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PLOS Neglected Tropical Diseases logoLink to PLOS Neglected Tropical Diseases
. 2023 Jul 13;17(7):e0011330. doi: 10.1371/journal.pntd.0011330

Characterization of Latin American migrants at risk for Trypanosoma cruzi infection in a non-endemic setting. Insights into initial evaluation of cardiac and digestive involvement

Pedro Laynez-Roldán 1,*,#, Irene Losada-Galván 1,2,*,#, Elizabeth Posada 1, Leonardo de la Torre Ávila 1, Aina Casellas 1, Sergi Sanz 1, Carme Subirà 1, Natalia Rodriguez-Valero 1, Daniel Camprubí-Ferrer 1, Isabel Vera 1, Montserrat Roldán 1, Edelweiss Aldasoro 3, Inés Oliveira-Souto 4, Antonia Calvo-Cano 5, Maria-Eugenia Valls 1,6, Míriam J Álvarez-Martínez 1,6, Montserrat Gállego 1,7,8, Alba Abras 9, Cristina Ballart 1,7, José Muñoz 1, Joaquim Gascón 1,8, Maria-Jesus Pinazo 1,8,*
Editor: Richard Reithinger10
PMCID: PMC10343076  PMID: 37440480

Abstract

Background

Trypanosoma cruzi causes Chagas disease (CD), a potentially fatal disease characterized by cardiac disorders and digestive, neurological or mixed alterations. T. cruzi is transmitted to humans by the bite of triatomine vectors; both the parasite and disease are endemic in Latin America and the United States. In the last decades, population migration has changed the classic epidemiology of T. cruzi, contributing to its global spread to traditionally non-endemic countries. Screening is recommended for Latin American populations residing in non-endemic countries.

Methods

The present study analyzes the epidemiological characteristics of 2,820 Latin American individuals who attended the International Health Service (IHS) of the Hospital Clinic de Barcelona between 2002 and 2019. The initial assessment of organ damage among positive cases of T. cruzi infection was analyzed, including the results of electrocardiogram (ECG), echocardiogram, barium enema and esophagogram.

Results

Among all the screened individuals attending the clinic, 2,441 (86.6%) were born in Bolivia and 1,993 (70.7%) were female. Of individuals, 1,517 (81.5%) reported previous exposure to the vector, which is a strong risk factor associated with T. cruzi infection; 1,382 individuals were positive for T. cruzi infection. The first evaluation of individuals with confirmed T. cruzi infection, showed 148 (17.1%) individuals with Chagasic cardiomyopathy, the main diagnostic method being an ECG and the right bundle branch block (RBBB) for the most frequent disorder; 16 (10.8%) individuals had a normal ECG and were diagnosed of Chagasic cardiomyopathy by echocardiogram.

Conclusions

We still observe many Latin American individuals who were at risk of T. cruzi infection in highly endemic areas in their countries of origin, and who have not been previously tested for T. cruzi infection. In fact, even in Spain, a country with one of the highest proportion of diagnosis of Latin American populations, T. cruzi infection remains underdiagnosed. The screening of Latin American populations presenting with a similar profile as reported here should be promoted. ECG is considered necessary to assess Chagasic cardiomyopathy in positive individuals, but echocardiograms should also be considered as a diagnostic approach given that it can detect cardiac abnormalities when the ECG is normal.

Author summary

Trypanosoma cruzi is a protozoan infection that can be transmitted to humans by triatomine insects, endemic from 21 Latin American countries. It can also be transmitted vertically (mother to child) and by blood transfusions, among other less frequent methods. T. cruzi infection is called Chagas Disease (CD) when causing organ damage, such as Chagasic cardiomyopathy (CC) and digestive involvement in 30–40% of cases. The large migration flows from Latin America to Europe have globalized the distribution of T. cruzi infection. Thus, screening is recommended for Latin Americans living in non-endemic countries. We have retrospectively analyzed the epidemiologic characteristics of individuals from endemic countries screened for T. cruzi infection in Barcelona over 17 years, revealing a great number of working-age women coming from highly endemic areas for T. cruzi infection, which reflect the migration movements of the last decades and help us to focus the screening and health promotion programs. We have also analyzed the initial organ damage assessment, which revealed a great proportion of right bundle branch block and left anterior fascicular block, considered typical CD lesions (although unspecific). We also found an important proportion of patients with an altered echocardiogram but having a normal ECG, which reinforces the echocardiogram as an essential test for the assessment of CC.

Introduction

American trypanosomiasis was first described by Carlos Chagas in 1909 [1]. Currently, we refer to Trypanosoma cruzi infection when no evidence of organ damage is present, while Chagas disease (CD) is the term used for the illness that results from T. cruzi infection. Up to 21 Latin American countries and the United States are considered endemic for T. cruzi infection and it is estimated to affect 6–7 million people [2]. Of all endemic countries, Bolivia has by far the highest reported prevalence, currently estimated at 6.1% [2]. Bites by triatomine vectors still represent the main route of transmission of T. cruzi to humans, but transmission is also possible orally (i.e., by ingestion of contaminated juices and foods) [3], congenitally from mother to child, by blood transfusion or organ donations [38].

In less than 5% of cases, individuals develop an acute symptomatic form of the disease [4]. After the acute phase is over, and if the infection remains untreated, T. cruzi progressively sets in the tissues with a high tropism for the heart and digestive tract. However, 60–70% of infected patients will not ever develop clinically significant organ damage [4]. Cardiac involvement is the most common organ damage, known as Chagasic cardiomyopathy (CC), which accounts for 25–30% of patients suffering from T. cruzi infection. Conduction disorders and dilatation of cardiac structures are typical manifestations, whose clinical spectrum comprise from asymptomatic to fatal outcomes [4]. Digestive involvement of CD (DCD) is less common (10–20%) and includes dilatation and dysfunction of digestive structures -mainly esophagus and colon [4].

