Azithromycin reduces bronchial wall thickening in infants with cystic fibrosis.

BACKGROUND: COMBAT-CF showed that children aged 0-3 years treated with azithromycin did clinically better than placebo but there was no effect on CT-scores. We reanalysed CTs using an automatic bronchus-artery (BA) analysis. METHOD: Inspiratory and expiratory CTs at 12 and 36 months were analysed. BA-analysis measures BA-diameters: bronchial outer wall (Bout), bronchial inner wall (Bin), artery (A), and bronchial wall thickness (Bwt) and computes BA-ratios: Bout/A and Bin/A for bronchial widening, Bwt/A and Bwa/Boa (bronchial wall area/bronchial outer area) for bronchial wall thickening. Low attenuation regions (LAR) were analysed using an automatic method. Mixed-effect model was used to compare BA-outcomes at 36 months between treatment groups. RESULTS: 228 CTs (59 placebo; 66 azithromycin) were analysed. The azithromycin group had lower Bwa/Boa (p = 0.0034) and higher Bin/A (p = 0.001) relative to placebo. Bout/A (p = 0.0088) was higher because of a reduction in artery diameters which correlated to a reduction in LAR. CONCLUSION: Azithromycin-treated infants with CF show a reduction in bronchial wall thickness and possibly a positive effect on lung perfusion.

Predicting lung function decline in cystic fibrosis: the impact of initiating ivacaftor therapy.

BACKGROUND: Modulator therapies that seek to correct the underlying defect in cystic fibrosis (CF) have revolutionized the clinical landscape. Given the heterogeneous nature of lung disease progression in the post-modulator era, there is a need to develop prediction models that are robust to modulator uptake. METHODS: We conducted a retrospective longitudinal cohort study of the CF Foundation Patient Registry (N = 867 patients carrying the G551D mutation who were treated with ivacaftor from 2003 to 2018). The primary outcome was lung function (percent predicted forced expiratory volume in 1 s or FEV1pp). To characterize the association between ivacaftor initiation and lung function, we developed a dynamic prediction model through covariate selection of demographic and clinical characteristics. The ability of the selected model to predict a decline in lung function, clinically known as an FEV1-indicated exacerbation signal (FIES), was evaluated both at the population level and individual level. RESULTS: Based on the final model, the estimated improvement in FEV1pp after ivacaftor initiation was 4.89% predicted (95% confidence interval [CI]: 3.90 to 5.89). The rate of decline was reduced with ivacaftor initiation by 0.14% predicted/year (95% CI: 0.01 to 0.27). More frequent outpatient visits prior to study entry and being male corresponded to a higher overall FEV1pp. Pancreatic insufficiency, older age at study entry, a history of more frequent pulmonary exacerbations, lung infections, CF-related diabetes, and use of Medicaid insurance corresponded to lower FEV1pp. The model had excellent predictive accuracy for FIES events with an area under the receiver operating characteristic curve of 0.83 (95% CI: 0.83 to 0.84) for the independent testing cohort and 0.90 (95% CI: 0.89 to 0.90) for 6-month forecasting with the masked cohort. The root-mean-square errors of the FEV1pp predictions for these cohorts were 7.31% and 6.78% predicted, respectively, with standard deviations of 0.29 and 0.20. The predictive accuracy was robust across different covariate specifications. CONCLUSIONS: The methods and applications of dynamic prediction models developed using data prior to modulator uptake have the potential to inform post-modulator projections of lung function and enhance clinical surveillance in the new era of CF care.

Structural Lung Disease and Clinical Phenotype in Bronchiectasis Patients: The EMBARC CT Study.

