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Objectives: The 22‐question SinoNasal Outcome Test (SNOT‐22) assesses chronic rhinosinusitis (CRS) severity. We aimed to identify predictors of SNOT‐22 score improvement following highly effective modulator therapy (HEMT) initiation and to corroborate the SNOT‐22 minimal clinically important difference (MCID) in adults with cystic fibrosis (CF). Methods: Prospective observational data was pooled from four studies across 10 US centers investigating people with CF (PwCF) and CRS. Three studies evaluated HEMT's impact on CRS. For participants enrolled prior to HEMT initiation, SNOT‐22 scores were obtained at baseline and after 3–6 months of HEMT. Multivariate regression identified predictors of improvement. Cronbach's alpha and four distribution‐based methods were used to assess internal consistency and calculate the MCID of the SNOT‐22. Results: A total of 184 PwCF participated with mean baseline SNOT‐22 scores ranging from 18.1 to 56.7. Cronbach's alpha was ≥0.90 across sites. Participants at sites with pre‐ and post‐HEMT data reported improvement in SNOT‐22 scores after initiating HEMT (all p < 0.05). Worse baseline SNOT‐22 score (odds ratio (OR): 1.05, p < 0.001, 95% CI: 1.02–1.08), F508del homozygosity (OR: 4.30, p = 0.040, 95% CI: 1.14–18.99), and absence of prior modulator therapy (OR: 4.99, p = 0.017, 95% CI: 1.39–20.11) were associated with greater SNOT‐22 improvement. The mean MCID calculated via distribution‐based methods was 8.5. Conclusion: Worse baseline sinonasal symptoms, F508del homozygosity, and absence of prior modulator therapy predicted greater improvement after HEMT initiation. The mean MCID for SNOT‐22 in PwCF is 8.5 points, similar to non‐CF individuals with CRS, and provides a threshold specifically for PwCF. The SNOT‐22 has strong internal consistency in PwCF. Level of Evidence: 3 Laryngoscope, 134:3965–3973, 2024 [ABSTRACT FROM AUTHOR]

Objectives: Appropriate management of chronic rhinosinusitis (CRS) among patients with cystic fibrosis (CF) is important in improving quality of life. Otolaryngologists play a critical role in reducing CRS symptom burden. This study seeks to evaluate the role of patient-reported quality-of-life measures in guiding interventions for CF-related sinus disease. Methods: We performed a prospective, cross-sectional study of 105 patients presenting to a CF-accredited clinic between July and September 2018. Demographic data and sinus surgery history were collected, in addition to Sino-Nasal Outcome Test (SNOT-22) and Questionnaire of Olfactory Disorders (QOD-NS) scores. Statistical analysis was conducted using correlation and non-parametric Mann-Whitney U tests. Results: Baseline well-care visits accounted for 71.4% of all clinical evaluations. Prior otolaryngology intervention was noted in 69 (66%) patients, where the majority of these patients (63/69; 91%) underwent endoscopic sinus surgery (ESS). Patients with a history of otolaryngology intervention had an average SNOT-22 score of 33.2 (SD = 20.6) compared to 24.9 (SD = 18.5) for patients without prior intervention (P =.048). The average QOD-NS score was 5.5 (SD = 6.4) among patients referred to otolaryngologists and 3.1 (SD = 5.7) for non-referred patients (P =.012). SNOT-22 and QOD-NS scores were modestly correlated (R of.43). Conclusion: CF patients with symptoms resulting in worse quality-of-life assessments were more likely to have established coordinated care with an otolaryngologist. Further validation of the utility of SNOT-22 and QOD-NS questionnaires as care coordination metrics is necessary in the CF population. [ABSTRACT FROM AUTHOR]

Our radiotherapy department is situated onsite at a university-affiliated hospital where medical students undertake clinical rotations. However, no formal programme for attachments to the radiation oncology service was previously in place. Student experience was limited to occasional classroom-based lectures and sporadic contact with cancer patients while rotating through other clinical services. Under-exposure to radiation oncology (RO) (and oncology generally) during medical school is common. A 2016 survey of medical students at two US universities found that only 4% of third year and 7% of fourth year students completed an RO rotation (Osvarak et al 2016). And 47% of Australian and New Zealand medical students recently reported that RO was not incorporated into their curriculum at all (Bravery et al 2020). We identified improving medical student