Multimodal probing of T-cell recognition with hexapod heterostructures.

Studies using antigen-presenting systems at the single-cell and ensemble levels can provide complementary insights into T-cell signaling and activation. Although crucial for advancing basic immunology and immunotherapy, there is a notable absence of synthetic material toolkits that examine T cells at both levels, and especially those capable of single-molecule-level manipulation. Here we devise a biomimetic antigen-presenting system (bAPS) for single-cell stimulation and ensemble modulation of T-cell recognition. Our bAPS uses hexapod heterostructures composed of a submicrometer cubic hematite core (α-Fe2O3) and nanostructured silica branches with diverse surface modifications. At single-molecule resolution, we show T-cell activation by a single agonist peptide-loaded major histocompatibility complex; distinct T-cell receptor (TCR) responses to structurally similar peptides that differ by only one amino acid; and the superior antigen recognition sensitivity of TCRs compared with that of chimeric antigen receptors (CARs). We also demonstrate how the magnetic field-induced rotation of hexapods amplifies the immune responses in suspended T and CAR-T cells. In addition, we establish our bAPS as a precise and scalable method for identifying stimulatory antigen-specific TCRs at the single-cell level. Thus, our multimodal bAPS represents a unique biointerface tool for investigating T-cell recognition, signaling and function.

Acute Pulmonary Exacerbation Phenotypes in Patients with Cystic Fibrosis.

Rationale: The etiology of cystic fibrosis (CF) pulmonary exacerbations (PEx) is likely multifactorial with viral, bacterial, and non-infectious pathways contributing. Objectives: To determine whether viral infection status and CRP (C-reactive protein) can classify subphenotypes of PEx that differ in outcomes and biomarker profiles. Methods: Patients were recruited at time of admission for a PEx. Nasal swabs and sputum samples were collected and processed using the respiratory panel of the FilmArray multiplex polymerase chain reaction (PCR). Serum and plasma biomarkers were measured. PEx were classified using serum CRP and viral PCR: "pauci-inflammatory" if CRP < 5 mg/L, "non-viral with systemic inflammation" if CRP ⩾ 5 mg/L and no viral infection detected by PCR and "viral with systemic inflammation" if CRP ⩾ 5 mg/L and viral infection detected by PCR. Results: Discovery cohort (n = 59) subphenotype frequencies were 1) pauci-inflammatory (37%); 2) non-viral with systemic inflammation (41%); and 3) viral with systemic inflammation (22%). Immunoglobulin G, immunoglobulin M, interleukin-10, interleukin-13, serum calprotectin, and CRP levels differed across phenotypes. Reduction from baseline in forced expiratory volume in 1 second as percent predicted (FEV1pp) at onset of exacerbation differed between non-viral with systemic inflammation and viral with systemic inflammation (-6.73 ± 1.78 vs. -13.5 ± 2.32%; P = 0.025). Non-viral with systemic inflammation PEx had a trend toward longer duration of intravenous antibiotics versus pauci-inflammation (18.1 ± 1.17 vs. 14.8 ± 1.19 days, P = 0.057). There were no differences in percent with lung function recovery to <10% of baseline FEV1pp. Similar results were seen in local and external validation cohorts comparing a pauci-inflammatory to viral/non-viral inflammatory exacerbation phenotypes. Conclusions: Subphenotypes of CF PEx exist with differences in biomarker profile, clinical presentation, and outcomes.

Duration of intravenous antibiotic treatment for acute exacerbations of cystic fibrosis: A systematic review.

