Long-term outcomes of early exposure to repeated general anaesthesia in children with cystic fibrosis (CF-GAIN): a multicentre, open-label, randomised controlled phase 4 trial.

BACKGROUND: Long-term effects of early, recurrent human exposure to general anaesthesia remain unknown. The Australasian Cystic Fibrosis Bronchoalveolar Lavage (ACFBAL) trial provided an opportunity to examine this issue in children randomly assigned in infancy to either repeated bronchoalveolar-lavage (BAL)-directed therapy with general anaesthesia or standard care with no planned lavages up to 5 years of age when all children received BAL-directed therapy under general anaesthesia. METHODS: This multicentre, randomised, open-label phase 4 trial (CF-GAIN) used the original ACFBAL trial randomisation at 3·6 months (SD 1·6) to BAL-directed therapy or standard-care groups to assess the impact of general anaesthesia exposures over early childhood. Children who completed the ACFBAL trial, with a mean age of 5·1 (SD 0·18) years, received standardised neurobehavioural and health-related-quality-of-life assessment and brain MRI scans between Oct 8, 2013, and June 30, 2017, at a mean age of 12·8 (SD 1·7) years at three hospitals in Australia and one hospital in New Zealand. The primary outcome was a composite score of performance on a standardised, computer-based assessment of child attention, processing speed, and response inhibition skills (Conners Continuous Performance test, second edition). Secondary outcomes included intellectual function, other neurobehavioural measures, and brain imaging as an exploratory outcome. The trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN 12613000057785) and is completed. FINDINGS: At 2 years, the BAL-directed therapy group (n=52) and standard-care group (n=45) had a median of 2·0 (IQR 1·0-3·0) and 0·0 (0·0-0·0) exposures, respectively. At completion of the ACFBAL trial, the BAL-directed therapy group had a median of 6·0 (4·0-9·5) exposures and the standard-care group 2·0 (1·0-4·0) exposures. At CF-GAIN completion, the BAL-directed therapy group had a median of 10·0 (IQR 6·5-14·5) exposures and the standard-care group 4·0 (3·0-7·0) exposures. Cumulative general anaesthesia exposure time was not prospectively collected but, for those with complete cumulative exposure time data to the end of the ACFBAL trial, the median cumulative exposure time for the BAL-directed therapy group (n=29) was 180 (IQR 140-285) min and for the standard-care group (n=32) was 48 (30-122) min. The mean Conners Continuous Performance test, second edition composite score was 51 (SD 8·1) in BAL-directed therapy group and 53 (8·8) in the standard-care group; difference -1·7 (95% CI -5·2 to 1·7; p=0·32) with similar performance on other neurobehavioural measures, including measures of executive function, intellectual quotient scores, and brain imaging. INTERPRETATION: Our findings suggest that repeated general anaesthesia exposure in young children with cystic fibrosis is not related to functional impairment in attention, intellectual quotient, executive function, or brain structure compared with a group with fewer and shorter cumulative anaesthesia durations. FUNDING: National Health and Medical Research Council Australia, Queensland Government Health Service and Clinical Innovation Fellowship, and the Children's Hospital Foundation Queensland.

Costs of Severe to Profound Hearing Loss & Cost Savings of Cochlear Implants.

OBJECTIVE: To estimate costs of severe to profound hearing loss, including costs and cost-savings associated with cochlear implantation. METHODS: Data was obtained from the National Health Interview Survey, the National Health and Nutrition Examination Survey and national Medicare rates. We used continuous time state transition models with individual patient simulations to estimate the costs of severe to profound hearing loss (SPHL) across the lifespan. The model included four states, normal hearing, severe to profound hearing loss, cochlear implantation, and death. RESULTS: The estimated lifetime cost of an individual born with SPHL is $489,274 [377,518; 616,519]. Costs are lower for those who received a cochlear implant before 18 months of age $390,931 [311,976; 471,475], compared to those who are not implanted $608,167 [442,544; 791,719]. For individuals with a later onset of hearing loss (60 years old) lifetime costs were $154,536 [7,093; 302,936]. The annual societal costs for the US population were estimated to be $37 [8; 187] billion. CONCLUSIONS: SPHL is a costly condition, with the primary driver being lost productivity. Medical costs were higher for cochlear implantation, however, the higher income earnings offset the higher medical costs. Overall, early implantation substantially reduced lifetime costs. Access to hearing health care and technology is critical given the documented benefits for language, education, and quality of life. Government and insurance policies should be modified to allow for equal access and coverage for hearing technology, which will ultimately reduce lifetime and societal costs. LEVELS OF EVIDENCE: N/A The current study used existing nationally representative datasets. Thus, these levels of evidence do not apply. Laryngoscope, 134:4358-4365, 2024.

