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. Author manuscript; available in PMC: 2022 Jul 15.
Published in final edited form as: Am J Cardiol. 2021 May 24;151:51–56. doi: 10.1016/j.amjcard.2021.04.010

Frequency of Irritable Bowel Syndrome in Patients with Brugada Syndrome and Drug-Induced Type 1 Brugada Pattern

Anil S Sarica a, Serhat Bor b, Mehmet N Orman c, Hector Barajas-Martinez d, Jyh-Ming Jimmy Juang e, Charles Antzelevitch d,f,g, Can Hasdemir a
PMCID: PMC9148266  NIHMSID: NIHMS1697112  PMID: 34034907

Abstract

Irritable bowel syndrome (IBS) is one of the most widely recognized functional bowel disorders (FBDs) with a genetic component. SCN5A gene and SCN1B loci have been identified in population-based IBS cohorts and proposed to have a mechanistic role in the pathophysiology of IBS. These same genes have been associated with Brugada syndrome (BrS). The present study examines the hypothesis that these two inherited syndromes are linked. Prevalence of FBDs over a 12 months period were compared between probands with BrS/drug-induced type 1 Brugada pattern (DI-Type 1 BrP) (n=148) and a control group (n=124) matched for age, female sex, presence of arrhythmia and co-morbid conditions. SCN5A/SCN1B genes were screened in 88 patients. Prevalence of IBS was 25% in patients with BrS/DI-Type 1 BrP and 8.1% in the control group (p=2.34×10−4). On stepwise logistic regression analysis, presence of current and/or history of migraine (OR of 2.75; 95% CI: 1.08 to 6.98; p=0.033) was a predictor of underlying BrS/DI-Type 1 BrP among patients with FBDs. We identified 8 putative SCN5A/SCN1B variants in 7 (12.3%) patients with BrS/DI-Type 1 BrP and 1 (3.2%) patient in control group. Five out of 8 (62.5%) patients with SCN5A/SCN1B variants had FBDs. In conclusion, IBS is a common co-morbidity in patients with BrS/DI-Type 1 BrP. Presence of current and/or history of migraine are a predictor of underlying BrS/DI-Type 1 BrP among patients with FBDs. Frequent co-existence of IBS and BrS/DI-Type 1 BrP necessitates cautious use of certain drugs among the therapeutic options for IBS that are known to exacerbate the Brugada phenotype.

Keywords: J Wave Syndromes, Functional Bowel Disorders, Irritable Bowel Syndrome, Epidemiology, Genetics

Introduction

Irritable bowel syndrome (IBS) based on the Rome III diagnostic criteria is one of the most widely recognized functional bowel disorders (FBDs), with more than 10% of the global adult population reporting symptoms compatible with the condition in population-based surveys.1,2 Previous reports suggest that there may be distinct, as well as, shared genetic underpinnings for IBS.3 Brugada syndrome (BrS) is an inherited cardiac arrhythmia syndrome characterized by a distinct ST-segment elevation in the right precordial leads in the absence of structural heart disease.4,5 Loss-of-function and gain-of-function variants in SCN5A gene and SCN1B locus among BrS susceptibility genes, identified in population-based IBS cohorts have been proposed to have a mechanistic role in the pathophysiology of IBS.6,7 In view of these observations, we extrapolated these findings to our BrS and drug-induced type 1 Brugada ECG pattern (DI-Type 1 BrP) cohort. The present study was designed to determine the period prevalence of FBDs, the prevalence of SCN5A and SCN1B gene variants, to investigate the demographic and clinical characteristics in probands with BrS/DI-Type 1 BrP and control group and to identify subset of clinical variables/co-morbidities to predict underlying BrS/DI-Type 1 BrP among patients with FBDs.

