Abstract
Rationale
Primary ciliary dyskinesia (PCD), an inherited lung disease, is characterized by abnormal ciliary function leading to progressive bronchiectasis. There is wide variability in respiratory disease severity at birth and later in life.
Objectives
To evaluate the association between neonatal hospital length of stay (neonatal-LOS) and supplemental oxygen duration (SuppO2) with lung function in pediatric PCD. We hypothesized that longer neonatal-LOS and SuppO2 are associated with worse lung function (i.e., forced expiratory volume in 1 second percent predicted [FEV1pp]).
Methods
We performed a secondary analysis of the Genetic Disorders of Mucociliary Clearance Consortium prospective longitudinal multicenter cohort study. Participants enrolled, during 2006–2011, were <19 years old with a confirmed PCD diagnosis and followed annually for 5 years. The exposure variables were neonatal-LOS and SuppO2, counted in days since birth. The outcome, FEV1pp, was measured annually by spirometry. The associations of neonatal-LOS and SuppO2 with FEV1pp were evaluated with a linear mixed-effects model with repeated measures and random intercepts, adjusted for age and ciliary ultrastructural defects.
Results
Included were 123 participants (male, 47%; mean enrollment age, 8.3 yr [range, 0 to 18 yr]) with 578 visits (median follow-up, 5 yr). The median neonatal-LOS was 9 d (range, 1 to 90 d), and median SuppO2 was 5 d (range, 0 to 180 d). Neonatal-LOS was associated with worse lung function (−0.27 FEV1pp/d [95% confidence interval, −0.53 to −0.01]; P = 0.04). SuppO2 was not associated with lung function.
Conclusions
Neonatal-LOS is associated with worse lung function in pediatric PCD, independent of age and ultrastructural defects. Future research on the mechanisms of neonatal respiratory distress and its management may help us understand the variability of lung health outcomes in PCD.
Keywords: primary ciliary dyskinesia, pediatric, neonatal, lung function
Primary ciliary dyskinesia (PCD) is an inherited, chronic airway disease characterized by abnormal ciliary function and impaired mucociliary clearance. Pediatric patients with PCD often manifest their first symptoms in the neonatal period, within 12–48 hours of birth, with neonatal respiratory distress (reported frequency, 24–91%) requiring prolonged hospitalization and supplemental oxygen (1–4). The severity of neonatal respiratory distress is variable with an average neonatal hospital length of stay ranging from 2 weeks to as long as a few months, with some infants requiring home oxygen after discharge (1–3). Despite neonatal respiratory distress being an early clinical presentation of PCD, the diagnosis is not typically made at birth but usually later in childhood or even in adulthood (5).
Recurrent pulmonary infections in people with PCD lead to progressive bronchiectasis, worsening airway obstruction, lung function decline, and impaired quality of life (3, 6–11). However, the severity of lung disease is variable with some adults having relatively well-preserved lung function whereas others may require lung transplantation (12). Identifying more severe phenotypes can be important for initiating or intensifying therapies to slow lung disease progression. Previous PCD studies have identified specific genotypes and ciliary ultrastructural defects determined with transmission electron microscopy (EM-defect) as risk factors for worse lung function (11). In addition, a recent study using topological data analysis found that patients with PCD without neonatal respiratory distress had better lung function than patients with neonatal respiratory distress (13). The association between the severity of neonatal illness and lung function in PCD has not been previously studied.
Our study objective was to evaluate the association of neonatal PCD clinical manifestations, specifically the hospital length of stay and supplemental oxygen duration, with subsequent lung function in pediatric patients. We hypothesized that longer hospital length of stay and supplemental oxygen duration would be associated with worse lung function.
Methods
Study Design
This secondary analysis used data from the Genetic Disorders of Mucociliary Clearance Consortium prospective longitudinal multi-center cohort study (NCT00450918 and NCT00722878) (1, 11). Participants in the study were enrolled at seven North American PCD centers between 2006 and 2011 and followed annually for 5 years for a total of six visits (11). In the original study analyses, participants 1) had a confirmed PCD diagnosis based on genotype or EM-defect, 2) were <19 years old at the time of enrollment, and 3) had at least two clinical site visits during the study. For our study, we further excluded participants who did not have any reproducible percent-predicted forced expiratory volume in 1 second (FEV1pp), were born prematurely (birth before 37 weeks’ gestation), and had complex congenital heart disease or other major congenital malformations. The participant enrollment flowchart is shown in Figure 1. Institutional review board or research ethics board approvals and informed consents and/or assents were obtained at each participating site.
