Informant-Reported Discrimination,Dementia,and Cognitive Impairment in Older Brazilians

Abstract

Background:

Self-reported discrimination is a source of psychosocial stress that has been previously associated with poor cognitive function in older African Americans without dementia.

Objective:

Here, we examine the association of discrimination with dementia and cognitive impairment in racially diverse older Brazilians.

Methods:

We included 899 participants 65 years or older (34.3% Black) from the Pathology, Alzheimer’s and Related Dementias Study (PARDoS), a community-based study of aging and dementia. A structured interview with informants of the deceased was conducted. The interview included the Clinical Dementia Rating (CDR) Scale for the diagnosis of dementia and cognitive impairment proximate to death and the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) as a second measure of cognitive impairment. Informant-reported discrimination was assessed using modified items from the Major and Everyday Discrimination Scales.

Results:

Discrimination was reported by informants of 182 (20.2%) decedents and was more likely reported by informants of Blacks than Whites (25.3% versus 17.6%, p = 0.006). Using the CDR, a higher level of informant-reported discrimination was associated with higher odds of dementia (OR: 1.24, 95% CI 1.08 –1.42, p = 0.002) and cognitive impairment (OR: 1.21, 95% CI: 1.06 –1.39, p = 0.004). Similar results were observed using the IQCODE (estimate: 0.07, SE: 0.02, p = 0.003). The effects were independent of race, sex, education, socioeconomic status, major depression, neuroticism, or comorbidities.

Conclusion:

Higher level of informant-reported discrimination was associated with higher odds of dementia and cognitive impairment in racially diverse older Brazilians.

Keywords

Cognitive impairment dementia discrimination race

INTRODUCTION

Dementia is a common and disabling condition estimated to affect approximately 50 million people worldwide. Projections indicate that the prevalence of dementia is expected to exponentially increase in the coming decades as a result of aging of the population [1]. Blacks and Latinos have a higher prevalence of dementia compared with non-Latino Whites [2 –5], but reasons for the disparity remain largely unexplained and medical risk factors that are more prevalent in diverse populations, like cardiovascular disease, do not appear to fully account for the differences [6]. Given the expected growth of these older diverse populations, it is important to identify unique factors that play a role in the higher prevalence rates.

From the 16th to the 19th centuries, 4.8 million Africans entered Brazil. Brazil was the last country in the Western hemisphere to abolish slavery. Nearly five centuries of admixture between Blacks and Whites in Brazil generated the concept of “Racial democracy” created in the 1930s and adopted until today by Brazilian officials to describe Brazil’s racial composition and to hide evidence of racial discrimination in Brazilian society [7]. Although the majority of the Brazilian population declares race as Black (9.4%) or as “Pardo” meaning Mixed (46.8%), the most recent national census data show clear evidence of systemic discrimination as illiteracy in older adults was nearly three times more prevalent among Blacks and Mixed compared to Whites, average income of Whites was about 70% higher than the income of Blacks and Mixed, and unemployment rates were about 5% higher among Blacks and Mixed [8 –10]. Yet, there is limited information on the relation of discrimination to dementia in older Brazilians.

Experiences of discrimination or unfair treatment are commonly reported sources of psychological stress for Blacks and Latinos in the United States [11 –13] and have been associated with a wide range of adverse mental and physical health outcomes [14 –17]. Discrimination has also been associated with a variety of risk factors for dementia including cardiovascular risk factors [18, 19] and diseases [20, 21], depressive symptoms [22, 23], psychological distress [24, 25], and inflammatory markers [26, 27] in studies in the US.

However, to our best knowledge there has been no prior study investigating the association of discrimination with dementia. Our group previously reported that self-reported discrimination is associated with poorer cognitive performance in multiple domains in African Americans without dementia. The association of discrimination with cognitive test performance was attenuated by depressive symptoms and modified by neuroticism [28]. Other groups reported similar findings with discrimination being associated with lower levels of cognitive function [26 , 29–32], especially memory performance and some showed that the association of discrimination and cognition was mediated by a variety of factors including depression [29, 30], inflammatory markers [26], and urbanicity [31]. One study did not find an association of discrimination and cognitive performance [33]. Here we use data from a large community-based, cross-sectional study to examine the association of informant-report discrimination with dementia and cognitive impairment in a racially diverse sample of nearly 900 older Brazilians.

