Abstract
Background:
Few oral health studies have been conducted in HIV-exposed uninfected children, who, like their HIV-infected peers, have altered immunity and perinatal drug exposures.
Aim:
To compare caregivers’ self-report of oral diseases, hygiene practices and utilization of routine dental care, between HIV-infected (HIV), HIV-exposed uninfected (HEU), and HIV-unexposed uninfected (HUU) children in Kenya.
Design:
This nested cross-sectional study was conducted at the Kenyatta National Hospital, Nairobi, Kenya. Caregivers of 196 children (104 HIV-infected, 55 HEU, and 37 HUU) participated in this study. Using a validated questionnaire from the WHO and photographs of HIV-related oral lesions, we collected data on oral diseases and oral health practices.
Results:
Caregivers of HIV-infected children reported at least one oral disease in their children (42%; HEU [27%]; HUU [17%; P = .008]). Oral candidiasis was the most common disease reported (HIV-infected [24%], HEU [5.5%], and HUU [2.8%; P < .05]). Baseline CD4% was associated with oral candidiasis (OR = 0.93, 95% CI: 0.88–0.98). Only 16% of children had ever visited a dentist, and most initiated brushing after 3 years of age (83%). Nearly all (98%) caregivers desired a follow-up oral examination.
Conclusions:
HIV infection/exposure and low CD4% were associated with increased odds of oral diseases. Most caregivers desired a follow-up oral examination for their children.
Keywords: children, global health, HIV, oral health
1 |. INTRODUCTION
Despite significant successes in the treatment for HIV, children with HIV continue to experience more oral diseases compared to uninfected children. HIV profoundly disrupts the oral mucosa, increasing the risk of oral opportunistic infections,1 severe invasive infections such as necrotizing ulcerative gingivitis and periodontitis,2 and dental defects such as enamel hypoplasias.3 Oral lesions are often among the earliest clinical signs of HIV in infected individuals,4 with herpes simplex virus (HSV), candidiasis, and linear gingival erythema being the most common oral manifestations of HIV in children.5 Antiretroviral therapy (ART) partially resolves inflammation and reduces the prevalence of opportunistic infections, but does not completely eliminate them.6,7 Resolution of opportunistic oral infections is observed as early as 1 month post-ART concurrent with immune restoration and improved T-cell function.8,9 Persistence of oral lesions after starting ART can therefore be an indication of ART treatment failure.10
Prevention of mother-to-child transmission (PMTCT) intervention coverage is rapidly increasing in the most high-burden African countries affected by HIV, and most countries now implement WHO Option B+,11 in which women initiate or continue lifelong combination ART during pregnancy. Consequent to Option B+ rollout, dramatic reductions in infant HIV infections have been accompanied by an increase in the number of HIV-exposed uninfected children (HEU). While the impact of HIV on the oral health of HIV-infected children is well-defined, less is known about the impact of HIV on oral health of HEU children. It is known that in utero drug exposure (eg tetracyclines) or maternal infections can alter tooth development (eg intrinsic stains, dental hypoplasia, and molar incisor hypomineralization).12–14 Drug exposure through maternal PMTCT has the potential to affect dental development and therefore increase risk for oral diseases in children. There is limited data on the oral health of HEU children after they exit PMTCT. It is relevant to bridge the gap of knowledge on the extent by which HIV and PMTCT impact children’s oral health.15 To date, there have been few studies comparing oral morbidities between HIV-infected, HIV-exposed uninfected, and HIV-unexposed uninfected children.
Oral health is a critical factor in determining quality of life. Pain from oral lesions may lead to decreased nutrient intake, dehydration, malnutrition, and stunting.5 Chronic oral conditions and related pain can lead to stress and depression.16 In Kenya, oral examinations are not part of routine medical examinations.17 Caregivers are the key stewards of children’s oral health and need to be actively engaged in the identification of oral health problems.18 Their knowledge, attitudes, and behaviours regarding oral hygiene and care-seeking set the stage for children’s oral health in both childhood and in the long-term as they assume responsibility for their own care.