Serological tests are the technique of choice for diagnosis of chronic T. cruzi infection [5]. Screening for cardiac involvement is indicated even in asymptomatic patients. The 12 lead ECG is the recommended test to detect conduction disorders and arrhythmias and should be offered to all patients [6,7]. Structural cardiomyopathy is classically assessed by thorax radiography, but last consensus recommends echocardiogram as it has more sensitivity and specificity [79]. Barium enema and esophagogram are recommended to assess digestive abnormalities due to CD but should only be performed when digestive symptoms are present [10].

In the last two decades, the global distribution of T. cruzi infection has changed due to population migration from endemic Latin America countries to Europe and other non-endemic settings [11]. In the early 2000s there was a large migration of Bolivian population towards Europe, mainly to large urban areas in Spain, due to the economic crisis and immigration restrictions in place in the USA [12].

A 2015 metanalysis estimated an average prevalence of T. cruzi infection of 4.2% in Latin American migrants living in European countries and, currently, Spain is the European country with the highest estimated prevalence [13]. Moreover, new cases of T. cruzi infection can occur in these traditionally non-endemic countries by non-vector-borne transmission. Thus, although screening for T. cruzi in populations originating from high endemic areas in Latin America should recommended in non-endemic countries, most European countries do not include this approach in their national health policies [14]. In Spain, there is no common legislation or initiative for T. cruzi screening; yet, in Catalonia an official program to detect and treat congenital T. cruzi infection has been implemented since 2010 [15].

In the last twenty years, several descriptions about clinical and epidemiological features of migrants at risk of T. cruzi infection have been published, but usually focused on blood donors or pregnant women, and the sample sizes of such studies were not large enough to describe the epidemiological profile of this population [1620]. Here we present the clinical and epidemiological profile of a large sample of Latin American migrants attending the International Health Service (IHS) of the Hospital Clínic of Barcelona, Spain, which is the reference center for tropical diseases in the region.

Materials and methods

Ethics statement

All participants provided written informed consent for screening and data collection, in compliance with all bioethical regulations. All participants were over 16 years of age. Thus, none of the participants required consent by representation, following applicable legislation [21]. This study has been approved by the Ethics Committee named “Comité de Ética de la Investigación con medicamentos del Hospital Clínic de Barcelona” (reference HCB/2021/0174).

Design, setting, and recruitment

Barcelona has been one of the urban areas in Spain where a large Bolivian migrant population settled in the early 2000s [12], and the IHS of Hospital Clinic de Barcelona and Barcelona Institute of Global Health (ISGlobal) has a 17-year of experience in the clinical management and follow-up of this population. We conducted a descriptive retrospective study of 2,820 individuals originating from endemic Latin American countries considered T. cruzi endemic areas. Study subjects attended the medical consultation outpatient clinic of the IHS from March 2002 to March 2019. Subjects came to IHS (i) voluntarily, (ii) for screening after a positive result of a relative, (iii) upon advice by family or friends, (iv) referred by another doctor and (v) following information, education, and communication (IEC) community outreach.

The following countries were considered T. cruzi endemic areas: Argentina, Belize, Bolivia, Brazil, Chile, Colombia, Costa Rica, Ecuador, El Salvador, Guatemala, French Guyana, Guyana, Honduras, Mexico, Nicaragua, Panama, Paraguay, Peru, Suriname, Uruguay and Venezuela. Exclusion criteria for individuals to be included in the cohort were: a) individuals born in a non-endemic country; b) individuals under 16-years-old; c) inconclusive serology test; d) individuals who had not signed the informed consent.

Epidemiological and clinical data were collected from electronic medical records and questionnaires over the study period and registered in a database [22], and published in a data repository [23]. Collected variables included age, sex, country and department of origin, date of arrival to Spain, risk factors for T. cruzi infection and T. cruzi serology result. Also, the results of complementary tests performed by protocol were collected: ECG and echocardiogram, and barium enema and esophagogram when performed. Patients were then classified as follows: T. cruzi infection with no evidence of organ damage, CC and DCD. Only the first evaluation was included in this study to ascertain the phase of the infection at diagnosis.

Diagnosis of T. cruzi infection and organ damage

Diagnosis of T. cruzi infection was performed by two serological tests using different antigens, two different enzyme-linked immunosorbent assays (ELISA) methods, ORTHO Trypanosoma cruzi ELISA Test System (Johnson and Johnson, High Wycombe, United Kingdom) and Bioelisa Chagas (Biokit, Lliçà d’ Amunt, Spain) during the period (2002–2012) and chemiluminescent microparticle assay (CMIA ARCHITECT Chagas Abbot) and ELISA (Chagas-ELISA Vircell, Spain) in the period (2013–2019). Indirect Immunofluorescence (IFA Vircell, Spain) and western blot were used in case of discordant serologic results [24].

Patients with two positive tests were classified as suffering from T. cruzi infection. CC was assessed through clinical history, physical exam, a 12-lead ECG, a thorax radiography, and echocardiogram. The following ECG abnormalities were considered as CC: bradycardia less than 50 beats per minute, auriculoventricular block (AVB), any type of bundle branch block or hemiblock, frequent ventricular premature beats, tachyarrhythmia of any origin, ST-T changes, electrically inactive areas, and pacemaker rhythm as it implies a conduction disorder [18]. The following echocardiogram abnormalities were considered as CC: any ventricular or atrial dilatation, contractility disorders, wall aneurisms and diastolic dysfunction [25,26]. Barium enema or esophagogram were performed when lower or upper digestive symptoms (respectively) compatible with CD were present. Colon dilatation in the barium enema was consider as DCD. Megacolon was defined as a diameter of more than 6.5 centimetres in descending colon, more than 8 centimetres in ascending colon and more than 12 centimetres in cecum [27,28]. Any gastroesophageal dysfunction or esophageal dilatation was also considered as DCD. Only the first evaluation for T. cruzi infection for each patient was included in this study.