MATERIALS AND METHODS

Decedents and informants

The study included decedents from the Pathology, Alzheimer’s and Related Dementia Study (PARDoS). PARDoS enrolls deceased individuals, 18 years or older, who died from non-forensic causes of death and received an autopsy in either Autopsy Services or Hospitals in the State of Sao Paulo. PARDoS includes data from two cross-sectional, community-based studies with similar eligibility criteria and a large overlap of clinical data collection at the item level by the same study team facilitating efficient merging of the data. The study PARDoS started in 2020 and the Study of Ancestry, Neurodegenerative Diseases and Stroke (SANDS), started in 2016. PARDoS enrollment prioritizes Black/Mixed individuals that are 65 years or older at death, and White decedents with 8 or fewer years of education. We also prioritize subjects born in Brazilian in states other than the three southern states of Paraná, Santa Catarina, and Rio Grande do Sul where the population is less admixed. Both studies were approved by local ethical committees and by Comissão Nacional de Ética em Pesquisa (CONEP), the Brazilian federal ethics committee. Because the index cases were decedents, the study was determined to be of non-human subjects in the US and IRB exempt.

At the time of the analyses, 899 deceased aged 65 years or older, had an informed consent signed by a legal representatives and complete data on the Clinical Dementia Rating (CDR) Scale and on the discrimination questionnaire. Representatives who were not able to understand the consent or who were overly distraught were excluded. We also excluded deceased who had a postmortem interval higher than 36 hours and trauma cases destined for the forensic pathologists. PARDoS consent rate was 39.7% of the representative approached. Decedents had a mean age at death of 79.7 years (SD = 8.9 years; range: 65–110 years) and a mean educational attainment of 4.9 years (SD = 3.8 years; range: 0–25 years); 53.5% were women; 34.3% were proxy-declared Black or Mixed. The majority of the legal informants were children (75.5%), followed by grandchildren (9.2%), siblings (4.5%), spouse (3.0%), and other (7.8%).

Clinical interview

After study consent was signed, a nurse interviewer asked the informant to participate in a 60–90-min interview to obtain information about the deceased. When more than one informant was present, the interviewer considered the answers given by the informant most closely related to the deceased. The clinical interview included deceased demographics, informant characteristics, cognitive assessment, risk factors, and psychosocial factors as detailed below.

Age and sex were obtained through deceased identification documents. Informant-declared race was classified as White, Black, or Mixed. For the analyses, we combined the Black and Mixed race groups to allow comparison with other studies especially those from countries that do not include Mixed as a race category in the census. The two categories together are referred as Black in this study. There was no difference between Blacks and Mixed-race on age of death, sex, education, or informant-report discrimination. Education was reported by the informant as the number of years the deceased attended school. Socioeconomic status was determined using a Brazilian scale that considers the number of different household goods and services including the number of color TVs, radios, bathrooms, cars, washing machines, VHS/DVD players, fridges, freezers in the household, the number of maids working in the household, and the level of educational attainment of the principal householder [34]. The scale scores range from 0 to 46.

We recorded the relationship of the informant with the deceased, the average number of days per week the informant had contact with the deceased over the year prior to death, and the number of years the informant knew the deceased. Informants reported mean contact with the deceased to be 2.2 (SD: 4.0) days per week and a relationship with the deceased for a mean of 46.3 years (SD: 11.9).

Assessment of dementia and cognitive impairment

We used the CDR to diagnose dementia and mild cognitive impairment (MCI) proximate to death [35]. The informant-specific parts of the CDR structured questionnaire were used for each of the six domains of the scale (memory, orientation, judgment and problem solving, community affairs, home and hobbies, personal care). An algorithm scored each of the domains based on the questionnaire responses and converted the six domain scores into an overall rating of no cognitive impairment (NCI, CDR = 0), MCI (CDR = 0.5), or dementia (CDR > 0.5). Cognitive impairment was diagnosed in participants with either MCI or dementia prior to death.

The informant also responded to the 26-item Informant Questionnaire of the Cognitive Decline in the Elderly (IQCODE) as a second measure of cognitive impairment, comparing performance in multiple cognitive activities prior to death with cognitive performance 10 years prior to death [36]. The IQCODE final score was calculated as the sum of all the item scores divided by the total number of applicable items to account for missing data.