BACKGROUND: Acute exacerbations of Cystic Fibrosis (AECF) are associated with significant morbidity. Recommendations are to treat for 2-3 weeks despite limited data. Spirometry is a measure of clinical response yet appears to plateau at 7-10 days. While durations <9 days have been associated with poorer outcomes, a duration of 10 days may be as effective as 14 days, potentially conferring advantages in terms of cost and adverse events. A 2019 Cochrane review by Abbott et al. did not identify any randomised controlled trials (RCT) comparing durations of treatment. Utilising data from non-randomised studies (NRS), we report a systematic review of intravenous antibiotic treatment, exploring changes in FEV1 (Forced Expiratory Volume in 1 second), CRP (C-reactive protein) and peripheral WBC (white blood cell) count in studies with different treatment durations. STUDY DESIGN AND METHODS: Systematic review of published literature following a search of MEDLINE, Embase, CINAHL and the Cochrane Clinical Trials register. Guidelines from the Preferred Reporting items for Systematic reviews and Meta-Analysis (PRISMA) and reporting Meta-analysis of Observational studies (MOOSE) statement were followed. RESULTS: No randomised controlled trials were identified that specifically examined duration of treatment during AECF. This study included all relevant RCTs and also NRS, grouping according to study characteristics, such as length of treatment, location, year, and also characteristics of the patient population. 52 studies, comprising 79 subgroups, and 1,597 patients, were identified. Mean change (95%CI) in ppFEV1 was 10.13 (9.21-11.05). There was no significant difference in change in ppFEV1 for studies treating for 10-12 days; 8.85 (7.47-10.23), vs 13-15 days; 10.68 (9.53-11.82). Similar changes in CRP and WBC were seen irrespective of treatment duration. CONCLUSION: This systematic review provides evidence that shorter durations of treatment may be associated with similar changes in FEV1, CRP and WBC compared with longer durations.

Split anterior tibialis tendon transfer to peroneus brevis for spastic equinovarus in children with hemiplegia.

PURPOSE: The aim of this study is to report the safety and eff-cacy of soft-tissue surgery incorporating split transfer of tibi-alis anterior to peroneus brevis (SPLATT-PB) for children with hemiplegic spastic equinovarus. METHODS: This was a retrospective case series of children and adolescents with spastic hemiplegia who had a novel combination of SPLATT-TB, intramuscular tenotomy of tibialis posterior and either spasticity management or gastrocsole-us lengthening as the index surgery. The principal outcome measures were changes in pain and difficulty with shoe wear and radiological parameters obtained from weight-bearing anteroposterior and lateral radiographs of the affected foot before and after surgery. RESULTS: A total of 63 patients with symptomatic spastic equinovarus met the inclusion criteria. Mean age at surgery was 9.8 years (6 to 18) and the mean follow-up was seven years (range 3 to 10 years). Foot pain and problems with shoe wear improved after surgery. Seven radiological criteria showed a clinically and statistically significant improvement at follow-up, the majority being in the normal range. There were 11 surgical adverse events, all classified as Modified Cla-vien-Dindo Grade II. Three patients required further surgery for recurrent equinus, eight patients required further surgery for valgus deformities and four patients required bony surgery for residual varus deformities. CONCLUSION: Soft-tissue surgery for spastic equinovarus was successful in the majority of children with spastic hemiplegia, particularly between ages eight and 12 years, resulting in a plantigrade, flexible foot with minimal pain or limitations in shoe-wear. Children younger than 8 years at index surgery were more prone to overcorrection into valgus. Children older than 12 years had persistent varus deformities requiring bony surgery. LEVEL OF EVIDENCE: Level IV, retrospective case series.

Fixation eye movement abnormalities and stereopsis recovery following strabismus repair.

We evaluated the effects of strabismus repair on fixational eye movements (FEMs) and stereopsis recovery in patients with fusion maldevelopment nystagmus (FMN) and patients without nystagmus. Twenty-one patients with strabismus, twelve with FMN and nine without nystagmus, were tested before and after strabismus repair. Eye-movements were recorded during a gaze-holding task under monocular viewing conditions. Fast (fixational saccades and quick phases of nystagmus) and slow (inter-saccadic drifts and slow phases of nystagmus) FEMs and bivariate contour ellipse area (BCEA) were analyzed in the viewing and non-viewing eye. Strabismus repair improved the angle of strabismus in subjects with and without FMN, however patients without nystagmus were more likely to have improvement in stereoacuity. The fixational saccade amplitudes and intersaccadic drift velocities in both eyes decreased after strabismus repair in subjects without nystagmus. The slow phase velocities were higher in patients with FMN compared to inter-saccadic drifts in patients without nystagmus. There was no change in the BCEA after surgery in either group. In patients without nystagmus, the improvement of the binocular function (stereopsis), as well as decreased fixational saccade amplitude and intersaccadic drift velocity, could be due, at least partially, to central adaptive mechanisms rendered possible by surgical realignment of the eyes. The absence of improvement in patients with FMN post strabismus repair likely suggests the lack of such adaptive mechanisms in patients with early onset infantile strabismus. Assessment of fixation eye movement characteristics can be a useful tool to predict functional improvement post strabismus repair.