We conducted a pilot study with the objective of describing and comparing the burden of and cofactors for the most common HIV-associated oral conditions among HIV infected, HIV-exposed uninfected, and HIV-unexposed children in Nairobi, Kenya. The study hypothesis was that oral manifestations of HIV would be significantly higher among HIV-infected compared to uninfected children. Working towards the long-term goal of integrating routine oral health care into the paediatric HIV care continuum, we additionally assessed history of oral healthcare, routine oral hygiene practices, and caregiver desire for routine dental examination towards feasibility for future combined oral health and HIV research trials.
2 |. METHODS
2.1 |. Study Population
The oral health study was nested into an ongoing cohort study of Kenyan HIV-infected children who were enrolled and initiated antiretroviral therapy (ART) as part of two clinical trials. All caregivers of children receiving care as part of the longitudinal study were eligible to complete the nested cross-sectional study, as long as they were willing to provide informed written consent for participation. This nested study was approved by the University of Washington Institutional Review Board (Study #44655) and the Kenyatta National Hospital/University of Nairobi Ethics and Research Committee (KNH/ERC/R/133). All children were recruited, enrolled, and followed up in the same study clinic at Kenyatta National Hospital, Nairobi, Kenya; details of their recruitment, enrolment, and clinical follow-up procedures are available elsewhere.19,20 From 2007 to 2010, the Optimizing Pediatric HIV Therapy (OPH) study enrolled children <12 months old and started ART immediately, regardless of CD4 or clinical status. At 24 months post-ART, OPH children underwent a planned treatment interruption to determine whether a pause in ART was safe and sustainable; all children resumed ART within 6 months and have continued follow-up to evaluate long-term outcomes (National Clinical Trials Registry: #NCT00428116).19 The Pediatric Adherence Diary (PAD) Study enrolled children aged 15 months to 12 years old from 2004 to 2005 who met contemporaneous clinical criteria for ART initiation (moderate (WHO clinical stage 2 with CD4 < 15%) to severe (WHO clinical stage 3 or 4) HIV-1 disease).21 OPH and PAD children received ART regimens in accordance with contemporaneous guidelines. From 2004 to 2010, HIV-unexposed (HUU) and HIV-exposed uninfected (HEU) children aged 0–5 years were enrolled from the same study site as controls to understand the potential impact of HIV infection and exposure on neurological development (INK Cohort). For OPH, PAD, and INK, demographic, obstetric, clinical data from caregiver-child dyads (including demographics, PMTCT exposure, maternal and child ART, virologic and CD4 and HIV RNA viral load were collected using standardized clinical assessments and questionnaires). The power of the sample of 92 children, with an observed difference in any oral pathology (HIV vs HEU and HUU), was 0.806, with an alpha of 0.05.
2.2 |. Clinical data
Demographics, HIV diagnosis and PMTCT history, baseline CD4 and HIV RNA viral load data were extracted from the primary study databases. The oral health questionnaire was administered to all caregivers with children in follow-up between December 2015 and October 2016. Study staff (nurses and medical officers) who have been providing routine HIV care to the families since enrolment administered the questionnaires, which were adapted from the World Health Organization Record Form for Oral Manifestations in HIV/ AIDS.22 In order to facilitate identification of oral lesions and minimize misclassification, we presented caregivers with a visual guide of clinical photographs showing each of the common oral manifestations of HIV. The questionnaire assessed whether the caregiver had ever observed or whether the child had ever been diagnosed with the following oral conditions: inflammation of lip corners (angular cheilitis), white thrush (oral candidiasis), parotid enlargement, inflamed gums (ulcerative gingivitis), herpes simplex vesicles, and aphthous ulcer. We additionally asked about utilization of routine and emergency dental care, oral hygiene practices and exposure to sugary food and drink.
2.3 |. Statistical analyses
Stata SE v14.2 (StataCorp) was used for data analysis; all tests were two-sided with alpha = 0.05. The primary exposure in this study was children’s HIV exposure status, and the primary outcomes were caregiver’s report of HIV oral manifestations, oral hygiene practices, and sweets intake. Descriptive statistics were calculated for all variables and presented by history of HIV exposure and infection status. Chi-squared and Fisher’s exact tests were used to compare proportions of caregivers reporting oral lesions among the three groups. Logistic regression was used to measure the association between putative correlates (HIV exposure, age, CD4, and HIV RNA level) and caregiver-reported oral lesions. The chi-squared test was used to compare oral hygiene and dietary exposures between HIV-infected, HEU, and HUU children.
