Dietary acrylamide intake and risk of women’s cancers: a systematic review and meta-analysis of prospective cohort studies

Published online by Cambridge University Press:  08 January 2021

This systematic review and meta-analysis was done to review earlier publications on the association between dietary acrylamide intake and risk of breast, endometrial and ovarian cancers. We performed a systematic search in the online databases of PubMed, ISI Web of Science and Scopus for relevant publications up to August 2020. Prospective cohort studies that considered dietary acrylamide as the exposure variable and breast, endometrial or ovarian cancer as the main outcome variable or as one of the outcome variables were included in this systematic review and meta-analysis. A total of fourteen cohort studies were included in the meta-analysis. We found no significant association between dietary acrylamide intake and the risk of breast (relative risk (RR) 0·95; 95 % CI 0·90, 1·01), endometrial (RR 1·03; 95 % CI 0·89, 1·19) and ovarian cancers (RR 1·02; 95 % CI 0·84, 1·24). In addition, we observed no significant association between dietary acrylamide intake and the risk of breast, endometrial and ovarian cancers in different subgroup analyses by smoking status, menopausal status, BMI status and different types of breast cancer. In conclusion, no significant association was found between dietary acrylamide intake and the risk of breast, endometrial and ovarian cancers.

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Keywords

AcrylamideBreast cancerEndometrial cancerOvarian cancer

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TypeFull PapersInformation

British Journal of Nutrition , Volume 126 , Issue 9 , 14 November 2021 , pp. 1355 – 1363

DOI: https://doi.org/10.1017/S0007114520005255[Opens in a new window]

Copyright

© The Author(s), 2021. Published by Cambridge University Press on behalf of The Nutrition Society

Women’s cancers including breast, endometrial and ovarian cancers are the most common causes of cancer deaths among women in the world^{(Reference Harbeck and Gnant1–Reference Roett and Evans4)}. Due to the high prevalence and high mortality rate of these conditions, finding modifiable risk factors is of high priority.

Acrylamide is a neurotoxin in the body, and a carcinogen in experimental animals, that has been reported to have several probable carcinogenic effects on human health by the International Agency for Research on Cancer⁽⁵⁾. Exposure to acrylamide occurs primarily through tobacco smoke, occupational exposure and specifically through diet^{(Reference Lipworth, Sonderman and Tarone6)}. According to prior investigations, several heat-treated, carbohydrate-rich foods, such as, French fries, potato chips, bread, breakfast cereals, cookies and coffee, have been reported to contain high levels of acrylamide^{(Reference Dybing, Farmer and Andersen7)}. Although, in general population, smoking was suggested to be the key source of acrylamide exposure, recent studies have clarified that dietary acrylamide intake plays a significant part in the incidence of various cancers, especially women’s cancers. However, such evidence was not provided for all types of women’s cancers. For instance, Netherlands Cohort Study data indicated a significant direct linkage between high dietary acrylamide intake and greater odds of postmenopausal endometrial and ovarian cancers, but not breast cancer^{(Reference Hogervorst, Schouten and Konings8)}. Another study from the Investigation into Cancer and Nutrition cohort, however, has demonstrated no noticeable association between increased women’s cancers risk and not only dietary acrylamide intake but also other acrylamide biomarkers such as acrylamide adducts to Hb^{(Reference Obon-Santacana, Lujan-Barroso and Travis9–Reference Obon-Santacana, Peeters and Freisling11)}. On the other hand, an increased risk of breast cancer was reported among postmenopausal women with higher levels of these adducts in a Danish prospective study^{(Reference Olesen, Olsen and Frandsen12)}. Different reasons might contribute to this inconsistency in the findings. The causality of the observed associations between acrylamide intake and cancer risk is equivocal, due to observational design of studies. Moreover, the underlying mechanisms through which acrylamide plays a carcinogenic role, including genotoxic pathway^{(Reference Dybing, Farmer and Andersen7)} and sex hormones modulation^{(Reference Besaratinia and Pfeifer13)}, are different for each type of cancer.

Given the controversial findings in previous publications and greater cancer risks in humans compared with predicted odds in rodent’s studies, this study was done to systematically review earlier publications on the association between dietary acrylamide exposure and women’s cancers including breast cancer, endometrial cancer and ovarian cancer and to perform a meta-analysis of relevant prospective studies in this regard.

