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Additional file 1: Table S1. Multivariable Fine–Gray proportional hazards analysis of the relationship between patient-reported outcomes and mortality in waitlisted patients, excluding those who underwent living-donor lung lobar transplantation after registration.

Additional file 1: Table S1. Results of 48-plex measurement in the sera of IPF patients (discovery cohort) and controls and the bronchoalveolar lavage fluid of IPF patients. Measurements (median and IQR) of 48 cytokines in the discovery cohort sera (n = 100) and the control group sera (n = 32), p-values for between-group comparisons, and the measurements of BALF in the discovery cohort (n = 30).

Additional file 3: Table S2. Multivariable Fine–Gray proportional hazards analysis of the relationship of LAS and patient-reported outcomes with mortality in patients waiting for lung transplantation.

BackgroundTherapy options for OSA and central sleep apnea (CSA) are limited, thus many patients remain untreated. Clinically, acetazolamide is sometimes used for CSA; however, given overlapping pathophysiologic properties of OSA and CSA, we hypothesized that acetazolamide is equally effective for both types. Prior reviews focused on specific subtypes of sleep apnea, study designs, and languages, thus including few studies (typically≤3) limiting insights.Research questionHow efficacious is acetazolamide for sleep apnea, and is its effect modified by sleep apnea type or acetazolamide dose?Study design and methodsWe queried MEDLINE, EMBASE, and ClinicalTrials.gov from inception until March 11, 2019. Any study in which adults with OSA/CSA received oral acetazolamide vsno acetazolamide (control) that reported sleep apnea-related outcomes was eligible, independent of study design or language. Two reviewers independently assessed eligibility and abstracted data. Primary outcomes were apnea-hypopnea index (AHI) and oxygen saturation nadir. Quality of evidence (QoE) was rated with the use of Grades of Recommendation Assessment, Development and Evaluation methods.ResultsWe included 28 studies (13 OSA/15 CSA; NSubjects,Acetazolamide= 542; NSubjects,Control= 553) that enabled meta-analyses for 24 outcomes. Acetazolamide doses ranged from 36 to 1000mg/d and treatment duration from 1 to 90d (median, 6 d). Overall, acetazolamide vscontrol lowered the AHI by -0.7 effect sizes (95%CI, -0.83 to -0.58; I2= 0%; moderate QoE) that corresponded to a reduction of 37.7%(95%CI, -44.7 to -31.3) or 13.8/h (95%CI, -16.3 to -11.4; AHIControl= 36.5/h). The AHI reduction was similar in OSA vsCSA, but significantly greater with higher doses (at least up to 500mg/d). Furthermore, acetazolamide improved oxygen saturation nadir by+4.4%(95%CI, 2.3 to 6.5; I2= 63%; no evidence of effect modification; very low QoE) and several secondary outcomes that included sleep quality measures and BP (mostly low QoE).InterpretationShort-term acetazolamide improved both OSA and CSA. Rigorous studies with long-term follow up are warranted to assess Acetazolamide's value for the chronic treatment of patients with sleep apnea.Clinical trial registrationPROSPERO (CRD42019147504).

Additional file 1: Supplementary methods. Definitions of the severity of obstructive sleep apnea (OSA) and of high/low for the other sleep parameters. The definitions severity of OSA and high/low sleep parameters in the current study. Cluster analysis. The detailed description of cluster analysis. Definitions of comorbidities. The detailed definition of the presence of major comorbidities in the current study. Supplementary results. Characteristics of four clusters obtained according to cluster analysis. Cluster 1 was characterized mainly by younger age, male population, dyslipidemia, and high BMI but low prevalence of severe OSA. Among the four clusters, the patients in this cluster had the lowest serum periostin levels. Cluster 2 composed mainly of subjects with mild to moderate OSA and those with abnormal glycometabolism. Clusters 3 and 4 were characterized by the accumulation of severe OSA cases. Albuminuria was present in eight subjects in cluster 4 and in no subject in cluster 3. Of the eight subjects, six were positive for microalbuminuria (four with DM) and two exhibited macroalbuminuria (one with DM). Compared with cluster 3, cluster 4 had higher mean ± SD serum periostin level (87.1 ng/mL ± 32.3 vs. 66.5 ± 21.8 ng/mL, p = 0.05); higher number of subjects with high serum periostin levels of ≥87 ng/mL, which was the highest quintile of serum periostin (p = 0.02); and higher prevalence of asthma. Figure S1. Serum periostin levels in patients with/without comorbidities. The presence of major comorbidities was not associated with serum periostin levels. The black bars and the numbers in the figure represent the mean serum periostin level. Figure S2. Distribution of the four clusters on the axes of apnea–hypopnea index and serum periostin levels. The details of each cluster are described in Table 3 and in the supplementary results (“Characteristics of four clusters obtained according to cluster analysis”). The encircled size represents the number of subjects in each cluster. The encircled number represents the cluster number in Table 3. Figure S3. Serum periostin level in OSA. Overweight/obesity has negative impacts on the serum periostin level in OSA, as observed in the general population. However, high intermittent hypoxia contributes to high serum periostin level. Furthermore, severe OSA and comorbid albuminuria show positive interactions for serum periostin level. A high serum periostin in patients with OSA despite being overweight/obese may indicate a phenotype of OSA (i.e., severe OSA with albuminuria). Table S1. Clinical effects of CPAP in patients with moderate OSA. The serum periostin level did not decrease in subjects with moderate OSA after CPAP treatment (p = 0.75).

Table S1. Sixteen radiological PPFE cases with a histopathological diagnosis. (DOCX 16 kb)

Treatment for IPF at baseline. Table S2. Univariate analyses utilized to predict clinical deterioration and mortality when 13 treated patients with IPF were excluded. (DOCX 24 kb)