Figure 1.
Flowchart of participant enrollment. FEV1pp = forced expiratory volume in 1 second percent predicted; PCD = primary ciliary dyskinesia.
Study Variables
The exposure variables of interest were neonatal hospital length-of-stay (neonatal-LOS) and duration of supplemental oxygen use in the neonatal period (SuppO2). Neonatal-LOS was defined as the continuous duration of time in days that the participant was admitted to the hospital since birth (i.e., minimum neonatal-LOS is 1 d). SuppO2 was defined as the continuous duration of time in days that the participant was on supplemental oxygen since birth. The exposure variables were collected at the time of study enrollment by parental report on standardized questionnaires. These reports were verified with medical records whenever possible.
The outcome variable was FEV1pp, calculated using the ERS Global Lung Function Initiative reference equations (14). We included all FEV1pp measurements from all study visits that met American Thoracic Society criteria for acceptability and reproducibility (15).
Potential confounding included age, PCD genotype, and EM-defect, classified as 1) outer dynein arm (ODA); 2) outer dynein arm and inner dynein arm (ODA/IDA); 3) absence of inner dynein arm with central apparatus and microtubular disorganization (IDA/CA/MTD); 4) normal ultrastructure on electron microscopy with genotype consistent with PCD (normal EM); 5) isolated central apparatus (CA); and 6) oligocilia. These variables and their associations with our main exposure and outcome variables are shown in the directed acyclic graph (Figure E1 in the data supplement).
Statistical Analysis
We described the population demographics and the variables of interest for the entire cohort, stratified by the EM-defect.
We evaluated the associations of our exposures of interest (i.e., neonatal-LOS and SuppO2) with FEV1pp using linear mixed-effects model with random intercepts and repeated measures. Genotype was confirmed to be collinear with EM-defect and therefore not included in the models. We first examined a model that used fixed effects for age, neonatal-LOS, SuppO2, and EM-defects. Given the skewed distribution of the exposure variables, we tested models that used splines to see how they might impact our results. Spline parameters were chosen as per published statistical recommendations (16). Model test statistics, using the lowest Akaike information criterion, were used to select the best model (17).
Because there is already a well-known association between lung function and EM-defect (11), we next sought to determine if the associations between our exposure variables (i.e., neonatal-LOS and SuppO2) and lung function were dependent on EM-defect. We did this by testing the interaction between EM-defect and exposure variables (i.e., neonatal-LOS and SuppO2) on FEV1pp. We also tested the interaction of age and the exposure variables on FEV1pp.
Finally, we conducted sensitivity analyses using right censoring (i.e., setting maximum duration for neonatal-LOS to be 30 d and SuppO2 to be 50 d) and truncating (i.e., removal of participants with neonatal-LOS of >30 d or SuppO2 of >50 d) of the exposure variables.
Statistical significance was defined as a two-tailed P < 0.05. Analyses were completed using RStudio Team 2015 (RStudio, Inc.).
Results
Of the 137 participants in the prospective cohort study, we excluded 9 subjects owing to absence of any acceptable FEV1pp and another 5 who were born prematurely. Among the 123 participants included in our analysis, there were 578 visits (median, 6; range, 1–6 visits per participant). The average enrollment age was 8.3 years (standard deviation, 4.6), and 58 (47.2%) were male (Table 1). Overall, 120 (97.6%) had chronic nasal congestion, 122 (99.2%) chronic wet cough, 116 (94.3%) otitis media, 60 (48.8%) laterality defect, and 99 (80.5%) presented with neonatal respiratory distress. A total of 86 (66.7%) required SuppO2 in the neonatal period. The median neonatal-LOS was 9 days (range, 1–90 d), and median SuppO2 was 5 days (range, 0–180 d). Figure 2 shows the distribution of neonatal-LOS. There were 51 participants with isolated ODA defects, 19 with ODA/IDA defects, 34 with IDA/CA/MTD defects, 10 with normal ciliary ultrastructure, 5 with an isolated CA defect, and 4 with oligocilia. As expected, the specific genotypes and EM-defects were highly correlated (Table 2).