Methods

Two hundred eighty-eight consecutive, unrelated patients and control subjects were included in a single-center, cross-sectional study between September 11th 2018 and November 20th 2018. Sixteen patients were excluded due to following reasons: incomplete filling of questionnaire (n=6), familial Mediterranean fever (n=3), inflammatory bowel disease (n=2), microscopic colitis (n=1), celiac disease (n=1), diverticular disease/colorectal polyps (n=1), spina bifida (n=1) and drug-induced thyrotoxicosis (n=1). The remaining 272 patients (126 women/146 men; mean age 41.8±11.8 years; range 18 to 72) formed the study population. Period prevalence (past 12 months) of FBDs and demographic/clinical characteristics were compared between probands with BrS/DI-Type 1 BrP (n=148, 62 women/86 men; mean age 42.8±11.4; range 18 to 72) and the control group (n=124, 64 women/60 men; mean age 40.6±12.1; range 18 to 66). Prevalence of putative SCN5A and SCN1B gene variants were screened in 88 patients. The control group consisted of patients with atrioventricular nodal reentrant tachycardia (AVNRT, n=24, 19 women/5 men; mean age 46.9±11.1; range 20 to 65), atrioventricular accessory pathways (AV-APs, n=42, 17 women/25 men; mean age 36.9±13; range 18 to 66) and “pure” control subjects (n=58, 28 women/30 men; mean age 40.7±10.7 years; range 18 to 63) with ajmaline challenge test negative for type 1 Brugada pattern. All study subjects were of Turkish (Anatolian Caucasian) descent. Study protocol was approved by the ethics committee of Ege University School of Medicine (Authorization Number:18–9/49). All patients agreed to participate in the study and gave written informed consent.

Ege University School of Medicine BrS/DI-Type 1 BrP cohort consisted of 246 patients referred to our tertiary referral hospital between January 2004 and November 2018. BrS was defined according to the J-Wave syndromes expert consensus conference report.5 Diagnosis of probable/definite BrS, possible BrS, or a nondiagnostic score were assigned scores of ≥3.5, 2 to 3, and <2 points, respectively.5 Type 1 BrP in V1 and/or V2 precordial leads during ajmaline challenge test with an assigned score of zero was defined as DI-Type 1 BrP.8,9 The proportions of diagnostic types in BrS/DI-Type 1 BrP cohort in the current study were as follows: probable/definite BrS (n=17), possible BrS (n=67), nondiagnostic BrS (n=7) and DI-Type 1 BrP (n=57). Eight patients with the diagnosis of probable/definite BrS received defibrillator for cardiac arrest (n=4), nocturnal agonal respiration (n=3) and unexplained syncope (n=1). The “pure” control group consisted of unrelated subjects with structurally normal hearts, no known heart disease and no history of any type of atrial and/or ventricular arrhythmia.

FBDs were defined according to the Rome III diagnostic criteria.10 The validated Turkish version of the questionnaire (27 questions) with pre-tested psycholinguistic and psychometric properties was used.11 FBDs were classified into 5 distinct categories: irritable bowel syndrome (IBS), functional constipation, functional diarrhea, functional abdominal bloating/distention, and unspecified FBD.10 IBS was subcategorized into four subtypes based on predominant stool pattern: constipation (IBS-C), diarrhea (IBS-D), a mix of constipation and diarrhea (IBS-M), or undefined predominant stool form (IBS-U). Period prevalence of FBDs was defined as the proportion of the study subjects having the characteristics at any point during a given time period of interest (past 12 months).

Presence of current and/or history of familial Mediterranean fever, inflammatory bowel disease, celiac disease, gastrointestinal or other malignancies, diverticular disease, colorectal polyps, prior major abdominal surgery including cholecystectomy, uncontrolled diabetes mellitus, hypo/hyperthyroidism and chronic opiate and/or any other medication use related with the study were considered as exclusion criteria. Patients were questioned for the presence of “warning” symptoms (rectal bleeding in the absence of documented bleeding hemorrhoids/anal fissures, unintentional weight loss, family history of colorectal cancer) for gastroenterology consultation.

A total of 306 patients and control subjects were initially contacted by telephone at random in order to question their interest to participate in the study. Eighteen patients declined to participate. All patients and control subjects interested in participating in the study were invited to our medical center and informed about the questionnaire in a face-to-face interview. Participants were encouraged to complete the questionnaire by themselves and mark the most suitable answer in each question by taking enough time. The final category of the FBDs of each patient was classified based on the flowchart of the questionnaire by co-authors (ASS and SB) blinded to the groups of study population. All patients and control subjects with the diagnosis of FBDs based on the questionnaire were subsequently further questioned for confirmation for the diagnosis and the category of FBDs, subtypes of IBS and history of gastrointestinal work-up after completion of the questionnaire.

