Although the human brain accounts for only 2.3% of our body weight,1 it utilizes one fourth of our oxygen intake.2 The brain is sensitive to oxygen availability, and respiratory conditions that result in reductions in oxygen to the brain can over time lead to decreased cognitive function.3–5 Poor pulmonary function is an in vivo indicator of reduced oxygen uptake. Poor pulmonary function is associated with diminished cognitive function6–8 and possibly dementia risk.6,7,9–11 Recently, a large body of evidence has demonstrated that suggest that risk factors for dementia need to be evaluated in early adulthood to midlife,11–17 long before neuropathologic changes have commenced, to establish temporality. To our knowledge, no prior study has evaluated PPF exclusively in adulthood to midlife in relation to long-term dementia risk. We examined if numerous markers of pulmonary function in a large diverse sample of individuals ages 35 to 50 is associated with an elevated risk of dementia more than 20 years later taking into account smoking and vascular disease.
This study follows members of Kaiser Permanente Northern California (KPNC), an integrated health care system with over 3 million individuals who are representative of the catchment area apart from the extremes of the income distribution.18–20 We included individuals who were 35 to 50 years old when they participated in at least 1 check-up associated with the Multiphasic Health Checkups (MHC), a series of optional checkups offered to members in San Francisco and Oakland, California, in the 1960s and 1970s. During MHC visits, health questionnaires and clinical measurements collected information on demographics, lifestyle, pulmonary function, and cardiovascular health indicators.
We linked data from 33,045 members of KPNC who were 35 to 50 during a MHC visit between 1964 and 1973 to medical health records starting in 1996. We excluded 2797 individuals without any measures of midlife pulmonary function, 2736 individuals missing height measurements, 2 individuals missing information on sex, 110 individuals missing race/ethnicity, and 13 missing weight. A total of 27,387 individuals were eligible and included in these analyses.
This study was approved by the Kaiser Internal Review and conducted in accordance with the Helsinki Declaration of 1975.
Midlife Pulmonary Function
Midlife pulmonary function was assessed during MHC visits between 1964 and 1973 by measuring forced expiratory volume in 1 second (FEV1), FEV in 2 seconds (FEV2), and vital capacity (VC). FEV is the volume (liters) of gas exhaled during the first second or two of expiration. VC is the total volume (liters) of air expelled after the deepest breath possible. Pulmonary function measurements were captured using a Vertek VR5000 Lung Function computer (Electro/Med. Instruments, Houston, TX).21 If individuals participated in >1 MHC visit, the first visit was used. Continuous measures of FEV1, FEV2, and VC were reverse coded ([maximum value+1]−original value) so that higher values represented worse pulmonary function. To examine possible nonlinear functional forms, each of the 3 measures of pulmonary function was divided into quintiles. Since sex is an important determinant of lung capacity, quintiles were created for each sex separately and then combined. Some individuals were missing 1 or 2 of the 3 pulmonary function tests: 26,858 individuals had FEV1 values, 16,289 had FEV2 values, and 27,384 had VC values.
To better account for height and race, we also estimated percent predicted FEV1 and VC based off reference spirometeric values from a sample of whites, African Americans, and Mexican Americans in the United States.22 Although we do not know the ancestry of the Hispanic population in our sample, the US Census reported that 78% of California’s Hispanic population in the 1970s were of Mexican descent.23 The age, sex, and race specific equations incorporated information with regard to height and age to calculate predicted FEV1 and VC. Percent predicted pulmonary function measures were then divided into quintiles.
Dementia diagnoses between January 1, 1996 and September 30, 2015 were ascertained from inpatient and outpatient electronic medical records. Consistent with previous studies in this population24–27 the following International Classification of Diseases, Ninth Revision (ICD-9) diagnosis codes were used to define dementia: Alzheimer’s disease (331.0), vascular dementia (290.4x), and other/nonspecific dementia (290.0, 290.1x, 290.2x, 290.3, 294.1, 294.2x, and 294.8). A similar set of codes had a sensitivity of 77% and a specificity of 95% compared with a consensus dementia diagnosis.28
Death was obtained through KPNC electronic medical records, California State Mortality File, and Social Security Death records.