3 |. RESULTS
3.1 |. Cohort characteristics
A total of 196 caregivers were interviewed representing 104 HIV-infected children, 55 HEU, and 37 HUU. Approximately half of the children (49%) were female and had a median of one sibling (IQR: 1–2). The median age of children in the cohort was 7.9 years (IQR: 7.0, 9.8). Due to differing enrolment criteria and follow-up times, the median ages of the cohorts were different, with the HIV-infected children being older than the HEU and HUU groups. The median age at ART initiation was 1.7 years (IQR: 0.42, 5.9), and children had been on ART for a median of 6.9 years (IQR: 5.9, 7.0) when their caregivers were interviewed. The median pre-ART HIV viral load was 5.62 log10 HIV RNA copies/mL (IQR: 3.3, 6.7), and the median enrolment CD4 per cent was 17% (IQR: 11, 25; Table 1).
TABLE 1.
Characteristics of HIV-infected, HIV-exposed uninfected and HIV-unexposed Kenyan children assessed for oral manifestations of HIV infection
| N (%) or median (IQR) |
||||
|---|---|---|---|---|
| Total | HIV-infected | HIV-exposed uninfected | HIV-unexposed | |
| Total children | 196 | 104 | 55 | 37 |
| Caregiver age at enrolmenta | 33 (28–39) | 33 (29–40) | 35 (31–39) | 27 (26–33) |
| Caregiver years of educationb | 8 (8–12) | 8 (8–12) | 8 (8–12) | 8 (8–12) |
| Number of siblings in family | 1 (1–2) | 1 (0–2) | 2 (1–3) | 1 (1–2) |
| Child female | 95 (49%) | 45 (43%) | 27 (49%) | 23 (62%) |
| Child age in years at assessment | 7.9 (7.0–9.8) | 8.1 (7.1–11) | 7.5 (6.1–8.7) | 8.2 (7.5–9.7) |
| Child age at ART initiation in years | - | 1.7 (0.42–5.9) | N/A | N/A |
| Child years on ART at assessment | - | 6.9 (5.6–8.1) | N/A | N/A |
| Child log10 HIV RNA level at enrolment | - | 5.62 (3.3–6.7) | N/A | N/A |
| Child CD4 per cent at enrolmentc | - | 17 (11–25) | N/A | N/A |
N = 194.
N = 189.
N = 102.
3.2 |. Oral manifestations of HIV
More than a third of the caregivers (42%) reported having observed at least one oral lesion in the HIV-infected children (Table 2). A history of oral lesions was less commonly reported in the HEU (27%) and HUU (17%) children (P = .008 for HIV+ vs HUU; P = .3 for HEU vs HUU), compared to the HIV-infected children. Oral candidiasis was the most common oral disease reported; nearly a quarter of HIV-infected children (24%) had experienced oral candidiasis while it was less frequently reported in the HEU (5.5%) and the HUU children (2.8%; P = .005 for HIV+ vs HUU; P ≥ .9 for HEU vs HUU). Herpes simplex and aphthous ulcers were also common in all children and did not differ significantly by HIV exposure.
TABLE 2.
Oral HIV manifestations in HIV-infected, HIV-exposed uninfected, and HIV-unexposed children
| HIV-infected N (%) |
HIV-exposed uninfected N (%) |
HIV-unexposed N (%) |
P value HIV+ vs HUU | P value HEU vs HUU | |
|---|---|---|---|---|---|
| Any oral pathology | 43/103 (42%) | 15/55 (27%) | 6/36 (17%) | .008 | .3 |
| Angular cheilitis | 10/103 (10%) | 1/55 (1.8%) | 0/36 (0%) | .06 | >.9 |
| Oral candidiasis | 24/102 (24%) | 3/55 (5.5%) | 1/36 (2.8%) | .005 | >.9 |
| Parotid enlargement | 9/103 (8.7%) | 2/55 (3.6%) | 0/36 (0%) | .1 | .5 |
| Ulcerative gingivitis | 1/103 (0.97%) | 1/55 (1.8) | 1/36 (2.8) | .5 | >.9 |
| Herpes simplex | 17/102 (16%) | 6/55 (11%) | 2 (5.6%) | .2 | .5 |
| Aphthous ulcer | 16/103 (16%) | 6/55 (11%) | 3/36 (8.3%) | .4 | >.9 |
Note: P value from Fisher’s exact test.