Methods and materials

The PROSPERO registration no. is CRD42020212620.

Search strategy

A systematic search was carried out in the online databases of PubMed, ISI Web of Science and Scopus for relevant publications up to August 2020. The keywords used in our search strategy were as follows: (acrylamide OR glycidamide) AND (‘ovarian cancer’ OR ‘ovarian neoplasm’ OR ‘ovarian malignancy’ OR ‘ovarian carcinoma’ OR ‘ovarian tumor’ OR ‘breast cancer’ OR ‘breast neoplasm’ OR ‘breast malignancy’ OR ‘breast carcinoma’ OR ‘breast tumor’ OR ‘endometrial cancer’ OR ‘endometrial neoplasm’ OR ‘endometrial malignancy’ OR ‘endometrial carcinoma’ OR ‘endometrial tumor’). We considered no restriction on time of publication and language. In addition, the reference lists of the relevant papers were also hand-searched to identify further relevant studies. In the search strategy, unpublished studies were excluded. Two reviewers independently screened the output of the search to identify potentially eligible publications (S. B. K. and A. S. M.).

Inclusion criteria

In our meta-analysis, eligible publications were selected in accordance with the following criteria: (1) all prospective cohort studies assessing the association between dietary acrylamide intake and women’s cancers including breast, endometrial and ovarian cancers; (2) studies that were of prospective design and (3) those that reported OR, relative risks (RR) or hazard ratios along with the 95 % CI for the relationship between dietary acrylamide intake and breast, endometrial and ovarian cancers.

Data extraction

Study selection and data extraction from each eligible study were carried out independently by two investigators (S. B. K. and A. S. M.), and any disagreements were figured out in consultation with the principal investigator (A. E.). In prospective studies, dietary acrylamide intake was the key exposure variable. Furthermore, the key outcome variable was the incidence of breast, endometrial or ovarian cancers during the follow-up. Any reported hazard ratio or RR for each of these cancers among individuals in the highest category of dietary intake of acrylamide compared with those in the lowest category were extracted. Information from each study was recorded as follows: first authors’ last name, year of publication, country of origin, age range at study baseline, cohort size, number of participants with incident breast, endometrial and ovarian cancers, duration of follow-up, methods used for assessing dietary intake of acrylamide and breast, endometrial and ovarian cancers, the maximally adjusted RR or hazard ratios with the corresponding 95 % CI and the study quality score.

Quality assessment of studies

We used the Newcastle–Ottawa Scale (NOS) to evaluate the quality of included studies^{(Reference Wells, Shea and O’Connell14)}. Based on this method, a maximum of nine points can be awarded to each prospective study: four for selection, two for comparability and three for assessment of outcomes (nine represented the highest quality). Any discrepancies were resolved by discussion. In the current study, those that had the NOS score of six or more were considered as high-quality publications (Table 1).

Table 1. Main characteristics of studies examining the association between dietary acrylamide intake and the risk of breast, endometrial and ovarian cancers

(Relative risk (RR) or hazard ratio (HR) and 95 % confidence intervals)

DQ, dietary questionnaire; T, tertile; Q, quartile or quintile.

* Including: France, the UK, the Netherlands, Germany, Sweden, Denmark, Norway, Italy, Spain and Greece.

Statistical analysis

All reported RR and hazard ratios and their 95 % CI for the risk of breast, endometrial and ovarian cancers were used to calculate log RR and their standard errors. Using a random effects model that incorporates between-study heterogeneity into account, the overall effect size was calculated. Between-study heterogeneity was examined using Cochrane’s Q test and I ². We considered I ² values of 25, 50, and 75 % as low, moderate, and high, respectively^{(Reference Higgins, Thompson and Deeks15)}. Subgroup analyses were used to identify possible sources of heterogeneity. The predefined criteria for subgroup analyses were as follows: smoking status (smoker/non-smoker), menopausal status (premenopausal/postmenopausal), different types of breast cancer (oestrogen receptor (ER) positive, progesterone receptor (PR) positive/ER positive, PR negative/ER negative, PR negative (ER+PR+/ER+PR−/ER−PR−)) and BMI status (<25 kg/m²/≥25 kg/m²). In these analyses, we used fixed effects models. Sensitivity analysis was used to explore the extent to which inferences might depend on a particular study or group of studies. Publication bias was assessed using Egger’s test^{(Reference Egger, Davey Smith and Schneider16)}. Statistical analyses were done in Stata, version 14 (Stata Corp.). Values of P<0·05 were considered statistically significant.

