Annals of the American Thoracic Society

Rationale: Nonexpandable lung is a recognized phenomenon that can create management challenges in patients with mesothelioma. Its prevalence and clinical importance are unknown.

Objectives: The aim of this study was to describe the prevalence of nonexpandable lung and to evaluate whether there was any association between nonexpandable lung and survival in a clinical cohort of patients with mesothelioma.

Methods: This was a prospective, observational cohort study of patients with mesothelioma who were seen in a single center between March 1, 2008, and August 3, 2017. Baseline characteristics were collected at diagnosis. Serial chest radiographs were assessed for the presence of pleural effusions and nonexpandable lung (defined as a lack of lung expansion after pleural aspiration or drainage). Patients were followed until they died or were censored on March 14, 2019.

Results: Of 229 patients, 192 (82.7%) had a pleural effusion at presentation, and nonexpandable lung was observed in 64 of these 192 patients (33.3%). Breathlessness and cough were more frequent in patients with pleural effusions, especially in those with underlying nonexpandable lung, whereas chest pain was more prevalent in patients without effusions. Patients with pleural effusions, both with and without underlying nonexpandable lung, were more likely to have epithelioid or early-stage disease and to receive chemotherapy than patients with no pleural effusion. Nonexpandable lung was an independent risk factor for short survival, with a hazard ratio for mortality of 1.80 (95% confidence interval, 1.16–2.80) compared with patients without nonexpandable lung. The presence of a pleural effusion did not appear to be associated with a worse prognosis compared with patients with an effusion (adjusted hazard ratio, 1.86; 95% confidence interval, 0.93–3.72).

Conclusions: This is the first study to describe the prevalence and clinical implications of nonexpandable lung in mesothelioma. It demonstrates that nonexpandable lung is a relatively common phenomenon that is associated with significant symptomatology and shorter survival.

Keywords: mesothelioma; nonexpandable lung; pleural effusion

Malignant pleural mesothelioma (MPM) is an aggressive malignancy of the pleural surface (1, 2). It carries a poor prognosis, with a median survival of 9–15 months from diagnosis (35). Morbidity is high and patients often experience multiple symptoms, predominantly breathlessness and chest pain, but also cough, fatigue, and weight loss (3, 618). Some of these symptoms are the result of pleural effusions, which are common, although the reported prevalence varies widely in the literature (6, 12).

Nonexpandable lung (NEL) is a condition in which the lung is unable to inflate fully due to either proximal obstruction of the major bronchi or encasement of the lung by thickened pleura (19). Pleural thickening may reflect an ongoing active and potentially reversible process, e.g., pleural infection, in which case the lung is referred to as “entrapped,” or a fixed fibrotic phenomenon that persists after the active process has resolved, in which case the lung is considered “trapped.” In MPM, tumor spreads circumferentially around the lung and can form a thick rind, preventing lung expansion. Although this is an active process, it is also permanent, and consequently the terms “trapped” or “entrapped” overlap. For the purpose of this study, the term “NEL” is used to describe the failure of lung reexpansion for any reason after fluid removal.

NEL can be diagnosed radiographically as a lack of pleural apposition after drainage or aspiration. Alternative diagnostic approaches include pleural manometry and M-mode ultrasonography; however, the clinical utility of these methods appears to be limited (1921).

The presence of NEL complicates the management of MPM. Lack of pleural apposition makes chemical pleurodesis likely to fail (22), and although indwelling pleural catheters (IPCs) can alleviate symptoms, care must be taken during drainage because aggressive fluid removal can cause chest pain due to negative intrathoracic pressure creating tension on the nonexpanding lung (23). The role of debulking surgery to release the NEL and alleviate symptoms is uncertain, and is currently under investigation in a randomized controlled trial (MesoTRAP [A Study Comparing Video-assisted Thoracoscopic Partial Pleurectomy/Decortication with Indwelling Pleural Catheter in Patients with Trapped Lung Due to Malignant Pleural Mesothelioma]; Identifier: NCT03412357).

The prevalence of NEL in MPM is unknown. In one retrospective series of patients undergoing diagnostic medical thoracoscopy, NEL was detected in five out of 40 patients (12.5%) with malignant pleural disease (24). A randomized trial of patients with mixed malignant pleural effusions reported NEL in 41 out of 923 patients (4.4%) at screening, and a further 32 of 250 patients (12.5%) were found to have NEL after a 10-day run-in period (25). Whether these figures can be generalized to MPM populations, however, is not known, and it is conceivable that the prevalence is higher in MPM due to its circumferential growth pattern.