Assessment of informant-reported discrimination

Informant-report discrimination for the decedent was measured using items from two validated discrimination scales [37]. Informants were asked to answer 7 questions indicating whether they witnessed or the decedents expressed instances of chronic or major unfair treatment over the life course. Four questions were adapted from the 9-item Everyday Discrimination scale and are intended to capture relatively minor experiences of unfair treatment in day-to-day situations including: 1. He/she was treated with less respect than others; 2. People acted as if they thought he/she was not smart; 3. People acted as if they were better than him/her; 4. He/she was called names or insulted. Three questions were adapted from the 11-item Major Lifetime Discrimination scale to document specific instances of bias or overt discrimination experienced by the decedent over the life course including 5. For unfair reasons, he/she was not hired for a job or was not promoted; 6. He/she was unfairly stopped, threatened or abused by the police; 7. He/she was unfairly discouraged by a teacher or classmate from continuing his/her education.

Each of the 7 questions was scored 0 for the answer “no” and 1 for the answer “yes”. Scores ranged from 0 to 7 and higher scores represent higher levels of discrimination. The internal consistency for the informant-reported discrimination questionnaire was estimated using the polychoric correlation. The ordinal coefficient alpha was estimated as 0.9.

Other scales

Neuroticism, a personality trait that reflects the tendency to experience distress, was examined with 6 questions based on the Revised NEO Personality Inventory (NEO-PI-R) [38]. We adapted questions from the Structured Clinical Interview for DSM (SCID) for the informants to diagnose major depression episodes of the decedents in the past [39]. We created a comorbidity index based on informant reports of 11 medical conditions or risk factors: memory complaints; stroke; claudication; coronary disease; diabetes; weight loss; fatigue; cancer; heart failure; smoking. Weight loss and fatigue were included in the index as criteria of frailty [40]. Frailty has been extensively associated with dementia [41]. Intermittent claudication, stroke and coronary disease were used as phenotypes of vascular disease.

Statistical analysis

We first analyzed whether informant-report discrimination varied by race or sex using chi-square tests. Next, we examined the association of informant-report discrimination with dementia by conducting logistic regression models adjusted for age at death, sex, education, and race. We repeated the models by adding socioeconomic status, informant contact with deceased (years the informant knew the deceased and number of days of contact in a week) behavioral/psychological factors (major depression and neuroticism) and the comorbidity index. To test whether the association of informant-report discrimination with dementia was modified by demographics (race, sex, education, and socioeconomic status), informant contact (years of contact and days of contact in a week), behavioral/psychological factors (neuroticism and major depression) and the comorbidity index we repeated logistic regression models by adding terms for the interactions of each of these factors with informant-report discrimination. There is a rational for all the factor used in the models. Socioeconomic disparities may be associated with discrimination and socioeconomic status has also been associated with dementia [42, 43]. Previous studies reported that major depression may mediate the association of discrimination with cognitive performance [28 –30]. Neuroticism is a personality trait that represents a tendency to experience adverse outcomes in response to negative life events like discrimination. A higher level of neuroticism has been associated with dementia [44]. As discrimination was previously associated with multiple morbidities [18 –21] and these comorbidities may also be related to dementia, we included a comorbidity index in the models.

Finally, we repeated the logistic regression models to test the associations of informant-report discrimination with cognitive impairment (CDR > 0) and conducted linear regression models to test for the association of informant-reported discrimination with the IQCODE scores. The models using cognitive impairment and IQCODE scores as outcomes were also tested for interactions.

A nominal threshold of p < 0.05 was used to determine significance. Analyses were performed using SAS/STAT software, version 9.4 (SAS Institute Inc. Cary, NC, USA).

RESULTS

Decedents had a mean age at death of 79.7 years (SD = 8.9 years; range: 65–110 years) and a mean educational attainment of 4.9 years (SD = 3.8 years; range: 0–25 years); 53.5% were women; 34.3 % were proxy-declared Black or Mixed. The majority of the legal informants were children (75.5%), followed by grandchildren (9.2%), siblings (4.5%), spouse (3.0%), and other (7.8%). Demographic and clinical characteristics of participants by race are shown in Table 1. Black decedents were younger at death, had lower education and lower socioeconomic status compared to Whites. Informants of Black decedents had slightly more contact with the deceased measured as days of contact per week. The frequency of dementia measured by the CDR and cognitive impairment measured by the IQCODE were similar among Blacks and Whites.