Sex and educational attainment were captured in the 1964 to 1973 MHC questionnaires. Educational attainment was captured as the highest grade completed and was recoded as high school or less (versus more than high school). Height, a well-established predictor of pulmonary function, weight, and blood pressure were measured during the 1964 to 1973 MHC. Height and weight were combined to calculate body mass index (BMI) and hypertension status was defined using blood pressure thresholds based off recommendations from the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7).29 Late-life heart failure, stroke, and diabetes were defined as ICD-9 diagnoses (Supplemental Table 1, http://links.lww.com/WAD/A197) identified in the electronic medical records between January 1, 1996 and January 1, 1997, preceding any possible dementia diagnosis that may have also occurred during that time period. KPNC records provided information on self-reported race and ethnicity (white (reference), African American, Asian, Hispanic, and “other racial/ethnic identity”) and age. Self-reported smoking was captured by MHC questionnaires and categorized as current, past, or never smoker. Missing indicators were used for missing information on midlife smoking (n=3669).
Method of Analysis
We examined the distribution of pulmonary function measures, demographics, height, smoking, and health conditions in midlife and late-life by dementia status at end of follow-up. For each of the pulmonary function measures, we ran a series of Cox proportional hazards models (age as timescale) examining the association of both continuous and quintile forms of pulmonary function with dementia. The highest quintile (ie, best) was the reference group in analyses examining the association between quintiles of pulmonary function. We also examined the risk of dementia associated with being in the worst quintile of all pulmonary function measures (ie, worst quintile of FEV1, FEV2, and VC) compared with not being in the worst quintile for any of the pulmonary measures.
Covariates were added to Cox proportional hazards models in 2 groups since midlife and late-life health indicators may behave as mediators. All models adjusted for age (as timescale), demographics, and height, a strong predictor of pulmonary function. Next, we further adjusted for midlife health indicators (BMI, hypertension, and smoking status) and late-life health indicators (diabetes, stroke, and heart failure). Although BMI is comprised of height and weight, BMI and height are not closely correlated (Pearson correlation coefficient=0.03) and it is common to concurrently adjust for both BMI and height when examining pulmonary function.7,10,30 For all Cox proportional hazards models, individuals were censored at date of dementia diagnosis, death, the start of a membership gap lasting >90 days, or the end of the study period on September 30, 2015.
We estimated and plotted the cumulative incidence of dementia associated with being in the worst versus best quintile of VC in 5-year increments from 10 to 35 years beginning at age 60. Estimates were conditional on survival free of dementia up to age 60. The Practical Incidence Estimator macro31 was used to obtain these estimates, which incorporates information on death rates and assumes that individuals who die without a dementia diagnosis never develop dementia.
We examined possible effect modification of the relationship between pulmonary function and dementia by midlife smoking by contrasting estimated effects of quintiles of pulmonary function among midlife smokers versus midlife never smokers; individuals who reported past smoking at midlife (4835 individuals) were excluded from these analyses. We also tested for possible effect modification of the relationship between being in the worst quintile for all 3 measures and dementia by smoking.
In sensitivity analyses, Cox proportional hazards models were implemented to examine the relationship between quintiles of percent predicted FEV1 and VC among whites, African Americans, and Hispanics in our sample. The highest quintiles reflected the best pulmonary function and served as the reference group. All models adjusted for age (as timescale), demographics, and height, and fully adjusted models also accounted for midlife and late-life health indicator.
On average, pulmonary function measures were taken when individuals were in their early 40s (mean age=41.8±4.2 y) (Table 1). The mean FEV1, FEV2, and VC were 2.7±0.8, 3.3±1.0, and 3.5±1.0 L, respectively. Overall, the sample was 67% white, 17% African American, 6% Asian, 6% Hispanic, and 4% were categorized as “Other racial/ethnic identity.” At midlife, 35% reported being current smokers, 18% were past smokers, and 34% were never smokers. The mean age at the start of follow-up for dementia in 1996 was 69.8±5.4 years old. At the end of follow-up, 7519 people (27%) received a dementia diagnosis, 8346 people died (30%), 4601 people (17%) were censored due to membership lapse, and 6921 people (25%) were alive, dementia free, and still members of KPNC.
