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10.1371/journal.pone.0296481
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Acquired syphilis in older people in Brazil from 2010–2020
Acquired syphilis in older people in Brazil
https://orcid.org/0000-0002-0462-5839
da Cunha Josiane Araújo Conceptualization Data curation Formal analysis Funding acquisition Investigation Methodology Resources Supervision Validation Visualization Writing – original draft 1 2 *
Marques dos Santos Marquiony Formal analysis 2 ¤
Costa de Lima Kenio Conceptualization Investigation Methodology Resources Supervision Validation Visualization Writing – review & editing 1 3
1 Graduate Program in Health Sciences, Federal University of Rio Grande do Norte, Natal, Rio Grande do Norte, Brazil
2 Laboratory of Technological Innovation in Health, Federal University of Rio Grande do Norte, Natal, Rio Grande do Norte, Brazil
3 Graduate Program in Collective Health, Federal University of Rio Grande do Norte, Natal, Rio Grande do Norte, Brazil
Hlashwayo Delfina Fernandes Editor
Eduardo Mondlane University: Universidade Eduardo Mondlane, MOZAMBIQUE
Competing Interests: The authors have declared that no competing interests exist.

¤ Current address: Federal University of Rio Grande do Norte, University Hospital Onofre Lopes, Natal, Rio Grande do Norte, Brazil

* E-mail: josianeac12@gmail.com
6 9 2024
2024
19 9 e029648127 1 2023
14 12 2023
© 2024 Cunha et al
2024
Cunha et al
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Background

The infection caused by Treponema pallidum remains a severe public health problem, with a high prevalence in individuals over 60 years. However, research into infections such as syphilis continues to be neglected in geriatrics. This study aims to evaluate data on the detection rate of syphilis in Brazil, in individuals between 60 and 120 years, by characterizing the epidemiological profile and respective factors associated with it, in addition to performing a temporal trend analysis, from 2010 to 2020.

Methodology

Ecological, time-series study, which started with the collection of notifications from the database of the Information System on Compulsory Notification of Diseases. The epidemiological profile was characterized based on sociodemographic variables. The Statistical Package for the Social Sciences program, version 19.0, was used for incidence and prevalence analysis. The 2010 census by the Brazilian Institute of Geography and Statistics and projections for older people were considered. In the trend analysis, the Joinpoint regression model was used.

Main findings

There was an upward variation in the detection of syphilis in older people from 2010 to 2018, with a peak in 2018. In 2019, there was a slight reduction in the notification of cases, which was accentuated in 2020. The prevalence of the infection was equivalent to 12.84 cases for each 100,000 Brazilians, with a mean age of 68.04 years (±7.15) for those between 60 and 120 years, being higher in white and black males. The highest proportion of older people with syphilis occurred in the South and Southeast regions. However, the trend analysis showed a significant and homogeneous increase in all regions of Brazil, for both sexes and all age groups.

Conclusions

There is a tendency for an increase in cases of syphilis in older people, which reinforces the need to plan health actions to combat the disease in this population.

The Coordination for the Improvement of Higher Education Personnel - Brazil (CAPES) - Finance Code 001 - is financing the payment of publication fees for the PLOS ONE journal. The funder had no involvement in the study design, data collection and analysis, publication decision, or manuscript preparation. Data AvailabilityAll relevant research data can be found in the document and the Zenodo data repository (https://doi.org/10.5281/zenodo.10086131).
Data Availability

All relevant research data can be found in the document and the Zenodo data repository (https://doi.org/10.5281/zenodo.10086131).
==== Body
pmcIntroduction

The Sexually Transmitted Infection (STI) caused by Treponema pallidum [1] remains a significant public health problem, although it was originated in the late 1400s and discovered in 1905 by Schaudinn & Hoffmann [2, 3]. The transmission is mainly through sexual intercourse (oral, vaginal, or anal). Most people with syphilis are asymptomatic, which contributes to maintaining the chain of transmission. However, if untreated, it may cause severe systemic complications after 3–5 years of infection [4].

Syphilis infection is divided into the stages of recent syphilis—primary, secondary, and recent latent, with one year of evolution—and late syphilis, late latent, and tertiary, with more than one year of evolution [5]. The primary stage is characterized by contagion and development of a chancre, usually only one and painless. Signs of secondary syphilis appear between three and eight weeks after the primary chancre. In this stage, cutaneous-mucosal manifestations are predominant, but they usually disappear within a few weeks [6]. The disease continues into the latent phase, without symptoms or signs, but with the risk of developing tertiary syphilis [7]. In the tertiary stage, the nervous and cardiovascular systems are affected [8].

Treponema pallidum can be detected in lesions of primary and secondary syphilis. Antibodies against the bacteria are detectable up to 15 days after the appearance of the chancre, and the disease can be diagnosed [9]. Indirect methods for diagnosing this STI have a complex interpretation in the case of reinfected patients since treponemal antibodies remain mostly positive throughout life. Therefore, tests are not as sensitive in early infection or when patients are contagious, and nontreponemal titers are more difficult to interpret after treatment [10].

Syphilis has been described as the great imitator due to its many and varied clinical manifestations. In 2020, 7.1 million new cases of infection by the Treponema pallidum were recorded, with a prevalence of 22.3 million. In the American continent, the prevalence in adults, in that same year, for both sexes, was 5,800,000. The incidence rate in adults per 1,000 people, in 2020, for both sexes, was 4.8, with the total number of cases being 2,500,000 [11]. Data indicate a potential increase in new cases of syphilis if adequate interventions to combat its spread do not occur [6].

In the United States, the incidence of syphilis has reached levels not seen in more than 20 years, with an increase in the number of cases reported for both sexes, indicating a growth in the spread of the disease [12, 13]. In China, a study by Tao et al. 2020 [14] found that the increasing proportion of asymptomatic latent syphilis diagnoses probably results from the scale-up of syphilis screening. For Peeling et al. 2017 [15], despite the availability of diagnostic tests and treatment, syphilis is re-emerging as a global public health problem.

From 2012 to 2022, 1,237,027 cases of acquired syphilis were reported in Brazil. Throughout the historical series, the disease detection rate showed an average annual growth of 35.4% until 2018, remaining stable in 2019. In 2020, there was a 23.4% decline in this rate, probably due to reduced diagnostics capacity during the COVID-19 pandemic. In 2021 and 2022, detection rates reached levels higher than the pre-pandemic period, with a 26.6% growth. From 2012 to June 2023, SINAN reported a total of 1,340,090 cases of acquired syphilis, of which 14.2% occurred in the Northeast region. In Rio Grande do Norte, from 2012 to 2022, the number of cases per 100,000 inhabitants increased from 275 to 2,576. By June 2023, there were already 1,546 cases [16].

As explained by Pagani et al. 2021 [8], an important factor that has changed the characteristics of patients with syphilis is its growth among older people. The increase in life expectancy and quality, in addition to the availability of drugs that allow for prolonged sex life, has reshaped sexual behavior, making these individuals more vulnerable to STIs, such as syphilis. The high prevalence of these infections in individuals over 60 years must be highlighted, including those in extreme age groups, aged 90 years or more [17–20].

On the other hand, sexually transmitted infections such as syphilis remain a neglected area of research in geriatrics and, therefore, further studies are needed on their prevalence in older populations [21]. Since the infection has a variable appearance, other diagnoses may be suggested, implying an underdiagnosis of STIs for older people [22].

In this sense, the relevance of proposing a study which verifies whether the increase in syphilis also occurred among older individuals in a 10-year time frame helps in combating the spread of the disease and outlining perspectives of fighting the disease in this age group, which sometimes is not considered at risk. Older people are usually forgotten when sexually transmitted infections are investigated since structural ageism prevents them from being seen as sexually active.