History of co-morbid conditions such as structural heart diseases, diabetes mellitus, systemic hypertension, epilepsy and migraine were obtained in all participants. Lifetime prevalence of migraine was defined as the proportion of the study subjects who, at some point in life has ever had migraine. Ajmaline challenge test (Gilurytmal®, CARINOPHARM GmbH, Germany) was performed according to the J-Wave syndromes expert consensus conference report.5

Genetic screening and analysis for SCN5A/SCN1B gene variants were performed in 88 patients (44 women/44 men; mean age 41±13 years): 57 with BrS/DI-Type 1 BrP and 31 control subjects. SCN5A/SCN1B gene variants were screened and analyzed by target gene in-depth sequencing by using the Agilent SureSelect Target Enrichment Kit (Agilent Genomics, Santa Barbara, CA, USA) and Illumina Hi-Seq 4000 machine. The identified variants were confirmed by Sanger sequencing. We compared the allele frequency of each identified variant in public databases including 1000 Human Genome Project Database (1000G), Genome Aggregation Database (gnomAD version 2.0.2) and NHLBI GO Exome Sequencing Project (ESP). Sorting Intolerant From Tolerant (SIFT) and Polymorphism Phenotyping-2 (PolyPhen-2) bioinformatics algorithms were used to assess the potential functional impacts of identified mutations. A rare variant was defined as a variant with a minor allele frequency of <0.01%.

Normally distributed variables were presented as mean ± standard deviation and compared using Student’s t-test. Non-normally distributed variables were presented as median and compared using Mann-Whitney U test. Categorical variables were compared using Pearson’s chi-squared and Fisher’s exact test. Comparisons were performed using Pearson’s chi-squared test and univariate logistic regression analysis. In order to identify the predictors for underlying BrS/DI-Type 1 BrP among patients with FBDs, multiple (full model) and backward method of stepwise logistic regression analysis were performed with clinical variables demonstrating significant association on univariate logistic regression analysis. P < 0.05 (two-sided) was considered statistically significant.

Results

There were a total of 94 (34.5%) patients with FBDs diagnosed based on the initial flowchart of the questionnaire in the whole study population. The diagnosis of FBDs was dropped out in 3 out of 94 (3.2%) patients and 5 out of 94 (5.3%) patients had a change in the category of FBDs following subsequent questioning of each patient with FBDs by co-authors.

Prevalence of FBDs (43.2% versus 21.8%, p=1.86×10−4) and IBS (25% versus 8.1%, p=2.34×10−4) was higher in patients with BrS/DI-Type 1 BrP compared to the control group, respectively (Table 1). Prevalence of functional constipation, functional diarrhea, functional abdominal bloating/distension and combination of functional constipation/diarrhea/abdominal bloating-distension were not statistically different between patients with BrS/DI-Type 1 BrP and the control group.

Table 1.

Demographic and Clinical Characteristics, Prevalence of Functional Bowel Disorders and Gastrointestinal Work-Up Characterisitcs in Patients with Brugada Syndrome/Drug-Induced Type 1 Brugada Electrocardiographic Pattern and Conrol Group

Variable Patients with BrS/DI-Type 1 BrP (n=148) Control Group (n=124) P-value
Demographic and Clinical Characteristics
 - Age (years) 42.8±11.4 40.6±12.2 0.135
 - Women 62 (41.9%) 64 (51.6%) 0.109
 - Presence of Arrhythmia 75 (50.7%) 66 (53.2%) 0.675
 - Presence of Co-Morbid Conditions 46 (31.1%) 17 (25.8%) 0.430
 - Presence of Migraine 96 (64.9%) 37 (29.8%) 8.64×10−9
Categories of Functional Bowel Disorders
 - Functional Bowel Disorders 64 (43.2%) 27 (21.8%) 1.86×10−4
  - Irritable Bowel Syndrome 37 (25%) 10 (8.1%) 2.34×10−4
   - Constipation subtype 17 (45.9%) 7 (70%) 0.177
   - Diarrhea subtype 11 (29.7%) 1 (10%) 0.204
   - Mix of Constipation and Diarrhea subtype 6 (16.2%) 1 (10%) 0.624
   - Undefined subtype 3 (8.1%) 1 (10%) 1.000
  - Functional Constipation 5 (3.4%) 2 (1.6%) 0.460
  - Functional Diarrhea 3 (2%) 2 (1.6%) 0.80
  - Functional Abdominal Bloating/Distension 19 (12.8%) 13 (10.5%) 0.548
  - Functional Constipation/Diarrhea/Abdominal Bloating/Distension 27 (18.2%) 17 (13.7%) 0.312
Gastrointestinal Work-Up in Patients with Functional Bowel Disorders *
 - History of Gastointestinal Consultations and Work-Up 38 (59.4%) 12 (44.4%) 0.191
 - History of Upper Endoscopy 24 (37.5%) 9 (33.3%) 0.706
 - History of Colonoscopy 11 (17.2%) 2 (7.4%) 0.223
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Data are given as mean ± SD, number of patients and percentages.