3.3 |. Correlates of oral HIV manifestations
HIV infection was associated with 2.5-fold increased odds of reporting at least one type of oral lesion (OR: 2.4; 95% CI: 1.3, 4.5; Table 3). HIV-infected children had a 6.7-fold (95% CI: 2.2, 20) increased odds of oral candidiasis and 9.7-fold increased odds of reporting angular cheilitis (95% CI: 1.2, 77) compared to uninfected children. HIV-infected or exposed uninfected children had a ~threefold increased odds (OR = 2.9, 95% CI: 1.1, 7.4) of any oral HIV manifestation compared to unexposed children; angular cheilitis and parotid enlargement were not reported in any HUU children. Among HIV-infected children, each 1% increase in baseline CD4% was associated with 7% lower odds of having reported oral candidiasis (OR = 0.93, 95% CI: 0.88, 0.98).
TABLE 3.
Correlates of HIV-associated oral manifestations
| Any oral condition | Oral candidiasis | Angular cheilitis | Parotid enlargement | Herpes simplex | Aphthous ulcer | |
|---|---|---|---|---|---|---|
| Age at assessment | 1.1 [0.97–1.2] | 1.0 [0.89–1.2] | 0.94 [0.73–1.2] | 1.2 [0.95–1.4] | 1.1 [0.90–1.2] | 1.1 [0.92–1.3] |
| HIV-infected (vs HEU and HUU) | 2.4 [1.3–4.5]* | 6.7 [2.2–20]** | 9.7 [1.2–77]*** | 4.3 [0.90–20] | 1.9 [0.78–4.8] | 1.7 [0.70–4.0] |
| Age in years at ART initiation | 1.02 [0.93–1.1] | 0.98 [0.87–1.1] | 0.99 [0.84–1.2] | 0.98 [0.82–1.2] | 0.98 [0.85–1.1] | 1.0 [0.91–1.2] |
| Baseline CD4 per cent | 0.97 [0.93–1.0] | 0.93 [0.88–0.98]**** | 0.99 [0.93–1.1] | 0.98 [0.91–1.0] | 0.98 [0.93–1.0] | 1.0 [0.98–1.1] |
| Baseline log10 HIV RNA copies/mL | 0.92 [0.72–1.2] | 0.94 [0.71–1.3] | 0.97 [0.63–1.5] | 0.98 [0.64–1.5] | 0.98 [0.70–1.4] | 0.87 [0.64–1.2] |
| HIV-exposed or infected (vs HUU) | 2.9 [1.1–7.4]*** | 7.3 [0.95–55] | a | a | 2.8 [0.62–12] | 1.8 [0.50–6.3] |
Note: HIV-exposed uninfected (HEU) and HIV-unexposed uninfected (HUU). Odds ratios and (95% confidence intervals) from logistic regression.
Odds ratio is undefined, only children with HIV exposure had angular cheilitis and parotid enlargement.
P = .006.
P = .001.
P = .03.
P = .01.
3.4 |. Oral hygiene practices, dietary exposures, and engagement in dental care
Only 31 (16%) of the children in the study had ever visited a dentist at the time of the survey (Table 4). Most caregivers reported that their children brush their teeth at least once daily (86%).Initiation of tooth brushing before the age of 3 years old, however, was uncommon (17%) in this cohort: 1.0% started before 1 year old, 1.5% started between 1 year and 2 years, 13% started between 2 and 3 years, and 74% started after 3 years. Only 22 (11%) children confirmed using fluoridated toothpaste while brushing, however most (173) caregivers were unsure or did not answer this question (data not shown).
TABLE 4.