Airway inflammation accelerates pulmonary exacerbations in cystic fibrosis.

Airway inflammation underlies cystic fibrosis (CF) pulmonary exacerbations. In a prospective multicenter study of randomly selected, clinically stable adolescents and adults, we assessed relationships between 24 inflammation-associated molecules and the future occurrence of CF pulmonary exacerbation using proportional hazards models. We explored relationships for potential confounding or mediation by clinical factors and assessed sensitivities to treatments including CF transmembrane regulator (CFTR) protein synthesis modulators. Results from 114 participants, including seven on ivacaftor or lumacaftor-ivacaftor, representative of the US CF population during the study period, identified 10 biomarkers associated with future exacerbations mediated by percent predicted forced expiratory volume in 1 s. The findings were not sensitive to anti-inflammatory, antibiotic, and CFTR modulator treatments. The analyses suggest that combination treatments addressing RAGE-axis inflammation, protease-mediated injury, and oxidative stress might prevent pulmonary exacerbations. Our work may apply to other airway inflammatory diseases such as bronchiectasis and the acute respiratory distress syndrome.

Psychometric performance of the CFQ-R-8D compared to the EQ-5D-3L and SF-6D in people with cystic fibrosis.

OBJECTIVE: This study aimed to compare the psychometric performance of the Cystic Fibrosis Questionnaire-Revised-8 Dimensions (CFQ-R-8D), a new, condition-specific, preference-based measure, with that of generic preference-based measures EQ-5D-3L and Short Form 6 dimensions (SF-6D). METHODS: Data from three trials of participants with CF aged ≥ 14 years who completed the CFQ-R and EQ-5D-3L or SF-6D were used. Analyses were undertaken to evaluate convergent validity based on correlations with CFQ-R domain scores. Known-group validity was assessed based on percent predicted forced expiratory volume in one second and pulmonary exacerbations. Responsiveness was based on correlation of change and sensitivity to change based on change in symptom severity. Effect sizes and standardized response means were estimated. RESULTS: CFQ-R-8D utilities and dimensions were strongly correlated with most of the overlapping CFQ-R domain scores (ρ > 0.5); EQ-5D-3L and SF-6D utilities and dimensions had moderate (ρ > 0.3) to strong correlations in dimensions capturing similar concepts. All measures showed evidence of known-group validity (P < 0.05). Change correlations were strong for CFQ-R-8D utilities and dimensions and CFQ-R, but they were moderate for SF-6D and mostly weak ((ρ > 0.1) for EQ-5D-3L. The SF-6D had the largest mean change over time and effect sizes, followed by CFQ-R-8D and then EQ-5D-3L. Neither CFQ-R-8D or SF-6D utility scores had ceiling effects (< 9% responses in full health) compared with those of EQ-5D-3L (61-62%). In participants classified as being in full health by EQ-5D-3L, CFQ-R-8D captured CF-specific health problems, particularly cough, abdominal pain, and breathing difficulty. CONCLUSIONS: The CFQ-R-8D reflected known-group differences and changes over time with stronger evidence of good psychometric performance than EQ-5D-3L and similar evidence as SF-6D. Additionally, the CFQ-R-8D captured more condition-specific symptoms than EQ-5D-3L or SF-6D, which are important determinants of health-related quality of life for people with CF.

Longitudinal Effects of Elexacaftor/Tezacaftor/Ivacaftor: Multidimensional Assessment of Neuropsychological Side Effects and Physical and Mental Health Outcomes in Adolescents and Adults.