Therefore, this study aims to evaluate the data on the detection rate of syphilis in Brazil, characterizing the epidemiological profile and respective factors associated with it, in addition to performing a temporal trend analysis, from 2010 to 2020.

Materials and methods

Type of study

This is an ecological, time-series study, involving all federative units of Brazil. The Brazilian territory is divided into five regions: North, Northeast, South, Southeast and Central-West, with a total of 203,080,756 inhabitants. Currently, the population aged 60 years or more totals 32,113,490 individuals. The demographic density in the last census survey was estimated at 23.8 inhabitants per square kilometer. Gini index data fell to 0.518 in 2022 and the current HDI is 0.759 [23].

Data source

Data on acquired syphilis were obtained from a database that receives input from the Notifiable Diseases Information System—SINAN (https://zenodo.org/doi/10.5281/zenodo.10086130) [24]. Therefore, there was no need to submit this research for an ethics review. This system is the main source of information on the notification and registration of cases of syphilis. Therefore, this work uses a national database that contains information that is legitimately associated with the testing/notification of cases of acquired syphilis and its increase in Brazil.

In Brazil, the epidemiological surveillance model comprises investigation and compulsory notification, sentinel services, and cross-sectional studies in population groups. Suspected or confirmed cases on the national list of compulsory notifications are registered at SINAN and follow a flow until the public disclosure of information. In SINAN, only the identification and demographic data of individuals (gender, age, race or skin color, schooling, and residence) are entered. Clinical, laboratory, and behavioral data variables are not included. In addition to SINAN, other systems can be routinely accessed to obtain additional information about STIs. The interoperability of data from municipal, state, and federal epidemiological surveillance services allows the extraction of information on deaths from the Mortality Information System and consultation of Hospital and Outpatient Information Systems, among others [25].

Among the indicators generated through data from the SINAN system, there are those provided by the regular input report in the system and those relevant to the management and innovation of the Unified Health System. Reports are generated from DBF databases of the NET or ONLINE versions of SINAN. This information helps in monitoring disease trends, as well as proposing prevention and control measures [26].

In this sense, SINAN is the main source of secondary data on syphilis notification in Brazil, in which all registered cases of the disease are available. Compulsory notification is mandatory and conducted upon suspicion or confirmation of the disease, being performed by health professionals or any member of the care team who cares for the patient first, within 24 hours. The health authorities that receive the notification must inform the other spheres of SUS management so that it can be recorded and shared among health information systems [27, 28].

To notify cases of acquired syphilis, the SINAN individual investigation/notification form must be used (S1 File https://doi.org/10.5281/zenodo.11638624). In 2017, the criteria for cases of this disease were redefined, in accordance with the guidelines of the Pan American Health Organization: asymptomatic individuals with a reactive non-treponemal test, with any titer, and reactive treponemal test and no record of previous treatment; or symptomatic individuals, with at least one reactive test, treponemal or non-treponemal, with any titer [29].

After the diagnosis of syphilis, the clinical stage is classified according to the time of infection. Patients are treated with benzathine benzylpenicillin, monitored with a non-treponemal test, and the case is reported. If there is a serological scar, patients must be oriented. To control cure, monitoring with a non-treponemal test should occur and, if possible, with the same diagnostic method. During follow-up, non-treponemal tests should be performed every three months until the 12th month of follow-up. The treated person may be released, subject to screening, according to sexual history and risk management for syphilis and other STI [30].

Study population

The data collection period comprises the beginning of the actual notification of acquired syphilis in Brazil, which became mandatory in 2010. The study was based on information collected from the official public health database system of the Brazilian Ministry of Health—The Notifiable Diseases Information System—SINAN. It included 71,289 older individuals, aged between 60–120 years old.

Variables

The information regarding all these variables was obtained from the SINAN database. The main variable considered for characterizing the epidemiological profile was the diagnosis of acquired syphilis in those aged 60 years or more. The independent variables corresponded to those of sociodemographic interest: the reporting of the first symptom onset; age group (60–64, 65–69, 70–74, 75–79, 80–84, 85–89, and 90 or more); gender (male and female); race/color (white, yellow, indigenous, and black); level of education (illiterate, primary, secondary, and higher education); region of the country in which the federative units are grouped; and classification of syphilis according to the cure or death statuses.

Descriptive analyses were performed, with the qualitative variables of interest expressed in percentage values. Missing data and information not reported by respondents were considered for all variables.

Analysis of the detection rate of acquired syphilis

The detection rate was calculated considering the 2010 census by the Brazilian Institute of Geography and Statistics (IBGE) and the projections for the Brazilian older population (individuals aged 60 years or more), from 2010 to 2020 [31]. Data analysis was based on the Statistical Package for the Social Sciences—SPSS®, version 19.0. The detection rate was obtained by the number of cases of syphilis divided by the number of older people in each period, posteriorly multiplied by a constant– 100,000.

Trend analysis

Based on the annual rates of acquired syphilis, a regression model based on inflection points was used (Joinpoint regression model) for analyzing temporal trends. This method verifies whether a line with multiple segments is statistically better to describe the temporal evolution of a data set when compared to a straight line or one with fewer segments. The model also allows calculating the trend of the Annual Percent Change–APC and Average Annual Percent Change–AAPC indicators, that is, the analysis of the acquired syphilis trend per year and throughout the period. The AAPC was categorized as increasing (APC/AAPC+ and p < 0.05), stable (p-value > 0.05), or decreasing (APC/AAPC- and p < 0.05), which is an important definition to understand the factors that influence the variation trend regarding syphilis [32–34].

The Joinpoint Trend Analysis Software identified moments (years) in which there was a significant change in the detection rate of this STI, observed at different points in time (inflection points). In each segment, the APC was estimated as a descriptive measure of the changes in time trends. A Confidence Interval of 95% (95% CI) and a significance level of 5% (p < 0.05) were considered [35]. The Microsoft Excel Office 2013 software was used to organize the databank, build indicators, and prepare tables.

Results

Analysis of the detection rate of acquired syphilis

This study sought to characterize, in the most reliable way, the epidemiological profile of older people infected with acquired syphilis who are users of the public health network.

When analyzing the detection rate of syphilis in Brazil, between 2010 and 2020, a progressive increase in this STI has been observed in older people—aged between 60 and 120 years—since 2011, which intensified in 2018 (Fig 1). Among the notified cases, the detection rate was equivalent to 12.84 cases for every 100,000 Brazilians, with 34.74 cases per 100 thousand individuals for males and 18.46 cases per 100 thousand individuals for females. About 38 older individuals (0.05%) presented no information regarding gender.

10.1371/journal.pone.0296481.g001 Fig 1 Detection rate of acquired syphilis, according to the year of reporting the first symptoms, from 2010 to 2020.

https://doi.org/10.5281/zenodo.11638624.

In this analysis, white, black, yellow, and indigenous older individuals presented the following detection rates per 100,000 people: 5.45; 5.11; 0.10, and 0.07 cases. For this variable, there was an abstention of 11,066 (15.50%) responses and 599 (0.84%) cases of missing data.

Regarding their level of education, 3,702 (5.19%) individuals were illiterate; 5,016 (7.04%) revealed having primary education; and 5,150 (7.22%) had high school education. On the other hand, only 1,480 (2.08%) older individuals had higher education. Of the total information, 28,037 (39.33%) individuals had their data on education level considered lost.

In this study, regarding the regions of Brazil, it is highlighted that the highest rates of syphilis detection in older individuals occurred in the South and Southeast (even higher than the national rate), and the lowest in the Northeast. In this sense, it is essential to emphasize the high detection rate of syphilis in older people when considering the number of existing cases in the total older population (Fig 2).

