Accepted Article

DR. RU DAI (Orcid ID : 0000-0002-2691-8544)

Article type : Original Article

Article type: Original article

The effect of milk consumption on acne: a meta-analysis of observational studies

Running head: Acne and milk consumption: Meta-Analysis

Ru Dai, MD12, Wei Hua, MD2, Wei Chen, MD2, Lidan Xiong, MM2, Li Li, MD, PhD2*

1
Department of Dermatology, Ningbo First Hospital, No. 59, Liuting Street, Ningbo, Zhejiang,

315010, P.R. China

2
Department of Dermatology, West China Hospital, Sichuan University, No. 37, Guo Xue

Xiang, Chengdu, Sichuan, 610041, P. R. China

This article has been accepted for publication and undergone full peer review but has
not been through the copyediting, typesetting, pagination and proofreading process,
which may lead to differences between this version and the Version of Record. Please
cite this article as doi: 10.1111/jdv.15204

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*Corresponding authors: Li Li, MD, PhD, Department of Dermatology, West China Hospital, Sichuan
University, No. 37, Guo Xue Xiang, Chengdu, 610041, P. R. China (Tel:
86+028-85422075; Fax: 86+028 -85422363; E-mail: hxskincos2017@qq.com)

E-mail addresses: dairu1121@foxmail.com (Ru Dai), huawei1007@qq.com (Wei Hua),

willcw@foxmail.com (Wei Chen), beardan0505@163.com (Lidan Xiong)

Funding: No external funding.

Conflicts of interest: The authors have no conflicts of interest to declare.

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 Abstract
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Background: Acne is a common skin condition in developed countries with western diets. The

effect of milk on acne has been highly controversial. In order to examine the association

between milk consumption and acne risk, we conducted a meta-analysis of available data.

Materials and Methods: We carried out comprehensive databases search of Pubmed, Embase,

Medline and Cochrane Library and identified 4 cohort studies and 9 case-control or

cross-sectional studies, including a total of 71819 participants. We evaluated the pooled odds
ratio (OR) with its 95% confidence interval (CI) using a random-effects model. Subgroup

analyses on acne severity, milk forms and milk intake levels were performed.

Results: Compared with nonconsumers, the pooled OR was 1.16 (95% CI 1.09-1.24) for

overall milk consumers in all included studies, and 1.17 (95% CI 1.10-1.24) in cohort studies,

and 1.16 (95% CI 1.09-1.24) in case-control or cross-sectional studies. Subgroup analysis on

milk forms determined a stronger association in skim milk consumers (OR=1.24, 95% CI

1.13-1.37) than in low-fat consumers (OR=1.14, 95% CI 1.08-1.22) and full-fat consumers

(OR=1.13, 95% CI 1.05-1.21). The pooled OR was greater for high intake level of milk

(OR=1.12, 95% CI 1.01-1.24) than medium intake level of milk (OR=1.08, 95% CI 1.00-1.17).

A subset study of moderate to severe acne also found a positive association with milk

consumption (OR 1.18, 95% CI 1.01-1.37), while no statistically significant association was

found between mild acne risk and milk consumption (OR 1.14, 95% CI 0.86-1.51).

Conclusion: This meta-analysis provides evidence of a positive association between milk

consumption and acne risk.

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 Key words: acne, acne vulgaris, milk, dairy, diet.
Accepted Article
1. Introduction

Acne is one of the most common skin conditions among adolescents, even in some adults. It

affects approximately 85% of teenagers,1 but half of them can persist into adulthood.2 The

prevalence of acne in adult women is about 54% and is about 40% in adult men.3 Although the

mortality of acne is rare, acne is more likely to cause physical and psychological disfigurement

as the frequent complication of acne scar. In the USA, the direct cost for acne is estimated to

over 4 billion dollars per year.4 Acne involves multiple disorders of increased sebum

production induced by insulin, insulin-like growth factor (IGF-1) and androgens,5,6

pilosebaceous hyperkeratosis, Propionibacterium acnes colonization and secondary

inflammation.1

A number of previous studies have suggested a positive association between milk consumption

and acne risk.7–9 In 2006, a prospective cohort study with 6094 female teenagers 9 to 15 years

of age investigated the impact of milk intake on acne. Girls were asked to report dietary

consumption through questionnaires from 1996 to 1998. They were also asked to self-assess

acne through questionnaires in 1999. An increasing prevalence of acne was associated with

total milk intake, low-fat milk intake and skim milk, while a following study focused on boys

found that acne was only associated with the intake of skim milk. Another prospective cohort

studies involving 2489 Norwegian subjects also found high intake of dairy products was

associated with acne. More recently, emerging case-control studies suggested that the

frequency of milk consumption was higher in patients with acne compared to the controls.10,11

All of the above studies supported a positive association between milk consumption and acne

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 risk. However, on the contrary, a number of studies suggested no association between milk
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consumption with acne.12,13 Therefore, it remains controversial whether any potential

relationship between milk drinking and acne risk. Besides, it is still uncertain whether the

acne-aggravating effect of milk is linked to its forms, such as full-fat, low-fat and skim milk. In

addition, whether the frequency of milk intake plays a critical role on acne pathogenesis, and

whether the function of milk varies with the severity of acne.