BACKGROUND: Italy initiated elexacaftor/tezacaftor/ivacaftor (ETI) for people with cystic fibrosis (pwCF) in July 2021. It has led to dramatic improvements in lung function, BMI, sweat chloride, and respiratory symptoms. However, few data are available on side effects or effects on a broad range of outcomes. RESEARCH QUESTION: How does ETI affect mental health, cognitive processing, neuropsychological side effects, GI symptoms, and health-related quality of life over time? STUDY DESIGN AND METHODS: This was a prospective, "real-world" longitudinal study. Participants were recruited consecutively and evaluated at initiation (T0) and after 1 month, 3 months, and 6 months of starting treatment. Assessments included depression (nine-item Patient Health Questionnaire), anxiety (seven-item Generalized Anxiety Disorder), cognition (Symbol Digit Modalities Test), GI Symptom Tracker, and health-related quality of life (Cystic Fibrosis Questionnaire-Revised). Based on literature, an ad hoc questionnaire was developed to assess side effects: insomnia, headache, memory problems, "brain fog," and concentration problems. Following descriptive analyses, longitudinal data were analyzed by using mixed models for repeated measures, controlling for age and sex when appropriate. RESULTS: Ninety-two consecutive pwCF (female/male, 46/46; mean age, 25.4 years) participated. FEV1 increased initially and then remained stable. BMI also increased significantly from T0 to 6 months (P < .01). Depression improved from T0 to 1 month (P < .001); however, no changes in anxiety were found. Cognitive processing improved from T0 to subsequent assessments. Positive changes were reported on the GI Symptom Tracker for stools and adherence challenges, although no changes were found for abdominal pain and digestion. Side effects occurred in 10% to 29%, with no reduction over time; insomnia increased significantly across time. Female participants reported more side effects than male participants (ie, insomnia, headache, concentration problems, brain fog). INTERPRETATION: This prospective study evaluated the effects of ETI using multiple measures. Significant improvements were found in many domains; however, side effects were reported by a substantial proportion of pwCF, with no improvements over time. Female participants reported more side effects than male participants. pwCF should be followed up systematically to assess the frequency of side effects after starting this new modulator.

Development and validation of a short form psychometric tool assessing the caregiving Challenge of Living with Cystic Fibrosis (CLCF-SF) in a child.

OBJECTIVE: Caring for a child with cystic fibrosis (CF) is a rigorous daily commitment for caregivers and treatment burden is a major concern. We aimed to develop and validate a short form version of a 46-item tool assessing the Challenge of Living with Cystic Fibrosis (CLCF) for clinical or research use. DESIGN: A novel genetic algorithm based on 'evolving' a subset of items from a pre-specified set of criteria, was applied to optimise the tool, using data from 135 families. MAIN OUTCOME MEASURES: Internal reliability and validity were assessed; the latter compared scores to validated tests of parental well-being, markers of treatment burden, and disease severity. RESULTS: The 15-item CLCF-SF demonstrated very good internal consistency [Cronbach's alpha 0.82 (95%CI 0.78-0.87)]. Scores for convergent validity correlated with the Beck Depression Inventory (Rho = 0.48), State Trait Anxiety Inventory (STAI-State, Rho = 0.41; STAI-Trait, Rho = 0.43), Cystic Fibrosis Questionnaire-Revised, lung function (Rho = -0.37), caregiver treatment management (r = 0.48) and child treatment management (r = 0.45), and discriminated between unwell and well children with CF (Mean Difference 5.5, 95%CI 2.5-8.5, p < 0.001), and recent or no hospital admission (MD 3.6, 95%CI 0.25-6.95, p = 0.039). CONCLUSION: The CLCF-SF provides a robust 15-item tool for assessing the challenge of living with a child with CF.

Cochlear Implantation and Educational and Quality-of-Life Outcomes in Adolescence.

Importance: Cochlear implants (CIs) have been shown to be effective in improving auditory skills and speech and language development. However, less is known about the long-term outcomes of CIs on educational functioning or quality of life. Objective: To evaluate long-term educational outcomes and quality of life in adolescents over 13 years postimplantation. Design, Setting, and Participants: This longitudinal cohort study included 188 children with bilateral severe to profound hearing loss with CIs from the Childhood Development After Cochlear Implantation (CDaCI) study from hospital-based CI programs; a cohort of 340 children with severe to profound hearing loss without CIs from a nationally representative survey (National Longitudinal Transition Study-2; NLTS-2), and results from the literature of comparable children without CIs. Exposure(s): Cochlear implantation (early and late). Main Outcomes and Measures: Adolescent performance on measures of academic achievement (Woodcock Johnson), language (Comprehensive Assessment of Spoken Language), and quality of life (Pediatric Quality of Life Inventory, Youth Quality of Life Instrument-Deaf and Hard of Hearing). Results: The CDaCI cohort included 188 children, 136 of whom completed the wave 3 postimplantation follow-up visits (77 [55%] female) with CIs; mean [SD] age was 11.47 [1.27] years. The NLTS-2 cohort included 340 children (50% female) with severe to profound hearing loss without CIs. Children with CIs had better academic performance compared with children without CIs with similar levels of hearing loss. The largest benefits were seen for children who received implants early (prior to age 18 months), who performed at or above age and gender norms for language and academic achievement. Similarly, adolescents with CIs reported better quality of life on the Pediatric Quality of Life Inventory compared with children without CIs. On a condition-specific measure (Youth Quality of Life Instrument-Deaf and Hard of Hearing), children who received implants early scored higher across all 3 domains than comparisons without CIs. Conclusions and Relevance: To our knowledge, this is the first study to evaluate long-term educational outcomes and quality of life in adolescents using CIs. This longitudinal cohort study showed better outcomes of CIs in terms of language, academic performance, and quality of life. While the greatest benefits were observed for children who received implants before age 18 months, benefits were also noted for children who received implants later, providing evidence that children with severe to profound hearing loss with CIs can achieve at or above expected levels compared with hearing peers.