RATIONALE: Chest computed tomography -scans (CTs) are essential to diagnose and monitor bronchiectasis (BE). To date, little quantitative data is available about the nature and extent of structural lung abnormalities (SLA) on CTs of BE patients. OBJECTIVES: to investigate SLA on CTs of patients with bronchiectasis and the relationship of SLAs to clinical features using the European Bronchiectasis Registry (EMBARC) Methods: CTs from BE patients included in the EMBARC registry were analyzed using the validated Bronchiectasis Scoring Technique for CT (BEST-CT). BEST-CT subscores are expressed as % of total lung volume. Scored items are: atelectasis/consolidation (%ATCON), bronchiectasis with and without mucus plugging (%BEMP, %BEwMP), airway wall thickening (%AWT), mucus plugging (%MP), ground-glass opacities (%GGO), bullae (%BUL), airways and parenchyma (%A,%P). Four composite scores were calculated: Total BE (%TBE=%BEMP+%BEwMP), total MP (%TMP=%BEMP+%MP), total inflammatory changes (%TinF=%ATCON+%BEMP+%MP+%GGO) and total disease (%DIS= all but %A & %P).¬ Measurments and Main Results: CTs of 524 BE patients were analyzed. Mean (range) of subscores were: %TBE 4.6 (2.3-7.7), %TMP 4.2 (1.2-8.1), %TinF 8.3 (3.5-16.7) and %DIS 14.9 (9.1-25.9). BE associated with primary ciliary dyskinesia was associated with more SLA, while COPD was associated with less SLA. Lower FEV1, longer disease duration, Pseudomonas aeruginosa and NTM infection, and severe exacerbations were all independently associated with worse SLA. CONCLUSION: Patients with bronchiectasis have highly heterogeneous type and extent of structural lung abnormalities. Strong relationships between radiological disease and clinical features suggest CT analysis may be a useful tool for clinical phenotyping.

External Validation of a Dynamic Prediction Model for Upper Limb Function After Stroke.

Objective: To externally validate the dynamic prediction model for prediction of upper limb (UL) function 6 months after stroke. The dynamic prediction model has been developed and cross-validated on data from 4 Dutch studies. Design: Data from a prospective Danish cohort study were used to assess prediction accuracy. Setting: A Danish neurorehabilitation hospital. Participants: In this external validation study, follow-up data for 80 patients in the subacute phase after stroke (N=80), mean age 64 (SD11), 43% women, could be obtained. They were assessed at 2 weeks, 3 months, and 6 months after stroke with the Action Research Arm Test (ARAT), Fugl-Meyer Motor Assessment upper limb (FMA), and Shoulder Abduction (SA) Finger Extension (FE), (SAFE) test. Intervention: Not applicable. Main Outcome Measures: Prediction accuracy at 6 months was examined for 3 categories of ARAT (0-57 points): mild (48-57), moderate (23-47), and severe (0-22). Two individual predictions of ARAT scores at ±6 months post-stroke were computed based on, respectively, baseline (2 weeks) and 3 months ARAT, FE, SA values. The absolute individual differences between observed and predicted ARAT scores were summarized. Results: The prediction model performed best for patients with relatively good UL motor function, with an absolute error median (IQR) of 3 (2-9), and worst for patients with severe UL impairment, with a median (IQR) of 30 (3-39) at baseline. In general, prediction accuracy substantially improved when data obtained 3 months after stroke was included compared with baseline at 2 weeks after stroke. Conclusion: We found limited clinical usability due to the lack of prediction accuracy 2 weeks after stroke and for patients with severe UL impairments. The dynamic prediction model could probably be refined with data from biomarkers.

Establishing how much improvement in lung function and distance walked is clinically important for adult patients with Pompe disease.

BACKGROUND AND PURPOSE: Pompe disease is a rare, inheritable, progressive metabolic myopathy. This study aimed to estimate the minimal clinically important difference (MCID) for an improvement in forced vital capacity in the upright seated position (FVCup) and the 6-min walk test (6MWT) after a year of treatment with enzyme replacement therapy. METHODS: Data were obtained from two prospective follow-up studies. Between-group and within-group MCIDs were estimated using anchor-based methods. Additionally, a distribution-based method was used to generate supportive evidence. As anchors, self-reported change in health and in physical functioning, shortness of breath and a categorization of the Short-Form 36 Physical Component Summary score were used. Anchor appropriateness was assessed using Spearman correlations (absolute values ≥0.29) and a sufficient number of observations in each category. RESULTS: In all, 102 patients had at least one FVCup or 6MWT measurement during enzyme replacement therapy. Based on the anchors assessed as appropriate, the between-group MCID for an improvement in FVCup ranged from 2.47% to 4.83% points. For the 6MWT, it ranged from 0.35% to 7.47% points which is equivalent to a distance of 2.18-46.61 m and 1.97-42.13 m for, respectively, a man and a woman of age 50, height 1.75 m and weight 80 kg. The results of the distribution-based method were within these ranges when applied to change in the outcome values. CONCLUSION: The MCIDs for FVCup and 6MWT derived in this study can be used to interpret differences between and within groups of patients with Pompe disease in clinical trials and cohort studies.