To address these issues, we conducted a meta-analysis of observational studies published on

milk consumption and acne.

2. Materials and methods

2.1 Search strategy and study selection

The meta-analysis was performed in accordance with the MOOSE. 14 Eligible studies were

identified by two authors (R. Dai and W. Hua) independently through a comprehensive search

of following databases: PubMed (1966 to Apr. 10 th 2018), Embase (1974 to Apr. 10th 2018),

Medline (1946 to Apr. 4th 2018) and Cochrane Library (up to March 2018). The search terms or

text terms were used as: (acne* OR acne vulgaris OR common acne) AND (milk* OR dairy*

OR dairy product*). In addition, the reference lists of the selected relevant papers were also

checked manually for potential eligible articles. When certain data was not available in

published form, a contact to authors for original information was performed. We included

studies evaluating the association of milk consumption and acne. No language limitation was

imposed. Studies were screened according to the following inclusion criteria: (1) cohort, case-

control or cross-sectional studies which reporting the milk intake and acne incidence or

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 prevalence; (2) independent data were from original papers; (3) studies estimating the odds
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radio (OR) or relative risk (RR) with corresponding 95% confidence intervals (CI) or sufficient

data to calculate them. Studies were excluded on the basis of following criteria: (1) not original

articles (e.g. review, meta-analysis or comment etc.); (2) not human studies (e.g. animal study

or in vitro study); (3) duplicated publication; (4) articles without necessary information. When

multiple studies were published based on the same data, we considered into the meta-analysis

only the most informative one (e.g. the most recent or informative one).

2.2 Data extraction and quality assessment

For each included study, the following data were extracted independently by two authors (W.

Chen and Lidan. Xiong): first author’s name, year of publication, country location, study

design, period of enrollment for case-control and cross-sectional studies or follow-up for cohort

studies, subjects baseline (sample size, mean age or age range and male number), the method to

diagnose acne, acne classification, milk types and intake levels, adjusted variables, odds ration

(OR) or relative ratio (RR) estimates and the corresponding 95% confidence interval (CI). Any

disagreement on data was resolved with consensus among all authors. Acne was divided into

two categories of mild and moderate to severe. When studies classified acne as

non-inflammatory, inflammatory and acne with both lesions, we recorded non-inflammatory

acne as mild one while other types as moderate to severe one. Milk products were divided into

three subtypes: full-fat or whole milk, low-fat milk and skim milk. Since different frequency of

total milk consumption was reported in studies, we defined the group with high intake as

consuming more than 1 glass of milk per day and the group with medium intake as drinking 1

glass of milk per day or less. The quality of each included study was assessed using the

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 Newcastle-Ottawa Scale (NOS).15 The studies that met 5 or more of the NOS items were
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considered as high quality.

2.3 Statistical analysis

The association between acne occurrence and milk consumption was evaluated by the RR in

cohort studies or the OR in case-control or cross-sectional studies. We adopted multivariate-

adjusted risk estimates; however, when unavailable, we used or computed unadjusted

RR/OR from the exposure distributions as reported in the published article. If a study did not

provide an overall RR/OR for milk consumer, but presented separate RR/OR for different

exposure level of milk. For reason given above, we combined the corresponding risk estimates

on the basis of Hamling’s method. 16 If a particular study reported several risk estimates of

milk varieties using independent reference category (e.g. independent estimates of whole and

low-fat milk), we considered each variety as a separate study.

Our primary meta-analysis compared the risk of acne between the milk drinkers with

nondrinkers, overall, by study design and by geographic area. Subgroup analysis was

conducted regarding the association between milk intake and the risk of acne subtypes (mild

and moderate to severe). We also calculated the corresponding estimates of acne for milk

subtypes (full-fat or whole, low-fat and skim milk) as well as for milk intake levels. A random

effects model was used to estimate pooled ORs/RRs in order to take into account the

heterogeneity of the risk estimates and to be more conservative compared with the fixed effects

model.17 Heterogeneity across studies was assessed by the chi-square statistic and quantified by

I2, which represents the percentage of total variation contributed by across-study variation.18,19

A study was defined to be heterogeneous if the p < 0.1 or I2 > 50%.18,19

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 Publication bias was evaluated by the Egger’s test,20 and the trim and fill method.21 All analyses
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were performed with Stata software version 13.0 (Stata Corporation, College Station, TX). The

significance level was set to p＜0.05.