Positive and negative impacts of elexacaftor/tezacaftor/ivacaftor: Healthcare providers' observations across US centers.

BACKGROUND: Elexacaftor/tezacaftor/ivacaftor (ETI) has been associated with unprecedented clinical improvements, transforming the management of cystic fibrosis (CF). However, side effects with implications for safety and well-being have been reported, including neuropsychiatric changes. This study aimed to better characterize the emerging positive and negative impacts of ETI. METHODS: The Cystic Fibrosis Foundation's Mental Health Advisory Committee distributed a 26-item survey to US CF care teams to assess clinician observations of patient-reported experiences with ETI. Survey responses measured the prevalence of these effects in five domains: (1) positive physical and psychological effects, (2) sleep difficulties, (3) cognitive difficulties, (4) worsening mental health, and (5) concerns about the future and finances. RESULTS: Seventy-five healthcare providers responded from a pediatric, adult, and combined centers. Positive physical effects of ETI and increased optimism were reported in the upper quartiles (50%-100%) and rated as having a significant impact on daily functioning. Sleep and cognitive difficulties were reported in 1%-24%, with slight impacts on functioning, and psychological symptoms (e.g., increased stress, depression, anxiety) and new psychiatric medications were reported in 1%-24%, with moderate impacts. Concerns about the future were reported in 1%-24%, with minimal impacts. CONCLUSION: Across US centers, providers most often observed positive physical effects of ETI. However, a variety of negative side effects were also reported, including sleep disruptions and worsening psychological functioning, which should be systematically monitored by CF teams. These national-level data are a first step in evaluating the prevalence and consequences of these side effects and can directly inform future studies.

National integration of mental health screening and treatment into specialized care for cystic fibrosis: What predicts success?

OBJECTIVES: The CF Foundation sponsored competitive awards for Mental Health Coordinators (MHCs) from 2016 to 2018 to implement the international guidelines for mental health screening and treatment in US CF centers. Longitudinal surveys evaluated success in implementing these guidelines using the Consolidated Framework for Implementation Research (CFIR). METHODS: MHCs completed annual surveys assessing implementation from preparation/basic implementation (e.g., using recommended screeners) to full implementation/sustainability (e.g., providing evidence-based treatments). Points were assigned to questions through consensus, with higher scores assigned to more complex tasks. Linear regression and mixed effects models were used to: (1) examine differences in centers and MHC characteristics, (2) identify predictors of success, (3) model the longitudinal trajectory of implementation scores. RESULTS: A total of 122 MHCs (88.4% responded): Cohort 1, N = 80; Cohort 2, N = 30; and Cohort 3, N = 12. No differences in center characteristics were found. Significant improvements in implementation were observed across centers over time. Years of experience on a CF team was the only significant predictor of success; those with 1-5 years or longer reported the highest implementation scores. Change over time was predicted by >5 years of experience. CONCLUSIONS: Implementation of the mental health guidelines was highly successful over time. Funding for MHCs with dedicated time was critical. Longitudinal modeling indicated that CF centers with diverse characteristics could implement them, supported by evidence from the CF Patient Registry showing nearly universal uptake of mental health screening in the United States. Years of experience predicted better implementation, suggesting that education and training of MHCs and retention of experienced providers are critical to success.

Pilot Evaluation of a Management Toolkit for Airway Clearance Therapy in Bronchiectasis (IMPACT BE).