Results

In our initial search, 381 articles were identified. After elimination of duplicates, 244 articles remained. Finally, 222 studies were excluded on the basis of the title and abstract and twenty-two articles remained for further assessment. Another eight publications were further excluded because of the following reasons: two studies were of case–control design^{(Reference Pelucchi, Galeone and Levi17,Reference Pelucchi, Galeone and Negri18)} . In addition, four nested case–control studies that examined the association of adduct levels of acrylamide and the risk of women’s cancers were also excluded^{(Reference Obon-Santacana, Lujan-Barroso and Travis9,Reference Olesen, Olsen and Frandsen12,Reference Xie, Terry and Poole19,Reference Obón-Santacana, Freisling and Peeters20)} . Five studies were conducted on the same population^{(Reference Hogervorst, Schouten and Konings8,Reference Hogervorst, van den Brandt and Godschalk21–Reference Pedersen, Hogervorst and Schouten24)} . To avoid including duplicate studies, we included the ones which had longer duration of follow-up^{(Reference Hogervorst, van den Brandt and Godschalk21–Reference Hogervorst, van den Brandt and Godschalk23)} and excluded two other studies^{(Reference Hogervorst, Schouten and Konings8,Reference Pedersen, Hogervorst and Schouten24)} . Finally, fourteen prospective studies were included in this systematic review (Fig. 1).

Fig. 1. Flow chart of the study selection process.

Results from the systematic review on dietary acrylamide intake and the risk of breast cancer

Seven studies examined dietary acrylamide intake in relation to the risk of breast cancer^{(Reference Hogervorst, van den Brandt and Godschalk21,Reference Kotemori, Ishihara and Zha25–Reference Mucci, Sandin and Balter30)} . These studies included 429 351 participants aged ≥25 years. The total number of subjects with breast cancer was 14 213 varying from 667 to 6301 between studies. These papers were published between 2005 and 2019; two were from the USA^{(Reference Wilson, Mucci and Rosner26,Reference Wilson, Mucci and Cho29)} , two from Sweden^{(Reference Larsson, Akesson and Wolk28,Reference Mucci, Sandin and Balter30)} , along with others from the Netherlands^{(Reference Hogervorst, van den Brandt and Godschalk21)}, Japan^{(Reference Kotemori, Ishihara and Zha25)} and the UK^{(Reference Burley, Greenwood and Hepworth27)}. Duration of follow-up ranged from 11 to 26 years among studies. To assess dietary acrylamide intake, all studies had used FFQ. To examine breast cancer, five studies had used cancer registries^{(Reference Hogervorst, van den Brandt and Godschalk21,Reference Kotemori, Ishihara and Zha25,Reference Burley, Greenwood and Hepworth27,Reference Larsson, Akesson and Wolk28,Reference Mucci, Sandin and Balter30)} and two other studies had used medical records^{(Reference Wilson, Mucci and Rosner26,Reference Wilson, Mucci and Cho29)} . Based on the NOS, all included studies were of high quality (Table 1).

Results from the systematic review on dietary acrylamide intake and the risk of endometrial cancer

Five studies examined dietary acrylamide intake in relation to the risk of endometrial cancer^{(Reference Obon-Santacana, Kaaks and Slimani10,Reference Hogervorst, van den Brandt and Godschalk23,Reference Wilson, Mucci and Rosner26,Reference Kotemori, Ishihara and Zha31,Reference Larsson, Hakansson and Akesson32)} . These studies included 541 116 participants aged ≥30 years. The total number of subjects with endometrial cancer was 3107 varying from 161 to 1382 between studies. These papers were published between 2009 and 2018, one each from Japan^{(Reference Kotemori, Ishihara and Zha31)}, the Netherlands^{(Reference Hogervorst, van den Brandt and Godschalk23)}, the USA^{(Reference Wilson, Mucci and Rosner26)}, Sweden^{(Reference Larsson, Hakansson and Akesson32)} and Europe^{(Reference Obon-Santacana, Kaaks and Slimani10)}. Follow-up duration ranged from 11 to 26 years. For dietary acrylamide intake assessment, all studies had used FFQ, except one study that had used a validated country-specific dietary questionnaire^{(Reference Obon-Santacana, Kaaks and Slimani10)}. For endometrial cancer assessment, three studies had used cancer registries^{(Reference Hogervorst, van den Brandt and Godschalk23,Reference Kotemori, Ishihara and Zha31,Reference Larsson, Hakansson and Akesson32)} , one had used medical records^{(Reference Wilson, Mucci and Rosner26)} and another one had used cancer registries and health insurance data^{(Reference Obon-Santacana, Kaaks and Slimani10)}. Based on the NOS, all included studies were of high quality (Table 1).