Children with severe asthma have substantial structural airway changes on computed tomography.

Background: In adults with severe asthma (SA) bronchial wall thickening, bronchiectasis and low attenuation regions (LAR) have been described on chest computed tomography (CT) scans. The extent to which these structural abnormalities are present in children with SA is largely unknown. Our aim was to study the presence and extent of airway abnormalities on chest CT of children with SA. Methods: 161 inspiratory and expiratory CT scans, either spirometer-controlled or technician-controlled, obtained in 131 children with SA (mean±SD age 11.0±3.8 years) were collected retrospectively. Inspiratory scans were analysed manually using a semi-quantitative score and automatically using LungQ (v2.1.0.1; Thirona B.V., Nijmegen, the Netherlands). LungQ segments the bronchial tree, identifies the generation for each bronchus-artery (BA) pair and measures the following BA dimensions: outer bronchial wall diameter (Bout), adjacent artery diameter (A) and bronchial wall thickness (Bwt). Bronchiectasis was defined as Bout/A ≥1.1, bronchial wall thickening as Bwt/A ≥0.14. LAR, reflecting small airways disease (SAD), was measured automatically on inspiratory and expiratory scans and manually on expiratory scans. Functional SAD was defined as FEF25-75 and/or FEF75 z-scores <-1.645. Results are shown as median and interquartile range. Results: Bronchiectasis was present on 95.8% and bronchial wall thickening on all CTs using the automated method. Bronchiectasis was present on 28% and bronchial wall thickening on 88.8% of the CTs using the manual semi-quantitative analysis. The percentage of BA pairs defined as bronchiectasis was 24.62% (12.7-39.3%) and bronchial wall thickening was 41.7% (24.0-79.8%) per CT using the automated method. LAR was observed on all CTs using the automatic analysis and on 82.9% using the manual semi-quantitative analysis. Patients with LAR or functional SAD had more thickened bronchi than patients without. Conclusion: Despite a large discrepancy between the automated and the manual semi-quantitative analysis, bronchiectasis and bronchial wall thickening are present on most CT scans of children with SA. SAD is related to bronchial wall thickening.

Key inflammatory markers in bronchoalveolar lavage predict bronchiectasis progression in young children with CF.

INTRODUCTION: Inflammation appears early in cystic fibrosis (CF) pathogenesis, with specific elevated inflammatory markers in bronchoalveolar lavage fluid (BALF) correlating with structural lung disease. Our aim was to identify markers of airway inflammation able to predict bronchiectasis progression over two years with high sensitivity and specificity. METHODS: Children with CF with two chest computed tomography (CT) scans and bronchoscopies at a two-year interval were included (n= 10 at 1 and 3 years and n= 27 at 3 and 5 years). Chest CTs were scored for increase in bronchiectasis (Δ%Bx), using the PRAGMA-CF score. BALF collected with the first CT scan were analyzed for neutrophil% (n= 36), myeloperoxidase (MPO) (n= 25), neutrophil elastase (NE) (n= 26), and with a protein array for inflammatory and fibrotic markers (n= 26). RESULTS: MPO, neutrophil%, and inducible T-cell costimulator ligand (ICOSLG), but not clinical characteristics, correlated significantly with Δ%Bx. Evaluation of neutrophil%, NE, MPO, interleukin-8 (IL-8), ICOSLG, and hepatocyte growth factor (HGF), for predicting an increase of > 0.5% of Δ%Bx in two years, showed that IL-8 had the best sensitivity (82%) and specificity (73%). Neutrophil%, ICOSLG and HGF had sensitivities of 85, 82, and 82% and specificities of 59, 67 and 60%, respectively. The odds ratio for risk of >0.5% Δ%Bx was higher for IL-8 (12.4) than for neutrophil%, ICOSLG, and HGF (5.9, 5.3, and 6.7, respectively). Sensitivity and specificity were lower for NE and MPO). CONCLUSIONS: High levels of IL-8, neutrophil%, ICOSGL and HGF in BALF may be good predictors for progression of bronchiectasis in young children with CF.