Background: Airway clearance therapies (ACTs) are recommended as an integral part of the management of non-cystic fibrosis bronchiectasis (BE) to prevent inflammation, mucus accumulation, and infection that occur because of ineffective secretion clearance. Adherence to ACTs is low, in part because of perceived burden and a lack of standardization of education and training programs for patients. Poor adherence is associated with more frequent exacerbations, worse health outcomes, and worse quality of life. Structured educational programs increase adherence to ACT among people with cystic fibrosis and may show similar results for people with BE. Objective: This pilot study evaluated the feasibility, clinical utility, sustainability, and expert opinions of this educational program addressing gaps in ACT knowledge and skills in people with BE. Methods: The Individual Management of Patient Airway Clearance Therapy- Bronchiectasis (IMPACT BE) was implemented in nine BE centers with 100 patients. Qualitative and quantitative data were collected from patients and providers. Results: The IMPACT BE program demonstrated good uptake in a clinic setting by multidisciplinary team members, with improvements in medical teams' evaluation of their ability to provide education to patients. All healthcare teams indicated that this program could become a sustainable part of their clinic. Qualitative responses from patients indicated the program was comprehensive and easy to use. Conclusion: In this pilot study, IMPACT BE was found to be useful in teaching airway clearance to people with BE. The open-access toolkit was well received by both patients and a diverse array of providers in a clinic setting.

Patient-Reported Symptom and Health-Related Quality-of-Life Validation and Responsiveness During the First 6 Months of Treatment for Mycobacterium avium Complex Pulmonary Disease.

BACKGROUND: Nontuberculous mycobacteria (NTM), predominately Mycobacterium avium complex (MAC), cause chronic pulmonary disease. Improvements in symptoms and health-related quality of life (HRQoL) are important treatment outcomes, but no validated patient-reported outcome (PRO) measure exists. RESEARCH QUESTION: What are the validity and responsiveness of the Quality of Life-Bronchiectasis (QOL-B) questionnaire respiratory symptoms scale and key HRQoL measures during the first 6 months of MAC pulmonary disease (MAC-PD) treatment? STUDY DESIGN AND METHODS: Comparison of Two- vs Three-antibiotic Therapy for Pulmonary Mycobacterium Avium Complex Disease (MAC2v3) is an ongoing randomized, multisite pragmatic clinical trial. Patients with MAC-PD were randomized to azithromycin-based two-drug or three-drug therapy; treatment groups were combined for this analysis. PROs were measured at baseline, 3 months, and 6 months. The QOL-B respiratory symptoms, vitality, physical functioning, health perceptions, and NTM symptom domain scores (on a scale of 0-100, with 100 being best) were analyzed separately. We performed psychometric and descriptive analyses in the population enrolled as of the time of analysis and calculated the minimal important difference (MID) using distribution-based methods. Finally, we evaluated responsiveness using paired t tests and latent growth curve analysis in the subset with longitudinal surveys completed by the time of analysis. RESULTS: The baseline population included 228 patients, of whom 144 had completed longitudinal surveys. Patients predominately were female (82%) and had bronchiectasis (88%); 50% were 70 years of age or older. The respiratory symptoms domain showed good psychometric properties (no floor or ceiling effects; Cronbach's α, 0.85) and an MID of 6.4 to 6.9. Vitality and health perceptions domain scores performed similarly. Respiratory symptoms domain scores improved by 7.8 points (P < .0001) and 7.5 points (P < .0001), and the physical functioning domain score improved by 4.6 points (P < .003) and 4.2 points (P = .01) at 3 and 6 months, respectively. Latent growth curve analysis confirmed a nonlinear, statistically significant improvement in respiratory symptoms and physical functioning domain scores by 3 months. INTERPRETATION: The QOL-B respiratory symptoms and physical functioning scales exhibited good psychometric properties in patients with MAC-PD. Respiratory symptoms scores improved beyond the MID by 3 months after treatment initiation. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT03672630; URL: www. CLINICALTRIALS: gov.

Comparison of mental health in individuals with primary ciliary dyskinesia, cystic fibrosis, and parent caregivers.

INTRODUCTION: Individuals with chronic respiratory diseases and caregivers are at higher risk for depression and anxiety. Primary ciliary dyskinesia (PCD) and cystic fibrosis (CF) are both rare genetic diseases, characterized by recurrent respiratory infections. This study compared depression and anxiety in people with PCD (pwPCD) and CF (pwCF), and caregivers, using the screening tools recommended in the CF guidelines. METHODS: Patient Health Questionnaire (PHQ-9) and Generalized Anxiety Disorder (GAD-7) were administered to a PCD and CF sample. Given that PCD is extremely rare, they were matched on age and sex to pwCF at a 1:2 ratio. Similar procedures were performed with parents. RESULTS: A total of 63 patients and 129 caregivers participated: 21 pwPCD and 42 pwCF (ages 12-34 years) plus 43 caregivers of pwPCD and 86 caregivers of pwCF. A high percentage of patients scored above the cut-off for depression (PCD: 33%; CF: 43%) and anxiety (PCD and CF both: 43%), mostly mild. Similarly, a high percentage of caregivers scored above the cut-off for depression (PCD: 42-54%; CF: 45-46%) and anxiety (PCD: 47-54%; CF: 39-56%). Suicidal ideation was endorsed by 9.5% of pwPCD, 20% of mothers and 10% of fathers and 5% of pwCF, 3% of mothers, but no fathers. CONCLUSION: A large percentage of patients and caregivers reported elevated psychological distress and suicidal ideation. Addressing psychological symptoms is critical given they are associated with poor adherence, missed clinic visits, increased inflammation and worse quality of life. Mental health screening and treatment should be integrated into PCD care.