10.1371/journal.pone.0296481.g002 Fig 2 Detection rate of acquired syphilis in older people, according to regions of Brazil, from 2010 to 2020.

https://doi.org/10.5281/zenodo.11638624.

As for the age groups most diagnosed with syphilis, there was a predominance of those between 60–64 and 65–69 years (Fig 3). The mean age was 68.04 years (±7.15).

10.1371/journal.pone.0296481.g003 Fig 3 Classification of older people, according to the detection rate of acquired syphilis by age group, from 2010 to 2020.

https://doi.org/10.5281/zenodo.11638624.

Regarding the clinical evolution of STIs in older people (Fig 4), of the total number of cases, approximately 33,322 individuals were cured between 2010 and 2020 (detection rate of 123.33 infected in every 100,000 older people in Brazil). As there are specific cases of patients with syphilis whose investigation was closed in 2021–892 cases out of 71,289—it is noteworthy that 344 individuals were cured in 2021 and eight died, two due to acquired syphilis and six due to other causes. In that year, for 148 cases, information on cure or death was ignored and for 392 individuals the information was absent.

10.1371/journal.pone.0296481.g004 Fig 4 Detection rate of the clinical evolution of acquired syphilis in older people, according to the year of completion of the investigation.

https://doi.org/10.5281/zenodo.11638624.

The highest cure rates occurred from 2014 to 2018, with a slight decrease in 2019. Of 255 deaths, 0.94 in every 100,000 older people occurred from 2010 to 2020, with 16.86% of them being due to syphilis infection and 83.14% due to other causes.

Notably, from 2010 to 2020, a representative rate, equivalent to 23.31% of cases, refers to the code “ignored”. It should be noted that, of 69,063 older people with syphilis in this period, 28.07% did not present information regarding the conclusion of the disease. For 1,334 individuals, that is, 1.87% of cases, there was no information on the year in which the disease ended.

Trend analysis

From the calculation of the annual percentage change (APC) and average annual percentage change (AAPC) of syphilis rates in older people, by region of Brazil and according to gender and three age groups (60–69 years; 70–79 years and 80 years or more), it was found that the growth trends of the disease were significantly homogeneous, considering the variables mentioned (Table 1).

10.1371/journal.pone.0296481.t001 Table 1 Trends of syphilis in older people, according to the region and gender of the individual, in Brazil.

Sex	Age Group	Period	APC	AAPC	p-value	CI 95%	Trend	
	Northeast Region	
Male	60 to 69	2010–2020	-	50.5*	<0.001	31.7–72.1	Increasing	
70 to 79	2010–2020	-	47.9*	<0.001	32.9–64.7	Increasing	
80 or more	2010–2020	-	47.5*	<0.001	32.1–64.8	Increasing	
Female	60 to 69	2010–2020	-	43.4*		24.0–65.7	Increasing	
2010–2018	70.3*	-	<0.001	55.6–86.3	Increasing	
2018–2020	-28.0	-		-68.5–64.8	Stable	
70 to 79	2010–2020		51.6*	<0.001	32.7–73.1	Increasing	
80 or more	2010–2020		35.3*		14.1–60.4	Increasing	
2010–2018	60.9*	-	<0.001	44.7–78.9	Increasing	
2018–2020	-32.3	-		-74.4–79.1	Stable	
	North Region	
Male	60 to 69	2010–2020	-	57.6*		38.0–79.9	Increasing	
2010–2013	125.5*	-	0.005	41.3–259.9	Increasing	
2013–2020	35.1*	-	0.001	19.3–53.1	Increasing	
70 to 79	2010–2020	-	47.5*	<0.001	32.6–64.1	Increasing	
80 or more	2010–2020	-	52.1*	0.001	24.9–85.2	Increasing	
Female	60 to 69	2010–2020	-	54.8*		26.9–88.8	Increasing	
2010–2012	170.5	-		-13.3–743.3	Stable	
2012–2020	34.6*	-	0.001	18.9–52.4	Increasing	
70 to 79	2010–2020	-	49.2*	<0.001	36.6–63.0	Increasing	
80 or more	2010–2020	-	33.6*	0.001	15.8–54.0	Increasing	
	Center-West Region	
Male	60 to 69	2010–2020	-	26.7*		14.9–39.8	Increasing	
2010–2018	38.6*	-	<0.001	30.3–47.3	Increasing	
2018–2020	-11.4	-		-49.4–55.3	Stable	
70 to 79	2010–2020	-	31.6*	<0.001	22.3–45.1	Increasing	
80 or more	2010–2020	-	36.4*	<0.001	21.6–53.1	Increasing	
Female	60 to 69	2010–2020	-	29.4*	<0.001	20.1–39.5	Increasing	
70 to 79	2010–2020	-	28.2*	<0.001	18.0–39.3	Increasing	
80 or more	2010–2020	-	37.5*	0.002	17.0–61.6	Increasing	
	Southeast Region	
Male	60 a 69	2010–2020	-	38.7*		19.1–61.6	Increasing	
2010–2012	329.1*	-	0.006	79.3–926.5	Increasing	
2012–2020	4.6	-		-4.9–15.1	Stable	
70 a 79	2010–2020	-	43.6*		23.2–67.5	Increasing	
2010–2012	401.6*	-	0.004	108.3–1107.8	Increasing	
	2012–2020	5.1	-		-4.6–15.6	Stable	
80 or more	2010–2020		27.5*		10.2–47.6	Increasing	
2010–2012	144.6*	-	0.04	5.9–465.1	Increasing	
2010–2020	8.4	-		-1.1–18.7	Stable	
Female	60 a 69	2010–2020	-	38.9*		15.2–67.4	Increasing	
2010–2012	385.6*		0.011	67.0–1312.1	Increasing	
2012–2020	1.6			-9.6–14.1	Stable	
70 a 79	2010–2020		38.2*		14.9–66.2	Increasing	
2010–2012	326.9*		0.015	48.6–1126.5	Increasing	
2012–2020	4.2			-7.1–16.9	Stable	
80 or more	2010–2020		36.5*		13.3–64.5	Increasing	
2010–2012	355.0*		0.013	56.5–1222.8	Increasing	
2012–2020	1.0			-10.1–13.5	Stable	
	South Region	
Male	60 a 69	2010–2020	-	91.5*		59.0–130.7	Increasing	
2010–2012	993.0*	-	0.002	277.4–3065.8	Increasing	
2012–2020	23.9*	-	0.004	10.3–39.2	Increasing	
70 a 79	2010–2020	-	67.4*		40.4–99.7	Increasing	
2010–2012	370.3*	-	0.009	71.7–1188.2	Increasing	
2012–2020	29.3*	-	0.001	15.9–44.3	Increasing	
80 or more	2010–2020		62.7*		23.8–113.7	Increasing	
2010–2012	281.8			-20.0–1721.6	Stable	
2012–2020	31.4*		0.008	10.8–55.8		
Female	60 a 69	2010–2020		67.7*		42.6–97.3	Increasing	
2010–2013	239.2*		0.002	91.3–501.6	Increasing	
2013–2020	24.0*		0.014	6.4–44.5	Increasing	
70 a 79	2010–2020		56.2*		32.3–84.5	Increasing	
2010–2015	113.2*		0.001	58.9–186.0	Increasing	
2015–2020	14.5			-14.7–53.6	Stable	
80 or more	2010–2020		54.5*		26.3–89.1	Increasing	
2010–2016	92.5*		0.001	48.1–150.4	Increasing	
2016–2020	11.1			-32.0–81.7	Stable	
* Statistical significance

Results of trend analysis by regions of Brazil

Given the data presented, it was observed that there was a significant increase in the trend of syphilis cases for males and all age groups in the Northeast region until the year 2020. As for females, in the age groups 60–69 and 80 years or more, the increasing annual percentage change was significant, especially up to 2018. For the 70–79 age group, the APC and AAPC were equivalently increasing.