involvement as a priority for our department. We collaborated with tutors at the University to arrange for medical students to have allocated RO rotations during their clinical attachments at the hospital. Agreed learning objectives fitted into three categories: -fundamental clinical skills in history taking and physical examination -care of cancer patients -an introduction to RO and its role in the care of cancer patients. A multidisciplinary effort with involvement of consultant and trainee radiation oncologists, radiation therapists, nurses, and university representatives allowed us to develop a programme to deliver these learning objectives. The programme began in January 2022. One radiation oncologist takes overall responsibility for day-to-day operations and acts as the primary point of contact for the students and other staff members in case of any issues. Students receive tutorials on oncological emergencies and are involved in academic sessions in the department. They are supervised as they spend time contouring organs at risk and clinical targets and also have dedicated sessions with radiation therapists where they observe the delivery of external beam radiotherapy. Clinical experience is gained via attendance at outpatient clinics and on the inpatient oncology ward. Feedback on history taking and clinical examination is provided via tutorials with radiation oncologists and trainees. Students provided feedback which indicated that they had enjoyed their experience of the specialty and found the rotation beneficial. The rotation has been well-received by students and the university tutors. The primary goal of incorporating RO rotations into the medical school curriculum was successful and these attachments will continue in future. Involvement of relevant stakeholders within the department and the university contributed to the successful implantation. [ABSTRACT FROM AUTHOR]

Background: The goal of cystic fibrosis transmembrane conductance regulator (CFTR) modulators is to reach normal CFTR function in people with cystic fibrosis. Vanzacaftor-tezacaftor-deutivacaftor restored CFTR function in vitro and in phase 2 trials in participants aged 18 years and older resulting in improvements in CFTR function, as measured by sweat chloride concentrations and lung function as measured by spirometry. We aimed to evaluate the efficacy and safety of vanzacaftor-tezacaftor-deutivacaftor compared with standard of care elexacaftor-tezacaftor-ivacaftor in individuals with cystic fibrosis aged 12 years and older., Methods: In two randomised, active-controlled, double-blind, phase 3 trials, individuals aged 12 years and older with stable cystic fibrosis with F508del-minimal function (SKYLINE Trial VX20-121-102) or with F508del-F508del, F508del-residual function, F508del-gating, or elexacaftor-tezacaftor-ivacaftor-responsive-non-F508del genotypes (SKYLINE Trial VX20-121-103) were enrolled at 126 and 159 international sites, respectively. Eligible individuals were entered into a 4-week run-in period, during which they received elexacaftor (200 mg once daily), tezacaftor (100 mg once daily), and ivacaftor (150 mg once every 12 h) as two fixed-dose combination tablets in the morning and one ivacaftor tablet in the evening. They were then randomly assigned (1:1) to either elexacaftor (200 mg once daily), tezacaftor (100 mg once daily), and ivacaftor (150 mg once every 12 h) as two fixed-dose combination tablets in the morning and one ivacaftor tablet in the evening, or vanzacaftor (20 mg once daily), tezacaftor (100 mg once daily), and deutivacaftor (250 mg once daily) as two fixed-dose combination tablets in the morning, for the 52-week treatment period. All participants received matching placebo tablets to maintain the treatment blinding. Randomisation was done using an interactive web-response system and stratified by age, FEV 1 % predicted, sweat chloride concentration, and previous CFTR modulator use, and also by genotype for Trial VX20-121-103. The primary endpoint for both trials was absolute change in FEV 1 % predicted from baseline (most recent value before treatment on day 1) through week 24 (with non-inferiority of vanzacaftor-tezacaftor-deutivacaftor shown if the lower bound of the 95% CI for the primary endpoint was -3·0 or higher). Efficacy was assessed in all participants with the intended CFTR genotype who were randomly assigned to treatment and received at least one dose of study treatment during the treatment period. Safety was assessed