Table 1

Demographics, informant and clinical characteristics of the sample by race

Characteristic ^*	Whites	Blacks	p	Total
	n = 591	n = 308		n = 899
Demographics
Male, n (%)	276 (46.7)	142 (46.1)	0.86	418 (46.5)
Age at death, y, mean (SD)	80.6 (8.9)	78.0 (8.7)	<0.001	79.7 (8.9)
Education, y, mean (SD)	5.3 (3.9)	4.0 (3.5)	<0.001	4.9 (3.8)
Socioeconomic status, mean (SD)	22.5 (6.5)	19.6 (4.7)	<0.001	21.5 (6.1)
Informant Characteristics
Know the deceased, y, mean (SD)	47.2 (12.1)	44.6 (11.5)	0.002	46.3 (11.9)
Days of contact/week (SD), mean (SD)	2.1 (3.7)	2.4 (4.4)	0.26	2.2 (4.0)
Informant-Report Discrimination
Discrimination, n (%)	104 (17.6)	78(25.6)	0.006	182 (20.2)
Clinical
Dementia, n (%)	171 (28.9)	83 (27.0)	0.53	254 (28.2)
Cognitive impairment, n (%)	222 (38.5)	103 (34.6)	0.25	325 (37.1)
IQCODE, mean (SD)	3.5 (0.8)	3.5 (0.7)	0.72	3.5 (0.7)
Neuroticism, mean (SD)	1.2 (0.5)	1.2 (0.5)	0.97	1.25 (0.5)
SCID depression, n (%)	34 (7.3)	12 (4.7)	0.18	46 (6.5)
Comorbidity index, mean (SD)	0.28 (0.16)	0.30 (0.16)	0.10	0.29 (0.16)

Discrimination was more frequently reported by informants of Blacks compared to informants of Whites (p = 0.006). More than a quarter of informants of Black decedents reported at least one of the items of the discrimination questionnaire as affirmative. Table 2 shows the frequency of each discrimination item by race. Reports of everyday discrimination (items 1 –4) were more frequently reported by informants of Blacks than Whites; there were no racial differences in reports of major discrimination (items 5 –7). Informant-report discrimination did not vary by sex (p = 0.69; data not shown).

Table 2

Informant-reported discrimination items distribution by race

Informant -reported discrimination questions	Whites	Blacks	p	Total
	n = 591	n = 308		n = 899
He/she was treated with less respect than others, n (%)	77 (13.0)	68 (22.1)	<0.001	145 (16.1)
People acted as if they thought he/she was not smart, n (%)	38 (6.4)	34 (11.0)	0.01	72 (8.0)
People acted as if they were better than him/her, n (%)	43 (7.3)	32 (10.4)	0.11	75 (8.3)
He/she was called names or insulted, n (%)	49 (8.3)	35 (11.4)	0.13	84 (9.3)
For unfair reasons, he/she was not hired for a job or was not promoted, n (%)	13 (2.2)	7 (2.2)	0.94	20 (2.2)
He/she was unfairly stopped, threatened or abused by the police, n (%)	4 (0.7)	2 (0.6)	0.96	6 (0.7)
He/she was unfairly discouraged by a teacher or classmate from continuing your education, n (%)	11 (1.9)	7 (2.3)	0.68	18 (2.0)

Association of informant-reported discrimination with dementia

The association of informant-report discrimination with odds of dementia was first examined in logistic regression models including age at death, sex, race, and education. Higher levels of Informant-report discrimination were associated with greater odds of dementia (OR: 1.24, 95% CI: 1.08–1.42, p = 0.002) with an estimate similar to three years of age for each higher point on the questionnaire. Results were similar after controlling for socioeconomic status (OR = 1.24, 95% CI: 1.08–,1.41, p = 0,0.002), informant contact with deceased (OR:1.25, 95% CI: 1.10–1.43, p = 0.001 for years the informant knew the deceased and OR: 1.25, 95% CI:1.09–1.43, p = 0.001 for days of contact in a week), major depression (OR: 1.22, 95% CI: 0.46–1.41, p = 0.0110), neuroticism (OR:1.19,95% CI: 1.04–1.37, p = 0.013) and the comorbidity index (OR: 1.90 95% CI: 1.03–1.37, p = 0.017). Detailed results of the models are shown in Table 3.