Considering males in the 60–69 age group in the North region, there are two increasing and significant annual percentage variation cut-off points—from 2010–2013, in which the increase was more pronounced, and from 2013–2020. The APC and AAPC are equivalently increasing and essential for the other age groups. Regarding females, there was a significant increase in syphilis rates for the 60–69 age group, starting in 2012. For the other age groups, the APC and AAPC follow the same pattern as for males.

Regarding the Center-West region, for males, the age group of 60–69 years showed a significant increase until 2018. In the succeeding age groups, the APC and AAPC increased equivalently and significantly up to 2020. For females, a significant increase in cases occurred in all age groups until 2020 (APC = AAPC). In the Southeast region, for all age groups and both genders, there was a significant annual percentage variation increasing significantly until 2012, remaining practically constant, especially for females.

In the South region, for males aged 60–69 and 70–79, the annual percentage variation significantly increased from 2010 to 2012 and from 2012 to 2020. The increase was significant since 2012, for those with 80 years or more. As for females, in the 60–69 age group, the increasing annual percentage variation was significant from 2010 to 2013 and 2013 to 2020. The increase was significant for the 70–79 age group, from 2010 to 2015. For those aged 80 years or more, the increase was significant from 2010 to 2016.

Discussion

This study contributes to the literature by demonstrating the impact of acquired syphilis on older individuals in Brazil.

When analyzing the detection rate of the disease, from 2010 to 2020, there was a progressive increase in STIs in older people, mainly in the years 2016 and 2017, with a peak in 2018. Despite the obligation, as of 2010, of health units to report cases of syphilis, which reflects a significant magnitude of the disease, data from the country still indicate underreporting. This compromises health actions aimed mainly at older people [36].

The underreporting of cases in the Notifiable Diseases Information System has relevant implications for the response to STIs in the country, as important information involving behaviors and vulnerabilities remains unknown. Furthermore, the lack of registration may compromise priority actions to combat the disease. In this sense, it is essential that there is timely notification of all cases, as well as continuous improvement in the quality of filling out the notification and investigation form [30].

The study highlighted the increase in cases of syphilis in older people. It is noteworthy that, in recent years, this increase has been observed in all age groups. This can be attributed, in part, to high-risk sexual activity with the reduction in the use of condoms and the improvement of the epidemiological surveillance system, which allows for increasingly effective reporting of data [30].

Although the growing trend may be caused by an increase in reporting, it is common knowledge that acquired syphilis has increased worldwide, including in Latin America, and has re-emerged in several regions, such as North America, Western Europe, China, and Australia [37]. In this context, compulsory notifications cannot be pointed out as the isolated reason for the increase in cases.

In the years 2018, 2019, 2020, 2021, 2022, in Brazil, 158,051, 152,915; 115,371; 167,523, 213,129 cases of acquired syphilis were reported, respectively. During 2020, there was a considerable reduction in the number of notifications [16, 38–41], probably due to the particularity of the COVID-19 pandemic, caused by SARS-CoV-2 [42]. Between 2018 and 2019, and 2021 and 2022, there was a 22.41% increase in notifications of acquired syphilis in Brazil [16, 38–41].

On the same premise, the pre-pandemic period, from 2012 to 2018, revealed a growing trend in the detection rates of acquired syphilis at all ages, with a greater number of cases as the age group decreased: 41.6% among individuals of 13 to 19 years old; 39.2% among those aged 20 to 29; 30.8% between those aged 30 and 39; 26.2% in those aged 40 to 49, and 25.4% in those aged 50 or over. Then, there was some stability in 2019 and a reduction in 2020. In the post-pandemic period, between 2021 and 2022, there was an increase in reported cases for all age groups, the percentage of which remained higher in individuals aged 40 to 49 and 50 or over [16].

Regarding the detection rate according to sex, the research found a more significant number of cases in males, probably because men less frequently seek specialized medical care [43, 44]. The current Syphilis Epidemiological Bulletin [16] showed that, between 2012 and 2022, 750,848 (42.3%) cases of acquired syphilis occurred in men and 485,115 (47.4%) in women.

Corroborating these findings, Barros et al. 2018 [45] detected a high prevalence of STIs among homeless men. Likewise, a study on syphilis acquired in a Reference Center on STIs and AIDS, in São Paulo/Brazil, observed that most cases were in males [46]. A global trend analysis, from 1990 to 2019, identified that the incidence rates of syphilis and other STIs increased considerably in men [47]. Research involving patients with neurosyphilis (aged 17–75 years) revealed that most of the infected were males [48].

Pinto et al. 2018 [49] when evaluating the prevalence and factors associated with HIV infection and syphilis, in men and women, between 15 and 64 years old, noted that the majority of cases were also in men. Bourchier et al. 2020 [50] when evaluating the incidence of STIs in women, found that the increase occurred mainly in older women, aged between 55 and 74 years. Yeganeh et al 2021 [51] reinforced that sexually transmitted infections in women can originate from the male sexual partners, who remains underdiagnosed and untreated due to lack of symptoms and decreased access to health care due to not seeking health services.

Most of the individuals analyzed in this research were white and black. When comparing notifications in older individuals from 2012 to 2022, the increase in the percentage of syphilis cases according to race/color was 50.7% for black and brown individuals [16]. Smock et al 2017 [52], when analyzing syphilis infections from 2001 to 2013, found that the incidence rate increased in all groups, especially among black individuals [53], when investigating the prevalence of syphilis in individuals aged 18–64 years, found that the majority were black. These circumstances highlight how interventions to combat STIs should be oriented, considering marginalized populations.

Most of the sample in this research had primary or secondary education. It is known that a good level of education is one of the key factors for understanding preventive measures against diseases such as syphilis [17, 54]. On the other hand, having a lower level of education is one of the risk factors for acquiring STIs [36, 54]. Individuals with a low educational level often have little or no access to health-related benefits such as educational programs [55].

In this study, older adults, in the 60–64 and 65–69 age groups, had more diagnoses of syphilis, presumably because they were more sexually active. Oliveira e Juskevicius, 2019 [56], in an analysis of HIV and STI epidemiological bulletins found an increase in the number of cases of acquired syphilis in older people.

From the same perspective, a trend analysis of syphilis detection in elderly people found an increase in the detection rate of this STI in individuals aged ≥ 60 years [18]. Takahashi et al. 2022 [21] when evaluating the national trend in the incidence of syphilis in Japan, in patients aged ≥ 50 years, identified a significant increase of this STI in these individuals.

In this study, the data showed higher cure rates for syphilis when observing the clinical evolution of patients with STIs. On the other hand, for some individuals, there is no information available on the outcome of the disease (cure or death), possibly due to flaws in the records of patients with suspected infection. In contrast, a comparative analysis developed by Barragan et al. 2017 [57] showed that older people aged 75 to 84 years and ≥ 85 years had the highest frequency of deaths from syphilis.

This study found an increasing trend in the detection rate of syphilis in older people in Brazil, from 2010 to 2020. Regarding the distribution of the disease in the Brazilian territory, although the South and Southeast regions concentrate the highest detection rates of syphilis in older people, growing trends of STIs in these individuals are pointed out, which are also significantly homogeneous (p-value in Table 1) in the five regions of the country, for both sexes and age groups of the population.

The increase in the detection rate highlights the need for adequate planning and development of actions to prevent and combat the disease for this population. The aging of the Brazilian population may be a predictor for an increasing number of syphilis cases in older people, while greater testing is expected in this group, which is increasingly sexually active.