There are few data regarding the clinical implications of NEL. The British Thoracic Society emphasizes the importance of 50% pleural apposition on chest radiograph as a threshold below which chemical pleurodesis is unlikely to succeed, although this figure is based on expert recommendation rather than existing evidence (20). Logically, breathlessness is more likely to occur in patients whose lung remains unexpanded after fluid has been removed than in those with an expandable lung. Equally, NEL implies visceral pleural thickening, most likely due to tumor infiltration, which has been associated with shorter survival times in previous observational studies (26).

We undertook a prospective study to describe the prevalence and clinical implications of NEL in a representative cohort of patients with MPM. To maximize case identification, we used an objective radiographic definition of NEL that included any degree of pleural nonapposition. The aim of this study was to determine whether NEL is associated with shorter survival. The secondary objectives of the study were to describe the natural history of NEL in MPM, symptoms associated with the condition, and potential management strategies.

Participants and Setting

Patients with undiagnosed pleural disease who presented to a single center in the United Kingdom between March 1, 2008, and August 3, 2017 were enrolled in a prospective observational study (Pleural Investigation Study, REC ref 08/H0102/11). Diagnoses were recorded independently by two senior clinicians 12 months after enrollment. Patients with MPM who were enrolled during the specified time period were included in this study. All MPM diagnoses had been ratified by the regional multidisciplinary team.

The research was granted ethical approval by the South West–Central Bristol Research Ethics Committee (08/H0102/11). All patients provided written, informed consent to participate in the study.

Data Collection

Baseline patient characteristics, performance status (PS), and tumor variables (laterality, histological subtype, and International Mesothelioma Interest Group stage [27]) were collected prospectively. The presence or absence of symptoms (breathlessness, chest pain, cough, and weight loss) was recorded at presentation, before pleural fluid was drained. Blood tests were performed at presentation and the neutrophil/lymphocyte ratio (NLR), an established prognostic marker in MPM, was calculated (28). Treatment decisions were made by the regional mesothelioma multidisciplinary team and recorded contemporaneously.

The presence and size of pleural effusions were evaluated on the baseline (i.e., before any pleural intervention) posterior–anterior chest radiograph by two independent clinicians using a previously published classification system (29). In summary, 0 = no pleural fluid present, 1 = blunting of the costophrenic angle, 2 = fluid occupying up to 25% of the hemithorax, 3 = fluid occupying 26–50% of the hemithorax, 4 = fluid occupying 51–75% of the hemithorax, and 5 = fluid occupying 76–100% of the hemithorax. Serial radiographs were assessed for the presence of NEL, defined as a lack of pleural apposition after pleural aspiration or drainage. The degree of NEL was assessed based on the degree of pleural nonapposition using the same criteria as above. Radiographs were performed at all clinic appointments and after any therapeutic pleural intervention, i.e., large volume thoracentesis, insertion of intercostal chest drain or indwelling pleural catheter, or medical or surgical thoracoscopy.

The NEL management strategy was determined from serial radiological imaging and patient records. The incidence of autopleurodesis, defined as a spontaneous cessation of pleural fluid accumulation with no further requirement for pleural drainage, was determined based on medical records.

Survival status was assessed on March 14, 2019. For deceased patients, the date of death was obtained from the National Cancer Registration and Analysis Service (NCRAS). Patients who were alive on March 14, 2019, were censored on that date (with a minimum follow-up of 20 mo). Survival was calculated from the date of enrollment in the study to the date of death or censoring.

Statistical Analysis

The explanatory variable was the presence of pleural effusion with NEL, hereafter referred to as NEL status. Patients were categorized as having no pleural effusion, pleural effusion without underlying NEL, or pleural effusion with NEL. The primary outcome was survival.

Patient characteristics and treatments were tabulated according to NEL status and compared visually.

The absolute number of deaths and death rates per 100 person-years were tabulated according to the presence or absence of a pleural effusion and, in patients with an effusion, the presence or absence of NEL. Poisson regression was used to test for a trend in event rates between groups. The Cox proportional hazards model was used to assess the relationship between survival and NEL status. An initial univariable analysis was performed, followed by multivariable modeling, adjusted for the presence of an effusion, age category, sex, World Health Organization PS, tumor laterality, tumor stage, nonepithelioid histology, NLR, effusion size, and whether the patient had received chemotherapy.