Statistical analysis

Data were described as frequencies, means (standard deviation, SD) or medians (interquartile range, IQR) for qualitative and quantitative variables, respectively. Chi-squared and Wilcoxon Rank Sum test were performed to assess differences between groups for qualitative and quantitative variables, respectively. Venn diagrams were used to summarize the relationship between T. cruzi infection risk factors. To quantify the relationship between patient characteristics and T. cruzi infection, odds ratios (OR) were estimated by means of logistic regression models. The significance level was set at 0.05. The analysis was carried out using Stata17 (@StataCorp. 2019. Stata Statistical Software: Release 16. College Station, TX: StataCorp LLC). For graphical representation R Foundation for Statistical Computing (@R Core Team. 2019. R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing. Vienna, Austria), with the package venneuler (Wilkinson, L. 2011. Venneuler: Venn and Euler Diagrams. R package version 1.1–0), were employed.

Results

General demographic and epidemiological variables

A total of 2,820 individuals born in T. cruzi endemic countries were included in the 17 years study period. The number of patients tested for T. cruzi infection per year progressively increased until 2009, when there was a peak of 356 individuals. The mean age was 36.8 years (SD 11.0). The median (IQR) of the duration of residence in Spain until the first visit to the IHS was six years (3.00–10.00) [2,813]. Most individuals came from Bolivia (Table 1), and 93.2% (n = 2,275/2,441) of these where from Cochabamba, Santa Cruz, and Chuquisaca Departments, all of which are considered highly endemic areas for T. cruzi transmission (Table 1). The overlap between reported risk factors is represented in the Fig 1. The greatest overlap (n = 987/1,889 individuals, 52.2%) was between the three risk factors related to the vector (rural area, adobe house, and exposure to the vector), while 101 individuals (N = 1,889; 5.35%) reported also having a mother with T. cruzi infection, and 114 (N = 1,889; 6.0%) had been residing in a rural endemic area and in an adobe house.

Table 1. General demographic and epidemiological variables of participants (N = 2,820).

Variable n Percentage (%)
Female sex (N = 2,820) 1,993 70.7
Age range1 (N = 2,820)
    <18 93 3.3
    18–34 1,175 41.7
    35–49 1,173 41.6
    50–65 356 12.6
    <65 23 0.8
Country of origin (N = 2,820)
    Bolivia 2,441 86.6
        Cochabamba department 991 40.8
        Santa Cruz department 783 32.2
        Chuquisaca department 501 21.0
        Other departments 155 6.4
        Unknown 9 0.4
    Ecuador 80 2.8
    Argentina 73 2.6
    Colombia 51 1.8
    Peru 46 1.6
    Paraguay 34 1.2
    Brazil 24 0.9
    Honduras 19 0.7
    Venezuela 16 0.6
    El Salvador 15 0.5
    Chile 6 0.2
    Mexico 6 0.2
    Uruguay 4 0.1
    Guatemala 3 0.1
    Nicaragua 2 0.1
Referral (N = 1,893)
    Advised by family member or friend 1,081 57.1
    Referred by a doctor2 495 26.2
    IEC3 129 6.8
    Own initiative 37 2.0
    Other 150 7.9
Vectorial risk factors (N = 1,889)
    Rural area 1,517 80.3
    Adobe house 1,506 79.7
    Contact with vector 1,517 81.5
Non-vectorial risk factors
    Blood transfusion receptor (N = 2,773) 188 6.7
    Mother with T. cruzi infection (N = 2,746) 232 8.5
Report a previous test before this assessment (N = 1,916)
    Yes 657 34.3
    No 1,259 65.7
Positive serology (N = 2,820) 1,382 49.0

1. Age range is expressed in years.

2. Among individuals referred by a doctor, 73.5% (n = 364/495) were referred by a primary care doctor.

3. IEC: Information, education, and communication.

Fig 1. Venn diagram showing the overlap between risk factors of T. cruzi infection. Venn diagram showing the overlap between risk factors of T. cruzi infection recorded in the database.

Fig 1

Each oval represents a risk factor. The numbers represent how many individuals have the corresponding risk factor to the area where it is located in the diagram.

Seropositivity and its associated factors

Among 2,820 participants, 1,382 participants were diagnosed of T. cruzi infection based on serology (Fig 2). Variables associated with T. cruzi infection were analyzed and are summarized in Table 2. Proportion of T. cruzi infection by country is detailed in Table 3.

Fig 2. Flowchart of screened individuals.

Fig 2

Flowchart of screened participants of this study. Diagnosis of T. cruzi infection was based on the serology.

Table 2. Variables associated with T. cruzi infection using a multivariable model.

Variable Positive serology
n/N (%)
p-value1 Adjusted OR (95% CI) p-value2
Sex Male 236 / 566 (41.7) 0.0091 1 0.0454
Female 638 / 1323 (48.2) 1.24 (1.00, 1.54)
Age in years <18 3 / 65 (4.6) <0.0001 1 <0.0001
18–34 313 / 733 (42.7) 10.07 (3.08, 32.90)
35–49 401 / 809 (49.6) 12.84 (3.93, 41.94)
50–65 150 / 267 (56.2) 19.50 (5.86, 64.93)
>65 7 / 15 (46.7) 15.34 (3.16, 74.56)
Born in Bolivia Yes 833/1,667 (50.0) <0.0001 3.12 (2.14, 546)
No 41/181 (18.5) 1 <0.0001
Resided in rural area Yes 768/1,517 (50.6) <0.0001 1.56 (1.15, 2.11) 0.0039
No 106/372 (28.5) 1
Resided in adobe house Yes 775/1,506 (51.5) <0.0001 1.73 (1.27, 2.35) 0.0004
No 99/383 (25.9) 1
Contact with vector Yes 795/1,540 (51.6) <0.0001 1.97 (1.46, 2.65) <0.0001
No 79/349 (22.6) 1
Total 874/1,889 (46.3)

1: Chi-squared test

2: Wald test

OR: Odds ratio, CI: confidence interval

Note that we are summarizing only those observations with complete data for the multivariable model (N = 1,889)

Table 3. Frequency of T. cruzi infection according to country of origin.