Table 3

Logistic regression models for the association of informant-reported discrimination and dementia, OR (95% CI), p

	Model 1, N = 899	Model 2, N = 889	Model 3, N = 713	Model 4, N = 866	Model 5, N = 863
Discrimination	1.24 (1.08–1.42)	1.23 (1.08,1.41)	1.22 (1.05,1.41)	1.19 (1.04–1.37)	1.19 (1.03–1.37)
	p = 0.002	p = 0.002	p = 0.01	p = 0.01	p = 0.02
Age at death	1.08 (1.06–1.10)	1.08 (1.06–1.10)	1.08 (1.06,1.11)	1.08 (1.06–1.10)	1.09 (1.07–1.12)
	p < 0.001	p < 0.001	p < 0.001	p < 0.001	p < 0.001
Male sex	0.92 (0.67,1.26)	0.91 (0.66–1.26)	0.79 (0.55–1.13)	0.91 (0.66–1.26)	0.87 (0.62–1.23)
	p = 0.59	p = 0.58	p = 0.20	p = 0.56	p = 0.43
Education	1.01(0.96–1.05)	0.99 (0.95–1.04)	1.02 (0.97–1.07)	1.01 (0.96–1.05)	1.02 (0.97–1.06)
	p = 0.92	p = 0.85	p = 0.49	p = 0.75	p = 0.50
Race	1.05 (0.75–1.47)	1.08 (0.77–1.52)	1.13 (0.78–1.65)	1.15 (0.82–1.61)	1.04 (0.72–1.49)
	p = 0.77	p = 0.64	p = 0.51	p = 0.43	p = 0.84
Socioeconomic status	–	1.01 (0.98–1.04)	–	–	–
		p = 0.59
Major depression	–	–	2.13 (1.13–4.03)	–	–
			p = 0.02
Neuroticism	–	–	–	1.38 (1.02–1.88)	–
				p = 0.04
Comorbidities	–	–	–	–	102.9 (35.6–297.6)
					p < 0.001

Next, we tested whether the association of informant-report discrimination with dementia was modified by demographics, informant contact, behavioral/psychological factors and comorbidities. We repeated logistic regression models by adding terms for the interactions of each variable with informant-report discrimination. The interactions were not significant for any demographics [race (p = 0.29), sex (p = 0.11), education (p = 0.87) and socioeconomic status (p = 0.97)], informant contact [years of contact (p = 0.62) and days of contact per week (p = 0.41)], behavioral and psychological factors [major depression (p = 0.49) and neuroticism (p =0.50)] or comorbidities (p = 0.61).

Association of informant-report discrimination with cognitive impairment

We repeated the models by replacing dementia (CDR > 0.5) with cognitive impairment (CDR > 0) as the outcome. Similar to the findings for dementia, logistic regression models including age at death, sex, race and education showed that higher levels of informed-report discrimination were associated with greater odds of cognitive impairment (OR:1.22, 95% CI:1.06–1.39, p = 0.004). Informant-report discrimination remained associated with cognitive impairment after adjustment for socioeconomic status, informant contact, major depression, and comorbidities (all ps < 0.05). The association of informant-report discrimination with cognitive impairment was marginal after adjustment for neuroticism (p = 0.05). Detailed results of these models are shown in Supplementary Table 1.

Similar to dementia, none of the interactions of informant-report discrimination with demographics, informant contact, behavioral/psychological factors, or comorbidities were significant for cognitive impairment (all ps > 0.05).

Finally, we conducted linear regression models using the IQCODE score as a continuous measurement of informant-report cognitive impairment as the outcome (Supplementary Table 2). Similar to the results for dementia and cognitive impairment based on the CDR, higher levels of informant-report discrimination were associated with greater cognitive impairment, controlling for age at death, sex, race, and education (estimate: 0.07, SE: 0.02, p = 0.003). Again, the association of informant-report discrimination with the IQCODE scores remained after controlling for demographic, informant and clinical variables presented above (all ps < 0.05) and none of the interactions of these variables with informant-report discrimination were significant (all ps > 0.05).