Results from the systematic review on dietary acrylamide intake and the risk of ovarian cancer

Five studies examined the association between dietary acrylamide intake and the risk of ovarian cancer as the main outcome^{(Reference Obon-Santacana, Peeters and Freisling11,Reference Hogervorst, van den Brandt and Godschalk22,Reference Wilson, Mucci and Rosner26,Reference Kotemori, Ishihara and Zha31,Reference Larsson, Akesson and Wolk33)} . These studies included 575 832 participants aged ≥30 years. The total number of subjects with ovarian cancer was 2470 varying from 122 to 1191 between studies. These papers were published between 2009 and 2018, one each from the Japan^{(Reference Kotemori, Ishihara and Zha31)}, the Netherlands^{(Reference Hogervorst, van den Brandt and Godschalk22)}, the USA^{(Reference Wilson, Mucci and Rosner26)}, Sweden^{(Reference Larsson, Akesson and Wolk33)} and Europe^{(Reference Obon-Santacana, Peeters and Freisling11)}. Duration of follow-up ranged from 11 to 26 years. For dietary acrylamide intake assessment, all studies had used FFQ, except one study that had used a validated country-specific dietary questionnaire^{(Reference Obon-Santacana, Peeters and Freisling11)}. To assess ovarian cancer, three studies had used cancer registries^{(Reference Hogervorst, van den Brandt and Godschalk22,Reference Kotemori, Ishihara and Zha31,Reference Larsson, Akesson and Wolk33)} , one study had used medical records^{(Reference Wilson, Mucci and Rosner26)} and one had used cancer registries and health insurance data^{(Reference Obon-Santacana, Peeters and Freisling11)}. Based on the NOS, all included studies were of high quality (Table 1).

Meta-analysis on dietary acrylamide intake and the risk of breast cancer

Combining seven effect sizes from seven studies^{(Reference Hogervorst, van den Brandt and Godschalk21,Reference Kotemori, Ishihara and Zha25–Reference Mucci, Sandin and Balter30)} , we found no significant association between dietary acrylamide intake and the risk of breast cancer (RR 0·95; 95 % CI 0·90, 1·01) (Fig. 2). We found no significant between-study heterogeneity (I ² = 2·4 %, P _{heterogeneity} = 0·40). A sensitivity analysis showed that no particular study significantly affected the summary effects. In addition, we observed no evidence of publication bias using Egger’s test (P = 0·36).

Fig. 2. Forest plot of studies that examined the association between dietary acrylamide intake and the risk of breast cancer using a highest v. lowest analysis. ES, effect size.

In the subgroup analysis, we observed no significant association between dietary acrylamide intake and the risk of breast cancer by smoking status (smoker/non-smoker), menopausal status (premenopausal/postmenopausal), type of breast cancer (ER+PR+/ER+PR−/ER−PR−) and BMI status (BMI < 25 kg/m²/≥25 kg/m²) (Table 2).

Table 2. Subgroup analysis for dietary acrylamide intake and the risk of breast, endometrial and ovarian cancers

(Relative risk (RR) or hazard ratio (HR) and 95 % confidence intervals)

ER, oestrogen receptor; PR, progesterone receptor.

Meta-analysis on dietary acrylamide intake and the risk of endometrial cancer

Combining five effect sizes from five studies^{(Reference Obon-Santacana, Kaaks and Slimani10,Reference Hogervorst, van den Brandt and Godschalk23,Reference Wilson, Mucci and Rosner26,Reference Kotemori, Ishihara and Zha31,Reference Larsson, Hakansson and Akesson32)} , we found no significant association between dietary acrylamide intake and the risk of endometrial cancer (RR 1·03; 95 % CI 0·89, 1·19) (Fig. 3). We found no significant between-study heterogeneity (I ² = 13·2 %, P _{heterogeneity} = 0·33). A sensitivity analysis showed that no particular study significantly affected the summary effects. In addition, we observed no evidence of publication bias using Egger’s test (P = 0·80).