Individualized Dynamic Prediction Model for Patient-Reported Voice Quality in Early-Stage Glottic Cancer.

OBJECTIVE: Early-stage glottic cancer (ESGC) is a malignancy of the head and neck. Besides disease control, preservation and improvement of voice quality are essential. To enable expectation management and well-informed decision-making, patients should be sufficiently counseled with individualized information on expected voice quality. This study aims to develop an individualized dynamic prediction model for patient-reported voice quality. This model should be able to provide individualized predictions at every time point from intake to the end of follow-up. STUDY DESIGN: Longitudinal cohort study. SETTING: Tertiary cancer center. METHODS: Patients treated for ESGC were included in this study (N = 294). The Voice Handicap Index was obtained prospectively. The framework of mixed and joint models was used. The prognostic factors used are treatment, age, gender, comorbidity, performance score, smoking, T-stage, and involvement of the anterior commissure. The overall performance of these models was assessed during an internal cross-validation procedure and presentation of absolute errors using box plots. RESULTS: The mean age in this cohort was 67 years and 81.3% are male. Patients were treated with transoral CO2 laser microsurgery (57.8%), single vocal cord irradiation up to (24.5), or local radiotherapy (17.5%). The mean follow-up was 43.4 months (SD 21.5). Including more measurements during prediction improves predictive performance. Including more clinical and demographic variables did not provide better predictions. Little differences in predictive performance between models were found. CONCLUSION: We developed a dynamic individualized prediction model for patient-reported voice quality. This model has the potential to empower patients and professionals in making well-informed decisions and enables tailor-made counseling.

Social-environmental phenotypes of rapid cystic fibrosis lung disease progression in adolescents and young adults living in the United States.

Background: Cystic fibrosis (CF) is a genetic disease but is greatly impacted by non-genetic (social/environmental and stochastic) influences. Some people with CF experience rapid decline, a precipitous drop in lung function relative to patient- and/or center-level norms. Those who experience rapid decline in early adulthood, compared to adolescence, typically exhibit less severe clinical disease but greater loss of lung function. The extent to which timing and degree of rapid decline are informed by social and environmental determinants of health (geomarkers) is unknown. Methods: A longitudinal cohort study was performed (24,228 patients, aged 6-21 years) using the U.S. CF Foundation Patient Registry. Geomarkers at the ZIP Code Tabulation Area level measured air pollution/respiratory hazards, greenspace, crime, and socioeconomic deprivation. A composite score quantifying social-environmental adversity was created and used in covariate-adjusted functional principal component analysis, which was applied to cluster longitudinal lung function trajectories. Results: Social-environmental phenotyping yielded three primary phenotypes that corresponded to early, middle, and late timing of peak decline in lung function over age. Geographic differences were related to distinct cultural and socioeconomic regions. Extent of peak decline, estimated as forced expiratory volume in 1 s of % predicted/year, ranged from 2.8 to 4.1 % predicted/year depending on social-environmental adversity. Middle decliners with increased social-environmental adversity experienced rapid decline 14.2 months earlier than their counterparts with lower social-environmental adversity, while timing was similar within other phenotypes. Early and middle decliners experienced mortality peaks during early adolescence and adulthood, respectively. Conclusion: While early decliners had the most severe CF lung disease, middle and late decliners lost more lung function. Higher social-environmental adversity associated with increased risk of rapid decline and mortality during young adulthood among middle decliners. This sub-phenotype may benefit from enhanced lung-function monitoring and personalized secondary environmental health interventions to mitigate chemical and non-chemical stressors.