DISCUSSION

Nearly 900 informants of older deceased participants of a community-based study on aging and dementia in the state of Sao Paulo, Brazil, underwent a structured interview designed to support the informant-based diagnosis of dementia and cognitive impairment and to provide lifetime discrimination reports. We found that higher levels of informant-report discrimination were associated with greater odds of dementia and cognitive impairment and that these associations were independent of race, sex, education, socioeconomic status, major depression, neuroticism, or comorbidities.

Although discrimination has been shown to be associated with a variety of established risk factors for dementia, we are not aware of any prior study examining the direct association of discrimination and dementia. Our study is innovative in that experiences of discrimination were assessed by an informant for the deceased, as opposed to being reported by the person experiencing the discrimination themselves. Yet, the associations were robust and withstood adjustment for many potential confounders. A previous study from our group in 407 older African Americans without dementia showed that self-report discrimination was associated with poor cognitive performance [28]. Here, we extend those findings in multiple ways. First, we use data from a larger sample with more than twice the participants. Second, we include participants with and without dementia and cognitive impairment prior to death. Third, we include a racially diverse sample of Black and White Brazilians.

Race did not attenuate or modify the association of informant-report discrimination with dementia and cognitive impairment, suggesting that the effect of informant-report discrimination over dementia is similar in Blacks and Whites. However, because discrimination was reported by legal informants of Black decedents at a significantly higher rate than informants of White decedents, experiences of discrimination may contribute to racial differences in the frequency of dementia and cognitive impairment. In Brazil, where national census data find persistent and deep racial inequalities [8 –10], Blacks and Mixed represent more than half of the population who would be more exposed to the deleterious effects of discrimination over cognition. This is also consistent with other studies showing higher levels of self-report discrimination in Black participants compared to Whites in the US [11 –13]. The findings of our study are especially relevant given the evidence of a higher prevalence of dementia among African Americans compared to Non-Latino Whites in the US and suggest that discrimination may be one of the factors contributing to the higher susceptibility of dementia in this population [2 –5].

The mechanisms underlying the association of discrimination with dementia and cognitive impairment are unknown. As previously mentioned, self-report discrimination has been associated with a variety of risk factors for dementia, including behavioral/psychological factors such as depression and neuroticism, and cardiovascular risk factors such as systemic arterial hypertension and coronary disease [18 –25]. Discrimination has been also associated with cognitive performance, especially memory and this association was shown to be mediated in part by depression and other factors [29, 31]. In contrast to these prior studies and with our previous study in African Americans [28], the association of informant-report discrimination with dementia and cognitive impairment was not modified by depression or neuroticism. Further, a comorbidities index including cardiovascular risk factors and cardiovascular disease also did not modify the association of informant-reported discrimination with dementia and cognitive impairment. Other mechanisms reported in the literature to be associated with cognition and discrimination, like inflammation or a direct effect of discrimination on brain function, were not included in our study [31 , 46]. Future studies including neuropathological indices are needed to better understand the biological mechanisms underlying the association of discrimination and dementia.

This study has strengths and limitations. The data is based on a large sample of racially diverse Brazilians with and without dementia and cognitive impairment. The clinical diagnosis of dementia and cognitive impairment is based on validated structured informant questionnaires. The use of three different outcomes increases confidence in our findings. A limitation that should be noted is that discrimination was based on informant report rather than self-report. Informant-report discrimination may differ from self-report in at least two ways. First, informants may report witnessed or known of experiences of unfair treatment that the participants would not feel comfortable reporting. Second, informants may not have witnessed or been told of all experiences of discrimination, particularly if the informant is reporting for his/her parent and the experience happened in the decedent’s early life. In an attempt to reduce differences between self and informant reports of discrimination, we prioritized reports from informants who had closer contact with the deceased. On average, informants knew the deceased for more than four and a half decades. Further, the level of contact of the informant with the deceased did not modify the association of informant-reported discrimination with dementia and cognitive impairment. Finally, our frequency of informant-reported discrimination of approximately one fifth of the sample is within the range of 16.8% to 37.0% of Brazilian studies examining the frequency of self-reported discrimination in older subjects [47, 48].

Footnotes

ACKNOWLEDGMENTS

We thank the informants and the staff of the study in the US and Brazil. The study was supported by NIA grant R01AG54058.

Authors’ disclosures available online ().

The supplementary material is available in the electronic version of this article: .

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