Table 1.
Baseline characteristics of study participants overall and stratified by ciliary ultrastructural defect
| Overall | ODA | ODA/IDA | IDA/CA/MTD | Normal EM | Isolated CA | Oligocilia* | |
|---|---|---|---|---|---|---|---|
| (n = 123) | (n = 51) | (n = 19) | (n = 34) | (n = 10) | (n = 5) | (n = 4) | |
| Male, n (%) | 58 (47.2%) | 24 (47.1%) | 12 (63.2%) | 15 (44.1%) | 3 (30.0%) | 1 (20.0%) | 3 (75.0%) |
| Age at enrollment, year, mean (SD) | 8.30 (4.55) | 9.37 (4.03) | 7.63 (5.72) | 6.85 (4.47) | 10.1 (3.90) | 9.20 (4.55) | 4.5 (1.91) |
| Age at diagnosis, year, mean (SD) | 4.24 (3.90) | 5.07 (4.48) | 3.39 (3.40) | 2.86 (3.12) | 5.75 (2.93) | 6.40 (3.29) | 2.88 (1.44) |
| FEV1pp at enrollment, mean (SD)† | 82.8 (19.4) | 88.2 (17.6) | 85.5 (21.4) | 71.0 (19.1) | 86.1 (16.4) | 80.9 (9.50) | NA |
| FEV1 z-score at enrollment, mean (SD)† | −1.46 (1.56) | −0.95 (1.45) | −1.35 (1.60) | −2.38 (1.50) | −1.18 (1.41) | −1.61 (0.79) | NA |
| Clinical features, n (%) | |||||||
| Laterality defect | 60 (48.8%) | 29 (56.9%) | 9 (47.4%) | 16 (47.1%) | 6 (60.0%) | 0 (0.0%) | 0 (0.0%) |
| Chronic nasal congestion | 120 (97.6%) | 50 (98.0%) | 18 (94.7%) | 33 (97.1%) | 10 (100%) | 5 (100%) | 4 (100%) |
| Chronic wet cough | 122 (99.2%) | 51 (100%) | 19 (100%) | 33 (97.1%) | 10 (100%) | 5 (100%) | 4 (100%) |
| Otitis media | 116 (94.3%) | 49 (96.1%) | 18 (94.7%) | 31 (91.2%) | 9 (90.0%) | 5 (100%) | 4 (100%) |
| Neonatal respiratory distress | 99 (80.5%) | 40 (78.4%) | 17 (89.5%) | 29 (85.3%) | 8 (80.0%) | 3 (60.0%) | 2 (50.0%) |
| Exposure variables, median (range) | |||||||
| neonatal-LOS, d, median (range) | 9 (1 to 90) | 8 (1 to 35) | 10 (1 to 21) | 11.5 (1 to 90) | 7 (1 to 14) | 10 (1 to 12) | 7.5 (1 to 17) |
| SuppO2, d, median (range) | 5 (0 to 180) | 5 (0 to 90) | 5 (0 to 180) | 8.5 (0 to 180) | 0 (0 to 10) | 0 (0 to 9) | 5 (0 to 180) |
Definition of abbreviations: CA = central apparatus; EM = electron microscopy; FEV1pp = forced expiratory volume in 1 second percent predicted; IDA = inner dynein arm; MTD = microtubular disorganization; NA = not applicable; neonatal-LOS = neonatal hospital length of stay in days since birth; ODA = outer dynein arm; SD = standard deviation; SuppO2 = supplemental oxygen duration in days since birth.
Oligocilia sample consisted of two identical twins and two siblings.
A total of 34 participants had missing FEV1pp at enrollment owing to the inability to perform an acceptable reproducible maneuver.
Figure 2.
Number of participants with a given neonatal hospital length of stay
Table 2.