Country of origin Positive for T. cruzi test
Bolivia (n = 2,441) 1,304 (53.4%)
Paraguay (n = 34) 17 (50.0%)
Argentina (n = 73) 31 (42.5%)
Brazil (n = 24) 8 (33.3%)
Chile (n = 6) 2 (33.3%)
Venezuela (n = 16) 4 (25.0%)
El Salvador (n = 15) 3 (20.0%)
Mexico (n = 6) 1 (16.7%)
Honduras (n = 19) 2 (10.5%)
Ecuador (n = 80) 6 (7.5%)
Peru (n = 46) 3 (6.5%)
Colombia (n = 51) 3 (5.9%)
Guatemala (n = 3) 0 (0.0%)
Nicaragua (n = 2) 0 (0.0%)
Uruguay (n = 4) 0 (0.0%)

Organ damage in patients with T. cruzi infection: Chronic Chagas disease

Out of 1,382 patients with a confirmed positive result for T. cruzi, the first ECG of 662 patients was recorded in the study database. Among them, 79.0% (n = 523/662) had a normal result, while 21.0% (n = 139/662) had an altered result and 22 of them were found to have more than one disorder in the ECG. Among the 178 patients with an echocardiogram performed and recorded in the database, a total of 122 patients (68.5%) had a normal result, while 56 of them (31.5%) had an altered result. Cardiac dilatation was the most frequent disorder (n = 19; 10.67%): 12 of them with ventricular dilatation (6.7%), seven patients with atrial dilatation (3.9%); two of them having a four-chamber dilatation (1.1%). Other findings, not considered to be CD related were: 14 patients with mild valve insufficiency, four of them with more than one valvopathy (11 cases of tricuspid insufficiency, six of mitral insufficiency, and one case of aortic insufficiency), and six had left ventricular hypertrophy. One patient had a severe pericardial effusion due to a non-chagasic etiology. Out of 153 patients with registered ejection fraction, six had a left ventricle ejection fraction (LVEF) of less than 35%, two patients had a LVEF between 35 and 45% and 145 had more than 45%. Main findings in the ECG and echocardiogram are summarized in Table 4.

Table 4. Main ECG and echocardiogram findings in patients with T. cruzi infection.

ECG findings Frequency Proportion among patients with altered ECG (n = 139) Proportion among patients with ECG performed (n = 662)
Normal ECG 523 - 79.0%
RBBB 64 46.0% 9.7%
LAFB 40 28.8% 6.0%
Sinus bradycardia 17 12.2% 2.6%
RBBB + LAFB 13 9.4% 2.0%
AVB 11 7.9% 1.7%
Nonspecific ST-T changes 7 5.0% 1.1%
VES 6 4.3% 0.9%
Supraventricular arrythms 6 4.3% 0.9%
Pacemaker 5 3.6% 0.8%
Electrically inactive area 2 1.4% 0.3%
Low voltage 1 0.7% 0.2%
LBBB 1 0.7% 0.2%
Other disorders 5 3.6% 0.8%
Echocardiogram findings Frequency Proportion among patients with altered echocardiogram (n = 56) Proportion among patients with echocardiogram performed (n = 178)
Normal echocardiogram 122 - 68.6%
Mild valve insufficiency 14 25.1% 7.9%
Ventricular dilatation 12 21.4% 6.7%
Diastolic dysfunction 10 17.9% 5.6%
Atrial dilatation 7 12.5% 3.9%
Contractility disorders 7 12.5% 3.9%
Ventricular hypertrophy 5 8.9% 2.8%
Wall aneurysm 4 7.1% 2.3%
Global hypokinesia 4 7.1% 2.3%
Other disorders 4 7.1% 2.%

RBBB. Right bundle branch block. LAFB: Left anterior fascicular block. AVB: Atrioventricular block. VES: Ventricular extrasystoles. LBBB: Left bundle branch block. LPFB: Left posterior fascicular block.

In sum, 148 participants were diagnosed with CC. Of them, 16 patients (10.8%) had a normal ECG but with altered echocardiogram, nine of whom due to diastolic dysfunction (56.3% of them).

An esophagogram was recorded in 66 patients. Of these, 89.4% had a normal test (n = 59) and seven patients had a gastroesophageal dysfunction. Barium enema was registered in 71 patients, of whom 30 (42.3%) had a normal test. Dolichocolon was present in 29 patients, colon dilatation in 11 patients, including two who met the megacolon criteria. Cardiac involvement was present in patients from Argentina (n = 2), Bolivia (n = 138), Brazil (n = 3), Colombia (n = 2), Ecuador (n = 1), Paraguay (n = 1) and Venezuela (n = 1), while it was not present in patients from other countries. Patients with digestive involvement were from Argentina (n = 1) and Bolivia (n = 22), while it was not present in patients from other countries. Regarding the frequency of cardiac or digestive involvement in the first evaluation, 148 patients (17.1%) were registered to have CC, while 23 patients (2.6%) were recorded as DCD and 703 patients (80.8%) did not have any evidence of organ damage. Due to missing data, 512 patients were excluded of this analysis.

Discussion

Several studies performed in non-endemic countries have assessed the clinical and epidemiological profile of people at risk for T. cruzi infection [13,1719,29,30]. However, most of these studies, especially in the USA [3133], had either small sample sizes or focused on specific populations (e.g., blood donors or pregnant women). Furthermore, prevalence of T. cruzi infection in these studies was very low because most of the migrants who settled in North America originated from countries with low T. cruzi prevalence [3133]. To our knowledge, this study describes one of the largest sample of patients at risk of T. cruzi infection in a non-endemic setting.