Automatic analysis of bronchus-artery dimensions to diagnose and monitor airways disease in cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) lung disease is characterised by progressive airway wall thickening and widening. We aimed to validate an artificial intelligence-based algorithm to assess dimensions of all visible bronchus-artery (BA) pairs on chest CT scans from patients with CF. METHODS: The algorithm fully automatically segments the bronchial tree; identifies bronchial generations; matches bronchi with the adjacent arteries; measures for each BA-pair bronchial outer diameter (Bout), bronchial lumen diameter (Bin), bronchial wall thickness (Bwt) and adjacent artery diameter (A); and computes Bout/A, Bin/A and Bwt/A for each BA pair from the segmental bronchi to the last visible generation. Three datasets were used to validate the automatic BA analysis. First BA analysis was executed on 23 manually annotated CT scans (11 CF, 12 control subjects) to compare automatic with manual BA-analysis outcomes. Furthermore, the BA analysis was executed on two longitudinal datasets (Copenhagen 111 CTs, ataluren 347 CTs) to assess longitudinal BA changes and compare them with manual scoring results. RESULTS: The automatic and manual BA analysis showed no significant differences in quantifying bronchi. For the longitudinal datasets the automatic BA analysis detected 247 and 347 BA pairs/CT in the Copenhagen and ataluren dataset, respectively. A significant increase of 0.02 of Bout/A and Bin/A was detected for Copenhagen dataset over an interval of 2 years, and 0.03 of Bout/A and 0.02 of Bin/A for ataluren dataset over an interval of 48 weeks (all p<0.001). The progression of 0.01 of Bwt/A was detected only in the ataluren dataset (p<0.001). BA-analysis outcomes showed weak to strong correlations (correlation coefficient from 0.29 to 0.84) with manual scoring results for airway disease. CONCLUSION: The BA analysis can fully automatically analyse a large number of BA pairs on chest CTs to detect and monitor progression of bronchial wall thickening and bronchial widening in patients with CF.

Lung function and secondhand smoke exposure among children with cystic fibrosis: A Bayesian meta-analysis.

BACKGROUND: Secondhand smoke exposure, an important environmental health factor in cystic fibrosis (CF), remains uniquely challenging to children with CF as they strive to maintain pulmonary function during early stages of growth and throughout adolescence. Despite various epidemiologic studies among CF populations, little has been done to coalesce estimates of the association between secondhand smoke exposure and lung function decline. METHODS: A systematic review was performed using PRISMA guidelines. A Bayesian random-effects model was employed to estimate the association between secondhand smoke exposure and change in lung function (measured as FEV1% predicted). RESULTS: Quantitative synthesis of study estimates indicated that second-hand smoke exposure corresponded to a significant drop in FEV1 (estimated decrease: -5.11% predicted; 95% CI: -7.20, -3.47). The estimate of between-study heterogeneity was 1.32% predicted (95% CI: 0.05, 4.26). There was moderate heterogeneity between the 6 analyzed studies that met review criteria (degree of heterogeneity: I2=61.9% [95% CI: 7.3-84.4%] and p = 0.022 from the frequentist method.) CONCLUSIONS: Our results quantify the impact at the pediatric population level and corroborate the assertion that secondhand smoke exposure negatively affects pulmonary function in children with CF. Findings highlight challenges and opportunities for future environmental health interventions in pediatric CF care.

Automatic bronchus and artery analysis on chest computed tomography to evaluate the effect of inhaled hypertonic saline in children aged 3-6 years with cystic fibrosis in a randomized clinical trial.

BACKGROUND: SHIP-CT showed that 48-week treatment with inhaled 7% hypertonic saline (HS) reduced airway abnormalities on chest CT using the manual PRAGMA-CF method relative to isotonic saline (IS) in children aged 3-6 years with cystic fibrosis (CF). An algorithm was developed and validated to automatically measure bronchus and artery (BA) dimensions of BA-pairs on chest CT. Aim of the study was to assess the effect of HS on bronchial wall thickening and bronchial widening using the BA-analysis. METHODS: The BA-analysis (LungQ, version 2.1.0.1, Thirona, Netherlands) automatically segments the bronchial tree and identifies the segmental bronchi (G0) and distal generations (G1-G10). Dimensions of each BA-pair are measured: diameters of bronchial outer wall (Bout), bronchial inner wall (Bin), bronchial wall thickness (Bwt), and artery (A). BA-ratios are computed: Bout/A and Bin/A to detect bronchial widening and Bwt/A and Bwa/Boa (=bronchial wall area/bronchial outer area) to detect bronchial wall thickening. RESULTS: 113 baseline and 102 48-week scans of 115 SHIP-CT participants were analysed. LungQ measured at baseline and 48-weeks respectively 6,073 and 7,407 BA-pairs in the IS-group and 6,363 and 6,840 BA-pairs in the HS-group. At 48 weeks, Bwt/A (mean difference 0.011; 95%CI, 0.0017 to 0.020) and Bwa/Boa (mean difference 0.030; 95% 0.009 to 0.052) was significantly higher (worse) in the IS-group compared to the HS-group representing more severe bronchial wall thickening in the IS-group (p=0.025 and p=0.019 respectively). Bwt/A and Bwa/Boa decreased and Bin/A remained stable from baseline to 48 weeks in the HS while it declined in the IS-group (all p<0.001). There was no difference in progression of Bout/A between two treatment groups. CONCLUSION: The automatic BA-analysis showed a positive impact of inhaled HS on bronchial lumen and wall thickness, but no treatment effect on progression of bronchial widening over 48 weeks.