Primary ciliary dyskinesia genotype of study participants overall and stratified by ciliary ultrastructural defect
| Total | ODA | ODA/IDA | IDA/CA/MTD | Normal EM | Isolated CA | Oligocilia | |
|---|---|---|---|---|---|---|---|
| (n = 123) | (n = 51) | (n = 19) | (n = 34) | (n = 10) | (n = 5) | (n = 4) | |
| Genotype, n (%) | |||||||
| Not yet identified | 12 (9.8%) | 3 (5.9%) | 3 (15.8%) | 5 (14.7%) | — | 1 (20.0%) | — |
| CCDC39 | 14 (11.4%) | — | — | 14 (41.2%) | — | — | — |
| CCDC40 | 15 (12.2%) | — | — | 15 (44.1%) | — | — | — |
| CCDC114 | 2 (1.6%) | 2 (3.9%) | — | — | — | — | — |
| DNAH5 | 34 (27.6%) | 34 (66.7%) | — | — | — | — | — |
| DNAI1 | 7 (5.7%) | 7 (13.7%) | — | — | — | — | — |
| DNAI2 | 5 (4.1%) | 5 (9.8%) | — | — | — | — | — |
| CCDC103 | 2 (1.6%) | — | 2 (10.5%) | — | — | — | — |
| DNAAF1 | 2 (1.6%) | — | 2 (10.5%) | — | — | — | — |
| DNAAF2 | 1 (0.8%) | — | 1 (5.3%) | — | — | — | — |
| DNAAF3 | 1 (0.8%) | — | 1 (5.3%) | — | — | — | — |
| DYX1C1 | 3 (2.4%) | — | 3 (15.8%) | — | — | — | — |
| HEATR2 | 2 (1.6%) | — | 2 (10.5%) | — | — | — | — |
| LLRC6 | 2 (1.6%) | — | 2 (10.5%) | — | — | — | — |
| PIH1D3 | 1 (0.8%) | — | 1 (5.3%) | — | — | — | — |
| SPAG1 | 2 (1.6%) | — | 2 (10.5%) | — | — | — | — |
| CCNO | 4 (3.3%) | — | — | — | — | — | 4 (100%) |
| RSPH1 | 1 (0.8%) | — | — | — | — | 1 (20.0%) | — |
| RSPH4A | 2 (1.6%) | — | — | — | — | 2 (40.0%) | — |
| RSPH9 | 1 (0.8%) | — | — | — | — | 1 (20.0%) | — |
| DNAH11 | 9 (7.3%) | — | — | — | 9 (90.0%) | — | — |
| RPGR | 1 (0.8%) | — | — | — | 1 (10.0%) | — | — |
Definition of abbreviations: CA = central apparatus; EM = electron microscopy; IDA = inner dynein arm; MTD = microtubular disorganization; ODA = outer dynein arm.
The median (range) duration of neonatal-LOS was longest in IDA/CA/MTD defects at 11.5 days (1–90 d), followed by ODA/IDA defects at 10 days (1–21 d), isolated CA defects at 10 days (1–12 d), ODA defect at 8 days (1–35 d), oligocilia at 7.5 days (1–17 d), and normal ciliary ultrastructure at 7 days (1–14 d). The median (range) duration of SuppO2 was longest in IDA/CA/MTD at 8.5 days (0–180 d), followed by ODA/IDA defects at 5 days (0–180 d), ODA defect at 5 days (0–90 d), oligocilia at 5 days (0–180 d), normal ciliary ultrastructure at 0 days (0–10 d), and isolated CA defect at 0 days (0–9 d) (Table 1 and Figures E3–E7).
Longer neonatal-LOS was associated with worse lung function (−0.27 FEV1pp per hospital day [95% confidence interval: −0.53 to −0.01]; P = 0.04) independent of the patient’s age and ciliary ultrastructural defect. There was no association between SuppO2 and lung function (0.07 FEV1pp per day receiving oxygen support [95% confidence interval, −0.01 to 0.16]; P = 0.09) (Table 3 and Figure E2). Adding the age of diagnosis to the model did not change the associations. Alternate statistical models, including using splines to model a nonlinear relationship between FEV1pp and age, did not improve the fit of the model (Table E1). There were no statistically significant interactions between exposure variables and either EM-defect or age.
Table 3.
Association between neonatal hospital length of stay and supplemental oxygen duration in the neonatal period with forced expiratory volume in 1 second percent predicted in pediatric primary ciliary dyskinesia
| Covariate | Sample Size | Regression Coefficient (per day) | 95% Confidence Interval | SE | P Value |
|---|---|---|---|---|---|
| neonatal-LOS | n = 123, N = 578 | −0.27 | −0.53 to −0.01 | 0.13 | 0.04 |
| SuppO2 | 0.07 | −0.01 to 0.16 | 0.04 | 0.09 |
Definition of abbreviations: FEV1pp = percent predicted forced expiratory volume in 1 second by global lung function initiative equations; n = number of participants; N = number of data points; neonatal-LOS = neonatal hospital length of stay in days since birth; SE = standard error; SuppO2 = supplemental oxygen duration in days since birth.