Trends in the influx of medical consultations are determined by Bolivian population migratory flows, since this population accounts for 86.6% of the participants. It is worth noting that patients from our study spent a median of six years in Spain before screening for T. cruzi infection was performed, which is longer than observed in other previous European studies [29,34]. This delay may be explained by barriers to healthcare, such as the population’s legal immigration and residential status, poor socio-economic conditions, and cultural barriers. It is estimated that a significant number of people living in Spain with T. cruzi infection are unaware of their condition. In fact, the index of underdiagnosed cases of T. cruzi infection is estimated to be of 71% [35] and, indeed, most of our participants had never been tested for T. cruzi infection prior to our assessment. The great predominance of women and working-age people from endemic countries reflects the demographic profile of Latin-American migrants who came to Europe in the early 2000’s, as job offers were usually as domestic workers, which was socially attributed to women [12].

Health promotion campaigns among the Bolivian community were decisive in defining the attendance trends in the medical attention seeking in the IHS of Hospital Clinic de Barcelona, as shown by several health promotion programs directed to communities from T. cruzi endemic countries [36]. Most patients came because they were advised by a family member or a friend, which reveals the great importance of the social capital in the knowledge and care of the disease.

This study presents higher proportion of T. cruzi infection among participants than other European studies [13]. However, a selection bias was present because the participants were attending a referral center to which sometimes they were directed after a positive test. For this reason, proportion of seropositivity from this study should never be used to estimate the prevalence of T. cruzi infection in the general Latin American population living in Spain, which was already estimated to be of 2.1% in a recent study [35]. Nevertheless, we must consider that Latin Americans in Barcelona come from highly endemic areas compared with those in other European cities [37]. In fact, most individuals were from the Bolivian departments of Cochabamba, Santa Cruz, and Chuquisaca, which are hyperendemic areas of T. cruzi infection [5].

Factors of potential vector exposure (adobe house, rural area, to have been in contact with the vector) were present in most patients, but there was a significant overlap among all the risk factors. Thus, many participants who had received a transfusion in an endemic country or whose mother had T. cruzi infection, have also had potential vector exposure.

Congenital and transfusion risks account for the possibility of new cases in Europe and justifies the implementation of screening programs for these risk groups as a priority in health public policies [14]. Moreover, screening for T. cruzi infection in all Latin American adults living in Europe has been shown to be cost-effective [37]. Additionally, young people infected with T. cruzi on an early chronic phase of T. cruzi infection seems to be the most benefited from an early diagnosis and anti-trypanosoma therapy [38,39]. Even more so in women of childbearing age, since treatment before pregnancy dramatically reduces the chances of congenital transmission [40,41].

Results from ECG assessment show RBBB as the most frequent and with the strongest association with T. cruzi infection, consistent with previously published studies [42]. LAFB was more frequent than sinus bradycardia, contrary to what was observed in previous studies [20,43]. Although the sensitivity of the ECG may be limited because it cannot evaluate function and morphology, it is an accessible and low-cost test capable of detecting potentially serious abnormalities. Indeed, more than 10% of patients with diagnosis of cardiac involvement had a normal ECG result and were diagnosed by echocardiogram. Similar data observing altered echocardiogram with normal ECG have been previously published [44,45]. Therefore, echocardiogram is considered a necessary test for this evaluation by most authors and guidelines [79], our findings pointing in the same direction. Typically, wall dilatation has been considered the main echocardiogram disorder in patients with T. cruzi infection, but diastolic dysfunction is suggested to be an earlier alteration of CC [26,46]. Our study shows diastolic dysfunction as the second most frequent disorder among patients with T. cruzi infection. Although this frequency is not very high compared with that of general population [47], its presence may be considered of Chagasic etiology, especially taking into account the young age of our patients. Presence of isolated mild tricuspid or mitral insufficiency without dilated ring should not be interpreted as a CC, as several studies have demonstrated a high prevalence (up to 80%) of mild regurgitation in healthy subjects [48] and, to our knowledge, there are no studies which associate it with disease progression. Regarding digestive involvement, dolichocolon was very frequent in patients with a barium enema performed. In agreement with previous work [10,49,50], dolichocolon was not considered as a digestive involvement for CD, thus the observed frequency of digestive involvement was relatively low. Furthermore, digestive involvement was only present in patients from southern countries of Latin America (Bolivia and Argentina). This would be consistent with the notion of tissue specific tropism of different strains of T. cruzi with characteristic geographic distribution [51], but the validity of this observation cannot be concluded since practically all the patients come from those same countries.

More than 80% of patients were not found to have CC or DCD in the first evaluation. This form of the disease is classically known as "indeterminate form" of chronic T. cruzi infection [4] or rather "chronic phase without demonstrable pathology" [52]. Most patients were young, so a number of them will develop some form of organ damage in the following years at a rate of 1–2% per year [53]. Hence, age could explain the lower prevalence of CC and DCD in studies from non-endemic countries compared with those from endemic countries [29]. The lack of clinical and biological markers of progression limits a more accurate follow-up in this big group of patients. The future availability of such tools should be highly relevant for patients’ clinical management and healthcare routes [54].

One limitation of this study is that comorbidities were not specifically addressed. We acknowledge that screening for comorbidities will become increasingly important with the aging of Latin American migrants, but we posit that the impact on the overall findings of this study would probably be small due to the mean and median age of the participants included in our study. Also recall bias could be present in the answers to the epidemiological questionnaires. As the participants were recruited in a regional reference center a selection bias was present. Observer bias could also be present as electrocardiogram is an observer-dependent test, and the questionnaires were filled in by different physicians. This bias was probably reduced as diagnostic criteria of electrocardiographic disorders were established in detail. We were able to include the status of the patient at the moment of the screening and at the moment of the initial diagnosis of T. cruzi infection, but not their follow-up, that is why the number of ECG and echocardiogram recorded for the analyses was little compared with total sample size. Despite this discordance, the absolute number of tests registered and analyzed was also high and allowed us to extract enough data for the analysis and discussion. It would be interesting to analyze the longitudinal evolution of this cohort in terms of the prognostic value of the alterations found in this first evaluation.