Estimates of the acquired syphilis trend highlight the need for a solid approach to disease control in the country. Therefore, it is essential to expand the qualification of health actions, in order to provide adequate conditions to combat the disease [58].

Corroborating our findings, Barros et al. 2023 [18] also found an increasing trend in the detection rate of syphilis in older people in Brazil, from 2011 to 2019, for all age groups and both sexes. Wang et al. 2021 [59] identified a significant increase in the incidence rate of syphilis in older people in Guangdong (China), greater than in young adults, from 2013 to 2018. They also observed a trend toward a significant increase in cases of tertiary syphilis (a substantial correlation between the late diagnosis of this STI and advanced age).

A decade-long trend analysis of acquired syphilis in Brazil, considering the different regions of the country, helped to visualize a significant growth in the disease notification rates [60]. Expanding access to rapid syphilis tests has increased its detection rate and, consequently, effective notification. On the other hand, the increase in testing coverage and reorganization of health units did not stabilize the upward curve of the disease [61].

In Brazil, strengthening the Family Health Strategy improved access to health. Among the factors that may explain the increase in the notification of syphilis cases in the country, the acquisition of rapid tests; national prevention campaigns; and the instrumentation of situation rooms in municipalities stand out [62, 63]. However, even with improved notification and high detection of cases, syphilis is still underreported [36].

On the other hand, improving the epidemiological surveillance system and bringing the professionals responsible for data input up to date helps to eliminate under-reporting. Furthermore, the interoperability of information systems enables the identification of the probable population covered by the geographic census, the groups affected by syphilis, and the resulting deaths [30].

The spread of the disease is believed to be driven by late diagnosis; discontinuity in treatment; and discrimination related to targeted sexuality education. With advancing age, it is observed that concerns about health issues are restricted to specific weaknesses related to aging [58, 64, 65]. The most common practice is to investigate neurodegenerative diseases and/or comorbidities, such as Chronic Non-Communicable Diseases. In this sense, public policies to contain the spread of syphilis among individuals over 60 years of age are still scarce [66].

We emphasize that the increase in syphilis rates in younger individuals today will reflect, in the future, on management problems for controlling cases of this STI in older people, a problem that is already observed when evaluating its current detection rates. If the problem is not seriously resolved for all age groups, the tendency is for syphilis to remain a national epidemic for a long time and a permanent concern for health managers.

It is important to emphasize that the increase in life expectancy and quality of life causes behavioral changes in older people. Unlike previous generations, old age is no longer linked to asexuality. The increase in STI rates reflects different practices, such as unprotected sex, probably due to limited knowledge. These individuals do not see themselves as belonging to risk groups [50] and therefore require greater attention from health teams [8].

In this regard, acknowledging change for preventing acquired syphilis and promoting health is expected. It is essential to reorganize services; train Primary Health Care professionals to develop intervention programs aimed at older people, thinking about specific approaches to their education and sexual orientation; and encourage the use of the rapid treponemal tests to detect syphilis and provide early treatment [67].

As for the limitations of this study, difficulties were encountered in data analysis due to a lack of records or underreporting of acquired syphilis. The gaps related to some variables are highlighted, and the absence of information such as disease stages and treatment. In addition, SINAN does not always update the data collected by the notification/investigation forms promptly. Such gaps indicate that the underreporting of the disease may be associated with incorrect completion of the notification forms [55]. However, since this study used national databases; this is the information available that comes closest to demonstrating the increase in acquired syphilis in older people, in Brazil.

Conclusion

Although the South and Southeast regions concentrate the highest detection rates of syphilis in older people, the temporal analysis research demonstrated a significant increase in the growth trends of syphilis in all five regions of Brazil, affecting both sexes, but mainly white and black individuals and those with low education.

It is observed that inequalities in syphilis care are directly related to individual socioeconomic and demographic characteristics. The increase in the detection rate of this STI among older people is reflected in changes in sexual behavior and highlights the need for targeted health promotion for them, such as guidance on safe sexual practices and commitment to early investigation, diagnosis, and treatment.

In this way, the trend of significant increase in syphilis cases in older people is reaffirmed, reinforcing the need for intersectoral planning of health surveillance actions, with the aim of engaging Primary Care to combat the spread of the disease, especially for this population.

Supporting information

S1 File https://doi.org/10.5281/zenodo.11638624.

(PDF)

We want to thank the Health Ministry for providing the data used in the confection of the manuscript.

10.1371/journal.pone.0296481.r001
Decision Letter 0
Hlashwayo Delfina Fernandes Academic Editor
© 2024 Delfina Fernandes Hlashwayo
2024
Delfina Fernandes Hlashwayo
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Submission Version0
27 Mar 2023

PONE-D-23-02461ACQUIRED SYPHILIS IN AGED PEOPLE IN BRAZIL FROM 2010-2020PLOS ONE

Dear Dr. Cunha,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

The reviewers have provided their comments for the improvement of the manuscript. They do raise some further points that I recommend are considered in any subsequent revision. These six key points that would need to be addressed can be summarized as:

Revise the introduction to provide a clear overview of syphilis epidemiology among older adults in Brazil and emphasize the study’s significance.

Clarify definitions of "incident" and "prevalent" cases in the study, considering diagnostic challenges.

Improve the discussion and conclusion based on reviewers' comments.

Adhere to appropriate reporting guidelines and include the checklist as a supplementary file.

Ensure all data underlying the findings are fully available.

Improve the article's clarity and readability through English proofreading.

==============================

Please submit your revised manuscript by May 11 2023 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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We look forward to receiving your revised manuscript.

Kind regards,

Delfina Fernandes Hlashwayo, M.Sc.

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: No

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: No

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors used epidemiological data on syphilis among older adults in order to investigate trends in syphilis incidence and prevalence among older adults in Brazil. Several critical questions remain unanswered based on the data presented.

1. Is it possible that the changes in reporting of syphilis were at least partially accounted for by the fact that the reporting system was implemented in 2010? The authors need to address the question of whether all health reporting systems were online and functional at the same point in time or whether rate increases might have been driven by the newness of the reporting system and the time required for it to be fully functional with a high compliance with reporting.

2. The authors present population based rates (diagnoses / population in the age range of interest), suggesting that rates have increased over time. However, this approach does not account for changes in clinical testing. Given that syphilis may be present and asymptomatic for decades, it is important to understand whether an increase in rates simply reflects more awareness of the issue and more testing among older adults.

3. The authors need to clarify their use of the terms incident cases and prevalent cases. Incident cases should refer to those who are newly infected. However, in the case of syphilis, an infection that is usually diagnosed serologically and can be clinically silent for decades, the only way to be certain the case truly represents a recent infection is based on having primary or secondary clinical symptoms or serial serologies that demonstrate a recent rise in titer on a nontreponemal test. Was this information available from the data source? Likewise, once syphilis is diagnosed, it should be treated and the infection should resolve. It is assumed that the use of the terms "prevalent" is being applied to cases of newly diagnosed syphilis that lack primary or secondary symptoms or were not previously tested with a demonstrated change in titer over time. The usual terminology for these would be latent or late stage syphilis. Clarification is important in order to understand these findings in the context of other literature on syphilis.

Reviewer #2: The article describes a 10 year prevalence, incidence, and trend of syphilis in people aged 60 years and above in Brazil. A 10 year trend analysis showed a significant increase in cases of syphilis in the entire region of Brazil. The study appears to be statistically sound. There is further scope for improvement. Here are my constructive comments:

Major issues

1.The introduction section does not provide background and information relevant to the study. It doesn’t reflect the significance of the study. It should be re-written to emphasize the importance of describing the epidemiology of syphilis among elderly people in Brazil

2.The discussion section needs major improvement.

