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Trikafta, a triple-combination drug, consisting of folding correctors VX-661 (tezacaftor), VX-445 (elexacaftor) and the gating potentiator VX-770 (ivacaftor) provided unprecedented clinical benefits for patients with the most common cystic fibrosis (CF) mutation, F508del. Trikafta indications were recently expanded to additional 177 mutations in the CF transmembrane conductance regulator (CFTR). To minimize life-long pharmacological and financial burden of drug administration, if possible, we determined the necessary and sufficient modulator combination that can achieve maximal benefit in preclinical setting for selected mutants. To this end, the biochemical and functional rescue of single corrector-responsive rare mutants were investigated in a bronchial epithelial cell line and patient-derived human primary nasal epithelia (HNE), respectively. The plasma membrane density of P67L-, L206W- or S549R-CFTR corrected by VX-661 or other type I correctors was moderately increased by VX-445. Short-circuit current measurements of HNE, however, uncovered that correction comparable to Trikafta was achieved for S549R-CFTR by VX-661 + VX-770 and for P67L- and L206W-CFTR by the VX-661 + VX-445 combination. Thus, introduction of a third modulator may not provide additional benefit for patients with a subset of rare CFTR missense mutations. These results also underscore that HNE, as a precision medicine model, enable the optimization of mutation-specific modulator combinations to maximize their efficacy and minimize life-long drug exposure of CF patients.

Purpose Cystic fibrosis (CF), caused by pathogenic variants in the CF transmembrane conductance regulator ( CFTR ), affects multiple organs including the exocrine pancreas, which is a causal contributor to cystic fibrosis–related diabetes (CFRD). Untreated CFRD causes increased CF-related mortality whereas early detection can improve outcomes. Methods Using genetic and easily accessible clinical measures available at birth, we constructed a CFRD prediction model using the Canadian CF Gene Modifier Study (CGS; n  = 1,958) and validated it in the French CF Gene Modifier Study (FGMS; n  = 1,003). We investigated genetic variants shown to associate with CF disease severity across multiple organs in genome-wide association studies. Results The strongest predictors included sex, CFTR severity score, and several genetic variants including one annotated to PRSS1 , which encodes cationic trypsinogen. The final model defined in the CGS shows excellent agreement when validated on the FGMS, and the risk classifier shows slightly better performance at predicting CFRD risk later in life in both studies. Conclusion We demonstrated clinical utility by comparing CFRD prevalence rates between the top 10% of individuals with the highest risk and the bottom 10% with the lowest risk. A web-based application was developed to provide practitioners with patient-specific CFRD risk to guide CFRD monitoring and treatment.

Background: Emergency department (ED) visits are critical events for older adults, but little is known regarding their experiences, particularly about their physical needs, the involvement of accompanying family members, and the transition back to the community. Objective: To explore experiences of an ED visit among patients aged 75 and older. Methods: In a mixed-methods study, a cohort of patients aged 75 and older (or a family member) discharged from the ED back to the community was recruited from 4 urban EDs. A week following discharge, structured telephone interviews supplemented with open-ended questions were conducted. A subsample (76 patients, 32 family members) was purposefully selected. Verbatim transcripts of responses to the open-ended questions were thematically analyzed. Results: Experiences related to physical needs included comfort, equipment supporting mobility and autonomy, help when needed, and access to drink and food. Family members required opportunities to provide patient support and greater involvement in their care. At discharge, patients/families required adequate discharge education, resolution of their health problem, information on medications, and greater certainty about planned follow-up medical and home care services. Conclusions: Our findings suggest several areas that could be targeted to improve patient and family perceptions of the care at an ED visit.