Current oral hygiene and dietary exposures in HIV+ and HIV-uninfected children
| Exposure measure | Total n (%) | HIV-infected n (%) | HIV-exposed uninfected n (%) | HIV-unexposed n (%) | P value |
|---|---|---|---|---|---|
| Ever visited a dentist | 31 (16%) | 16 (15%) | 10 (18%) | 5 (14%) | .8 |
| Interested in follow examination | 192 (98%) | 101 (97%) | 55 (100%) | 36 (97%) | .5 |
| Toothache during the past year | 26 (13%) | 14 (13%) | 8 (15%) | 4 (11%) | .9 |
| Toothbrushing at least once dailya | 168 (86%) | 93 (89%) | 46 (84%) | 29 (78%) | .4 |
| Started brushing before 3 y oldb | 31 (17%) | 15 (16%) | 11 (21%) | 5 (14%) | .7 |
| Using fluoride toothpastec | 22 (11%) | 22 (21%) | 0 (0%) | 0 (0%) | <.001 |
| Frequency of sweets intaked | |||||
| Never or occasionally | 116 (59%) | 71 (68%) | 28 (51%) | 17 (46%) | .05 |
| Every day or most days | 78 (40%) | 32 (31%) | 27 (49%) | 19 (51%) | |
| Frequency sugary food between mealse | |||||
| Never or occasionally | 110 (56%) | 67 (64%) | 26 (47%) | 17 (46%) | .09 |
| Every day or most days | 83 (42%) | 35 (34%) | 29 (53%) | 19 (51%) | |
| Sweetens tea for childf | |||||
| Never or occasionally | 2 (1.0%) | 1 (0.96%) | 0 | 1 (2.7%) | .6 |
| Every day or most days | 191 (97%) | 101 (97%) | 55 (100%) | 35 (95%) | |
Note: P value from chi square. Unsure or missing:
6
15
173
2
3
3.
Bold numbers indicate statistical significance (P≤ .05).
Nearly all caregivers reported giving sweetened tea to their children (97%). A similar and substantial proportion of children from each HIV exposure group had experienced a toothache during the past year (13% overall). The proportion of caregivers reporting their children ingested ‘sweets, including chocolates’ reported as ‘every day or most days’ was slightly lower in the HIV-infected children compared to other groups (P = .05), as was ingesting ‘sugary foods between meals’ (P = .09).
When caregivers were asked whether they would like for the study to arrange a free dental examination for their child, 192 (98%) caregivers answered ‘yes’, with the proportion desiring follow-up care for their children similarly high across patient groups (P = .5); with 46 (23%) preferring to arrange the examination as soon as possible, 122 (62%) preferring to schedule it at the child’s next study visit, and 24 (12%) preferring to schedule it at a visit separate from their routine study visit (data not shown).
4 |. DISCUSSION
In this cohort of children living with HIV infection and those with and without HIV exposure, a high proportion of caregivers of children living with HIV reported a history of oral manifestations of HIV infection. The rate of HIV-associated oral morbidities was also high among HEU children, consistent with other studies suggesting altered immunity and an overall increased risk of infectious morbidity in HEU children.15 Caregivers reported high uptake of routine home oral hygiene practices, but low uptake of routine professional dental care, late initiation of brushing, and high exposure to nutritional risk factors for dental caries.
This is one of the few studies to date comparing oral manifestations of HIV infection between HIV-infected, exposed and unexposed children.23 As expected, overall oral morbidity was highest in the infected children HIV-infected (42%) and HEU (27%), and lowest in the HUU (17%) children. The most commonly reported conditions were candidiasis and oral HSV ulcers, which is consistent with findings in both treated and ART-naïve populations.24 The high rate of oral morbidities in the HEU infants is notable, and could reflect immunologic abnormalities due to HIV exposure, or increased exposure to maternal pathogens, including HSV.25 Consistent with earlier studies, HIV infection and exposure was associated with a higher odds of oral candida, and higher baseline CD4 per cent was associated with a decreased odds of candida.
Less commonly reported conditions and those associated with more severe immunodeficiency (OHL,26 molluscum contagiosum, and Kaposi sarcoma) were not reported in any children in the study clinical records (data not shown), a reflection of possibly having started ART early in life, high ART compliance, and relatively high CD4 counts in this cohort. Reliance on assessment using caregiver report, however, could have missed mild presentations of Acute Necrotizing Ulcerative Gingivitis (ANUG), parotid enlargement, xerostomia,24 or necrotizing stomatitis, although severe cases would likely have been detected.
Oral hygiene and dietary behaviours were mostly similar among the three groups of children, although caregivers of HIV-infected children were less likely to report regular exposure to sweets. An explanation of this finding may be that caregivers of children with chronic illnesses might be more vigilant in maintaining a healthy diet. In Kenya, tea is commonly drunk with added sugar, and most caregivers reported their children having sweetened tea daily. Providers could counsel caregivers about the potential cariogenic impact of this practice, but such culturally embedded norms may be difficult to change.