Development of the Cystic Fibrosis Questionnaire-Revised-8 Dimensions: Estimating Utilities From the Cystic Fibrosis Questionnaire-Revised.

OBJECTIVES: Cystic fibrosis (CF) limits survival and negatively affects health-related quality of life (HRQOL). Cost-effectiveness analysis (CEA) may be used to make reimbursement decisions for new CF treatments; nevertheless, generic utility measures used in CEA, such as EQ-5D, are insensitive to meaningful changes in lung function and HRQOL in CF. Here we develop a new, CF disease-specific, preference-based utility measure based on the adolescent/adult version of the Cystic Fibrosis Questionnaire-Revised (CFQ-R), a widely used, CF-specific, patient-reported measure of HRQOL. METHODS: Blinded CFQ-R data from 4 clinical trials (NCT02347657, NCT02392234, NCT01807923, and NCT01807949) were used to identify discriminating items for a classification system using psychometric (eg, factor and Rasch) analyses. Thirty-two health states were selected for a time trade-off (TTO) exercise with a representative sample of the UK general population. TTO utilities were used to estimate a preference-based scoring algorithm by regression analysis (tobit models with robust standard errors clustered on participants with censoring at -1). RESULTS: A classification system with 8 dimensions (CFQ-R-8 dimensions; physical functioning, vitality, emotion, role functioning, breathing difficulty, cough, abdominal pain, and body image) was generated. TTO was completed by 400 participants (mean age, 47.3 years; 49.8% female). Among the regression models evaluated, the tobit heteroscedastic-ordered model was preferred, with a predicted utility range from 0.236 to 1, no logical inconsistencies, and a mean absolute error of 0.032. CONCLUSION: The CFQ-R-8 dimensions is the first disease-specific, preference-based scoring algorithm for CF, enabling estimation of disease-specific utilities for CEA based on the well-validated and widely used CFQ-R.

Development and preliminary validation of the challenges of living with cystic fibrosis (CLCF) questionnaire: a 46-item measure of treatment burden for parent/carers of children with CF.

OBJECTIVE: Treatments for cystic fibrosis (CF) are complex, labour-intensive, and perceived as highly burdensome by caregivers of children with CF. An instrument assessing burden of care is needed. DESIGN: A stepwise, qualitative design was used to create the CLCF with caregiver focus groups, participant researchers, a multidisciplinary professional panel, and cognitive interviews. MAIN OUTCOME MEASURES: Preliminary psychometric analyses evaluated the reliability and convergent validity of the CLCF scores. Cronbach's alpha assessed internal consistency and t-tests examined test-retest reliability. Correlations measured convergence between the Treatment Burden scale of the Cystic Fibrosis Questionnaire-Revised (CFQ-R) and the CLCF. Discriminant validity was assessed by comparing CLCF scores in one vs two-parent families, across ages, and in children with vs without Pseudomonas aeruginosa (PA). RESULTS: Six Challenge subscales emerged from the qualitative data and the professional panel constructed a scoresheet estimating the Time and Effort required for treatments. Internal consistency and test-retest reliability were adequate. Good convergence was found between the Total Challenge score and Treatment Burden on the CFQ-R (r=-0.49, p = 0.02, n = 31). A recent PA infection signalled higher Total Challenge for caregivers (F(23)11.72, p = 0.002). CONCLUSIONS: The CLCF, developed in partnership with parents/caregivers and CF professionals, is a timely, disease-specific burden measure for clinical research.

Non-respiratory health-related quality of life in people with cystic fibrosis receiving elexacaftor/tezacaftor/ivacaftor.

Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be safe and efficacious in people with cystic fibrosis (CF) heterozygous for F508del and a minimal function mutation (F/MF) or homozygous for F508del (F/F) in two pivotal Phase 3 trials, significantly improving percentage predicted forced expiratory volume in 1 second, Cystic Fibrosis Questionnaire-Revised, Respiratory Domain (CFQ-R RD) scores, and sweat chloride concentration. Here, we analyzed the 11 non-respiratory domains (non-RDs) of the CFQ-R, which assess general health-related quality of life (i.e., Physical Functioning, Role Functioning, Vitality, Health Perceptions, Emotional Functioning, and Social Functioning) and quality of life impacted by CF (i.e., Body Image, Eating Problems, Treatment Burden, Weight, and Digestive Symptoms), for participants in these two Phase 3 trials. ELX/TEZ/IVA treatment led to higher scores in all CFQ-R non-RDs, with improvements in most domains compared with control treatments. These findings demonstrate that ELX/TEZ/IVA improves a range of CF-specific symptoms and general functioning and well-being.

Patient engagement in the development of CF-CBT: A cystic fibrosis-specific cognitive-behavioral intervention for adults.

Individuals with cystic fibrosis (CF) are at high risk for depression and anxiety, with negative consequences for health and quality of life. Cystic Fibrosis Foundation/European Cystic Fibrosis Society guidelines recommend routine screening, treatment, and preventative efforts. Cognitive-behavioral therapy (CBT) has a large evidence-base for depression/anxiety prevention and treatment. However, traditional CBT protocols require adaptation to address the emotional challenges of coping with CF, stressors related to disease management, and barriers to access to care. The goal of this study was to partner with the CF community to develop an innovative CBT-based intervention for the prevention and treatment of depression and anxiety tailored to CF-specific needs. In-depth feedback was collected via audio-recorded telephone interviews with 16 adults with CF from 3 U.S. CF centers, with purposive sampling across gender, age, ethnicity, and disease severity. A semi-structured interview guide elicited discussion of patient experiences of coping with CF, and perspectives on the acceptability of the content, structure, and delivery model of the proposed intervention. Qualitative analysis utilized a content analytic approach. Participants ranged from 21 to 53 years (M = 35); eight were female; three were Hispanic. Patient-reported most recent FEV1, a measure of lung function based on forced expiratory volume in in one second, ranged from 25 to 113% predicted (M = 72). One participant was post-double lung transplant. Qualitative interviews were analyzed thematically revealing core themes related to the experience of coping with CF. The most frequently cited CF-related stressors were Treatment Burden, Illness Uncertainty, and Financial/Insurance Stress. Participants talked about the interaction of physical symptoms and emotional distress in their daily lives, a topic not typically discussed in routine CF care. Resilience was also a major theme with participants describing strategies they use to cope with CF and hospitalizations. Description of patients' experiences was incorporated into the program's intervention manual and patient workbook. Participants also provided direct feedback on the proposed program. Feedback was largely positive regarding program content and structure, suggesting the acceptability of a CF-specific CBT-based intervention for adults with CF. Features to increase accessibility of care including telehealth, inpatient delivery, and team-based care were perceived as advantageous, and participants emphasized the value of a CF-specific mental health intervention. Qualitative findings directly informed the development of CF-CBT, a cognitive-behavioral skills-based program to promote emotional well-being for adults with CF.

Airway clearance physiotherapy and health-related quality of life in cystic fibrosis.

OBJECTIVE: Airway clearance physiotherapy is recommended in cystic fibrosis, but limited evidence exists to suggest how much treatment is enough. As a secondary analysis of a prior study investigating the safety, efficacy, and participants' perceptions of a novel airway clearance technique, specific cough technique (SCT) compared to forced expiration technique (FET), we aimed to evaluate whether the intervention was associated with changes in health-related quality of life (HRQoL). METHODS: We conducted randomised, controlled individual trials with six adults (N-of-1 RCTs). Each trial included eight weeks of treatment, twice a week, using saline inhalation in horizontal positions, one with SCT and one with FET, in random order. Efficacy was measured by sputum wet weight (g) after each session. Perceived usefulness and preference were self-reported at the end of the study. Lung function was assessed at baseline and at the end of study. HRQoL was measured using the Cystic Fibrosis Questionnaire-Revised (CFQ-R) at baseline (week 1) and at completion of the study (week 8). Individual HRQoL scores (0-100) were coded and analysed using CFQ-R Software Program, version 2.0. RESULTS: Patient-reported outcomes were completed by all subjects. Individual CFQ-R-Respiratory Symptoms Scores (CFQ-R-RSS) showed a positive change, meeting the minimal important difference (MID) ≥ 4 points in five participants and a negative change in one individual. A strong correlation (r = 0.94 (p<0.01) was found between total sputum weight (g) and the positive changes in CFQ-R-RSS, and between changes in lung function and CFQ-R-RSS (r = 0.84 (p = 0.04). CONCLUSION: The airway clearance intervention was associated with clinically meaningful changes in patient-reported symptoms on the CFQ-R in the majority of the participants. This finding warrants further investigation regarding treatment, duration and frequency. A long-term study may reveal beneficial effects on other clinically meaningful endpoints, such as pulmonary exacerbations, high-resolution computed tomography scores and HRQoL. TRIAL REGISTRATION: The study was registered in ClinicalTrials.gov, under the number NCT0 1266473.