A separate analysis was performed to evaluate the relationship between symptoms and survival. An a priori subgroup analysis was undertaken in patients with NEL to determine whether there was any relationship between NEL size and survival. Statistical analyses were undertaken using STATA v14.2 (StataCorp LLC) with an α value of 0.05.

Participant Characteristics

A total of 229 participants (196 [85.6%] of whom were male) were enrolled during the study period. The mean age was 64 years (range 40–93 yr, standard deviation [SD] = 8.4) and the majority of participants were PS 0 (n = 62 [27.1%]) or 1 (n = 111 [48.5%]). Right-sided tumors were more common than left-sided tumors (n = 134 [58.5%] and n = 94 [41.1%], respectively), and one participant (0.4%) had bilateral disease. One hundred and forty-six patients (63.8%) had epithelioid disease, 45 (19.7%) had sarcomatoid or desmoplastic disease, and 18 (7.9%) had biphasic disease. For 20 participants (8.7%) the histological subtype was not specified. Staging information was available for 186 patients: 65 (35%) were stage I, eight (4.3%) were stage II, 72 (38.7%) were stage III, and 41 (22%) were stage IV. The median NLR for the 197 patients in whom it was available was 4.37 (interquartile range, 2.99–6.37). A total of 167 participants (72.9%) were offered chemotherapy and 98 (42.8%) ultimately received it.

Breathlessness was the most common symptom at presentation, occurring in 183 participants (79.9%), followed by chest pain, which occurred in 100 participants (43.7%). Weight loss was reported by 90 patients (39.3%), and cough was reported by 88 (38.4%). Ten patients (4.4%) were asymptomatic at presentation.

Pleural Effusion and NEL

A total of 192 participants (192/229; 83.8%) had a pleural effusion at presentation, the majority of which occupied over 25% of the hemithorax (130/192; 67.7%). Sixty-four of the 192 patients with pleural effusions (33.3%) had NEL, and 49 of these 64 patients (76.6%) demonstrated preserved pleural apposition over at least 50% of the hemithorax (Table 1). For most patients with NEL (38/64, 59%), the degree of NEL was smaller than the size of the overlying pleural effusion.

Table 1. Characteristics of patients presenting without pleural effusion, with pleural effusion but no nonexpandable lung, and pleural effusion with nonexpandable lung

 No Pleural Effusion (n = 37)Pleural Effusion without NEL (n = 128)Pleural Effusion with NEL (n = 64)
Male, n (%)30 (81.1)104 (81.3)62 (96.9)
Age, mean (SD)74 (7.33)73 (8.83)74 (7.97)
 <65 yr2 (5.4)18 (14.8)6 (9.4)
 65–69 yr9 (24.3)25 (19.5)15 (23.4)
 70–74 yr8 (21.6)30 (23.4)14 (21.8)
 75–79 yr9 (24.3)27 (21.1)9 (14.1)
 80+ yr9 (24.3)27 (21.1)20 (31.3)
Performance status, n (%)   
 011 (30.6)34 (26.6)17 (26.6)
 117 (47.2)65 (50.8)29 (45.3)
 28 (22.2)13 (10.2)10 (15.3)
 30 (0)12 (9.4)8 (12.5)
 40 (0)1 (0.8)0 (0)
 Not recorded1 (2.7)3 (2.3)0 (0)
Laterality, n (%)   
 Left21 (56.8)51 (39.8)22 (34.4)
 Right15 (40.5)77 (60.2)42 (65.6)
 Bilateral1 (2.7)0 (0)0 (0)
Histology, n (%)   
 Epithelioid19 (51.4)84 (65.6)43 (67.2)
 Sarcomatoid/desmoplastic9 (24.3)23 (18.0)13 (20.1)
 Biphasic4 (10.8)7 (5.5)7 (10.9)
 Not otherwise specified5 (13.5)14 (10.9)1 (1.6)
Stage, n (%)   
 I5 (13.5)38 (29.7)22 (34.4)
 II1 (2.7)4 (3.1)3 (4.7)
 III13 (35.1)42 (32.8)17 (26.6)
 IV13 (35.1)20 (15.6)8 (12.5)
 Not recorded5 (13.5)24 (18.8)14 (21.9)
Received chemotherapy, n (%)12 (33.3)53 (42.7)33 (53.2)
Neutrophil lymphocyte ratio, median (IQR)4.6 (3.0–6.8)4.3 (2.9–6.3)4.3 (3.2–6.3)
Size of effusion, n (%)  
 Blunting of costophrenic angle14 (10.9)2 (3.1)
 Fluid occupying 25% of hemithorax38 (29.7)8 (12.5)
 Fluid occupying 25–50% of hemithorax37 (28.9)14 (21.9)
 Fluid occupying 50–75% of hemithorax31 (24.2)24 (37.5)
 Fluid occupying >75% of hemithorax8 (6.3)16 (25.0)
Size of NEL, n (%) 
Lack of pleural apposition affecting 
  Costophrenic angle only3 (4.7)
  25% of hemithorax18 (28.1)
  25–50% of hemithorax28 (43.8)
  50–75% of hemithorax12 (18.8)
  >75% of hemithorax3 (4.7)
Symptoms, n (%)   
 Breathlessness20 (54.1)105 (82.0)58 (90.6)
 Chest pain24 (64.9)54 (42.2)22 (34.4)
 Weight loss17 (46.0)47 (36.7)26 (40.6)
 Cough8 (21.6)48 (37.5)33 (51.6)
 Asymptomatic2 (5.4)6 (4.7)2 (5.4)