in all participants who received at least one dose of study drug during the treatment period. These trials are registered with ClinicalTrials.gov, NCT05033080 (Trial VX20-121-102) and NCT05076149 (Trial VX20-121-103), and are now complete., Findings: In Trial VX20-121-102 between Sept 14, 2021, and Oct 18, 2022, 488 individuals were screened, of whom 435 entered the 4-week run-in period, and subsequently 398 were randomly assigned and received at least one dose of elexacaftor-tezacaftor-ivacaftor (n=202) or vanzacaftor-tezacaftor-deutivacaftor (n=196). Median age was 31·0 years (IQR 22·6-38·5), 163 (41%) of 398 participants were female, 235 (59%) were male, and 388 (97%) were White. In Trial VX20-121-103, between Oct 27, 2021, and Oct 26, 2022, 699 individuals were screened, of whom 597 entered the 4-week run-in period, and subsequently 573 participants were randomly assigned and received at least one dose of elexacaftor-tezacaftor-ivacaftor (n=289) or vanzacaftor-tezacaftor-deutivacaftor (n=284). Median age was 33·1 years (IQR 24·5-42·2), 280 (49%) of 573 participants were female, 293 (51%) were male, and 532 (93%) were White. The absolute change in least squares mean FEV 1 % predicted from baseline through week 24 for Trial VX20-121-102 was 0·5 (SE 0·3) percentage points in the vanzacaftor-tezacaftor-deutivacaftor group versus 0·3 (0·3) percentage points in the elexacaftor-tezacaftor-ivacaftor group (least squares mean treatment difference of 0·2 percentage points [95% CI -0·7 to 1·1]; p<0·0001), and for Trial VX20-121-103, was 0·2 (SE 0·3) percentage points in the vanzacaftor-tezacaftor-deutivacaftor group versus 0·0 (0·2) percentage points in the elexacaftor-tezacaftor-ivacaftor group (least squares mean treatment difference 0·2 percentage points [95% CI -0·5 to 0·9]; p<0·0001). Most adverse events were mild or moderate, with the most common being infective pulmonary exacerbation (133 [28%] of 480 participants in the pooled vanzacaftor-tezacaftor-deutivacaftor group vs 158 [32%] of 491 in the pooled elexacaftor-tezacaftor-ivacaftor group), cough (108 [23%] vs 101 [21%]), COVID-19 (107 [22%] vs 127 [26%]), and nasopharyngitis (102 [21%] vs 95 [19%])., Interpretation: Vanzacaftor-tezacaftor-deutivacaftor is non-inferior to elexacaftor-tezacaftor-ivacaftor in terms of FEV 1 % predicted, and is safe and well tolerated. Once daily dosing with vanzacaftor-tezacaftor-deutivacaftor reduces treatment burden, potentially improving adherence, compared with the twice daily regimen of the current standard of care. The restoration of CFTR function and the potential variants treated are also considerations that should be compared with currently available CFTR modulators., Funding: Vertex Pharmaceuticals., Competing Interests: Declaration of interests TF, PM, PRS, NN, RZ, HM, NA, and AL are employees of Vertex Pharmaceuticals and own stock or stock options in that company. FV reports grants from HIT-CF Project, Research Foundation Flanders Strategic Basic Research, University KU Leuven Internal Funds, Cystic Fibrosis Foundation, and King Baudouin Foundation; a service agreement with Ziphius vaccines; a consulting agreement with Vertex Pharmaceuticals; and financial support from Viatris and Mylan. DP reports grants, consulting fees, and speaker fees from Vertex Pharmaceuticals. RWL reports grants from Vertex Pharmaceuticals and Cystic Fibrosis Foundation, and consulting fees and travel support from Vertex Pharmaceuticals. AT reports support from Vertex Pharmaceuticals and Cystic Fibrosis Foundation, travel support from Cystic Fibrosis Foundation, and is a board member of the local Cystic Fibrosis Foundation chapter. TK reports speaker fees and travel support from Vertex Pharmaceuticals. JM reports grants from Cystic Fibrosis Foundation, 4D Molecular Therapeutics, Boehringer Ingelheim, Clarametyx Biosciences, and Spirovant Pharmaceuticals. ATB reports grants from Vertex Pharmaceuticals and Cystic Fibrosis Foundation. MO reports speaker fees and travel support from Arrowhead Pharmaceuticals, and speaker fees from Vertex Pharmaceuticals. SS reports grants, consulting fees, and speaker fees from Vertex Pharmaceuticals, Boehringer Ingelheim, and Insmed; and grants and speaker fees from AstraZeneca. BR reports grants from the US National Institutes of Health (NIH) and the Cystic Fibrosis Foundation, consulting fees from Vertex Pharmaceuticals, Cystetic Medicines, and Sionna Therapeutics; and participation on a data safety monitoring or advisory board for the