3. Results

3.1 Characteristics of included studies

Through a comprehensive search, a total of 212 articles were retrieved, among which 31

articles were excluded for duplication. The remaining 181 articles were screened for titles and

abstracts and 26 articles were considered of interest and full texts were assessed for further

evaluation. Among them, 13 articles did not provide sufficient data and 1 article used same

data. One additional article was identified after reviewing references of all 26 articles. Finally,

4 cohort studies,7–9,22 5 case-control,10–13,23 and 4 cross-sectional studies24–27 were included into

our meta-analysis. The detail steps were illustrated in Fig. 1.

Among the 13 studies, 6 were from Europe (Norway, Turkey, Italy, Portugal and France), 3

were from America (America), 2 from Asia (Malaysia and Korea), 1 from South America

(Brazil) and 1 from Africa (Egypt). Articles were published between 2005 and 2017. In sum,

the number of the participants included in individual studies ranged from n=60 to n=47355 (M=

5524, SD=12227) and a total of 10968 (26%) males were included. The age of the entire

samples ranged from 9 to 60 year. With regard to the diagnostic method of acne, 9 out of 13

studies were assessed through skin examination while 4 studies were validated by self-report.

10 studies (77%) reported at least 1 adjusted risk estimate, and 8 (80%) of them provided

multivariate-adjusted risk estimates adjusted for more than one variable. The study conducted

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 by Duquia reported two milk varieties independently and was considered as two separate
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studies.24 The details for the included studies were described in Table 1.

According to NOS system, 11 out of 13 include studies were considered as high quality, while

the remaining 2 only met 4 NOS criteria. 9,23 Table S1 provided detail information on NOS

quality assessment as well as a total score for each study.

3.2 Milk consumption and acne incidence

The pooled random effects ORs for milk consumption (drinkers versus nondrinkers) and acne

incidence, by study design, were showed in Fig. 2. The overall OR, base on 4 cohort and 10

case-control or cross-sectional studies, was 1.16 (95% CI 1.09-1.24). The pooled OR was 1.17

(95% CI 1.10-1.24) for cohort studies, and 1.16 (95% CI 1.09-1.24) for case-control or

cross-sectional studies separately. The results indicated that there was a significant increase of

acne incidence in milk drinkers. There was no substantial heterogeneity in overall outcome and

the subgroup analysis of cohorts (overall: p=0.113, I2=32.7%; cohort study group: p=0.606,

I2=0%). However, a mild heterogeneity was observed in the analysis with cross-sectional

studies (p=0.05, I2=46.8%).

Fig. 3 showed the forest plots overall by geographic area. The corresponding estimates for

drinkers versus nondrinkers were 1.28 (95% CI 1.12-1.46) among Europe, 1.16 (95% CI

1.10-1.24) among America, 2.25 (95% CI 0.43-11.77) among Africa, 1.79 (95% CI 0.45-7.13)

among Asia and 1.07 (95% CI 0.97-1.17) among South America. No substantial heterogeneity

was observed in Europe, America and South America subgroup meta-analyses (Europe:

p=0.375, I2=6.5%; America: p=0.497, I2=0%; South America: p=0.891, I2=0%), while there

was substantial heterogeneity in the outcome of Asia subgroup (p=0.012, I2=84.3%).

3.3 Subgroup analysis

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Accepted Article
Among theses included studies, 3 and 5 studies were included in the analysis of the risk of milk

consumption in mild and moderate to sever acne, as showed in Fig. 4. No significant difference

was found in milk consumption and mild acne (OR 1.14, 95% CI 0.86-1.51). However, a

significant difference was detected between milk consumption and moderate to severe acne

(OR 1.18, 95% CI 1.01-1.37). There was no obvious heterogeneity over the included studies

(mild: p=0.837, I2=0%; moderate to severe: p=0.107, I2=47.4%).

Fig. 5 presented the association between intake of types of milk and acne. The pooled ORs were

1.13 (95% CI 1.05-1.21) for full-fat milk, 1.14 (95% CI 1.08-1.22) for low-fat milk and 1.24

(95% CI 1.13-1.37) for skim milk. There was no substantial heterogeneity among included

studies (full-fat: p=0.248, I2=24.8%; low-fat: p=0.667, I2=0%; skim: p=0.214, I2=33%).