A clinical investigation into the ability of subjects with lung disease to provide breath specimens using the EvidenzerIRL evidential breath analyser in alcohol intoxicant driving in criminal justice evidence.

The EvidenzerIRL instrument has been in use as an evidential breath analyser in the application of drink driving laws in the Republic of Ireland since 2011. The result of the analysis is used as evidence in prosecutions before the Courts in per se offences of driving under the influence of alcohol as distinct from screening results at the roadside. This study aims to assist doctors, lawyers and judges in assessing drivers' failure to provide valid evidential breath specimens. Since the introduction of the EvidenzerIRL, approximately 10% of evidential breath tests annually result in failure or refusal to provide a successful breath specimen, this is an offence under Irish road traffic laws. The presence of lung disease has been given as a reason for the driver failing to provide evidential breath specimens. The aim of this study is to assess the ability of subjects with lung disease to provide breath specimens using the EvidenzerIRL. Pulmonary function tests (PFT) were carried out on volunteers from outpatients of the pulmonary laboratory in St Vincent's University Hospital, Dublin (n = 58) and a control group with no underlying lung disease (n = 19). After the PFTs all volunteers were asked to provide breath specimens using the EvidenzerIRL. Fourteen (24%) out of 58 lung disease volunteers failed to provide a breath specimen, no one from the control group was unsuccessful. Thirteen females and one male volunteer could not successfully provide. Female volunteers were more likely to fail to provide than male volunteers. A significant difference was found between the median age of successful (62.2 years) and unsuccessful (69.2 years) lung disease volunteers. Only one PFT, percentage predicted of Forced Expiratory Volume in 1 second (FEV1), had a significant difference between the mean of successful (86.6%) and unsuccessful (66.5%) lung disease volunteers. A subject with lung disease was more likely to be successful than unsuccessful. Drivers' effort and operators' guidance through the process were found to be crucial parts to a successful outcome.

Laser writing of nitrogen-doped silicon carbide for biological modulation.

Conducting or semiconducting materials embedded in insulating polymeric substrates can be useful in biointerface applications; however, attainment of this composite configuration by direct chemical processes is challenging. Laser-assisted synthesis has evolved as a fast and inexpensive technique to prepare various materials, but its utility in the construction of biophysical tools or biomedical devices is less explored. Here, we use laser writing to convert portions of polydimethylsiloxane (PDMS) into nitrogen-doped cubic silicon carbide (3C-SiC). The dense 3C-SiC surface layer is connected to the PDMS matrix via a spongy graphite layer, facilitating electrochemical and photoelectrochemical activity. We demonstrate the fabrication of arbitrary two-dimensional (2D) SiC-based patterns in PDMS and freestanding 3D constructs. To establish the functionality of the laser-produced composite, we apply it as flexible electrodes for pacing isolated hearts and as photoelectrodes for local peroxide delivery to smooth muscle sheets.

A clinical investigation into the ability of subjects with a lung disease to provide breath specimens using the Dräger 6510.

In the enforcement of drink driving laws failing to provide a breath specimen for alcohol analysis at the roadside when requested by a Police Officer is an offence in many countries. Some drivers claim that a lung disease prevented their ability to be successful. This study aims to investigate the relationship between the presence of a lung disease and the ability to provide a successful breath specimen using the Dräger 6510 screening device. Sixty participants with lung disease and nineteen control participants underwent pulmonary function tests and were then tested with a Dräger 6510 screening device. Only one participant was unsuccessful using the Dräger 6510, this participant suffered from interstitial lung disease. The pulmonary function test results did not indicate if someone would be successful or how many attempts would be needed to be successful. The presence of a lung disease did not indicate if a driver would be unsuccessful however all participants were free from infection and the participants with a lung disease were stable at the time of testing. Correct instruction, subject cooperation and the technique used by the driver to provide a breath specimen were found to be important factors in the success of a breath test.