NIH. MAM reports grants from the German Research Foundation, German Ministry for Education and Research, German Innovation Fund, Vertex Pharmaceuticals, and Boehringer Ingelheim; consulting fees from AbbVie, Boehringer Ingelheim, Enterprise Therapeutics, Kither Biotec, Prieris, Recode, Splisense, and Vertex Pharmaceuticals; speaker fees from Vertex Pharmaceuticals; travel support from Boehringer Ingelheim and Vertex Pharmaceuticals; participation on a data safety monitoring board or advisory board for AbbVie, Boehringer Ingelheim, Enterprise Therapeutics, Kither Biotec, Pari, and Vertex Pharmaceuticals; and is a Fellow of the European Respiratory Society. JLT-C reports grants and consulting fees from Vertex Pharmaceuticals and 4D Molecular Therapeutics; a grant from Eloxx; participation on a data safety monitoring board or advisory board for AbbVie; and serving as the adult patient care representative for the Cystic Fibrosis Foundation Board of Trustees, on the Cystic Fibrosis Foundation Clinical Research Executive Committee, as immediate past Chair of the Cystic Fibrosis TDN's Sexual Health, Reproduction and Gender Research Working Group, as Co-chair of the Health Equity Team Science Awards study section and on the Racial Justice Working Group, on the scientific advisory board for Emily's Entourage, on the American Thoracic Society Respiratory Health Awards and Scientific Grant Review Committees, as Chair-elect of the International Conference Committee, as Associate Editor for the Journal of Cystic Fibrosis, as a member of the International Advisory Board for The Lancet Respiratory Medicine, and on the Clinical Trials Review study section for the NIH. EFM reports grants and speaker fees from Vertex Pharmaceuticals, travel support from Menarini, and participation on a data safety monitoring board or advisory board for Cystic Fibrosis Storm Clinical Trial, Vertex Pharmaceuticals, Janssen, AbbVie, Insmed, and Enterprise Therapeutics. ET reports grants from St Michael's Hospital and consulting fees, speaker fees, and travel support from Vertex Pharmaceuticals. AH reports grants from Cystic Fibrosis Trust, Cystic Fibrosis Foundation, and Vertex Pharmaceuticals; consulting and speaker fees from Vertex Pharmaceuticals; and serves as the Chair of the Cystic Fibrosis Trust Clinical Trials Accelerator Platform and Chair of the National Institute for Health and Care Research (NIHR) Respiratory Translational Research Collaboration. LMY and CK declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

The approval of aztreonam lysine for inhalation solution (AZLI) raised concerns that additional antibiotic exposure would potentially affect the susceptibility profiles of Pseudomonas aeruginosa isolates from cystic fibrosis (CF) patients. This 5-year, prospective, observational study tracked susceptibility changes and clinical outcomes in CF patients in the United States with chronic P. aeruginosa infection. Sputum cultures were collected annually (2011 to 2016). The primary study endpoint was the proportion of subjects whose least susceptible P. aeruginosa isolate had an aztreonam MIC that was >8 μg/ml (parenteral breakpoint) and increased ≥4-fold compared with the least susceptible isolate from the previous year. Annualized data for pulmonary exacerbations, hospitalizations, and percent of predicted forced expiratory volume in 1 s (FEV 1 % predicted) were obtained from the CF Foundation Patient Registry and compared between subjects meeting and those not meeting the primary endpoint. A total of 510 subjects were enrolled; 334 (65%) completed the study. A consistent proportion of evaluable subjects (13 to 22%) met the primary endpoint each year, and AZLI use during the previous 12 months was not associated with meeting the primary endpoint. While the annual declines in lung function were comparable for subjects meeting and those not meeting the primary endpoint, more pulmonary exacerbations and hospitalizations were experienced by those who met it. The aztreonam susceptibility of P. aeruginosa remained consistent during the 5-year study. The relationship between P. aeruginosa isolate susceptibilities and clinical outcomes is complex; reduced susceptibility was not associated with an accelerated decline in lung function but was associated with more exacerbations and hospitalizations, likely reflecting increased overall antibiotic exposure. (This study has been registered at ClinicalTrials.gov under identifier NCT01375036.)., (Copyright © 2021 Keating et al.)