Association between changes in pulmonary function and in patient reported outcomes during enzyme therapy of adult patients with late-onset Pompe disease.

Pompe disease is a rare, progressive, and metabolic myopathy. Reduced pulmonary function is one of the main problems seen in adult patients with late-onset Pompe disease (LOPD). We aimed to explore the association between changes over time in pulmonary function and in patient-reported outcome measures (PROMs), in these patients treated with enzyme replacement therapy (ERT). This is a post hoc analysis of two cohort studies. Pulmonary function was assessed as forced vital capacity in the upright position (FVCup ). As PROMs, we assessed the physical component summary score (PCS) of the Medical Outcome Study 36-item Short-Form Health Survey (SF-36) and daily life activities (Rasch-Built Pompe-Specific Activity [R-PACT] scale). We fitted Bayesian multivariate mixed-effects models. In the models of PROMs, we assumed a linear association with FVCup , and adjusted for time (nonlinear), sex, and age and disease duration at the start of ERT. One hundred and one patients were eligible for analysis. PCS and R-PAct were positively associated with FVCup , while their relation with time was nonlinear (initial increase then decrease). A 1%-point increase in FVCup is expected to increase PCS by 0.14 points (95% Credible Interval: [0.09;0.19]) and R-PACT by 0.41 points [0.33;0.49] at the same time point. In the first year of ERT, we expect a change of PCS and R-PAct scores by +0.42 and +0.80 points, and in the 5th year of +0.16 and +0.45, respectively. We conclude that the physical domain of quality of life and daily life activities improve when FVCup increases during ERT.

Lung Function Decline in Cystic Fibrosis: Impact of Data Availability and Modeling Strategies on Clinical Interpretations.

Rationale: Studies estimating the rate of lung function decline in cystic fibrosis have been inconsistent regarding the methods used. How the methodology used impacts the validity of the results and comparability between studies is unknown. Objectives: The Cystic Fibrosis Foundation established a work group whose tasks were to examine the impact of differing approaches to estimating the rate of decline in lung function and to provide analysis guidelines. Methods: We used a natural history cohort of 35,252 individuals with cystic fibrosis aged ⩾6 years in the Cystic Fibrosis Foundation Patient Registry (CFFPR), 2003-2016. Modeling strategies using linear and nonlinear forms of marginal and mixed-effects models, which have previously quantified the rate of forced expiratory volume in 1 second (FEV1) decline (percent predicted per year), were evaluated under clinically relevant scenarios of available lung function data. Scenarios varied by sample size (overall CFFPR, medium-sized cohort of 3,000 subjects, and small-sized cohort of 150), data collection/reporting frequency (encounter, quarterly, and annual), inclusion of FEV1 during pulmonary exacerbation, and follow-up length (<2 yr, 2-5 yr, entire duration). Results: Rate of FEV1 decline estimates (percent predicted per year) differed between linear marginal and mixed-effects models; overall cohort estimates (95% confidence interval) were 1.26 (1.24-1.29) and 1.40 (1.38-1.42), respectively. Marginal models consistently estimated less rapid lung function decline than mixed-effects models across scenarios, except for short-term follow-up (both were ∼1.4). Rate of decline estimates from nonlinear models diverged by age 30. Among mixed-effects models, nonlinear and stochastic terms fit best, except for short-term follow-up (<2 yr). Overall CFFPR analysis from a joint longitudinal-survival model implied that an increase in rate of decline of 1% predicted per year in FEV1 was associated with a 1.52-fold (52%) increase in the hazard of death/lung transplant, but the results exhibited immortal cohort bias. Conclusions: Differences were as high as 0.5% predicted per year between rate of decline estimates, but we found estimates were robust to lung function data availability scenarios, except short-term follow-up and older age ranges. Inconsistencies among previous study results may be attributable to inherent differences in study design, inclusion criteria, or covariate adjustment. Results-based decision points reported herein will support researchers in selecting a strategy to model lung function decline most reflective of nuanced, study-specific goals.