The regression coefficients correspond to the estimated difference in FEV1pp response associated with a 1-unit change in the covariate. The regression coefficients were calculated from the linear mixed effects model with repeated measures (i.e., repeated lung function measures during each follow-up) and random intercept. The outcome variable for the model was FEV1pp and the exposure variables were neonatal-LOS and SuppO2. The model was adjusted for participant’s age and ciliary ultrastructural defect on transmission electron microscopy (fixed effects) and participant (random effect).
Sensitivity analyses showed that neither right censoring nor truncation of our exposure variables changed the associations between neonatal-LOS or SuppO2 and FEV1pp.
Discussion
In this multicenter, North American cohort study of pediatric patients with a confirmed diagnosis of PCD, we found that longer neonatal-LOS was associated with worse lung function, even after adjustment for ciliary ultrastructural defect and the patient’s age. The magnitude of association between neonatal-LOS and lung function may at first glance appear small relative to age and ciliary ultrastructural defect (11), but it is important to note that the units for neonatal-LOS was in days. For instance, if we took two patients with PCD with identical ages, sex, and EM-defects, our study shows that for a patient with a neonatal-LOS of 3 days (i.e., 25th percentile for neonatal-LOS) versus 15 days (i.e., 75th percentile for neonatal-LOS), the expected difference in lung function, FEV1pp, would be 11.7%. Therefore, a longer neonatal-LOS may be associated with a clinically significant decrement in FEV1pp. This novel finding suggests that in addition to ciliary ultrastructural defect and genotype, the neonatal manifestations of PCD may hold clues to identifying more severe pulmonary phenotypes.
Interestingly, the duration of supplemental oxygen since birth was not significantly associated with lung function, which was unexpected. SuppO2 was right skewed, which may be owing to measurement bias in neonates who were discharged home with oxygen therapy. The discontinuation of oxygen therapy is considered on a daily basis in hospital, whereas at home this would be considered periodically by the outpatient healthcare provider, which may take place every few weeks or even months. However, our sensitivity analyses using right censoring or truncation of the oxygen therapy duration at 50 days did not change our result. In addition, duration of supplemental oxygen may be an unreliable proxy measure for lung disease, as practitioners’ thresholds for initiating and discontinuing oxygen therapy may vary based on practice preferences, perceptions of work of breathing, and suspicion for the diagnosis of chronic lung diseases such as PCD. In contrast, the duration of hospital stay may be more sensitive to comorbidities associated with lung disease in infants, such as difficulties in feeding and growing.
One of the key clinical features of PCD is neonatal respiratory distress (7), owing to its increased frequency (24–91%) (1–4) compared with the general population (5% of term infants) (2). The phenotype of neonatal respiratory distress in PCD (compared with term infants from the general population) typically has a later onset, requires prolonged oxygen therapy, and has an increased frequency of lobar collapse (2). This is different from neonatal respiratory distress in term infants who have transient tachypnea and present within the first few hours of life and only require oxygen for 1–2 days (2). The mechanism for PCD neonatal respiratory distress is not understood. Current research has shown that postnatal lung fluid resorption is mediated by the airway epithelial sodium channels (ENaC), and dysfunction in ENaC are associated with neonatal respiratory distress (18). ENaC are found on the ciliary surface of epithelial cells that line the airways (19) and may have an impact on the relative mucin concentration (20), suggesting a possible mechanism for PCD neonatal respiratory distress. Davis and colleagues previously demonstrated that patients with PCD with mutations in CCDC39/CCDC40 (corresponding to IDA/CA/MTD EM defects) had worse lung function (11). We found that these patients also had the longest neonatal-LOS. This association suggests that in PCD, neonatal-LOS could be a marker of lung disease severity. The apparent association between neonatal-LOS and subsequent lung function does not confirm causality. Additional studies determining the mechanism(s) involved in PCD neonatal respiratory distress are warranted and could provide insights into how early manifestations may be linked with future lung function. Moreover, further studies that include detailed data on respiratory therapies, such as the use of noninvasive ventilation, high-flow respiratory systems, and invasive ventilation, may help to further our understanding of PCD in the neonatal period and the impact on future lung function.