Osteoarthritis is associated with increased failure of proximal femoral fracture fixation.

PURPOSE: The purpose of this study was to evaluate whether the presence of hip osteoarthritis at the time of hip fracture increases treatment failure rates when using either a sliding hip screw (SHS) or proximal femoral nail (PFN) for fracture fixation. METHODS: A retrospective study of a consecutive series of 455 women and 148 men (median age, 83.8 years) treated with SHS or PFN was performed. Osteoarthritis was evaluated based on pre-operative radiographs using the Kellgren and Lawrence grading system. Treatment failure, which was defined as non-union, avascular necrosis, backing out of the implant, cut out of the proximal screws, peri-prosthetic fracture, implant breakage, or conversion to hemi- or total hip arthroplasty, was evaluated for a follow-up period of four to seven years. Optimal placement of the implant (tip-apex distance (TAD) and 3-point fixation) and the effects of age, sex, the quality of reduction, implant type, fracture stability, fracture type, and time to failure were considered confounders of the relationship between failure and osteoarthritis (OA). RESULTS: Among the 32 cases (5.3%) of treatment failure, 12 (2%) showed evidence of osteoarthritis. After controlling for age, sex, the quality of reduction, implant type, fracture stability, fracture type, and TAD, osteoarthritis was associated a greater than threefold increase in treatment failure compared with that of patients without pre-operative evidence of osteoarthritis (OR, 3.26; 95% CI, 1.4-7.65; P = 0.006). CONCLUSIONS: After adjusting for potential confounding factors, radiographic evidence of hip osteoarthritis at the time of hip fracture increases the incidence of treatment failure.

Oculomotor, Vestibular, and Reaction Time Effects of Sports-Related Concussion: Video-Oculography in Assessing Sports-Related Concussion.

OBJECTIVE: The purpose of the study was to test the ability of oculomotor, vestibular, and reaction time (OVRT) metrics to serve as a concussion assessment or diagnostic tool for general clinical use. SETTING AND PARTICIPANTS: Patients with concussion were high school-aged athletes clinically diagnosed in a hospital setting with a sports-related concussion (n = 50). Control subjects were previously recruited male and female high school student athletes from 3 local high schools (n = 170). DESIGN: Video-oculography was used to acquire eye movement metrics during OVRT tasks, combined with other measures. Measures were compared between groups, and a subset was incorporated into linear regression models that could serve as indicators of concussion. MEASURES: The OVRT test battery included multiple metrics of saccades, smooth pursuit tracking, nystagmoid movements, vestibular function, and reaction time latencies. RESULTS: Some OVRT metrics were significantly different between groups. Linear regression models distinguished control subjects from concussion subjects with high accuracy. Metrics included changes in smooth pursuit tracking, increased reaction time and reduced saccade velocity in a complex motor task, and decreased optokinetic nystagmus (OKN) gain. In addition, optokinetic gain was reduced and more variable in subjects assessed 22 or more days after injury. CONCLUSION: These results indicate that OVRT tests can be used as a reliable adjunctive tool in the assessment of concussion and that OKN results appear to be associated with a prolonged expression of concussion symptoms.

Longitudinal Trends in Real-World Outcomes after Initiation of Ivacaftor. A Cohort Study from the Cystic Fibrosis Registry of Ireland.