Conclusions

Currently, T. cruzi infection is distributed throughout Europe due to migratory flows from Latin America of the last two decades. Big Spanish cities have received the largest population at risk. Although arrivals from endemic countries have decreased in the last years, we still observe many individuals at risk who have not been previously tested. Moreover, since universal testing of pregnant women is not widely implemented, children with T. cruzi infection may be born and remain undiagnosed. In this study, individuals from endemic countries settled in Barcelona were mostly working-age women who came between 2004 and 2007. Migrants with a similar epidemiological profile, especially of Bolivian origin or descent, should be the target for a national or European screening program. Thus, health promotion programs and an adequate information to the patient in the consultation are essential to carry out the screening program.

In concurrence with other studies, previous contact with the vector was the most frequent and strongly associated risk factor with T. cruzi infection among those related with vector exposure.

The primary assessment in patients with chronic T. cruzi infection should include an ECG and echocardiogram. RBBB and LAFB were the most typical ECG disorders among T. cruzi infection patients in our series, while wall dilatation and diastolic dysfunction were the most frequent findings in the echocardiogram. In our series, as well as in other previous studies, a relevant proportion of patients with CC were diagnosed by echocardiogram having a normal ECG, which reinforces the echocardiogram as an essential test in the assessment of CC. Although dolichocolon was the most frequent finding in barium enema, it should not be interpreted as a digestive involvement of CD. It is expected that prevalence of CC and DCD will gradually increase in Europe as migrant populations settled in these countries age.

We are gradually learning more about T. cruzi infection, but there are still important knowledge gaps regarding this infection, especially about the lack of clinical or biological prognostic factors. Further studies will be necessary for a better understanding of its epidemiological and clinical behaviour.

Supporting information

S1 Table. The Supporting Information file contains the numbers used for the generation of Fig 1.

The file consists of five columns, one for each risk factor, and a sixth column indicating the number of subjects in the corresponding situation. For each risk factor, its presence or absence is indicated by TRUE or FALSE, respectively.

(CSV)

Acknowledgments

We first would like to thank all the participants of this study. We also thank the Hospital Clínic de Barcelona and ISGlobal, as well as the nursing team, the medical team, and the staff who have helped in this project.

Data Availability

The data present in this study are available upon request from the “Catalan Open Research Area” with the identifier https://doi.org/10.34810/data223 (contact address: ubioesdm@isglobal.org), access to the data is restricted due to ethical reasons. The complete data dictionary (data_dictionary.pdf) listing the dataset variables, and the dataset details (readme.txt) are available without restriction. Additionally, the publication includes a supporting information file to facilitate reproducibility of Fig 1 (S1 Table).

Funding Statement

ISGlobal work is supported by the Departament d’Universitats i Recerca de la Generalitat de Catalunya, Spain (AGAUR; 2017SGR00924) and by the Instituto de Salud Carlos III (ISCIII) RICET Network for Cooperative Research in Tropical Diseases (ISCIII; RD16/0027/0004 - PI1290) and FEDER. MJP research is supported by the Ministry of Health, Government of Catalonia (PERIS 2016-2010 SLT008/18/00132). The research of MJP and JG is supported by the Departament d’Universitats i Recerca de la Generalitat de Catalunya, Spain (AGAUR; grant 2014SGR26). ILG research is supported by “Centro de Excelencia Severo Ochoa 2019-2023” Program (CEX2018-000806-S), from the Spanish Ministry of Science and Innovation and State Research Agency. Specific funding has not been received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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PLoS Negl Trop Dis. doi: 10.1371/journal.pntd.0011330.r001

Decision Letter 0

Ana Rodriguez, Richard Reithinger

5 Jan 2023

Dear Mr Laynez-Roldán,

Thank you very much for submitting your manuscript "Characterization of Latin American migrants at risk for Trypanosoma cruzi infection in a non-endemic setting. Insights into initial evaluation of cardiac and digestive involvement" for consideration at PLOS Neglected Tropical Diseases. As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. In light of the reviews (below this email), we would like to invite the resubmission of a significantly-revised version that takes into account the reviewers' comments.

We cannot make any decision about publication until we have seen the revised manuscript and your response to the reviewers' comments. Your revised manuscript is also likely to be sent to reviewers for further evaluation.

When you are ready to resubmit, please upload the following:

[1] A letter containing a detailed list of your responses to the review comments and a description of the changes you have made in the manuscript [please make sure to indicate where changes have been made by specifying either paragraph or line numbers]. Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

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Sincerely,

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Academic Editor

PLOS Neglected Tropical Diseases

Ana Rodriguez

Section Editor

PLOS Neglected Tropical Diseases

***********************

Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #1: The authors present epidemiological and clinical data of Latin American immigrants to Spain who were found to have Trypanosoma cruzi infection at their hospital in Barcelona.

-The objectives were to define risk factors for infection and describe clinical features of persons found to be infected. The objectives of this retrospective, descriptive study were straightforward and clear. As a descriptive study, hypotheses were not stated, but associations were presented, and their strength tested.

-The study design was appropriate for this descriptive, retrospective study.

-The population was clearly described.

-The number of infected immigrants with T. cruzi infection identified and studied is perhaps the largest reported in the literature to date. The numbers were sufficient for robust analysis.

-Standard and appropriate statistical analyses were performed

-There are no ethical concerns.

Reviewer #2: This manuscript does not tackle a specific research question.

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Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #1: The analysis of data was straightforward and appropriate.

Data were presented clearly. However, it's not necessary to present hundredths (decimal points) in the percentages; round numbers or tenths of a percent are sufficient.