Fig. 6 considered the association between acne and milk intake level. The estimated ORs were

1.08 (95% CI 1.00-1.17) for medium intake of milk and 1.12 (95% CI 1.01-1.24) for high

intake of milk, respectively. No substantial heterogeneity was observed in the subgroup of

medium intake of milk (p=0.114, I2=49.6%), while substantial heterogeneity was detected in

high intake subgroup (p=0.04, I2=60.1%).

3.4 Publication bias

Fig. 7 showed the filled funnel plot of all included studies regarding the association between

milk consumption and acne risk. The graphs appeared to be symmetrical, suggesting no

obvious evidence of publication bias. Consistently, we found no publication bias according to

the Egger’s test (p=0.073).

4. Discussion

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 Using data from 13 observational studies, our study was the first meta-analysis to estimate the
Accepted Article
risk of acne and milk consumption. In the present meta-analysis, we showed that milk intake

was associated with an increased risk of acne. The result was consistent in the analysis of cohort

studies (OR=1.17), case control or cross-sectional studies (OR=1.18), and studies of both

designs (OR=1.16). In addition, the association persisted across all subgroups stratified by milk

forms and milk intake level while the association was more prominent for skim milk and high

intake level of milk, respectively. A further analysis revealed that the risk of milk consumption

differed with acne severity. The moderate to sever acne was linked to milk consumption while

the mild one showed no association. Although the same positive association was found among

American and European population, no association was found in Asia, Africa and South

America.

The role of milk in the development of acne has been controversial. Although several cohort

and case-control studies have been done, few randomized controlled trials and systematic

studies have been conducted. Our results supported the hypothesis that milk intake contributes

to acne.28,29 In particular, our meta-analysis provided further evidence into milk forms. The

pooled estimates showed an increased risk in total milk consumers (in despite of milk forms)

(OR=1.16), however, the OR increased to 1.24 across skim milk consumers while decreased

into 1.14 and 1.13 across low-fat milk consumers and full-fat milk consumers respectively. As

a result, the fat content in milk is unlikely to be main factor for acne. Based on our study, we

hypothesize that the full-fat milk intake may induce a higher grade of satiety due to its higher

fat content, which results in a lower intake of milk protein compared to skim milk. On the

contrary, the skim milk intake is associated with a lower degree of satiety while inducing a
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 higher intake of milk protein. Therefore, it is of critical concern that the total whey protein
Accepted Article
intake from milk contributes to acne pathogenesis.

Milk mainly acts on insulin/ IGF-1/ multi-component mechanistic target of rapamycin complex

1 (mTOCR1) signaling to regulate the anabolism. mTORC1 is a nutrient- and growth factor-

sensitive kinase. Milk is capable of increasing mTORC1 and driving mTORC1-dependent

translation and lipogenesis.30,31 A study reported that the serum IGF-1 level was higher in

patients with acne than those without acne. 32 Another more recent study even found that not

only serum IGF-1 level but also tissue IGF-1 expression in epidermis and sebaceous gland

increased in acne patients, which might be related to BMI- and nutrient- regulation.33 In fact,

milk contains androgens, 5α-reduced steroids and other nonsteroidal growth factors, all of

which can exaggerate IGF-1 level.34 However, we should realize that it is not the IGF-1 content

of milk but the milk-driven production of IGF-1 by the transfer of amino acids that promotes

IGF-1 synthesis.30 In addition, milk-derived essential branched-chain amino acids (BCAAs)

can induce postprandial insulin secretion and increase serum IGF-1 level.35 The major whey

protein α-lactalbumin in milk is another important factor for IGF-1 synthesis. All of insulin,

IGF-1, milk-derived BCAAs and proteinα-lactalbumin can active mTORC1.31,36 The increased

mTORC1 signaling promotes sebaceous lipogenesis,37 increases the synthesis of gonadal and

androgen, enhances the bioactivity of androgen and stimulates the androgen receptor

signaling,35 all of which contribute to acne pathogenesis critically. Thus, hormonal contents,

α-lactalbumin and BCAAs of milk may be responsible for the development of acne.

Our meta-analysis also investigated whether the association between milk consumption and

acne risk is different with countries. Based on our results, we found a significant association in

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 both Europe and America and the association was slightly stronger in Europe (OR=1.28) than
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in America (OR=1.16). However, no significant association was found in other geographical

regions. Potential explanations for these findings included: (1) Both European and American is

the main population used for western diets and milk has been one of their main courses for a

long time. On the contrary, population in other continents adopts western diets with milk until

globalization. The time difference for consuming milk may account for the finding. (2) Europe

and America is consisted of Caucasian race primarily, while other regions are mainly

composed by Mongoloid race and Negroid race. The genetic difference may be another factor.