Strengths and Limitations
The strengths of our research include the use of a large multicenter, prospective, and geographically diverse PCD cohort and the availability of data on important confounders such as the participant’s genotype, ciliary ultrastructural defect, age, prematurity, and congenital malformations. We know from literature that the patient’s PCD genotype, ciliary ultrastructural defect and age are important risk factors that affect lung outcomes in PCD (11, 21), and our model accounts for these. We removed other potential confounders to the model by limiting our dataset to patients of term gestation and without complex congenital heart disease or other major malformations.
There are limitations to our study. First, the exposure variables were collected primarily using enrollment surveys which could lead to measurement error and recall bias, particularly with patients who were older (i.e., up to age 16) at enrollment (22) and from patients with more severe PCD disease. However, this would be expected to lead to random measurement error, which would bias our results toward the null, making our results more conservative. Second, we have used neonatal-LOS as a marker of more severe neonatal lung disease, and we do not have other objective measures, such as respiratory rate or infant pulmonary function testing, to validate this assumption. However, previously, Davis and colleagues (1) found that patients with PCD with IDA/CA/MTD ciliary ultrastructural defects had worse infant pulmonary function tests than those with ODA or ODA/IDA defects. This supports our hypothesis that neonatal-LOS could be a surrogate for more severe lung disease, as the IDA/CA/MTD group had the longest neonatal-LOS. By our study design, we excluded other major neonatal morbidities that may lead to increased hospital length of stay, such as congenital heart disease, major malformations, and prematurity.
Conclusions
We found that neonatal-LOS is significantly associated with lung function in a cohort of North American children with PCD followed into early adulthood. This suggests that neonatal-LOS may be an early marker of more severe PCD phenotypes in pediatrics. Understanding the mechanisms involved in this association, such as the role of ENaC channels and mucin concentrations, may lead to a better understanding of the variability in lung disease and potential treatments for patients with PCD. In addition, improving treatments for lung disease in the neonatal period may shorten neonatal-LOS and may also lead to improved lung health outcomes for people with PCD.
Acknowledgments
Acknowledgment
The authors thank Dr. Jaclyn Stonebraker and Elizabeth Schecterman for technical, and Dr. Hong Dang for the bioinformatics assistance. The authors thank Dr. Shrikant Mane and Dr. Francesc Lopez-Giraldez from the Yale Center for Mendelian Genomics (UM1 HG006504) for providing whole exome sequencing and bioinformatics support.
Footnotes
Supported by National Institutes of Health (NIH) grant U54HL096458. The Genetic Disorders of Mucociliary Clearance Consortium (U54HL096458) is part of the National Center for Advancing Translational Sciences (NCATS) Rare Diseases Clinical Research Network (RDCRN) and supported by the RDCRN Data Management and Coordinating Center (DMCC) (U2CTR002818). RDCRN is an initiative of the Office of Rare Diseases Research (ORDR) funded through a collaboration between NCATS and National Heart, Lung, and Blood Institute (NHLBI). S.D.S. was also supported by NIH/NCATS Colorado CTSA #UL1 TR002535. S.D.Dell was also supported by BCCHRI/UBC establishment grant. M.R.K. and M.A.Z. were additionally supported through the PCD-RO1 grant (NIH/NHLBI grant R01HL071798).
Author Contributions: S.D.Dell conceived the study. W.B.W. and S.D.Dell planned the initial analyses. M.W.L., S.D.Davis, M.R., K.M.S., M.G.S., T.W.F., M.R.K., C.M., M.A.Z., and S.D.Dell recruited patients to the study and collected data. W.B.W. and K.M.S. cleaned the data. W.B.W. conducted the analyses. E.P. supervised the statistical analyses. W.B.W., S.D.Dell and E.P. interpreted the data, with critical review from all authors. W.B.W. and S.D.Dell drafted the manuscript, and the remaining authors revised it critically for important intellectual content. All authors give final approval of the version to be submitted.
This article has a data supplement, which is accessible from this issue’s table of contents at www.atsjournals.org.
Author disclosures are available with the text of this article at www.atsjournals.org.
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