RATIONALE: Patient registries have the potential to collect and analyze high-quality postauthorization data on new medicines. OBJECTIVES: We used cystic fibrosis (CF) registry data to assess outcomes after the initiation of ivacaftor, a CF transmembrane conductance regulator (CFTR) potentiator approved for the treatment of CF with a defective gating CFTR mutation. METHODS: Longitudinal trends were examined using mixed-effects regression analysis in 80 ivacaftor-treated patients with CF aged 6 to 56 years registered with the CF Registry of Ireland with at least 36 months of before and after commencement data. The effects of ivacaftor treatment on forced expiratory volume in 1 second (FEV1) % predicted, body mass index (BMI), hospitalization for pulmonary exacerbation, and oral and intravenous antibiotic use were assessed. RESULTS: In the 36 months after ivacaftor initiation, FEV1% predicted improved by 2.26% per annum (95% confidence interval [CI], 0.2 to 4.3) for patients aged younger than 12 years, remained unchanged for 12- to younger than 18-year-olds (95% CI, -1.9 to 2.9), and declined in adults by 1.74% per annum (95% CI, -3.1 to -0.4). BMI in adults increased 0.28 kg/m2 per annum (95% CI, 0.03 to 0.5), and there was no significant change in BMI z-score in children (95% CI, -0.01 to 0.1). In the year after ivacaftor initiation, intravenous antibiotic treatment reduced by 46% (95% CI, -62.5% to -23.3%, oral antibiotic treatment reduced by 49% (95% CI, -61.1% to -32.1%), and there was no significant reduction in hospitalization (95% CI, -59.2% to 9.7%). CONCLUSIONS: In this study of real-world CF registry data, clinical outcomes improved and healthcare resource utilization decreased after commencing ivacaftor.

Classifying Adverse Events Following Lower Limb Orthopaedic Surgery in Children With Cerebral Palsy: Reliability of the Modified Clavien-Dindo System.

BACKGROUND: The modified Clavien-Dindo (MCD) system is a reliable tool for classifying adverse events (AEs) in hip preservation surgery and has since been utilized in studies involving lower limb surgery for ambulant and nonambulant children with cerebral palsy (CP). However, the profile of AEs recorded in children with CP compared with typically developing children is different, and the reliability of the MCD in CP is unknown. This study aimed to evaluate the interrater and intrarater reliability of the MCD system for classifying AEs following lower limb surgery in children with CP. METHODS: Eighteen raters were invited to participate, including clinicians from surgical, nursing, and physical therapy professions, and individuals with CP. Following a MCD familiarization session, participants rated 40 clinical scenarios on 2 occasions, 2 weeks apart. Fleiss' κ statistics were used to calculate interrater and intrarater reliability. RESULTS: The overall Fleiss' κ value for interrater reliability in the first rating was 0.70 (95% confidence interval, 0.61-0.80), and increased to 0.75 (95% confidence interval, 0.66-0.84) in the second rating. The average Fleiss' κ value for intrarater reliability was 0.78 (range, 0.48 to 1.00). Grading of more severe AEs (MCD III to V) achieved near perfect agreement (κ, 0.87 to 1.00). There was a lower level of agreement for minor AEs (MCD I-II) (κ, 0.53 to 0.55). A κ score of 0 to 0.2 was deemed as poor, 0.21 to 0.4 as fair, 0.41 to 0.6 as good, 0.61 to 0.8 as very good, and 0.81 to 1.0 as almost perfect agreement. CONCLUSIONS: The MCD System demonstrates a very good interrater and intrarater reliability following lower limb surgery in children with CP. The MCD can be used by clinicians from different health care professions with a high level of reliability. The MCD may improve standardization of AE recording with a view to accurate audits and improved clarity in outcome studies for CP. LEVEL OF EVIDENCE: Level II-diagnostic.

Estimating Direct Cost of Cystic Fibrosis Care Using Irish Registry Healthcare Resource Utilisation Data, 2008-2012.