Uptake of routine dental examination was low, although most caregivers reported that their children brushed at least once a day. These data are consistent with the generally low prioritization of professional oral healthcare services in resource-limited settings but demonstrates that caregiver knowledge of appropriate provision of routine home hygiene care is high. One area identified for intervention is the need for earlier initiation of brushing in children, as a preventative measure for early childhood caries (ECC); most caregivers reported that their children did not start brushing until they were >3 years old, and it is well established that routine home cleaning of gums and primary teeth from infancy is important in preventing tooth decay and gingivitis.27
Nearly all caregivers wished to arrange a follow-up oral examination for their children, and many (62%) preferred to integrate this into their routine study visits, if possible. This suggests a potential under-utilized opportunity to leverage existing well-child and HIV treatment programs to better integrate oral health assessments and referrals.
Limitations of our study include assessment of oral morbidities by caregiver report and recall bias. Case counts are thus likely to be an underestimate, with caregivers reporting the most clinically obvious and severe conditions. Given the low sample size in the HEU and HUU groups, we have low statistical power to detect a small difference in proportion between these groups (power = 0.19) and cannot rule out a difference that might have been found with a bigger sample size. The younger age and relatively shorter follow-up time of HEU and HUU children introduce potential bias. This analysis compared children that were derived from several different research protocols with different eligibility criteria, leading to many sources of unaddressed potential confounding. We unfortunately did not have information on maternal CD4 count or drug exposures in pregnancy, which are likely important predictors of both infant HIV status and oral disease, and thus a source of confounding for which we were unable to control.
Finally, this study highlights opportunities for inter-professional collaboration between oral health and HIV researchers that can be achieved within ongoing research projects. While oral HIV research in developing countries is needed, limitations often include deficient infrastructure and well-trained human capacity.28 Integrating oral health within existing robust research networks like HIV will not only enhance current HIV groundwork but facilitate opportunities for further training of oral health professionals, thus, impacting on public health research and dental care delivery systems while reflecting the community’s cultural competence.
WHY THIS PAPER IS IMPORTANT TO PAEDIATRIC DENTISTS.
Despite the early initiation of ART and high compliance of treatment over several years, HIV infection, HIV exposure, and CD4% were associated with increased odds of oral HIV-associated comorbidities reported by caregivers of HIV-infected children in Kenya. Oral morbidities were also commonly reported in HEU children and understanding the mechanism of this high risk can improve care strategies for this population.
The routine clinical care schedule for HIV-infected children provides an opportunity to engage parents in more prompt diagnosis of oral morbidities, improve access to appropriate treatment, and increase inter-professional HIV and oral health research.
There is low uptake, but high demand for routine oral care among caregivers of HIV-exposed and HIV-infected children. Training HIV care providers or caregivers in the identification and management of oral comorbidities may improve referrals and early treatment.
ACKNOWLEDGEMENTS
We thank the study participants and their families, and the administrative, clinical, and data teams for their dedication and support. We thank the Kizazi Mother Infant Working Group, the UW Global Center for Integrated Health of Women, Adolescents and Children (Global WACh), Kenya Research and Training Center (KRTC) and the UW Timothy A. DeRouen Center for Global Oral Health for their thoughtful input during development of this manuscript. Dr. Ailin Cabrera adapted the WHO survey for use in the study. Pooja Rajanbabu assisted on formatting and editing.
Funding information
The Impact of HIV, Immune Activation and ART on Child Neurodevelopment in Kenya (INK) Study was supported by National Institutes of Neurological Disorders and Stroke (NINDS) grant K01 NS080637 [to SBN] and a Center for AIDS Research (CFAR) New Investigator Award. The Optimizing Pediatric HIV-1 Therapy (OPH03) Study was supported by the National Institutes of Child Health and Development grant R01 HD023412 [to GJS]. GJS was also supported by NIH grant K24 HD054314. The Pediatric Adherence Diary (PAD) Study was funded the Global Research Initiative Program, Social Science grant R01TW007632. Field site and biostatistical support were provided by the University of Washington International and Biometrics Cores of CFAR, a National Institutes of Health (NIH) funded program (P30 AI027757), supported by the following NIH Institutes and Centers (NIAID, NCI, NIMH, NIDA, NICHD, NHLBI, and NCCAM).
Footnotes
CONFLICT OF INTEREST
The authors declare no conflict of interests.
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