Built environment factors predictive of early rapid lung function decline in cystic fibrosis.

BACKGROUND: The extent to which environmental exposures and community characteristics of the built environment collectively predict rapid lung function decline, during adolescence and early adulthood in cystic fibrosis (CF), has not been examined. OBJECTIVE: To identify built environment characteristics predictive of rapid CF lung function decline. METHODS: We performed a retrospective, single-center, longitudinal cohort study (n = 173 individuals with CF aged 6-20 years, 2012-2017). We used a stochastic model to predict lung function, measured as forced expiratory volume in 1 s (FEV1 ) of % predicted. Traditional demographic/clinical characteristics were evaluated as predictors. Built environmental predictors included exposure to elemental carbon attributable to traffic sources (ECAT), neighborhood material deprivation (poverty, education, housing, and healthcare access), greenspace near the home, and residential drivetime to the CF center. MEASUREMENTS AND MAIN RESULTS: The final model, which included ECAT, material deprivation index, and greenspace, alongside traditional demographic/clinical predictors, significantly improved fit and prediction, compared with only demographic/clinical predictors (Likelihood Ratio Test statistic: 26.78, p < 0.0001; the difference in Akaike Information Criterion: 15). An increase of 0.1 µg/m3 of ECAT was associated with 0.104% predicted/yr (95% confidence interval: 0.024, 0.183) more rapid decline. Although not statistically significant, material deprivation was similarly associated (0.1-unit increase corresponded to additional decline of 0.103% predicted/year [-0.113, 0.319]). High-risk regional areas of rapid decline and age-related heterogeneity were identified from prediction mapping. CONCLUSION: Traffic-related air pollution exposure is an important predictor of rapid pulmonary decline that, coupled with community-level material deprivation and routinely collected demographic/clinical characteristics, enhance CF prognostication and enable personalized environmental health interventions.

HER2-Low Breast Cancer: Incidence, Clinicopathologic Features, and Survival Outcomes From Real-World Data of a Large Nationwide Cohort.

Patients with breast cancer (BC) with low levels of human epidermal growth factor receptor 2 (HER2) expression (HER2-low) could benefit from novel antibody-drug conjugates. However, there is conflicting information regarding the characteristics of HER2-low BC and its outcome. We assessed the clinicopathologic characteristics and outcomes of HER2-low BC using real-world data from the Dutch National Pathology Registry. This retrospective study incorporated all patients with primary invasive BC, without neoadjuvant therapy, reported in the Dutch National Pathology Registry synoptic reporting module between 2014 and 2022. HER2 status was categorized as HER2-0 (defined as an immunohistochemistry score of 0 according to the current American Society of Clinical Oncology/College of American Pathologists guidelines) or HER2-low (immunohistochemistry score 1+ or 2+ without amplification). Clinicopathologic characteristics and overall survival of HER2-low BC were compared with HER2-0, adjusted for estrogen receptor (ER) status. We included 65,035 patients with BC, resulting in 69,424 tumors. The proportion of HER2-low BC was 62% in the ER+ cohort and 38% in the ER- cohort. A substantial number of patients had a different HER2 category between the needle biopsy and the corresponding surgical resection (28%) or among multiple tumors (28%). After multivariable logistic analysis, HER2-low tumors were significantly associated with histologic subtype, a higher ER, and lower progesterone receptor expression in the ER+ cohort, whereas within the ER-cohort, HER2-low tumors were associated with a lower tumor grade. However, the absolute differences were limited, and there was no significant difference in overall survival between HER2-low and HER2-0 tumors within the ER+ or ER- cohort. The classification of HER2 expression (HER2-0 vs HER2-low) varies between biopsies and corresponding resection specimens and within multiple tumors in the same patient, which could affect clinical decision making in case only HER2-low cases are eligible for novel HER2-targeting agents. The limited follow-up time and the lack of substantial clinicopathologic differences between HER2-low and HER2-0-cases could explain the lack of differences in overall survival.