BACKGROUND: Understanding the determinants of cost of cystic fibrosis (CF) care and health outcomes may be useful for financial planning for the delivery of CF services. Registries contain information otherwise unavailable to healthcare activity/cost monitoring systems. We estimated the direct medical cost of CF care using registry data and examined how cost was affected by patient characteristics and CF gene (CF Transmembrane Conductance Regulator [CFTR]) mutation. METHODS: Healthcare resource utilisation data (2008-2012) were obtained for CF patients enrolled with the Irish CF Registry by 2013 from linked registry and national hospitalisation database records. Mean annual hospitalisation and medication per-patient costs were estimated by demographic profile, CFTR mutation, clinical status, and CF co-morbidity, and were presented in 2014 euro values. A mixed-effects regression model was used to examine the effect of demographic, CFTR mutation, and clinical outcomes on the log10 cost of direct medical CF care. RESULTS: Using 4261 observations from 1100 patients, we found that the median annual total cost per patient increased over the period 2008-2012 from €12,659 to €16,852, inpatient bed-day cost increased from €14,026 to €17,332, and medication cost increased from €5863 to €12,467. Homozygous F508-CFTR mutation (class II) cost was highest and milder mutation (class IV/V) cost was 49% lower. Baseline estimated cost in 2008 for a hypothetical underweight, homozygous F508del-CFTR 6-year-old female without chronic Pseudomonas aeruginosa/Staphylococcus aureus, CF-related diabetes (CFRD) or methicillin-resistant S. aureus (MRSA), and with a poor percent predicted forced expiratory volume in 1 s (ppFEV1) was €10,113, and was €21,082 in a 25-year-old with the same hypothetical profile. Chronic P. aeruginosa infection increased baseline cost by 39%, CF co-morbidity diabetes by 18%, and frequency of pulmonary exacerbation by 15%. Underweight, declining ppFEV1, chronic S. aureus colonisation, and time also influenced cost. CONCLUSIONS: CFTR mutation is an important factor influencing the cost of CF care. Costs differ among cohorts of CF patients eligible to access new and emerging CFTR repair therapies. These findings support the evaluation of outcome-associated cost in CFTR mutation-specific CF patient groups.

Restoring Cystic Fibrosis Transmembrane Conductance Regulator Function Reduces Airway Bacteria and Inflammation in People with Cystic Fibrosis and Chronic Lung Infections.

RATIONALE: Previous work indicates that ivacaftor improves cystic fibrosis transmembrane conductance regulator (CFTR) activity and lung function in people with cystic fibrosis and G551D-CFTR mutations but does not reduce density of bacteria or markers of inflammation in the airway. These findings raise the possibility that infection and inflammation may progress independently of CFTR activity once cystic fibrosis lung disease is established. OBJECTIVES: To better understand the relationship between CFTR activity, airway microbiology and inflammation, and lung function in subjects with cystic fibrosis and chronic airway infections. METHODS: We studied 12 subjects with G551D-CFTR mutations and chronic airway infections before and after ivacaftor. We measured lung function, sputum bacterial content, and inflammation, and obtained chest computed tomography scans. MEASUREMENTS AND MAIN RESULTS: Ivacaftor produced rapid decreases in sputum Pseudomonas aeruginosa density that began within 48 hours and continued in the first year of treatment. However, no subject eradicated their infecting P. aeruginosa strain, and after the first year P. aeruginosa densities rebounded. Sputum total bacterial concentrations also decreased, but less than P. aeruginosa. Sputum inflammatory measures decreased significantly in the first week of treatment and continued to decline over 2 years. Computed tomography scans obtained before and 1 year after ivacaftor treatment revealed that ivacaftor decreased airway mucous plugging. CONCLUSIONS: Ivacaftor caused marked reductions in sputum P. aeruginosa density and airway inflammation and produced modest improvements in radiographic lung disease in subjects with G551D-CFTR mutations. However, P. aeruginosa airway infection persisted. Thus, measures that control infection may be required to realize the full benefits of CFTR-targeting treatments.

Relationship between pulmonary hyperinflation and dyspnoea severity during acute exacerbations of cystic fibrosis.

BACKGROUND AND OBJECTIVE: Acute exacerbations of cystic fibrosis (CF) occur frequently throughout the course of the disease. Dyspnoea is the most common and distressing symptom experienced by patients during these episodes. We tested the hypothesis that pulmonary hyperinflation is an important determinant of dyspnoea severity during acute exacerbations. METHODS: We studied patients during an acute exacerbation of CF. Lung volumes, spirometry and dyspnoea scores were measured at Day 0, Day 7, at the end of treatment (EOT) and 14 days following the EOT. RESULTS: At the start of treatment, mean residual volume (RV)/total lung capacity (TLC) was 54.9%, which decreased significantly with treatment, as did vital capacity (VC), inspiratory capacity (IC) and dyspnoea scores. IC was the only independent predictor of dyspnoea severity. CONCLUSION: Our study demonstrates significant improvements in hyperinflation, spirometry and dyspnoea scores with treatment of acute exacerbations of CF. Hyperinflation, rather than airflow limitation, may contribute towards the increased dyspnoea during exacerbations.