Results are clearly presented, but 2 small issues--table 2: OR said to be adjusted but not clear if ORs were adjusted or if adjusted, adjusted for what; OR for Bolivia is reversed

Not sure that map (figure 3) is necessary given highly selected study population

Reviewer #2: Tables are clear and well-structured in general.

On the firgures, I think

a) presenting a map may be misleadingly taken as real prevalence of T. cruzi infection (not the intention of the authors).

b) A Venn diagram describing 5 factors includes too many numbers, making it difficult to the reader. I suggest to think in a different format to present this information.

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Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #1: -Conclusions largely are supported by data with several exceptions.

One is that all the ECG and echocardiographic abnormalities were evidence of Chagas heart disease. Given the nonspecific nature of many of the abnormalities, the authors should acknowledge that the estimates of Chagas heart disease may be overestimates.

The second has to do with the echocardiogram. The authors point out that 10% of infected persons with a normal ECG had an abnormal echocardiogram, but 90% of these had diastolic dysfunction (a rate less than the general population!!); isolated diastolic dysfunction may not be an early manifestation of Chagas disease (this remains to be shown), and it may not predict progression, which is the hallmark of Chagas cardiomyopathy. Although current guidelines recommend an echocardiogram for initial evaluation, it should be clearly stated that techniques more sensitive than the ECG (such as the echocardiogram) will find minor abnormalities in high numbers of persons with T cruzi infection (see Am J Trop Med Hyg 2020;103:1480.). It has long been known the many people with "indeterminate" Chagas disease will have subtle abnormalities on more sensitive testing-the significance of these findings is unclear, but longitudinal data suggest strongly that most do not progress. The recommendation for doing echocardiograms in all persons with positive tests for T cruzi may have the unintended consequence of labelling someone as having classic Chagas cardiomyopathy (with its well-known bad long-term prognosis), when in fact the disease will never progress. The other downside of the guideline is that requiring an echocardiogram in all infected persons will provide yet another financial barrier for persons to undergo needed medical evaluation.

-Major limitations of the study are pointed out by the authors. These primarily are a consequence of the highly selected study population (mostly Bolivian from a few areas, mostly women, many already diagnosed, many referred to study by doctor or because of disease). This limits the generalizability of study to other nonendemic countries.

-An important limitation of the study is lack of information on comorbidities (especially hypertension, coronary disease and risk factors, diabetes) . Comorbidities could account for the ECG abnormalities and interactions with Chagas disease will become increasingly important as the infected immigrant population ages.

-In terms of discussing how the data could be used to advance understanding of Chagas disease in immigrant populations, the authors should mention the importance of long-term follow-up of their cohort to answer some of the questions about progression of disease outside of endemic areas.

-The public health relevance of the study speaks for itself and is appropriately emphasized by the authors

Reviewer #2: Yes, in general, authors conclusions are based on their reported data.

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Editorial and Data Presentation Modifications?

Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend “Minor Revision” or “Accept”.

Reviewer #1: Although there is no major problem with the overview of Chagas disease, it is extremely long and may distract from the major point of the paper, which is to describe experience in a nonendemic country. This will be up to the Journal editors ultimately, but we would strongly recommend decreasing the introduction to a few paragraphs in order to focus on the important parts of the paper.

There are some small items in the introduction that need attention if it is retained. Some of the statements may be outdated as noted. Numbers refer to line number in the text

Line 92: Does in fact traditional vectorborne transmission still account for most new infections? It does account for most existing infections.

Line 93-4: Metacyclic tryptomastigotes do not penetrate the blood through the skin

94. T infestans was the most important vector—is it still?

96. Rather than say oral transmission is possible would point out its importance as a route of transmission. Over 5000 cases of oral transmission have been reported and in many areas this route of transmission far outweighs traditional vector borne transmission.

104-105 Rates of transfusion transmitted infection depend on the blood product being transfused; the 10-20% data are old and probably reflect transmission of whole blood rather than individual products; currently, platelets are the most common vehicle; risk of transfusion-induced transmission may vary among geographic areas and presence or absence of ongoing vectorborne transmission.

106-7. Would clarify that transmission in North America is in the United States and not Canada; Mexico is part of North America but is high rates of active borne transmission.

110. "Orography” pertains to mountains primarily and although relevant to Bolivia, may be confusing to readers.

Line 125: Infection in the GI tract most significantly involves the autonomic ganglia.

Line 144. Would say the DNA amplification not useful for diagnosis of chronic infection rather than saying it has little relevance in the chronic phase as pointed out in 149—this may be confusing to readers as written

In the Discussion, first paragraph, a more extensive review of studies outside of Europe would be appropriate for this paper, which focuses on experiences in nonendemic countries. For instance, see Curr Trop Med Rep 2022, Sept 10:1-9 (available through pub med) for summary of US studies.

Reviewer #2: 1. The text equates Trypanosoma cruzi infection with Chagas diseases. I think this is not correct, as the later term refers to the fraction of the population developing abnormalities.

2. The intro section (line 150-1529) states that a 12-lead ECG should be taken to all seropositive individuals. However, the data presented in this report suggest it lacks sensitivity to detect cardiac abnormalities. This fact should be addressed in the discussion

3. The statement "anti-Trypanosoma therapy could reduce disease progression.." (lines 389-390) may be unsubstantiated. The authors selectively cite a published observational study, excluding two randomized trials, with opposite results (one of them unpublished, but presented as abstract in at least one medical meeting).

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Summary and General Comments

Use this section to provide overall comments, discuss strengths/weaknesses of the study, novelty, significance, general execution and scholarship. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. If requesting major revision, please articulate the new experiments that are needed.

Reviewer #1: The authors present their experience over the last 17 years evaluating immigrants from Latin America for Chagas disease; the group has the largest experience in nonendemic countries, and for this reason the current paper is very welcome.

The paper could be improved by condensing and focusing the introduction, and tightening up the discussion, which is lengthy. If this paper is meant to be followed by a long-term follow-up study (hopefully so!) the authors might mention this. They might also mention the importance of comorbidities and aging on the outcome of T cruzi infection.