(3) There were not enough data to evaluate African, Asian and South American regions. Thus,

further research in these regions required.

In the present meta-analysis, we found no association between mild acne and milk

consumption, but a positive association (OR=1.18) with moderate to severe acne. We

hypothesized that milk played a role in the inflammatory process of acne, while the potential

mechanism remained unclear. We also found a greater OR for high milk intake (OR=1.12) than

medium milk intake (OR=1.08). Therefore, we considered that a dose-risk relationship might

exist between them. In 2016, a case-control study conducted among 225 American participants

with moderate acne or no acne found that the amount of low-fat and skim milk consumption in

patients with acne was significantly higher than those without acne.38 Another cross-sectional

study involving 248 American subjects also suggested a greater consumption of milk per day in

patients with moderate to severe acne (0.7±0.7 cups) compared with those with no acne

(0.3±0.5 cups) and with mild acne (0.5±0.7 cups). 39 However, since few study reported the

numbers or quantity of milk consumption per day or per week, it was incapable for us to

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 dose-response analysis. Consequently, more research is needed to understand the dose-
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response effect.

Several limitation of our meta-analysis should be considered. First, only 4 cohort studies

included in our meta-analysis, which limited the further subgroup analysis by study design.

Therefore, the results of our study lacked certain representation. Second, our study was also

limited by the self-reported diagnosis of acne as well as the ambiguous diagnostic criteria for

acne in several included studies, both of which could result in a potential mis-validation of acne

status and a recall and selection bias. Third, our meta-analysis did not provide information on

the pasteurization status of milk and dairy products. It is now clear from literatures that the

pasteurized milk still contains bioactive microRNAs, 40,41 that function as epigenetic

regulators,42 whereas microRNAs such as microRNA-148a are destroyed in ultra-heated or

boiled milk.43 MicroRNA-148a, the most abundant microRNA found in milk, targets the

mRNA of DNA methyltransferase 1, 40,42 which is critically involved in the epigenetic

regulation of IGF-1 and androgen receptor gene expression.44–46 Intriguingly, it was reported

that the mortality- and bone fracture-increasing effects of milk intake had only been detected in

relation to intake of pasteurized milk but not to fermented dairy products such as yogurts or

cheeses.47,48 Therefore, it is important that the milk processing and pasteurization status and

microRNA bioavailability involving in milk-acne relation should be appreciated and be

presented detailedly in future studies. Fourth, the evaluation results from NOS system in our

study showed that two included studies were not considered as high quality. Therefore, the

quality of our study was unsatisfied. Besides, a significant heterogeneity of the analysis for

case-control or cross-sectional studies was found, which was likely to be attributed to the

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 variation in study design and quality. Finally, because of the relative small number of studies in
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subgroup meta-analysis, we only conducted the Egger’s test and the trim and fill method for

publication bias across all included studies while no analysis of publication bias was done

among subgroup. Therefore, publication bias might exist in the subgroup analysis.

In conclusion, our meta-analyses provided evidence that milk consumption was associated with

an increase risk of acne. Thus, diet recommendation for acne prevention should consider

limiting intake of milk. However, due to the existing limitations in our study we suggest that

more efforts should be made to confirm these findings and make a better understanding of

potential mechanisms. For example future studies should compare the capacity of skin milk

versus full-fat milk in activating mTORC1 and should explore the effect of milk processing,

pasteurization status and microRNA bioavailability on acne pathogenesis.

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 Fig 1. Flow diagram of study search in this meta-analysis.
Accepted Article

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 Fig 2. Meta-analysis of acne risk and milk consumption by study design.
Accepted Article
Footnotes: OR, odds ratio; CI, confidence interval.
 Fig 3. Meta-analysis of acne risk and milk consumption by geographic area.
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Footnotes :OR, odds ratio; CI, confidence interval.
 Fig 4. Meta-analysis of mild/moderate to severe acne and milk consumption.
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Footnotes :OR, odds ratio; CI, confidence interval.
 Fig 5. Meta-analysis of acne risk and full-fat/low-fat/skim milk consumption.
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Footnotes :OR, odds ratio; CI, confidence interval.
 Fig 6. Meta-analysis of acne risk and high/medium intake level of milk.
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Footnotes :OR, odds ratio; CI, confidence interval.
 Fig 7. The filled funnel plot of studies on the association between milk consumption and acne
Accepted Article
risk.

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