* =

By Primary Care Physician and/or Gastroenterologist, BrS = Brugada syndrome, DI-Type 1 BrP = Drug-Induced Type 1 Brugada ECG pattern.

The BrS/DI-Type 1 BrP cohort was matched to the control group in terms of age, female sex, presence of arrhythmia and co-morbid conditions (Table 1). The BrS/DI-Type 1 BrP cohort had higher lifetime prevalence of migraine (64.9% versus 29.8%, p=8.64×10−9) compared to the control group (Table 1). None of the patients and control subjects had “warning” symptoms.

There was no statistical difference in terms of mean age (41.7±10.7 years versus 43.8±11.2 years, p=0.387), female sex (46.9% versus 51.9%, p=0.664) and co-morbid conditions (31.3% versus 15%, p=0.155) among patients with FBDs with BrS/DI-Type 1 BrP and the control group, respectively. Patients with BrS/DI-Type 1 BrP and FBDs had higher lifetime prevalence of migraine (71.9% versus 48.1%, p=0.030) compared to the control group with FBDs, respectively. Prevalence of IBS (57.8% versus 37%, p=0.070) and combination of functional constipation/diarrhea/abdominal bloating-distension (42.2% versus 63%, p=0.070) was not statistically different between patients with BrS/DI-Type 1 BrP and the control group, respectively, among patients with FBDs.

Univariate, multivariable logistic regression analysis and multivariable backward method of stepwise logistic regression analysis were performed to identify subset of clinical variables to predict underlying BrS/DI-Type 1 BrP among patients with FBDs. On stepwise logistic regression analysis, presence of current or history of migraine (OR of 2.75; 95% CI: 1.08 to 6.98; p=0.033) was a predictor of underlying BrS/DI-Type 1 BrP.

We identified 8 putative variants in SCN5A (n=4) and SCN1B (n=4) genes in 7 out of 57 patients with BrS/DI-Type 1 BrP and 1 out of 31 patients in control group (12.3% versus 3.2%, p=0.158), respectively. Demographic, clinical and SCN5A and SCN1B variant characteristics are presented in Table 2. The prevalence of SCN5A and SCN1B variants in BrS/DI-Type 1 BrP patients with FBDs (n=25) was not statistically different from control group (n=7) (20% versus 0%, p=0.56), respectively.

Table 2.