For the 3 pulmonary function measures, each 1 L difference below the reference value was associated with 15% to 17% increased risk of dementia in models adjusting for demographics and height, and 13% to 14% in fully adjusted models (Table 2). For all 3 pulmonary function measures, in minimally and fully adjusted models, there were strong dose-response associations between quintiles of pulmonary function and dementia risk with the lowest (ie, worst) quintile at the greatest risk of dementia. For example, in fully adjusted models, individuals in the first, second, and third quintile of VC were at 28% (hazard ratio [HR]=1.28; 95% confidence interval [CI], 1.17-1.39), 20% (HR=1.20; 95% CI, 1.11-1.30), and 13% (HR=1.13; 95% CI, 1.05-1.22) greater risk of dementia than individuals in the best VC quintile. Individuals in the fourth quintile of VC were not at significantly greater risk of dementia (HR=1.07; 95% CI, 0.99-1.16). In fully adjusted models, compared with not being in the worst quintile for any of the 3 pulmonary measures, being in the worst quintile for all 3 measures was associated with an 28% increase in dementia risk compared with individuals who were in the best quintile for the 3 measures (HR=1.28; 95% CI, 1.16-1.41).
Estimates of the cumulative incidence of dementia were consistently higher for individuals in the worst quintile of VC compared with those in the best quintile (Table 3 and Fig. 1). The 30-year incidence of dementia among individuals in the worst quintile of VC was 35.7% (95% CI, 33.7%-37.3%) compared with 30.4% (95% CI, 28.3%-32.0%) for individuals in the best VC quintile. Overall, there was a dose-response association across quintiles of pulmonary function and cumulative incidence of dementia risk.
Although effect estimates of FEV1, FEV2, and VC quintiles tended to be slightly larger among midlife smokers than nonsmokers, there was little evidence of effect modification by smoking: the CIs overlapped and P-values for interaction terms were >0.30 (Table 4). The worst quintile of FEV2 was associated with a 28% increased risk of dementia for those who were never smokers in midlife (HR=1.28; 95% CI, 1.07-1.53) and 30% for those who were midlife smokers (HR=1.30; 95% CI, 1.07-1.58). Overall, there was a dose-response relationship between pulmonary function and dementia for both midlife smokers and nonsmokers. Compared with not being in the worst quintile for any of the 3 pulmonary measures, being in the worst quintile for all 3 was associated with a 31% increase in dementia risk for never smokers at midlife (HR=1.31; 95% CI, 1.12-1.54) and a 20% increase for midlife smokers (HR=1.20, 95% CI, 1.02-1.41).
Among whites, African Americans, and Hispanics, there were strong dose-response associations between quintiles of percent predicted FEV1 and dementia risk in minimally and fully adjusted models (Supplemental Table 2, http://links.lww.com/WAD/A198). For example, adjusting for demographics, individuals in the first, second, and third quintile of percent predicted FEV1 were at 20% (HR=1.20; 95% CI, 1.11-1.29), 14% (HR=1.14; 95% CI, 1.05-1.23), and 9% (HR=1.09; 95% CI, 1.01-1.18) greater risk of dementia compared with those in the highest quintile of percent predicted FEV1. Individuals in the fourth quintile of percent predicted FEV1 were not at significantly greater risk of dementia (HR=1.00; 95% CI, 0.92-1.08). Individuals in the first and second quintile of percent predicted VC were at 24% (HR=1.24; 95% CI, 1.15-1.34) and 14% (HR=1.14; 95% CI, 1.05-1.23) increased risk of dementia compared with those in the highest quintile of percent predicted VC. Individuals in the third and fourth quintile of percent predicted FEV1 were not at significantly greater risk of dementia (HR3rd quintile=1.00; 95% CI, 0.93-1.08; HR4th quintile=1.01; 95% CI, 0.94-1.09).