Feasibility and acceptability of a CF-specific cognitive-behavioral preventive intervention for adults integrated into team-based care.

BACKGROUND: A cystic fibrosis (CF)-specific cognitive-behavioral therapy intervention (CF-CBT) was developed in partnership with the CF community to advance preventive mental health care. Multidisciplinary providers across three centers were trained to deliver CF-CBT for this pilot assessing feasibility/acceptability and preliminary effectiveness of an integrated model of care. METHODS: The 8-session CF-CBT was delivered to 14 adults with mild depression and/or anxiety symptoms in-person and via audio telehealth. Assessment of attrition, engagement, homework completion, treatment satisfaction, and treatment fidelity informed feasibility/acceptability assessment. Mental health outcomes included depression, anxiety, quality of life (Cystic Fibrosis Questionnaire-Revised [CFQ-R), perceived stress and coping. Preliminary effectiveness was evaluated with Cohen's d metric of effect sizes (ES) of pre-post mean change scores. RESULTS: A total of 108 sessions were conducted; 13 adults completed the intervention; 1 discontinued early. Engagement, homework completion, and treatment acceptability were highly rated (mean = 30; SD = 2, range: 27-32 on a 32-point scale). Fidelity scores ranged from 85.7% to 93.6%. Large ES changes reflected improvements in depressive symptoms (-0.83), CFQ-R (Vitality scale: 1.11), and Relaxation Skills (0.93); moderate ES for CFQ-R Role Functioning (0.63), Awareness of Tension (0.62), Coping Confidence (0.70) and CF-specific Coping (0.55); and small ES for anxiety symptoms (-0.22), perceived stress (-0.25), Behavioral Activation (0.29), and several CFQ-R domains, including Emotional Functioning (0.29). Two CFQ-R subscales decreased (Body Image, Eating Concerns). CONCLUSIONS: Results indicated feasibility and acceptability of CF-CBT and its integration into team-based CF care with promising effectiveness, especially for depression. A multicenter randomized controlled trial of CF-CBT will further examine effectiveness of a CF-specific integrated care model.

Stress and mental health in adolescents and young adults with cystic fibrosis 1 year after the COVID pandemic: Findings from an Italian sample.

BACKGROUND: The spread of COVID-19 was associated with increased stress and new mental health concerns for people with cystic fibrosis (pwCF), already at increased risk for depression and anxiety. This study assessed stress and mental health in adolescents and young adults with CF 1 year from when the pandemic began. METHODS: Sixty-six pwCF (mean age = 24; range 14-36) completed a new measure of the impact of COVID-19 (COVID-19 Exposure and Family Impact Scale-Adolescence and Young Adult; CEFIS-AYA); the Patient Health Questionnaire-9, and the Generalized Anxiety Disorder-7. The Italian translation of the CEFIS-AYA was performed. RESULTS: On the CEFIS-AYA, the mean Exposure score was 5.2 (SD = 2.6) out of 28. The mean Impact score was 1.8 (SD = 0.7; negative valence > 2.5). Individuals were more sedentary and undertaking less exercise. Average stress rating was 5.9 (SD = 2), indicating moderate stress. No significant differences were found between those who did (N = 12) and who did not have a COVID infection (N = 54). A high percentage of participants scored above the clinical cut-off for depression (45%) and anxiety (41%), with a low proportion reporting moderate-severe symptomatology. CONCLUSION: After 1 year, the pandemic was having a less significant impact on patients' daily lives. Sedentary activity and reduced exercise were common. Despite expectations that this group was particularly vulnerable, depression and anxiety scores were similar to the rates described for this population before the pandemic. Overall, these results suggested that pwCF are highly resilient and nearly 1 year after the onset of COVID-19, have returned to similar daily activities and emotional health.