Acute administration of ivacaftor to people with cystic fibrosis and a G551D-CFTR mutation reveals smooth muscle abnormalities.

BACKGROUND: Airflow obstruction is common in cystic fibrosis (CF), yet the underlying pathogenesis remains incompletely understood. People with CF often exhibit airway hyperresponsiveness, CF transmembrane conductance regulator (CFTR) is present in airway smooth muscle (ASM), and ASM from newborn CF pigs has increased contractile tone, suggesting that loss of CFTR causes a primary defect in ASM function. We hypothesized that restoring CFTR activity would decrease smooth muscle tone in people with CF. METHODS: To increase or potentiate CFTR function, we administered ivacaftor to 12 adults with CF with the G551D-CFTR mutation; ivacaftor stimulates G551D-CFTR function. We studied people before and immediately after initiation of ivacaftor (48 hours) to minimize secondary consequences of CFTR restoration. We tested smooth muscle function by investigating spirometry, airway distensibility, and vascular tone. RESULTS: Ivacaftor rapidly restored CFTR function, indicated by reduced sweat chloride concentration. Airflow obstruction and air trapping also improved. Airway distensibility increased in airways less than 4.5 mm but not in larger-sized airways. To assess smooth muscle function in a tissue outside the lung, we measured vascular pulse wave velocity (PWV) and augmentation index, which both decreased following CFTR potentiation. Finally, change in distensibility of <4.5-mm airways correlated with changes in PWV. CONCLUSIONS: Acute CFTR potentiation provided a unique opportunity to investigate CFTR-dependent mechanisms of CF pathogenesis. The rapid effects of ivacaftor on airway distensibility and vascular tone suggest that CFTR dysfunction may directly cause increased smooth muscle tone in people with CF and that ivacaftor may relax smooth muscle. FUNDING: This work was funded in part from an unrestricted grant from the Vertex Investigator-Initiated Studies Program.

Chest CT abnormalities and quality of life: relationship in adult cystic fibrosis.

BACKGROUND: To evaluate the relationship between lung parenchymal abnormalities on chest CT and health-related quality of life in adult cystic fibrosis (CF). METHODS: The chest CT scans of 101 consecutive CF adults (mean age 27.8±7.9, 64 males) were prospectively scored by two blinded radiologists in consensus using a modified Bhalla score. Health-related quality of life was assessed using the revised Quittner Cystic Fibrosis Questionnaire (CFQ-R). Multiple regressions were performed with each of the CFQ-R domains and all clinical and imaging findings to assess independent correlations. RESULTS: There were 18 inpatients and 83 outpatients. For the cohort of inpatients, CT abnormalities were significantly (P<0.005 for all) associated with Respiratory Symptoms (Air Trapping), and also with Social Functioning (Consolidation) and Role Functioning (Consolidation). For outpatients, CT abnormalities were significantly (P<0.005 for all) associated with Respiratory Symptoms (Consolidation) and also with Physical Functioning (Consolidation), Vitality (Consolidation, Severity of Bronchiectasis), Eating Problems (airway wall thickening), Treatment Burden (Total CT Score), Body Image (Severity of Bronchiectasis) and Role Functioning (Tree-in-bud nodules). Consolidation was the commonest independent CT predictor for both inpatients (predictor for 2 domains) and outpatients (predictor in 3 domains). Several chest CT abnormalities excluded traditional measures such as FEV1 and BMI from the majority of CFQ-R domains. CONCLUSIONS: Chest CT abnormalities are significantly associated with quality of life measures in adult CF, independent of clinical or spirometric measurements.