In this large longitudinal study, several indicators of midlife pulmonary function were consistently associated with dementia risk. A Each 1 L difference below the reference value of FEV1, FEV2, or VC was associated with 15% to 17% increase risk of dementia. There was a strong dose-response relationship with individuals with FEV1, FEV2, or VC measurements in the lowest (ie, worst) quintile at the greatest risk of dementia. For example, individuals in the lowest quintile of VC were at 34% greater risk of dementia than individuals in the highest VC quintile. The 30-year cumulative incidence of dementia was 17% greater for individuals in the lowest VC quintile than those in the highest quintile. There was no evidence of effect modification by midlife smoking status. For FEV2, the worst quintile was associated with 28% greater risk of dementia for midlife nonsmokers and 30% for midlife smokers. In analyses restricted to whites, African Americans, and Hispanics, quintiles of percent predicted FEV1 and VC, which better account for height and race, were inversely associated with dementia risk. Those in the worst quintile of percent predicted FEV1 and VC were at 20% and 24% increased risk of dementia compared with those in the best quartiles in models accounting for demographics. To our knowledge, this is the first study to exclusively examine individuals 35 to 50 years old. In addition, this is the largest and most diverse sample in the United States in which this relationship has been examined, and includes 4620 African Americans, 1709 Asians, and 1733 Hispanics.
Our study is consistent with a body of research examining the longitudinal association between midlife pulmonary function and dementia risk. Guo et al10 found that for every 1 SD increase in any of the 3 measures of pulmonary function (FEV1, VC, and peak expiratory flow) there was a decrease in the risk of dementia by about 25%. However, their sample was comprised of 1135 women older than 44 years at the time of pulmonary function measurement, limiting generalizability to younger adults and men. Studies have since shown an association between pulmonary function and dementia incidence among men and women aged 45 and 64 years,6,7,10 although 1 study did not find evidence of a relationship.11 The largest study examining the association between pulmonary function and dementia risk is a meta-analysis involving 54,671 people ages 16 to 100 that found that individuals in the worst quartile of pulmonary function were at double the risk of dementia mortality than those in the best quartile of pulmonary function.32
The mechanisms underlying the association between poor pulmonary function and long-term dementia risk remain unclear. Poor pulmonary function is associated with dementia risk factors such as a proinflammatory state33–35 and white matter hyperintensities.36 Poor pulmonary function may increase dementia risk due to hypoxia and hypoperfusion.10 Cerebral hypoxia is associated with oxidative stress, a possible trigger for neuroinflammation resulting in neuronal apoptosis.37 Hypoxia alters the ability of the brain to metabolize glucose and glucose hypometabolism may lead to a reduction in dendritic synaptic density and neuronal degeneration.38 Hypoxia may also increase tau hyperphosphorylation and the level of amyloid precursor protein that is then converted to Aβ,38,39 suggesting a direct role of hypoxia on neurodegenerative pathology. It is also possible that the association between pulmonary function and dementia is spurious and due to associations of cardiovascular disease, socioeconomic status,40 and physical activity41 with both pulmonary function and dementia risk. In the current study the association between pulmonary function and dementia persisted even after controlling for a number of both midlife and late-life cardiovascular risk factors and comorbidities (eg, blood pressure, heart failure, and stroke), suggesting that this is not a spurious association due to comorbid cardiovascular disease. Although we adjusted for educational attainment, residual confounding by socioeconomic status and other unmeasured confounders is possible. Smoking does not appear to explain the association between poor pulmonary function and dementia. Consistent with prior work, poor pulmonary function continued to have a strong dose-response relationship with dementia risk among nonsmokers in this sample.10
Strengths of this study include a long follow-up and a well-characterized, large, diverse, sample, starting in their mid-30s. The MHC and the electronic medical records provide prospectively collected information on a wide range of midlife and late-life health indicators associated with pulmonary function, dementia, and cardiovascular health. In sensitivity analyses we calculated percent predicted pulmonary function to more carefully adjust for difference by height and race/ethnicity. Unfortunately, the reference predictive equations we implemented did not provide reference values for racial and ethnic groups other than whites, African Americans, and Mexican Americans.22 Pulmonary function is associated with increased mortality risk and we were unable to assess if people who were censored due to death during follow-up would have otherwise developed dementia; this likely underestimated the true effect of pulmonary function on dementia risk. Lack of neuroimaging data restricted our ability to examine the structural cerebral differences associated with poor pulmonary function. Lastly, we were unable to examine possible biological pathways linking pulmonary function and dementia risk.
The results of this study suggest that pulmonary function is a strong predictor of dementia risk beginning in one’s mid-30s independent of smoking, midlife and late-life cardiovascular risk factors, and other comorbidities. A dose-response relationship with dementia risk was present for all 3 measures of pulmonary function among both smokers and nonsmokers. Further research is needed to delineate the neurobiological mechanisms through which poor pulmonary function elevates risk of dementia decades later.