Definition of abbreviations: IQR = interquartile range; NEL = nonexpandable lung; SD = standard deviation.

Right-sided tumors were more frequently associated with pleural effusions and with underlying NEL, whereas left-sided tumors were more common in patients without effusions (Table 1). The NEL group had a higher proportion of men (96.9%) than the effusion-without-NEL group (81.3%) and the no-effusion group (81.1%). Breathlessness was more frequently reported in patients with NEL (90.6%) than in patients with effusions but no NEL (82%), who in turn were more likely to be breathless than patients without effusions (54.1%). A similar pattern was seen with cough (51.6%, 37.5%, and 21.6%, respectively). In contrast, chest pain was most common in patients without effusions and least common in patients with NEL (64.9%, 42.2%, and 34.4%, respectively).

NEL was usually diagnosed at presentation or within 14 days of receiving a diagnosis of MPM (53/64; 82.8%). The median time between a diagnosis of MPM and detection of NEL was −4.5 days, with an upper limit of 818 days. NEL was managed with an IPC in 31 of 64 patients (48.4%). The remaining 33 patients were managed conservatively, i.e., they did not undergo any further pleural intervention. This was usually because the degree of NEL was small and reaccumulation of fluid filled the resultant space but did not result in a large pleural effusion, or because aspiration of fluid yielded no symptomatic benefit. Five patients (2.2%) in the conservatively managed group died within 6 weeks of receiving a diagnosis of NEL. Interestingly, in 18 out of 64 patients with NEL (28.1%), subsequent disease progression led to obliteration of the pleural space and autopleurodesis.


Median survival was 11.1 months, with 15 patients (6.6%) alive at the time of analysis. Follow-up for living patients ranged from 20 months to 123 months.

A similar proportion of patients died in each group (94.6%, 93.8%, and 92.3% in patients with no pleural effusion, pleural effusion without NEL, and pleural effusion with NEL, respectively; see Table 2). Event rates for death were also comparable across the groups, and an unadjusted survival analysis demonstrated no convincing association between the presence of NEL and mortality. However, in the adjusted model, the presence of NEL was associated with an increased risk of dying compared with the absence of NEL (hazard ratio [HR], 1.80; 95% confidence interval [CI], 1.16–2.80). The multivariable model controlled for the presence or absence of a pleural effusion, suggesting that the relationship between NEL and survival was an independent association related to lung expansion rather than the presence of pleural fluid. In fact, the presence of a pleural effusion was not associated with survival in either the unadjusted (HR, 1.02; 95% CI, 0.70–1.46) or adjusted (HR, 1.86; 95% CI, 0.93–3.72) model. Full results of the survival model are shown in Appendix A in the online supplement.