Fig. 3. Forest plot of studies that examined the association between dietary acrylamide intake and the risk of endometrial cancer using a highest v. lowest analysis. ES, effect size.

In the subgroup analysis, we observed no significant association between dietary acrylamide intake and the risk of endometrial cancer by smoking status (smoker/non-smoker), menopausal status (premenopausal/postmenopausal), and BMI status (BMI < 25 kg/m²/≥25 kg/m²) (Table 2).

Meta-analysis on dietary acrylamide intake and the risk of ovarian cancer

Combining the five effect sizes^{(Reference Hogervorst, Schouten and Konings8,Reference Obon-Santacana, Peeters and Freisling11,Reference Wilson, Mucci and Rosner26,Reference Kotemori, Ishihara and Zha31,Reference Larsson, Akesson and Wolk33)} , no significant association was observed between dietary acrylamide intake and the risk of ovarian cancer (RR 1·02; 95 % CI 0·84, 1·24) (Fig. 4). Results showed no significant between-study heterogeneity (I ² = 40·0 %, P _{heterogeneity} = 0·15). We observed no evidence of publication bias (Egger’s test = 0·86).

Fig. 4. Forest plot of studies that examined the association between dietary acrylamide intake and the risk of ovarian cancer using a highest v. lowest analysis. ES, effect size.

In the subgroup analysis, we observed no significant association between dietary acrylamide intake and the risk of ovarian cancer by smoking status (smoker/non-smoker), menopausal status (premenopausal/postmenopausal), and BMI status (BMI < 25 kg/m²/≥25 kg/m²) (Table 2).

Discussion

Findings from this systematic review and meta-analysis on fourteen prospective cohort studies revealed no significant association between dietary acrylamide intake and the risk of breast, endometrial and ovarian cancers. In addition, no significant association was observed in different subgroup analyses including smoking status, menopausal status, BMI status and different types of breast cancer.

The association between acrylamide intake, a probable human carcinogen, and the risk of cancer has been debated for many years. In this systematic review and meta-analysis, we summarised findings from earlier publications on the association between dietary acrylamide intake and the risk of breast, endometrial and ovarian cancers. In the body, acrylamide is metabolised to glycidamide, which is a DNA-reactive epoxide^{(Reference Zödl, Schmid and Wassler34)}. Both acrylamide and glycidamide can interact with Hb to construct Hb–acrylamide adducts and Hb–glycidamide adducts, respectively. These metabolites are considered as relevant biomarkers of internal exposure, which represent one’s exposure over the lifespan^{(Reference Obon-Santacana, Lujan-Barroso and Travis9)}. Several studies have examined the association between acrylamide–Hb adduct levels in relation to the risk of cancer. Nested case–control studies found no significant association between Hb adduct levels of acrylamide and the risk of ovarian cancer^{(Reference Obon-Santacana, Lujan-Barroso and Travis9,Reference Xie, Terry and Poole19)} . Another nested case–control study revealed a significant positive association between acrylamide–Hb adduct levels and the risk of ER+ breast cancer^{(Reference Olesen, Olsen and Frandsen12)}. In addition, no significant association was observed between biomarkers of acrylamide exposure and the risk of endometrial cancer^{(Reference Obón-Santacana, Freisling and Peeters20)}. Due to limited number of studies on the association between acrylamide–Hb adduct levels and the risk of women’s cancers, we did not perform meta-analysis in this regard. Given these findings, it seems that acrylamide does not contribute to the risk of breast, endometrial and ovarian cancers. Further studies are needed to reach a definite conclusion.

In the subgroup analysis by menopausal status, we found no significant association between dietary acrylamide intake and risk of women’s cancers. Pedersen et al. reported a statistically non-significant increased risk of ER+, PR+ and joint-receptor positive breast cancer in postmenopausal women^{(Reference Pedersen, Hogervorst and Schouten24)}. Another study found no significant interaction between acrylamide intake and menopausal status and risk of breast, ovarian and endometrial cancers^{(Reference Wilson, Mucci and Rosner26)}. Hormonal mechanisms might be involved in the association of acrylamide and risk of women’s cancers. Further studies are required in this field to elucidate this association more precisely.