1. Krompecher ST, Lipák J. A simple method for determining cerebralization. Brain weight and intelligence. J Comp Neurol. 1966;127:113–120.
2. Luo Q, Li LZ, Harrison DK, et al. International Society on Oxygen Transport to Tissue. Annual Meeting Wuhan C Oxygen Transport to Tissue XXXVIII. Switzerland: Springer; 2016.
3. Olaithe M, Bucks RS, Hillman DR, et al. Cognitive deficits in obstructive sleep apnea: Insights from a meta-review and comparison with deficits observed in COPD, insomnia, and sleep deprivation. Sleep Med Rev. 2018;38:39–49.
4. Torres-Sanchez I, Rodriguez-Alzueta E, Cabrera-Martos I, et al. Cognitive impairment in COPD: a systematic review. J Bras Pneumol. 2015;41:182–190.
5. Mikkelsen ME, Christie JD, Lanken PN, et al. The adult respiratory distress syndrome cognitive outcomes study: long-term neuropsychological function in survivors of acute lung injury. Am J Respir Crit Care Med. 2012;185:1307–1315.
6. Pathan SS, Gottesman RF, Mosley TH, et al. Association of lung function
with cognitive decline and dementia
: the Atherosclerosis Risk in Communities (ARIC) Study. Eur J Neurol. 2011;18:888–898.
7. Giltay EJ, Nissinen A, Giampaoli S, et al. Apolipoprotein E genotype modifies the association between midlife lung function
and cognitive function in old age. Dement Geriatr Cogn Disord. 2009;28:433–441.
8. Chyou PH, White LR, Yano K, et al. Pulmonary function
measures as predictors and correlates of cognitive functioning in later life. Am J Epidemiol. 1996;143:750–756.
9. Vidal JS, Aspelund T, Jonsdottir MK, et al. Pulmonary function
impairment may be an early risk factor for late-life cognitive impairment. J Am Geriatr Soc. 2013;61:79–83.
10. Guo X, Waern M, Sjogren K, et al. Midlife respiratory function and incidence of Alzheimer’s disease: a 29-year longitudinal
study in women. Neurobiol Aging. 2007;28:343–350.
11. Exalto LG, Quesenberry CP, Barnes D, et al. Midlife risk score for the prediction of dementia
four decades later. Alzheimers Dement. 2014;10:562–570.
12. Gilsanz P, Mayeda ER, Glymour MM, et al. Female sex, early-onset hypertension, and risk of dementia
. Neurology. 2017;89:1886–1893.
13. Albanese E, Launer LJ, Egger M, et al. Body mass index in midlife and dementia
: Systematic review and meta-regression analysis of 589,649 men and women followed in longitudinal
studies. Alzheimers Dement (Amst). 2017;8:165–178.
14. Barnes DE, Yaffe K, Byers AL, et al. Midlife vs late-life depressive symptoms and risk of dementia
: Differential effects for alzheimer disease and vascular dementia
. Arch Gen Psychiatry. 2012;69:493–498.
15. Gottesman RF, Albert MS, Alonso A, et al. Associations between midlife vascular risk factors and 25-year incident dementia
in the atherosclerosis risk in Communities (ARIC) cohort. JAMA Neurol. 2017;74:1246–1254.
16. Johansson L, Guo X, Waern M, et al. Midlife psychological stress and risk of dementia
: a 35-year longitudinal
population study. Brain. 2010;133:2217–2224.
17. Rusanen M, Kivipelto M, Quesenberry CP Jr, et al. Heavy smoking in midlife and long-term risk of Alzheimer disease and vascular dementia
. Arch Intern Med. 2011;171:333–339.
18. Gordon NP. Similarity of the Kaiser Permanente senior member population in northern California to the non-Kaiser Permanente covered and general population of seniors in northern California: Statistics from the 2009 California Health Interview Survey. Oakland, CA: Kaiser Permanente Northern California Division of Research; 2012.
19. Gordon NP, Kaplan GA. Some evidence refuting the HMO “favorable selection” hypothesis: the case of Kaiser Permanente. Adv Health Econ Health Serv Res. 1991;12:19–39.
