–tezacaftor–deutivacaftor or tezacaftor–ivacaftor active control for 4 weeks, following a 4-week tezacaftor–ivacaftor run-in period. Primary endpoints for part 1 and part 2 were safety and tolerability and absolute change in ppFEV1 from baseline to day 29. Secondary efficacy endpoints were absolute change from baseline at day 29 in sweat chloride concentrations and Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score. These clinical trials are registered with ClinicalTrials.gov, NCT03911713 and NCT03912233, and are complete. Findings: In study VX18-561-101, participants treated with deutivacaftor 150 mg once daily (n=23) or deutivacaftor 250 mg once daily (n=24) had mean absolute changes in ppFEV1 of 3·1 percentage points (95% CI –0·8 to 7·0) and 2·7 percentage points (–1·0 to 6·5) from baseline at week 12, respectively, versus –0·8 percentage points (–6·2 to 4·7) with ivacaftor 150 mg every 12 h (n=11); the deutivacaftor safety profile was consistent with the established safety profile of ivacaftor 150 mg every 12 h. In study VX18-121-101, participants with F/MF genotypes treated with vanzacaftor (5 mg)–tezacaftor–deutivacaftor (n=9), vanzacaftor (10 mg)–tezacaftor–deutivacaftor (n=19), vanzacaftor (20 mg)–tezacaftor–deutivacaftor (n=20), and placebo (n=10) had mean changes relative to baseline at day 29 in ppFEV1 of 4·6 percentage points (−1·3 to 10·6), 14·2 percentage points (10·0 to 18·4), 9·8 percentage points (5·7 to 13·8), and 1·9 percentage points (−4·1 to 8·0), respectively, in sweat chloride concentration of −42·8 mmol/L (–51·7 to –34·0), −45·8 mmol/L (95% CI –51·9 to –39·7), −49·5 mmol/L (–55·9 to –43·1), and 2·3 mmol/L (−7·0 to 11·6), respectively, and in CFQ-R respiratory domain score of 17·6 points (3·5 to 31·6), 21·2 points (11·9 to 30·6), 29·8 points (21·0 to 38·7), and 3·3 points (−10·1 to 16·6), respectively. Participants with the F/F genotype treated with vanzacaftor (20 mg)–tezacaftor–deutivacaftor (n=18) and tezacaftor–ivacaftor (n=10) had mean changes relative to baseline (taking tezacaftor–ivacaftor) at day 29 in ppFEV1 of 15·9 percentage points (11·3 to 20·6) and −0·1 percentage points (−6·4 to 6·1), respectively, in sweat chloride concentration of −45·5 mmol/L (−49·7 to −41·3) and −2·6 mmol/L (−8·2 to 3·1), respectively, and in CFQ-R respiratory domain score of 19·4 points (95% CI 10·5 to 28·3) and −5·0 points (−16·9 to 7·0), respectively. The most common adverse events overall were cough, increased sputum, and headache. One participant in the vanzacaftor–tezacaftor–deutivacaftor group had a serious adverse event of infective pulmonary exacerbation and another participant had a serious rash event that led to treatment discontinuation. For most participants, adverse events were mild or moderate in severity. Interpretation: Once-daily dosing with vanzacaftor–tezacaftor–deutivacaftor was safe and well tolerated and improved lung function, respiratory symptoms, and CFTR function. These results support the continued investigation of vanzacaftor–tezacaftor–deutivacaftor in phase 3 clinical trials compared with elexacaftor–tezacaftor–ivacaftor. Funding: Vertex Pharmaceuticals.

