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Objective: Elexacaftor/tezacaftor/ivacaftor (E/T/I) has provided life‐changing pharmacotherapy for many people with cystic fibrosis (CF), but conflicting literature exists regarding the effect on mental health. While some reports suggest E/T/I may induce adverse psychiatric symptoms, others report improvements in mental health symptoms. To add to this growing body of knowledge, we retrospectively analyzed depression and anxiety symptoms before and after E/T/I initiation in adults with CF at a single large US CF center. Method: Patient Health Questionnaire‐9 (PHQ‐9) and Generalized Anxiety Disorder‐7 (GAD‐7) scores recorded in a database were studied. Patients with scores collected before and after E/T/I initiation were included. Regression analyses described associations between score changes and age, race, ethnicity, sex, CFTR variant, and prior depression and/or anxiety diagnoses. Secondary analyses examined possible confounding effects of the COVID‐19 pandemic. Results: There was no change in mean GAD‐7 (0.5 ± 5.3, p = 0.41) or PHQ‐9 (−0.02 ± 6.0, p = 0.97) scores following initiation of E/T/I (N = 86). A trend between a prior diagnosis of depression and worsening in PHQ‐9 post‐E/T/I was observed (OR 3.58; p = 0.054). Conclusions: Treatment with E/T/I does not lead to changes in depression or anxiety symptoms at the population level in this single center cohort study. A prior diagnosis of depression trended towards an increased odds of worsening PHQ‐9 scores after E/T/I initiation. [ABSTRACT FROM AUTHOR]

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]

Purpose: To explore the feasibility of measuring ventilation defect percentage (VDP) using 19F MRI during free‐breathing wash‐in of fluorinated gas mixture with postacquisition denoising and to compare these results with those obtained through traditional Cartesian breath‐hold acquisitions. Methods: Eight adults with cystic fibrosis and 5 healthy volunteers completed a single MR session on a Siemens 3T Prisma. 1H Ultrashort‐TE MRI sequences were used for registration and masking, and ventilation images with 19F MRI were obtained while the subjects breathed a normoxic mixture of 79% perfluoropropane and 21% oxygen (O2). 19F MRI was performed during breath holds and while free breathing with one overlapping spiral scan at breath hold for VDP value comparison. The 19F spiral data were denoised using a low‐rank matrix recovery approach. Results: VDP measured using 19F VIBE and 19F spiral images were highly correlated (r = 0.84) at 10 wash‐in breaths. Second‐breath VDPs were also highly correlated (r = 0.88). Denoising greatly increased SNR (pre‐denoising spiral SNR, 2.46 ± 0.21; post‐denoising spiral SNR, 33.91 ± 6.12; and breath‐hold SNR, 17.52 ± 2.08). Conclusion: Free‐breathing 19F lung MRI VDP analysis was feasible and highly correlated with breath‐hold measurements. Free‐breathing methods are expected to increase patient comfort and extend ventilation MRI use to patients who are unable to perform breath holds, including younger subjects and those with more severe lung disease. [ABSTRACT FROM AUTHOR]

Purpose: To quantitatively compare dynamic 19F and single breath hyperpolarized 129Xe MRI for the detection of ventilation abnormalities in subjects with mild cystic fibrosis (CF) lung disease. Methods: Ten participants with stable CF and a baseline FEV1 > 70% completed a single imaging session where dynamic 19F and single breath 129Xe lung ventilation images were acquired on a 3T MRI scanner. Ventilation defect percentages (VDP) values between 19F early‐breath, 19F maximum‐ventilation, 129Xe low‐resolution, and 129Xe high‐resolution images were compared. Dynamic 19F images were used to determine gas wash‐in/out rates in regions of ventilation congruency and mismatch between 129Xe and 19F. Results: VDP values from high‐resolution 129Xe images were greater than from low‐resolution images (P =.001), although these values were significantly correlated (r = 0.68, P =.03). Early‐breath 19F VDP and max‐vent 19F VDP also showed significant correlation (r = 0.75, P =.012), with early‐breath 19F VDP values being significantly greater (P <.001). No correlation in VDP values were detected between either 19F method or high‐res 129Xe images. In addition, the location and volume of ventilation defects were often different when comparing 129Xe and 19F images from the same subject. Areas of ventilation congruence displayed the expected ventilation kinetics, while areas of ventilation mismatch displayed abnormally slow gas wash‐in and wash‐out. Conclusion: In CF subjects, ventilation abnormalities are identified by both 19F and HP 129Xe imaging. However, these ventilation abnormalities are not entirely congruent. 19F and HP 129Xe imaging provide complementary information that enable differentiation of normally ventilated, slowly ventilated, and non‐ventilated regions in the lungs. [ABSTRACT FROM AUTHOR]

Mutation of threonine for isoleucine at codon 73 (I73T) in the human surfactant protein C (hSP-C) gene (SFTPC) accounts for a significant portion of SFTPC mutations associated with interstitial lung disease (ILD). Cell lines stably expressing tagged primary translation product of SP-C isoforms were generated to test the hypothesis that deposition of hSP-CI73T within the endosomal system promotes disruption of a key cellular quality control pathway, macroautophagy. By fluorescence microscopy, wild-type hSP-C (hSP-CWT) colocalized with exogenously expressed human ATP binding cassette class A3 (hABCA3), an indicator of normal trafficking to lysosomal-related organelles. In contrast, hSP-CI73T was dissociated from hABCA3 but colocalized to the plasma membrane as well as the endosomal network. Cells expressing hSP-CI73T exhibited increases in size and number of cytosolic green fluorescent protein/microtubule-associated protein 1 light-chain 3 (LC3) vesicles, some of which colabeled with red fluorescent protein from the gene dsRed/hSP-CI73T. By transmission electron microscopy, hSP-CI73T cells contained abnormally large autophagic vacuoles containing organellar and proteinaceous debris, which phenocopied ultrastructural changes in alveolar type 2 cells in a lung biopsy from a SFTPC I73T patient. Biochemically, hSP-CI73T cells exhibited increased expression of Atg8/LC3, SQSTM1/p62, and Rab7, consistent with a distal block in autophagic vacuole maturation, confirmed by flux studies using bafilomycin A1 and rapamycin. Functionally, hSP-CI73T cells showed an impaired degradative capacity for an aggregation-prone huntingtin-1 reporter substrate. The disruption of autophagy-dependent proteostasis was accompanied by increases in mitochondria biomass and parkin expression coupled with a decrease in mitochondrial membrane potential. We conclude that hSP-CI73T induces an acquired block in macroautophagy-dependent proteostasis and mitophagy, which could contribute to the increased vulnerability of the lung epithelia to second-hit injury as seen in ILD. [ABSTRACT FROM AUTHOR]