A.The authors should focus on the most important findings in this study and present it in a well-organized manner.

B.The discussion should be presented in a well organized manner. For example, page 14, line number 280, discusses about prevalence according to gender and again page 16, line number 313-316, discusses about incidence of syphilis among women. This are same idea presented separately but can be discussed under one paragraph . the same applies for the discussion on trend analysis, page 16-17, line number 337-359 and discussion on prevalence and incidence on page 14, line number 260-268

C.Please compare your findings with the findings of other local studies as much as possible.

D.Avoid unnecessary sentences that doesn’t add any value to the discussion. For example, the sentence stated on line number 391-408, page 19, have no relevance to your discussion.

3.The conclusion is lengthy and doesn’t precisely summarize the findings of the study. The conclusion should be summarize the study findings clearly and precisely.

4.While the study appears to be sound, the language is unclear, making it difficult to follow. I advise the authors to work with a writing coach or copyeditor to improve the flow and readability of the text.

Minor issues

1.Substitute “observational, times series study” on page 2, line number 36 with “cross-sectional, time series study”

2.Please follow the STROBE guideline for reporting cross-sectional study and provide the cehck list as supplementary file

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Reviewer #1: No

Reviewer #2: No

**********

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10.1371/journal.pone.0296481.r002
Author response to Decision Letter 0
Submission Version1
17 May 2023

We appreciate the opportunity to improve this study and hope that we have responded to the requests of the editors and reviewers.

Attachment Submitted filename: Response to reviewers.pdf

10.1371/journal.pone.0296481.r003
Decision Letter 1
Hlashwayo Delfina Fernandes Academic Editor
© 2024 Delfina Fernandes Hlashwayo
2024
Delfina Fernandes Hlashwayo
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Submission Version1
16 Jun 2023

PONE-D-23-02461R1ACQUIRED SYPHILIS IN OLDER PEOPLE IN BRAZIL FROM 2010-2020PLOS ONE

Dear Dr. Cunha,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Jul 31 2023 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Delfina Fernandes Hlashwayo, M.Sc.

Academic Editor

PLOS ONE

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

Reviewer #3: (No Response)

Reviewer #4: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #3: No

Reviewer #4: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: I Don't Know

Reviewer #3: Yes

Reviewer #4: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: (No Response)

Reviewer #3: Yes

Reviewer #4: No

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #3: No

Reviewer #4: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors have adequately addressed prior comments, significantly improving on the manuscript. It is noted that there are still a few small inconsistencies (not noted on prior review) or questions that should be corrected before the manuscript is published.

1. Discussion of low level of education as related to syphilis (357). It is not clearly that low education is causally related to syphilis or even truly associated. In order to study an association, one would have to have a comparison group and show that people with syphilis have lower educational achievement than population norms for this age in Brazil. In addition, the discussion about education has a somewhat pejorative tone "lower education level is associated with lower health concerns...."

2. The conclusion (432) notes black race as associated with syphilis whereas the data (191) demonstrated slightly higher diagnoses in whites (though strikingly similar rates in white and black populations.

3. Proof carefully for pejorative language (334) such as "men tend to be negligent with their health."

4. Finally, when discussing deaths due to syphilis, be certain that syphilis was the cause of death (as opposed to dying with untreated syphilis where syphilis was not the cause of death.

Reviewer #3: The introduction revels lack of knowledge about syphilis. The data and its analysis do not support the conclusions. There is no way to check the quality of thes reported cases, no data about trends on use of public services and no prevalence data.

Reviewer #4: The topic is relevant to the public health area and presents important aspects for evidence-based practice by addressing a sexually transmitted infection in the elderly population. Despite the relevance and excellence in the preparation of the manuscript, it has weaknesses that put in check the uniqueness of the manuscript, since there are national publications on the subject with data from 2022 and the manuscript presents a temporal limitation with the use of data only until 2020. The study design is questionable, since modern epidemiologists such as Lash et al. Modern Epidemiology present scientific evidence for such aspects. However, the study also has a high descriptive potential, and the statistical analysis used constitutes only one of the first analyses of the composite possibility in the context of time series that are naturally defined as ecological study. Nevertheless, the categorization of the age range is also questionable, as there is no evidence of age up to 120 years, which raises the questioning of the quality of the data. The discussion presents relevant points, but little expressive regarding the importance of completeness and completion of official documents of notification of diseases that should be exalted in the limitations of the study. Another important point is that despite understanding that the data are of free access, it should be made clear that the research was not submitted for ethical review. Finally, despite the relevance of the theme and quality of the writing, I recommend that the authors make the necessary adjustments and submit the manuscript for publication in a public health section.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #3: No

Reviewer #4: No

**********

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While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

10.1371/journal.pone.0296481.r004
Author response to Decision Letter 1
Submission Version2
19 Jul 2023

We submit a revised version of the manuscript that addresses the points raised during the review process.

We included a rebuttal letter that responds to each point raised by the academic editor and reviewers. We upload this letter as a separate file labeled 'Response to Reviewers'.

We send A marked-up copy of my manuscript that highlights changes made to the original version, labeled 'Revised Manuscript changes tracked with text highlights; and we send an unmarked version of revised paper without tracked changes, labeled 'Manuscript'.

We thank you for the guidelines sent and reinforce our desire to publish in a mega journal such as PlosOne.

Attachment Submitted filename: Response to Reviewers.docx

10.1371/journal.pone.0296481.r005
Decision Letter 2
Hlashwayo Delfina Fernandes Academic Editor
© 2024 Delfina Fernandes Hlashwayo
2024
Delfina Fernandes Hlashwayo
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Submission Version2
4 Oct 2023

PONE-D-23-02461R2ACQUIRED SYPHILIS IN OLDER PEOPLE IN BRAZIL FROM 2010-2020PLOS ONE

Dear Dr. Cunha,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

In addition to the comments made by the three reviewers please address the following points in the revised version of the manuscript:

1. Writing Clarity:

Please enhance writing clarity, refine sentence structure, and minimize the use of parentheses for a more fluid narrative. Additionally, ensure the use of bias-free language throughout your manuscript.

2. Supplemental Files:

Ensure that supplemental files are appropriately cited in the document and adhere to the correct naming conventions.

Please exclude the list of figures as a supplemental file.

The supplemental file "notification_acquired syphilis" is currently in Portuguese. Please also include an English translation for this file.

The remaining supplemental files are currently named in Portuguese, and their content is not clearly specified. To align with the publication standards, it is advisable to rename these files in English and provide concise descriptions to elucidate their respective contents.

3. Abstract:

Please address the temporal discrepancy in the abstract, where main findings refer to data up to 2018 while the research scope extends to 2020.

4. Introduction:

It would be beneficial to include additional references when stating "Some studies highlight a high prevalence of these infections in individuals over 60 years, including those in extreme age groups"

Consider substituting the figurative language "invisible" in the statement "There is structural ageism, making their sexuality invisible."

5. Methods:

Please include a link to the database when referencing the data source.

Clarify the statement "It is essential to point out that not all information contained in the SINAN notification form is made public" particularly regarding the transparency of the data presented in this manuscript.

Consider using "was obtained" instead of "came from" in the statement "The information regarding these variables came from the SINAN database."

6. Results:

Please provide clarification regarding the statistical significance of the observed difference mentioned in the statement "It was higher in males (34.74 cases per 100,000 individuals) than in females (18.46 cases per 100,000 individuals)."

Consider changing the caption of Fig 2, reflecting the prevalence of acquired syphilis in older people among different regions of Brazil.

Kindly note that Fig 3 contains words in Portuguese. Please ensure compliance with language standards.