Outcomes after right ventricular outflow tract reconstruction with valve substitutes: A systematic review and meta-analysis.

Introduction: This study aims to provide an overview of outcomes after right ventricular outflow tract (RVOT) reconstruction using different valve substitutes in different age groups for different indications. Methods: The literature was systematically searched for articles published between January 2000 and June 2021 reporting on clinical and/or echocardiographic outcomes after RVOT reconstruction with valve substitutes. A random-effects meta-analysis was conducted for outcomes, and time-related outcomes were visualized by pooled Kaplan-Meier curves. Subgroup analyses were performed according to etiology, implanted valve substitute and patient age. Results: Two hundred and seventeen articles were included, comprising 37,078 patients (age: 22.86 ± 11.29 years; 31.6% female) and 240,581 patient-years of follow-up. Aortic valve disease (Ross procedure, 46.6%) and Tetralogy of Fallot (TOF, 27.0%) were the two main underlying etiologies. Homograft and xenograft accounted for 83.7 and 32.6% of the overall valve substitutes, respectively. The early mortality, late mortality, reintervention and endocarditis rates were 3.36% (2.91-3.88), 0.72%/y (95% CI: 0.62-0.82), 2.62%/y (95% CI: 2.28-3.00), and 0.38%/y (95%CI: 0.31-0.47) for all patients. The early mortality for TOF and truncus arteriosus (TA) were 1.95% (1.31-2.90) and 10.67% (7.79-14.61). Pooled late mortality and reintervention rate were 0.59%/y (0.39-0.89), 1.41%/y (0.87-2.27), and 1.20%/y (0.74-1.94), 10.15%/y (7.42-13.90) for TOF and TA, respectively. Endocarditis rate was 0.21%/y (95% CI: 0.16-0.27) for a homograft substitute and 0.80%/y (95%CI: 0.60-1.09) for a xenograft substitute. Reintervention rate for infants, children and adults was 8.80%/y (95% CI: 6.49-11.95), 4.75%/y (95% CI: 3.67-6.14), and 0.72%/y (95% CI: 0.36-1.42), respectively. Conclusion: This study shows RVOT reconstruction with valve substitutes can be performed with acceptable mortality and morbidity rates for most patients. Reinterventions after RVOT reconstruction with valve substitutes are inevitable for most patients in their life-time, emphasizing the necessity of life-long follow-up and multidisciplinary care. Follow-up protocols should be tailored to individual patients because patients with different etiologies, ages, and implanted valve substitutes have different rates of mortality and morbidity. Systematic review registration: [www.crd.york.ac.uk/prospero], identifier [CRD42021271622].

Statistical primer: an introduction to the application of linear mixed-effects models in cardiothoracic surgery outcomes research-a case study using homograft pulmonary valve replacement data.

OBJECTIVES: The emergence of big cardio-thoracic surgery datasets that include not only short-term and long-term discrete outcomes but also repeated measurements over time offers the opportunity to apply more advanced modelling of outcomes. This article presents a detailed introduction to developing and interpreting linear mixed-effects models for repeated measurements in the setting of cardiothoracic surgery outcomes research. METHODS: A retrospective dataset containing serial echocardiographic measurements in patients undergoing surgical pulmonary valve replacement from 1986 to 2017 in Erasmus MC was used to illustrate the steps of developing a linear mixed-effects model for clinician researchers. RESULTS: Essential aspects of constructing the model are illustrated with the dataset including theories of linear mixed-effects models, missing values, collinearity, interaction, nonlinearity, model specification, results interpretation and assumptions evaluation. A comparison between linear regression models and linear mixed-effects models is done to elaborate on the strengths of linear mixed-effects models. An R script is provided for the implementation of the linear mixed-effects model. CONCLUSIONS: Linear mixed-effects models can provide evolutional details of repeated measurements and give more valid estimates compared to linear regression models in the setting of cardio-thoracic surgery outcomes research.