Background: Cystic Fibrosis is the most common autosomal recessive genetic condition in the Caucasian population. Oral health in adults with Cystic Fibrosis is an area lacking in research, due to their historic low life expectancy. The age profile of people with Cystic Fibrosis (CF) is increasing, due in part to improved therapies. Further study is needed in order to ascertain their dental needs and improve provision of care to these medically vulnerable individuals.Methods: A cross sectional survey was carried out. A structured, anonymous online questionnaire, with both quantitative and qualitative aspects, was used to obtain information regarding their feelings towards dentists and dental appointments. The final version of the questionnaire was based on a collaborative effort between researchers at Cork University Dental School and Hospital and Cystic Fibrosis patient advocates from Cystic Fibrosis Ireland. The inclusion criteria were people over the age of 18 years with a diagnosis of CF. Participants were recruited via CF Ireland’s mailing list and social media channels. The quantitative portion of the questionnaire underwent statistical analysis using IBM SPSS. The qualitative portion underwent inductive thematic analysis.Results: A total of 71 adults with CF responded to the survey. 54.9% of respondents were unhappy with their teeth. 63.4% felt that CF had an impact on oral health. 33.8% were anxious about attending their dentist. 54.9% felt that dentists should be part of the multidisciplinary team. Respondents believed that CF has impacted on their oral health due to the medications and dietary requirements involved, as well as tiredness and other side effects of CF. Some reasons for being anxious about attending the dentist involve cross infection concerns, issues with the dentist, with tolerating treatment, and with the teeth themselves. They wanted dentists to be aware of the practicalities of dental treatment for people with CF, especially their discomfort with lying back. They also want the dentist to be aware of the impact that their medication, treatment and diet has on their oral health.Conclusions: Over a third of PWCF reported anxiety about attending the dentist. Reasons for this included fear, embarrassment, cross infection concerns and problems with treatment, especially being in the supine position. PWCF want dentists to be aware of the impact that CF can have upon dental treatment and oral health care.

To evaluate the dental attendance, oral hygiene habits, and dietary habits of adults with Cystic Fibrosis in the Republic of Ireland.A cross-sectional study was carried out using a structured anonymous questionnaire. A total of 71 adults with Cystic Fibrosis responded. While the majority of respondents (66.2%) saw a dentist in the preceding year, 15.5% had not attended a dentist for over 2 years. Smoking and alcohol consumption levels were low. 63.4% brushed twice or more daily, with 70.4% using a Fluoride containing toothpaste. 62% did not use any interdental cleaning aid. 5.6% changed their toothbrush at least once a month, but for 22.5% it was over 6 months. 70.4% used fluoride toothpaste. 38% snacked three or more times daily and 29.5% consumed fizzy drinks at least once daily.The alcohol and tobacco consumption in this study group was low. However, a large proportion frequently consumed sugar-rich foods, and they did not change their toothbrush, brush their teeth, or attend the dentist as regularly as is advised. More targeted advice may be necessary to improve the oral hygiene habits of adults with Cystic Fibrosis.

Emily O’Reilly,1 Deborah Casey,1 Hisham Ibrahim,1 Alice McGrath,1 Tomás McHugh,1 Punitha Vairamani,1 Jill Murphy,1 Barry Plant,1,2 Desmond M Murphy1,2 1Department of Respiratory Medicine, Cork University Hospital, Cork, Ireland; 2Health Research Board Clinical Research Facility, University College Cork, Cork, IrelandCorrespondence: Desmond M Murphy, Department of Respiratory Medicine, Cork University Hospital, Wilton, Cork, Ireland, Email desmond.murphy@hse.ie

Schools in Australia and internationally are responding to calls to offer new and innovative learning opportunities in STEM. STEM stands for Science, Mathematics, Engineering and Mathematics, but when amalgamated into the acronym ‘STEM’ can potentially mean more than the sum of the four parts. In choosing how to respond to the STEM ‘push’, schools must first navigate through the many ‘versions’ of STEM emerging within the education community, and then face the task of upskilling teachers in content and language, teaching approaches, and new technology and equipment. Professional development of teachers plays an important part in assisting teachers and schools in this period of innovation and change. This chapter describes one such professional development project where teachers from ten schools in regional Victoria, Australia, were supported in developing new knowledge, language, pedagogy, and curriculum to support their development of a ‘STEM vision’ for their schools. The activities developed by these schools are outlined to illustrate that they each have taken a different approach to STEM, with case studies showing how these activities were developed. The factors critical to the success of the program are outlined, which have implications for a policy response, as well as challenges that may threaten the sustainability of such initiatives.