Summary of Demographic, Clinical and SCN5A/SCN1B Gene Variant Characteristics

Patient No. Age Sex Cardiac Dx Type of FBDs Gene Exon Type and Function of Mutation Change in Nucleotide Change in Amino Acid MAF (1000genome) MAF (ESP) MAF (gnomAD) SIFT-Prediction Polyphen-2 Prediction Gene References
1 31 M BrS IBS-C SCN5A 22 Missense LofF c.3878T>C p.Phe1293Ser NA NA 0.0005892 Tolerated Benign Sommariva E, et al. Cardiogenetics 2012; 2:e11.
2 32 F BrS IBS-C SCN1B NA Intronic Unknown IVS5+36G>A NA NA NA NA NA NA NA
3 34 F BrS IBS-C SCN5A 22 Missense LofF c.3878T>C p.Phe1293Ser NA NA 0.0005892 Tolerated Benign Sommariva E, et al. Cardiogenetics 2012; 2:e11.
4 35 F DI-Type 1 BrP Functional AB/D SCN1B 5 Missense Unknown c.638G>A p.Gly213Asp 0.0002 0 0.00001768 Damaging Possibly Damaging NA
5 44 M BrS IBS-D SCN5A 27 Missense Unknown c.4789G>A p.Val1597Met NA NA 0.0000177 Damaging Probably Damaging Hedley PL, et al. Hum Mutat. 2009;30:1486–1511.
6 45 F BrS None SCN1B 4 Missense Unknown c.503T>C p.Val168Ala 0 0 NA Tolerated Benign Hasdemir C, et al. Heart Rhythm. 2015;12:1584–1594.
7 57 M BrS None SCN1B 3 Missense LofF c.259G>C p.Glu87Gln 0 0 0.000003978 Tolerated Benign Watanabe H, et al. J Clin Invest. 2008;118:2260–2268.
8 58 F Control None SCN5A 17 Missense Unknown c.3067C>T p.Arg1023Cys NA NA 0.00002018 Tolerated Probably Damaging Watanabe H, et al. Int J Cardiol. 2013;165:e21–3.
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BrS = Brugada Syndrome, DI-Type 1 BrP = Drug-Induced Type 1 Brugada Pattern, Dx = Diagnosis, ESP = Exome Sequencing Project, Functional AB/D = Abdominal Bloating/Distension, FBD = Functional Bowel Disorders, gnomAD = Genome Aggregation Database, IBS-C = Irritable Bowel Syndrome Constipation, IBS-D = Irritable Bowel Syndrome Diarrhea, LofF = Loss of Function, MAF = Minor Allele Frequency, 1000 genome = 1000 Human Genome Project Database, Polyphen-2 = Polymorphism Phenotyping 2, SIFT = Sorting Intolerant From Tolerant

Discussion

There are several important aspects of the correlation between IBS and BrS/ DI-Type 1 BrP. First is the high prevalence of IBS among patients with BrS/ DI-Type 1 BrP and the epidemiology of both diseases; second is the clinical implications of co-morbidity of IBS; third is the clinical implications of migraine as a predictor of underlying BrS/DI-Type 1 BrP among patients with FBDs; and fourth is the underlying genetic characteristics and the mechanistic link between FBDs and BrS/DI-Type 1 BrP.

An analysis from a global epidemiological study for functional gastrointestinal disorders, including data from 29,609 adults surveyed in 14 countries, estimated a 10.1% prevalence of IBS based on the Rome III diagnostic criteria.2 The prevalence of IBS was 9.8% in Turkish population.2 The world-wide prevalence of a Brugada ECG pattern (type1/2/3) in general population is estimated to be 0.5 to 1.6 per 1000.5 The prevalence of DI-Type 1 BrP in Turkish population was 4.8%.9 Prevalence of IBS among patients with BrS/DI-Type 1 BrP was 25% in our study. The 25% of the 4.8% of the Turkish population with BrS/DI-Type 1 BrP (~1% of the general population) may have co-occurring IBS and BrS/DI-Type 1 BrP. Prevalence of IBS in Turkish general population and in our control group is ~10%. If these results could be extrapolated to the entire IBS population, we estimate that there would be nearly 1 in every 10 patients with IBS in general population may have underlying BrS/DI-Type 1 BrP. As a result, each patient with BrS/DI-Type 1 BrP should be questioned routinely for the presence and severity of symptoms of IBS or vice versa during history taking.

The coexistence of IBS and BrS/DI-Type 1 BrP is of potential clinical relevance for the appropriate management of patients in terms of cautious use of certain drugs known to exacerbate the Brugada phenotype.12 Among the therapeutic options for IBS, certain drugs (prescribed off-label) with cardiac INa channel blocking properties such as tricyclic antidepressants and certain selective serotonin reuptake inhibitors (fluoxetine and paroxetine) used for abdominal pain are classified as “to be avoided” or “preferably avoided” in patients with BrS.12 Drugs (not listed in the international database) with potential cardiac INa and IKs/IKr channel blocking properties such as certain opioid agonists (loperamide) used for diarrhea is known to be a pro-arrhythmic agent.13

Patients with IBS often have co-morbidities.14 A high lifetime prevalence of migraine in patients with BrS/DI-Type 1 BrP has been recently reported.15 Our current study showed that the lifetime prevalence of migraine was higher (64.9% versus 29.8%) in patients with BrS/DI-Type 1 BrP compared to the control group. Lifetime prevalence of migraine was even higher (71.9% versus 48.1%) in patients with BrS/DI-Type 1 BrP and FBDs compared to the control group with FBDs. Bidirectional co-morbidity of IBS, BrS/DI-Type 1 BrP and migraine may represent a genetic overlap. The identification of genetic overlap and specific genetic variants shared across these disorders can be used to assess the validity of the clinical diagnosis and classification of patients.