Reviewer #2: This is an informative, well-organized, well-written manuscript, based on two decades of clinical assessments to immigrants from Latin-American countries, potentially carrying T. cruzi infection. The authors deserve all credit and should be congratulated for completing this work over the years.

I found, however, difficulty reading it as an original research article. The paper describes different aspects of patients attending a tropical medicine clinic, after using conventional methods for their diagnosis and clinical assessment. It does not entail a specific research question. Further, with an unusually long introduction, covering mostly general aspects of Chagas disease, the text reads initially as a narrative review/tutorial.

Their main findings, that Bolivian immigrants made 85% of the participants, that 48% were seropositive, and that their clinical characteristics were (as expected) similar as those of infected individuals living elsewhere can hardly be seen as novel. There would also be validity concerns, if we were to see this as a survey/registry of infected patients, mainly because of selection bias. Firstly, as a sample of the infected population: this is a single center study, including mostly asymptomatic patients from a region in Bolivia (the fifth country of origin of Latin American immigrants to Spain) attending the clinics for different reasons. Secondly, as assessment of the study population: only half of the participants had an ECG taken, and 12.8% had an echocardiogram, not necessarily based on prior ECG findings.

I think this report raises awareness about Chagas disease as a global health problem. However, in its current format, I cannot see this report as a research manuscript. Authors may want to elaborate more specific questions, taking advantage of the information at hand. Alternatively, this may be re-arranged as a narrative/tutorial review that is illustrated with the experience/data.

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Reviewer #1: No

Reviewer #2: Yes: Juan Carlos Villar

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PLoS Negl Trop Dis. doi: 10.1371/journal.pntd.0011330.r003

Decision Letter 1

Ana Rodriguez, Richard Reithinger

27 Mar 2023

Dear Mr Laynez-Roldán,

Thank you very much for submitting your manuscript "Characterization of Latin American migrants at risk for Trypanosoma cruzi infection in a non-endemic setting. Insights into initial evaluation of cardiac and digestive involvement" for consideration at PLOS Neglected Tropical Diseases. As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. The reviewers appreciated the attention to an important topic. Based on the reviews, we are likely to accept this manuscript for publication, providing that you modify the manuscript according to the review recommendations.

Thank you for addressing all of the reviewers' concerns. I did think that the manuscript warranted some small re-structuring and tightening of the language. Please see my edits in the attached file for proposed changes. Let me know if these are agreeable to you.

Please prepare and submit your revised manuscript within 30 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email.

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Important additional instructions are given below your reviewer comments.

Thank you again for your submission to our journal. We hope that our editorial process has been constructive so far, and we welcome your feedback at any time. Please don't hesitate to contact us if you have any questions or comments.

Sincerely,

Ana Rodriguez

Section Editor

PLOS Neglected Tropical Diseases

Ana Rodriguez

Section Editor

PLOS Neglected Tropical Diseases

***********************

Thank you for addressing all of the reviewers' concerns. I did think that the manuscript warranted some small re-structuring and tightening of the language. Please see my edits in the attached file for proposed changes. Let me know if these are agreeable to you.

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To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

References

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article's retracted status in the References list and also include a citation and full reference for the retraction notice.

Attachment

Submitted filename: PNTD-D-22-01254R1 manuscript. changes highlight RR.docx

PLoS Negl Trop Dis. doi: 10.1371/journal.pntd.0011330.r005

Decision Letter 2

Ana Rodriguez, Richard Reithinger

24 Apr 2023

Dear Mr Laynez-Roldán,

We are pleased to inform you that your manuscript 'Characterization of Latin American migrants at risk for Trypanosoma cruzi infection in a non-endemic setting. Insights into initial evaluation of cardiac and digestive involvement' has been provisionally accepted for publication in PLOS Neglected Tropical Diseases.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. A member of our team will be in touch with a set of requests.

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Thank you again for supporting Open Access publishing; we are looking forward to publishing your work in PLOS Neglected Tropical Diseases.

Best regards,

Richard Reithinger

Academic Editor

PLOS Neglected Tropical Diseases

Ana Rodriguez

Section Editor

PLOS Neglected Tropical Diseases

***********************************************************

Thank you for accepting all of the suggested edits and changes.

PLoS Negl Trop Dis. doi: 10.1371/journal.pntd.0011330.r006

Acceptance letter

Ana Rodriguez, Richard Reithinger

14 Jun 2023

Dear Mr Laynez-Roldán,

We are delighted to inform you that your manuscript, "Characterization of Latin American migrants at risk for Trypanosoma cruzi infection in a non-endemic setting. Insights into initial evaluation of cardiac and digestive involvement," has been formally accepted for publication in PLOS Neglected Tropical Diseases.

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Thank you again for supporting open-access publishing; we are looking forward to publishing your work in PLOS Neglected Tropical Diseases.

Best regards,

Shaden Kamhawi

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

Paul Brindley

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Table. The Supporting Information file contains the numbers used for the generation of Fig 1.

    The file consists of five columns, one for each risk factor, and a sixth column indicating the number of subjects in the corresponding situation. For each risk factor, its presence or absence is indicated by TRUE or FALSE, respectively.

    (CSV)

    Attachment

    Submitted filename: ResponseToReviewers.docx

    Attachment

    Submitted filename: PNTD-D-22-01254R1 manuscript. changes highlight RR.docx

    Attachment

    Submitted filename: cover letter. response minor revisions.docx

    Data Availability Statement

    The data present in this study are available upon request from the “Catalan Open Research Area” with the identifier https://doi.org/10.34810/data223 (contact address: ubioesdm@isglobal.org), access to the data is restricted due to ethical reasons. The complete data dictionary (data_dictionary.pdf) listing the dataset variables, and the dataset details (readme.txt) are available without restriction. Additionally, the publication includes a supporting information file to facilitate reproducibility of Fig 1 (S1 Table).


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