Provide an explanation for the use of '*' in some numbers in Table 1.

7. Discussion:

Please correct the capitalization of "Covid-19" for precision.

Prioritize the interpretation of data before drawing comparisons with other studies. Additionally, always describe the statistical significance when stating that a particular statistical pattern is more or less pronounced.

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Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #5: All comments have been addressed

Reviewer #6: (No Response)

Reviewer #7: (No Response)

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #5: Yes

Reviewer #6: Partly

Reviewer #7: Yes

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #5: Yes

Reviewer #6: N/A

Reviewer #7: Yes

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4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #5: Yes

Reviewer #6: Yes

Reviewer #7: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #5: Yes

Reviewer #6: No

Reviewer #7: No

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #5: Reviewer's report

Title of the article

ACQUIRED SYPHILIS IN OLDER PEOPLE IN BRAZIL FROM 2010-2020

Reference number

PONE-D-23-02461R2

Comments:

Thank you for the opportunity to review your interesting manuscript. I enjoyed reading it as I feel it improved thanks to the addressing of other reviewers’ comments and suggestions. However, as a Clinician, I do agree with Reviewer #3 as several points of the introduction must be improved (see Major Compulsory Revisions). Moreover, I do suggest updating the references by referring to recently published major articles in Infectious Diseases as Peeling RW, et al. Lancet. 2023. doi: 10.1016/S0140-6736(22)02348-0 (see Major Compulsory Revisions). I believe that this manuscript would benefit from a publication in a Public Health Journal. All things considered, I think that this manuscript might be accepted after major revisions.

- Major Compulsory Revisions

Please, at least at the beginning of the text, try to correctly address the name of the pathogen which is Treponema pallidum pallidum (in italics).

The authors state that “the primary and secondary types are easy to diagnose”. I appreciate the numerous historical events cited by the authors: considering this, the authors should know that syphilis has been always considered “the great imitator” by clinicians. Syphilis is not an easy disease to diagnose. Not only for its various clinical features, but also for the extremely complex interpretation of non-treponemal titers [Marchese V, et al. J Clin Med. 2022. doi: 10.3390/jcm11247499]. Please, try to mitigate your statement, and try to expand the clinical presentations by referring to the extremely wide differential diagnosis [Tiecco G, et al. Pathogens. 202. doi: 10.3390/pathogens10111364].

Please, try to update epidemiologic data from all over the world by referring to recently published major articles in Infectious Diseases [Peeling RW, et al. Lancet. 2023. doi: 10.1016/S0140-6736(22)02348-0].

Quality of written English

English syntax is optimal.

Reviewer #6: This study summarized the rate of syphilis diagnosis reported to SINAN system in Brazil, with a focus on elders aged 60-120. The study showed that the detection rate is increasing in this population, with some differences in different regions. This information is valuable. However, the manuscript is not written concisely and sometimes hard to follow the main point. The conclusion in the abstract is directly supported by the result, while the conclusion from lines 437 to 446 are not supported by this study, more like for discussion. There is lack of the details how the case was defined/diagnosed, how cure/death was tracked, and how some detection rates were calculated. To understand the significance of increased detection rate in elders, it should be compared with the change of detection rate in younger adults. If the detection rate in younger adults was similarly or more increased, then the public health should remain focused on younger adults.

1. Introduction is very long and should be more focused. Paragraph 3 can be shortened to one sentence. Paragraph 4 is not relevant other than penicillin. Remove 84 to 85.

2. Give more introduction of SINAN, either in the introduction part or in Materials and Methods, such as who is doing the reporting, how it is reported and what is the reporting criteria? How to ensure all cases are reported consistently over the years. The study is performing the temporal trend analysis, that could be invalid if the reporting criteria has been changed over the years. As introduced between lines 99 and 100, the improvement of reporting may explain the increase in syphilis cases in Brazil. Is there data to describe the improvement of reporting, such as the potential population covered by the reporting system? This is useful to understand the increased detection rate, that is based on geographic census. As indicated by authors in the reply, the information of disease stage is not available, this should be specified in Materials and Methods.

3. Line 135-137, need more clarification to understand ‘therefore’ and ‘secondary data’? Is this a portion of data since 2010?

4. Line 140-141, unclear the criteria for the diagnosis of acquired syphilis.

5. Lin 146-147, unclear how the reporting system works and how to track the cure and death history.

6. Line 132-133 and Line 153-155 are both about detection rate calculation. Please combine. Line 157-158, not clear what ‘constant’ was used and why?

7. Line 182, need to specify the age group of older people to avoid confusion.

8. Line 184-185, not sure how 12.84 is derived? It is not implicated in fig 1 and does not fit with male and female results (34.74 and 18.46). Is it the journal style to use ‘34,74’ cases instead of ’34.74’? It is more confusing when reading the fig 1 and fig 5 with ‘,’ instead of ‘.’

9. In fig 1, what is first symptoms? What is difference between fig 1 and fig 5. There is some difference but very small. Need more introduction in Materials and Methods or in figure legends. In both fig 1 and fig 5, please include the rate change among younger adults. This will help the readers to understand the significance of increased detection rate among elders.

10. Line 194-200, calculation of % in every 100,000 older people is misleading, if it is not adjusted for % of each level of education in every 100,000 older people. In other words, calculate detection rate in every 100,000 illiterate older people, or every 100,000 older people with high school education… Such information is required for later discussion in line 357-362.

11. Line 202-203, not sure the meaning of ‘even higher than the national rate’. Certain regions are expected to have rates higher than national rate, if the rate is not same across different regions. Does it mean national rate in total population? Please specify. It is better to show the detection rate in total population or younger adults in each region.

12. Line 210-211 and fig 3, the comparison should include the younger adults from 18 to 60, ideally split to different age sub-groups. This will help to understand the significance of the detection rate among elders. Line 45-46 should have the same context to indicate that the mean age of 68.04 years is for adults aged 60-120.

13. Line 216-222 and fig 4, without the introduction of how disease was tracked and how cure or death was reported, it is difficult to understand this part, especially in the absence of disease stage information. Also need to relatively compare with the changes in younger adults in order to justify the significance of changes in elders.

14. Line 285-287, 298-305 should be moved to introduction or Materials and Methods.

15. Line 326-332, not sure whether the difference in white and black is significant in this study. Does not seem to be relevant.

16. Line 336-337, did not address previous reviewer comment, need proof, such as a reference. Or correlate with other cited references from line 339-345.

17. Line 346-350, please discuss why the cited reference is relevant or different with this study, and what is the implication.

18. Line 351-352, similar to reference 30, please compare with the detection rate in younger adults in order to discuss the significance of increased detection rate in elders.

Reviewer #7: Dear Editor,

Thanks for the opportunity to review the manuscript entitled Acquired Syphilis in Aged People in Brazil from 2010-2020. It presents important local data on syphilis among older people, which represent an emergent population at high risk of Syphilis.

My review is based on the R2 version.

My suggestions:

Abstract

Background: I suggest the authors bring the syphilis concern among older people.

Methodology: consider the appointments below.

Conclusion: The conclusion should be focused on your results on older people.

Introduction

Page 3, line 56- “…although it was discovered in the late 1400s [2]”.

The sentence and reference two need to be more appropriate. This is a secondary reference that discusses the origin of Syphilis, not the discovery.

Page 3, line 61- Please review reference 4 in the context of this sentence.

I suggest deleting lines 68 to 77 and 78 to 83. This information is unnecessary.

Material and Methods

This is an ecological study because the unit is “time”, despite the authors using public micro or macro data!

Line 137. Is there any case aged 120 years?

The authors should show the characteristics of Brazil to the readers: number of regions, number of inhabitants, number of people aged 60 years and over, human development index, etc. Also, they need to describe clearly how the Brazilian system defines acquired syphilis.