The association between dietary acrylamide intake and the risk of women’s cancers has been examined in earlier meta-analyses^{(Reference Je35,Reference Pelucchi, Bosetti and Galeone36)} . Nevertheless, these previous meta-analyses have included prospective cohort studies published before 2014. In comparison with the previous meta-analyses, our study included fourteen prospective cohort studies, including the additional six studies that were not included in previous ones^{(Reference Obon-Santacana, Peeters and Freisling11,Reference Hogervorst, van den Brandt and Godschalk21–Reference Hogervorst, van den Brandt and Godschalk23,Reference Kotemori, Ishihara and Zha25,Reference Kotemori, Ishihara and Zha31)} . Thus, despite some overlap in the data included in our study and the previous meta-analyses, we believe that the present study is more comprehensive than previous ones in terms of the data contributing to the summary estimates. In addition, we performed several subgroup analyses based on menopausal status, smoking status, BMI status and different types of breast cancer, which may better clarify the association between dietary acrylamide intake and risk of women’s cancers.

In animal studies, a positive dose–response relationship has been shown between acrylamide exposure and cancer in several organs^{(Reference Rice37)}, especially in hormone-sensitive organs such as the uterus and the mammary gland^{(Reference Johnson, Gorzinski and Bodner38,Reference Friedman, Dulak and Stedham39)} . However, epidemiological studies on the association between dietary acrylamide intake and risk of breast, endometrial and ovarian cancers are scarce. In addition, most of these studies did not find any significant association. Lack of association between dietary acrylamide intake and risk of breast, endometrial and ovarian cancers in epidemiological studies may be due to low levels of acrylamide from foods^{(Reference Larsson, Akesson and Wolk28)}.

Several potential mechanisms may explain the association of dietary acrylamide intake with the risk of cancer. Acrylamide conversion to glycidamide, a DNA-reactive epoxide, is one of the hypothesised mechanisms for the carcinogenic effects of acrylamide^{(Reference Dybing, Farmer and Andersen7)}. Some epidemiological studies showed a positive association between dietary acrylamide intake and the risk of hormone-related cancers including ER+ breast, endometrial and ovarian cancers^{(Reference Hogervorst, Schouten and Konings8,Reference Olesen, Olsen and Frandsen12)} , which may suggest another pathway for the carcinogenic effects of acrylamide. Another proposed mechanism for acrylamide carcinogenicity is that acrylamide may modulate sex hormone systems^{(Reference Besaratinia and Pfeifer13)}, which can in turn explain carcinogenicity effects of acrylamide for ER+ and PR+ breast cancer.

The current study has some strengths. Our study included fourteen prospective cohort studies with a large sample size which can provide sufficient power to detect the associations between dietary acrylamide intake and the risk of breast, endometrial and ovarian cancers. This study was conducted on prospective cohort studies in which minimising the possibility of recall or selection bias occurs in case–control studies. In addition, we did several subgroup analyses by smoking status, menopausal status, BMI status and type of breast cancer to assess the relationship between dietary acrylamide intake and the risk of women’s cancers. However, some points need to be considered when interpreting our findings. In all included studies, the dietary acrylamide intake was assessed by questionnaires. Therefore, self-reported dietary acrylamide intake through questionnaires might inevitably result in measurement error and misclassification of study participants. In addition, large variations in acrylamide levels among different foods due to different processing methods might influence our results. Acrylamide formation is affected by several factors such as cooking temperature and duration of temperature that could have contributed to the variability of total acrylamide intake. However, we did not consider these variables in our study due to lack of data. Finally, the current study includes studies that enrolled subjects from different countries with different dietary habits and racial factors, which may be associated with different risks for cancer.

Conclusion

In conclusion, we observed no significant association between dietary acrylamide intake and the risk of breast, endometrial and ovarian cancers.

Acknowledgements

This research received no specific grant from any funding agency, commercial or not-for-profit sectors.

S. B. K., A. S. M. and A. E. contributed to the conception, design, data extraction, statistical analyses, data interpretation and manuscript drafting. Z. S. R. contributed to the data interpretation and manuscript drafting. All authors contributed to the approval of the final version of the manuscript and agreed for all aspects of the work.

None of the authors had any conflicts of interest.

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