20. Krieger N. Overcoming the absence of socioeconomic data in medical records: validation and application of a census-based methodology. Am J Public Health. 1992;82:703–710.
21. Collen MF. Multiphasic Health Testing Services. New York: John Wiley; 1978.
22. Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample of the general US population. Am J Respir Crit Care Med. 1999;159:179–187.
23. U.S. Bureau of the Census. Subject Reports: Persons of Spanish Origin. Table 3. Age of Persons of Spanish Origin by Sex and Urban and Rural Residence: 1970.
24. Mayeda ER, Glymour MM, Quesenberry CP, et al. Inequalities in dementia
incidence between six racial and ethnic groups over 14 years. Alzheimers Dement. 2016;12:216–224.
25. Whitmer RA, Sidney S, Selby J, et al. Midlife cardiovascular risk factors and risk of dementia
in late life. Neurology. 2005;64:277–281.
26. Whitmer RA, Gustafson DR, Barrett-Connor E, et al. Central obesity and increased risk of dementia
more than three decades later. Neurology. 2008;71:1057–1064.
27. Gilsanz P, Mayeda ER, Glymour MM, et al. Association between birth in a high stroke mortality state, race, and risk of dementia
. JAMA Neurol. 2017;74:1056–1062.
28. Katon WJ, Lin EH, Williams LH, et al. Comorbid depression is associated with an increased risk of dementia
diagnosis in patients with diabetes: a prospective cohort study. J Gen Intern Med. 2010;25:423–429.
29. Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure: the JNC 7 report. JAMA. 2003;289:2560–2572.
30. Maiolo C, Mohamed EI, Carbonelli MG. Body composition and respiratoryfunction. Acta Diabetologica. 2003;40:s32–s38.
31. Beiser A, D'Agostino RB Sr, Seshadri S, et al. Computing estimates of incidence, including lifetime risk: Alzheimer’s disease in the Framingham Study. The practical incidence estimators (PIE) macro. Stat Med. 2000;19:1495–1522.
32. Russ TC, Starr JM, Stamatakis E, et al. Pulmonary function
as a risk factor for dementia
death: an individual participant meta-analysis of six UK general population cohort studies. J Epidemiol Community Health. 2015;69:550–556.
33. Gan WQ, Man SFP, Sin DD. The interactions between cigarette smoking and reduced lung function
on systemic inflammation. Chest. 2005;127:558–564.
34. Ahmadi-Abhari S, Kaptoge S, Luben RN, et al. Longitudinal
Association of C-Reactive Protein and Lung Function
Over 13 Years: The EPIC-Norfolk Study. Am J Epidemiol. 2014;179:48–56.
35. Michaud M, Balardy L, Moulis G, et al. Proinflammatory cytokines, aging, and age-related diseases. J Am Med Dir Assoc. 2013;14:877–882.
36. Guo X, Pantoni L, Simoni M, et al. Midlife respiratory function related to white matter lesions and lacunar infarcts in late life. The Prospective Population Study of Women in Gothenburg, Sweden. Stroke. 2006;37:1658–1662.
37. Snyder B, Shell B, Cunningham JT, et al. Chronic intermittent hypoxia induces oxidative stress and inflammation in brain regions associated with early-stage neurodegeneration. Physiol Rep. 2017;5:e13258.
38. Daulatzai MA. Death by a thousand cuts in Alzheimer's disease: hypoxia—the prodrome. Neurotox Res. 2013;24:216–243.
39. Blass JP. Brain metabolism and brain disease: is metabolic deficiency the proximate cause of Alzheimer dementia
? J Neurosci Res. 2001;66:851–856.
40. Gray LA, Leyland AH, Benzeval M, et al. Explaining the social patterning of lung function
in adulthood at different ages: the roles of childhood precursors, health behaviours and environmental factors. J Epidemiol Community Health. 2013;67:905–911.
41. Nystad W, Samuelsen SO, Nafstad P, et al. Association between level of physical activity and lung function
among Norwegian men and women: The HUNT Study. Int J Tuber Lung Dis. 2006;10:1399–1405.
lifecourse; longitudinal; dementia; pulmonary function; lung function
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