Table 2. Total number of deaths, event rate for death, and hazard ratios for death in patients with and without a pleural effusion, and in patients with an effusion with and without nonexpandable lung

 No. of PatientsNo. of Deaths (%)Person-YearsEvent Rate, per 100 Person-Years (95% CI)PCrude HR for Death (95% CI)PAdjusted HR for Death (95% CI)P
No pleural effusion3735 (94.6)46.175.9 (54.5–105.7)0.98810.93510.081
Pleural effusion192179 (93.2)235.176.1 (65.7–88.1)1.02 (0.70–1.46)1.86 (0.93–3.72)
 In patients with no NEL128120 (93.8)157.276.3 (63.8–91.3)0.95210.91110.008
 In patients with NEL6459 (92.3)78.075.6 (58.6–97.6)1.02 (0.67–1.56)1.80 (1.16–2.80)

Definition of abbreviations: CI = confidence interval; HR = hazard ratio; NEL = nonexpandable lung.

Chest pain was associated with shorter survival (HR, 1.89; 95% CI, 1.26–2.83), but other symptoms were not markers of poor prognosis (see Appendix B in the online supplement).

A subgroup analysis of patients with NEL showed no association between the degree of NEL and survival (HR, 0.85; 95% CI, 0.66–1.10; P = 0.213), or between the presence of clinically relevant NEL (defined as NEL with a lack of pleural apposition affecting >25% of the hemithorax) and survival (HR, 0.78; 95% CI, 0.45–1.33; P = 0.362). However, with only 64 patients in the subgroup, it is unlikely that the analysis had sufficient power to detect a relationship.

This is the first study to report the prevalence of NEL in MPM, and it does so using data from a prospective, clinical cohort study in a high-incidence country. This study demonstrates that NEL is a relatively common phenomenon, and that it is associated with significant symptomatology and shorter survival.

The prevalence of NEL in this cohort of patients with MPM was higher than what was reported in previous studies of general malignant pleural effusion (MPE) populations (33% vs. 12.5%) (24, 25). There are several potential explanations for this. The first is that the MPE studies evaluated the presence of NEL at a single time point, early in the disease course, and could have missed patients who developed NEL as a late phenomenon. In the current study we assessed serial chest radiographs throughout the disease course and therefore would have detected a greater number of cases of NEL. An alternative explanation is that NEL is more common in patients with MPM than in those with MPE. This hypothesis is plausible, given the circumferential growth pattern of MPM tumors, which is more likely to result in lung encasement and subsequent NEL.

This study demonstrates that NEL is an independent predictor of poor prognosis. Instinctively, one may think that this is a reflection of bulky, advanced-stage tumors being more likely to cause NEL; however, the relationship between NEL and survival persisted after adjustment for tumor stage. In fact, patients with pleural effusions (with and without NEL) were more likely to present with early-stage disease than those without pleural effusions. This is in contrast to most other cancer types, in which the presence of a pleural effusion reflects metastatic spread and consequently a higher disease stage. However, because MPM is a primary malignancy of the pleural surface, pleural effusions may be present in early disease, as seen here, and do not influence disease staging. Tanrikulu and colleagues (6) and Yates and colleagues (7) suggested that pleural effusions are a poor prognostic factor in MPM, but this has not been consistently demonstrated, and our data do not support that conclusion. It is possible that the previously observed relationship between pleural effusions and shorter survival in MPM was due to underlying NEL, as lung expansion was not reported or adjusted for in the study by Tanrikulu and colleagues (6).

In addition to earlier disease stage, NEL was associated with other positive prognostic factors, including a greater proportion of epithelioid tumors and higher chemotherapy treatment rates. These differences in patient characteristics explain the discrepancy between the crude and adjusted HRs for death. The favorable characteristics attenuated the negative outcomes associated with NEL, thus introducing confounding to the unadjusted result. However, based on the fully adjusted model, NEL was an independent predictor of short survival in MPM. This finding may reflect tumor-specific biological factors and growth pathways, the evaluation of which was outside the scope of this study. Future research could focus on proteomic and metabolomic evaluations of tumor samples and pleural fluid in patients with NEL to explore this hypothesis further.