We hypothesized that IBS and BrS/DI-Type 1 BrP co-occur because they share a common genetic background. IBS is known to aggregate in families most likely due to shared genetic and/or environmental factors.16,17 BrS and IBS are genetic diseases and share common features such as oligogenic/polygenic genetic architecture, same causal common and/or rare variants and worsening of phenotype by gene dysregulation induced by environmental factors (fever and drugs in patients with BrS and certain foods or beverages and hormones in patients with IBS).5–7,18,19

The voltage sensitive and the mechanosensitive Na+ channels (Nav1.5) encoded by the SCN5A gene highly expressed in human cardiac myocytes as well as human intestinal interstitial cells of Cajal (ICC) and smooth muscle cells.20 Loss-of-function variants in SCN5A, SCN1B, SCN2B and SCN3B genes have been causally related to BrS in ~20–25% of cases.5 There is mounting evidence of the association of sodium-channel defects and functional gastrointestinal disorders.20 Loss-of-function and gain-of-function variants in SCN5A gene have been identified in patients with wide-range of gastrointestinal symptoms, FBDs, and functional dyspepsia.6,21–24 SCN5A missense mutations (mostly loss-of-function) were present in 13 (2.2%) patients with IBS.6 A greater proportion of patients with SCN5A mutation met criteria for IBS-C than for IBS-D. SCN5A loss-of-function mutations in patients with IBS have been shown to generate NaV1.5 currents of smaller density and reduced mechanosensitivity.6 Two out of 7 patients with BrS/DI-Type 1 BrP and SCN5A/SCN1B variants in our study population (Patients 1 and 3 in Table 2) had loss-of-function SCN5A variant (p.Phe1293Ser) and IBSC. Interestingly, this particular SCN5A variant has been previously reported in patients with IBS-C and proposed to have a mechanistic role in the pathophysiology of IBS.25,26 A recent GWAS meta-analysis from 5 population-based cohorts implicated ion channel genes in the pathogenesis of IBS.7 Suggestive GWAS signals were identified in 7 genomic regions, harboring 64 gene candidates to affect IBS risk via altered function and/or expression of ion channels. Interestingly, one of the suggestive risk loci was BrS-related SCN1B gene.7 SCN1B gene encodes the β1 and β1B subunits of the cardiac sodium channel which is also highly expressed by ICC in the mouse colon.27

The major limitations of this study are that the current Rome IV diagnostic criteria were not used in our study because of lack of validation of the questionnaire in Turkish population. Comparative characteristics of IBS and identification of biological and/or clinical variables that point to an underlying type1-BrP among patients with IBS were not possible between BrS/DI-Type 1 BrP cohort and the control group because of relatively low number of patients with IBS in the control group.

In conclusion, recognition of co-existence of BrS/DI-Type 1 BrP and IBS will allow physicians to treat their patients more effectively without exposing them to hidden drug cardiotoxicities. Larger studies are necessary to confirm the co-existence of BrS/DI-Type 1 BrP and IBS and to further define the phenotypical characteristics, the molecular genetic overlap and the role of ajmaline challenge test in these patients.

Acknowledgments

Financial Support: This work was supported by grants from the NIH (HL47678, HL138103 and HL152201), W.W. Smith Charitable Trust and Wistar and Martha Morris Fund

Footnotes

CRediT Author Statement

Anil S. Sarica: Formal analysis, Methodology, Validation, Investigation, Data Curation, Writing - Original Draft, Writing - Review & Editing

Serhat Bor: Conceptualization, Methodology, Validation, Investigation, Data Curation, Writing - Original Draft, Writing - Review & Editing, Visualization, Supervision, Project administration

Mehmet N. Orman: Formal analysis, Visualization

Hector Barajas-Martinez: Investigation, Writing - Review & Editing

Jyh-Ming Jimmy Juang: Investigation, Writing - Review & Editing

Charles Antzelevitch: Methodology, Validation, Investigation, Data Curation, Writing - Original Draft, Writing - Review & Editing, Funding acquisition

Can Hasdemir: Conceptualization, Methodology, Validation, Investigation, Data Curation, Writing - Original Draft, Writing - Review & Editing, Visualization, Supervision, Project administration

Declaration of interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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