Page 6, line 114. Is there someone aged 120 years?

Please present the percentual of missing data for each variable.

Jointpoint Regression – please include the reference of the software.

Results

Table 1 presents data only for North, Northeast, and Mid-West Regions! In addition, there is no legend! Please review it.

Discussion

Line 292. It would be best if you were more precise. What do you mean about it? Underreporting of death and cure? Or underreporting of syphilis diagnosis?

Line 293. I suggest replacing “manifestation of the disease” with “notification of the disease.”

Line 298-310. I suggest moving this information to Material and Methods.

Line 311 to 317. If the decrease in syphilis cases is due to COVID-19 (and very likely is), then It should be desirable to evaluate the syphilis trend forward.

Lines 322 and 323 – “On the other hand, the increase in testing coverage and reorganization of health units did not stabilize the upward curve of the disease.”

It is noteworthy, according to your data, in 2019, before the COVID-19 Pandemic, there was a slight reduction in cases. This could be a trend-forward that was interrupted due to the pandemic.

Lines 336-337 –Please provide a reference.

Lines 339-345 – Bernstein et al. is not an appropriate reference. The discussion is about the higher syphilis frequency among men vs. women. Does it occur in Brazil? Why does it happen? I think you should also compare your data with other Brazilian studies.

Lines 347-350- I didn’t understand the references 28 and 19 in this context! Please review it.

Lines 351 – 356 – Please discuss your data about syphilis. Syphilis among older people!

Lines 371-375 – I think this paragraph is loose!

Lines 376 and 381 - Provide references. In Brazil? Please rewrite this paragraph more clearly.

Lines 384 to 389 – Despite the data's fragility, they showed a high cure rate for syphilis. Discuss it!

I suggest an extensive English review.

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Reviewer #5: No

Reviewer #6: No

Reviewer #7: No

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10.1371/journal.pone.0296481.r006
Author response to Decision Letter 2
Submission Version3
15 Nov 2023

Dear all, we have responded to all the suggestions and proposals made by the reviewers. We are very grateful for the contributions provided.

Attachment Submitted filename: Response to Reviewers.docx

10.1371/journal.pone.0296481.r007
Decision Letter 3
Hlashwayo Delfina Fernandes Academic Editor
© 2024 Delfina Fernandes Hlashwayo
2024
Delfina Fernandes Hlashwayo
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Submission Version3
14 Dec 2023

ACQUIRED SYPHILIS IN OLDER PEOPLE IN BRAZIL FROM 2010-2020

PONE-D-23-02461R3

Dear Dr. Cunha,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

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Kind regards,

Delfina Fernandes Hlashwayo, Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Please consider removing the "Notifiable Diseases Information System - Older people of 60 to 120 Years old.xlsx DOI 10.5281/zenodo.10086130." below the figure caption.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #5: All comments have been addressed

Reviewer #7: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #5: Yes

Reviewer #7: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #5: Yes

Reviewer #7: I Don't Know

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #5: Yes

Reviewer #7: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #5: Yes

Reviewer #7: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #5: I feel the manuscript much improved after addressing all reviewers' comments. No issue was detected.

Reviewer #7: The authors responded to the previous suggestions, improving the quality of the manuscript. However, I still have some points, as described below:

I suggest that the authors delete the phrase “although it originated in the late 1400s and was discovered in 1905 by Schaudinn & Hoffmann [2,3]”. Because this information is not appropriate, nor is its reference. Furthermore, it did not add any important information.

I think the article is too long. I understand that the authors included several suggestions from the reviewers. However, they could be more concise. For example, lines 83-87 are unnecessary. The author previously presented global and American syphilis data where the study was conducted. I think this is enough.

In lines 90-98, the authors could only present general Brazilian data, not including regional data.

Line 226, I think the 120-year-old information is a typo. Please reconsider this information because maintaining it disqualifies your data.

Table 1. Describe the APC, AAPC, and CI in the legend.

The discussion could also be more objective and concise.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #5: No

Reviewer #7: No

**********

10.1371/journal.pone.0296481.r008
Acceptance letter
Hlashwayo Delfina Fernandes Academic Editor
© 2024 Delfina Fernandes Hlashwayo
2024
Delfina Fernandes Hlashwayo
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
16 Jun 2024

PONE-D-23-02461R3

PLOS ONE

Dear Dr. Cunha,

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team.

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2 Watts PJ , Greenberg HL , Khachemoune A . Unusual primary syphilis: Presentation of a likely case with a review of the stages of acquired syphilis, its differential diagnoses, management, and current recommendations. Int J Dermatol. 2016; 55 (7 ): 714–28. doi: 10.1111/ijd.13206 Epub 2016 Jan 12. 26756536
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5 McNamara M , Yingling C . The Reemergence of Syphilis: Clinical Pearls for Consideration. Nurs Clin North Am. 2020; 55 (3 ):361–377. doi: 10.1016/j.cnur.2020.06.009 32762856
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7 Devanand NA , Sundararajan K . Gummatous neurosyphilis in an elderly patient in the Australian outback: a case report. J Med Case Rep. 2021; 15 : 552. doi: 10.1186/s13256-021-03153-1 34749803
8 Pagani DM , Pacheco FB , Venier NAB , Silva IL , Richter GK , Luzzatto L , et al . Atypical presentation of secondary syphilis: annular lesions in an elderly patient. Rev Inst Med Trop. 2021; 3;63 : e68. doi: 10.1590/S16789946202163068
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11 World Health Organization. Global progress report on HIV, viral hepatitis and sexually transmitted infections, 2021. Accountability for the global health sector strategies 2016–2021: actions for impact. Web Annex 1. Key data at a glance ISBN 978-92-4-003098-5 electronic version, 2021.
12 Ghanem KG , Ram S , Rice PA . The Modern Epidemic of Syphilis. N Engl J Med. 2020 Feb 27;382 (9 ):845–854. doi: 10.1056/NEJMra1901593 32101666
13 Kidd SE , Grey JA , Torrone EA , Weinstock HS . Increased Methamphetamine, Injection Drug, and Heroin Use Among Women and Heterosexual Men with Primary and Secondary Syphilis—United States, 2013–2017. MMWR Morb Mortal Wkly Rep. 2019 Feb 15;68 (6 ):144–148. doi: 10.15585/mmwr.mm6806a4 30763294
14 Tao Y , Chen MY , Tucker JD , Ong JJ , Tang W , Wong NS , Chu M , Zhuang X , Fairley CK , Zhang L . A Nationwide Spatiotemporal Analysis of Syphilis Over 21 Years and Implications for Prevention and Control in China. Clin Infect Dis. 2020 Jan 1;70 (1 ):136–139. doi: 10.1093/cid/ciz331 31237616
15 Peeling RW , Mabey D , Kamb ML , Chen XS , Radolf JD , Benzaken AS . Syphilis. Nat Rev Dis Primers. 2017; 12:3 :17073. doi: 10.1038/nrdp.2017.73 29022569
16 Brasil Ministério da Saúde. Boletim Epidemiológico de Sífilis Número Especial. 2023. Versão eletrônica. ISSN: 2358-9450. https://www.gov.br/saude/pt-br/centrais-de-conteudo/publicacoes/boletins/epidemiologicos/especiais/2023/boletim-epidemiologico-de-sifilis-numero-especial-out.2023/
17 Gomes NCRC , Meier DAP , Pieri FM , Alves E , Albanese SPR , Lentine EC , et al . Prevalence and factors associated with syphilis in a Reference Center. Rev. Soc. Bras. Med. Trop.2017; 50 (01 ). doi: 10.1590/0037-8682-0102-2016 28327799
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