This study demonstrates that breathlessness was more common in the context of pleural effusions and NEL, whereas chest pain was more prevalent in “dry MPM.” This is almost certainly a result of reduced respiratory capacity due to lung compression and compromised diaphragmatic function due to the presence of fluid (30). Notably, in NEL, reduced lung capacity cannot be reversed by fluid drainage, although removal of fluid may improve respiratory dynamics and ameliorate symptoms (19, 30). The higher incidence of cough in patients with NEL is a novel observation, and is likely to reflect negative intrathoracic pressures stimulating highly sensitive cough receptors on the visceral pleura (31, 32).

There is little evidence regarding the management of NEL, and a recent international review concluded that clinical trials are required to elucidate the optimal treatment strategy (19). IPCs have been shown to be effective for controlling symptoms, but our results revealed that conservative management may also be appropriate in the right setting (30, 33). The observation that NEL was a preterminal event in a small number of patients, alongside the finding that over a quarter of patients with NEL subsequently auto-pleurodesed, supports a symptom-based approach to management.

Strengths and Weaknesses

The collection of prospective data from consecutive patients with MPM minimized the risk of selection bias and enhanced the generalizability of the study findings. The external validity of the results is supported by the similarity between the characteristics of our patients and those of existing cohorts, specifically with respect to age, male/female ratio, distribution of histological subtypes, and prevalence of pleural effusions (6, 7, 914, 16). Survival rates were similar to national figures, and the relationship between certain known prognostic variables (e.g., sarcomatoid histology, tumor stage, and NLR) and survival was replicated (35, 3436).

Previous research studies of NEL have been complicated by different definitions of NEL and varying thresholds for the degree of lung nonexpansion that can be considered clinically relevant (19). A strength of this study is the use of a robust definition for NEL that identified patients with any degree of lung nonexpansion, with additional data collected on the extent of NEL based on the degree of pleural nonapposition. An exploratory subgroup analysis of patients with NEL failed to elucidate what degree of NEL is clinically relevant in terms of survival. However, the number of patients was small, and type II errors were possible. Future studies would require larger numbers of patients to evaluate the relationship between the degree of NEL and clinically important outcomes such as symptoms and survival.

In this study we used chest radiography to detect NEL and determine the degree of NEL, as this technology is readily available and the results are easily interpretable. It is acknowledged that there is no validated system for measuring the size of NEL; hence, we used a scoring system that was previously used for pleural effusions (29). Computed tomography (CT) may be more sensitive for detecting NEL and is likely to yield more accurate information about the degree of pleural apposition. Additionally, CT could enable volumetric quantification of NEL, which may provide further prognostic information. Future research could explore the correlation between NEL size on chest radiograph and size on CT to determine whether either of them is associated with survival.

Imaging was undertaken based on clinical practice rather than on a predefined study schedule. It is possible, therefore, that some NEL cases may have been missed because imaging was not performed at the relevant time point. This would have resulted in an underestimation of NEL prevalence and may have affected outcomes, as these patients would be more likely to be asymptomatic. However, most patients underwent some form of imaging every few months, and therefore the likelihood of missing NEL in the brief periods between radiographs was small.

This study did not have the capacity to ascertain symptom severity or to collect serial data on symptom evolution throughout the disease process. A multicenter, prospective, observational study is currently underway in the United Kingdom in which such data are being collected using repeat-measure, patient-reported symptom scores and quality-of-life questionnaires alongside serial radiological imaging (ASSESS-meso, ISRCTN61861764). The results are awaited with interest.


In summary, NEL affected one-third of patients with MPM and effusions, and was associated with breathlessness and cough. The presence of NEL was an independent predictor of poor survival even after adjustment for tumor stage, presence of effusion, and treatment received.

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Correspondence and requests for reprints should be addressed to Anna C. Bibby, M.B.Ch.B., B.Sc., M.R.C.P., D.T.M.&H., Academic Respiratory Unit, University of Bristol, 2nd Floor, Learning & Research Building, Southmead Hospital, Bristol BS10 5NB, UK. E-mail: .

Author Contributions: A.C.B. and N.A.M. conceived and designed the study. A.C.B. cleaned and analyzed the data, interpreted the results, and wrote the manuscript. P.H., D.D.F., A.J.M., and S.S. helped refine the methodology, assisted with data collection and analysis, and contributed to writing of the manuscript. All authors reviewed and approved the final document. A.C.B. is the guarantor for the published study, including all data and analyses.

This article has an online supplement, which is accessible from this issue’s table of contents at

Author disclosures are available with the text of this article at

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