Schistosomiasis is widespread in sub-Saharan Africa (SSA) where it constitutes major health 93 problem. Human infection is caused by six species of a trematode of the genus Schistosoma. 94 Schistosomiasis is transmitted by the eggs of the parasite present in stools and/or urine of infected 95 people, which contaminate the nearby water, then freshwater snails from which infective larvae are 96 released and penetrate the skin of people during contact with infested water. The disease is 97 multifactorial: its transmission is very focal and lies on environmental, parasitic, vector and host 98 factors, including socio-economic and behavioural factors amongst them the lack of proper and 99 adequate sanitation, safe water, and hygiene (WASH). It represents a major cause of global 100 disability, morbidity, and mortality in the affected regions [1, 2] . Recent estimates suggest that 101 nearly 800 million people are at risk for schistosomiasis, while 240 million are infected worldwide 102 [3] . More than 90% of all infected people live in sub-Saharan Africa [4] . The main control strategy 103 is the population-based preventive chemotherapy (PCT) using praziquantel (PZQ) [5] . 104 In SSA, four species of Schistosoma including Schistosoma mansoni which causes 105 intestinal schistosomiasis, S. haematobium, the agent of genitourinary schistosomiasis, S. 106 intercalatum and S. guineensis [6] . 107 Democratic Republic of Congo (DRC) has the third highest reported number of cases in 108 SSA (15 million), just after Nigeria (29 million) and United Republic of Tanzania (19 million) [7] .
Intestinal schistosomiasis is one of the major neglected tropical and poverty-related 114 diseases. S. mansoni thrives in tropical and sub-tropical regions with poor sanitation conditions [1, 115 4, 9] . S. mansoni alone threatens about 393 million people in Africa, the Middle East, Brazil, 116 Venezuela, Suriname and the Caribbean, and about 54 million are infected [10] . Children bear the 117 highest burden of infection because of their inadequate hygiene and frequent contact with infected 118 waters [11] . 119 In the DRC, the current burden of this neglected tropical disease (NTD) is unknown [12] . 120 The DRC suffers from a recent history of war and ongoing tribal and armed conflicts, the results 121 of which have led to economic deterioration, severe poverty, and badly functioning health services.
Data from the available large surveys are more than twenty-years old [8, 13] [37] . Therefore, it is urgent to update our knowledge regarding the distribution of the intestinal 137 schistosomiasis to undertake appropriate intervention and assessment. 138 The aim of this work was (i) to characterize the prevalence and intensity of S. mansoni 139 infection and (ii) to identify key risk factors of S. mansoni infection in Ituri province, north-eastern 140 DRC.
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Ethics statement 144 This study was approved by the Swiss Ethical Commission is characterized by a great geographical and demographic variability ( Figure S1 ). Aru territory, in 162 the north, is a plateau area of about 1,100 m above sea level and covered with a half-wooded and 163 half-grassy savannah and forest galleries. Next is Mahagi territory, showing almost the same 164 vegetation characteristics as that of Aru. However, the altitude peaks at around 1,800 m followed 165 All rights reserved. No reuse allowed without permission.
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The copyright holder for this preprint this version posted August 13, 2020 . . https://doi.org/10.1101 /2020 by a steep slope which descends to lake Albert to the east. Djugu is the high hill (up to 2,300 m 166 above sea level in the Blue Mountains chain) territory of the Ituri province. The largest area is 167 covered with grassy savannah and few forest galleries in the west. The mountains slope steeply 168 towards Lake Albert to the east. Irumu territory shows the same characteristics than Djugu in the 169 east whereas it is covered with dense forest in the west. Mambasa territory is a lowland region 170 totally covered with equatorial dense forest. Sudanese, Nilotic, Bantu, Nilo-Hamite, and Pygmy ethnicities live in Ituri province ( Figure S3 ).
About 91% of the population live in 45.0% of the northern and eastern areas of the province. As 182 unemployment is a major scourge in DRC, the majority of the population, both in rural and urban 183 areas, is mainly engaged in subsistence farming. Some, however, raise small and large livestock.
Young people are involved in the artisanal exploitation of minerals such as gold, diamonds and 185 coltan. Cattle breeding is mainly practiced in Djugu, Irumu, Mahagi and Aru territories. Fishing is 186 the main activity of people living by the lake and timber harvesting for commercial and domestic 187 purposes is widely practised in the forested areas of the province, particularly in the Mambasa 188 territory. These occupations coupled with the general lack of safe water put the population in 189 All rights reserved. No reuse allowed without permission.
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The copyright holder for this preprint this version posted August 13, 2020 . . https://doi.org/10.1101 /2020 frequent contact with contaminated waters of streams and lake which increases the exposure to 190 water-transmitted parasites.
For more than two decades, Ituri province has been subject to war, turmoil, and social 192 conflict. The socioeconomic situation in Ituri province is challenging, with a high degree poverty 199 According to data from the Food and Agricultural Organization (FAO), Ituri province measures Ituri province is experiencing its first Ebola epidemic and as the COVID-19 pandemic emerges 202 currently as a huge global problem, this will make the situation even more complicated, not to 203 mention all the people that will get ill and die. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint this version posted August 13, 2020 . . https://doi.org/10.1101 /2020 Study design and population 209 Two community-based studies were carried out across Ituri province during the long school 210 holidays corresponding to the second dry season of the year (June to July) so as to include as much 211 as possible children and their families in the study. First, in 2016, a cross-sectional study was 212 carried out in 46 randomly selected villages to assess the geographical distribution of S. mansoni 213 infection and infection intensity. Second, in 2017, an in-depth, cross-sectional study was 214 conducted in 12 purposively selected villages. For both studies, people aged one year and older 215 were eligible to participate.
The 2016 cross-sectional study used a two-stage random sampling procedure. First, 12 217 health districts were randomly selected across the province. Second, two to five villages were 218 randomly selected per health district, proportional to the density of the population. Fifty to 100 219 participants were enrolled in each village.
For the 2017 in-depth study, twelve health districts with high S. mansoni prevalence were 221 purposively selected. Three of the selected health districts could not be visited due to security 222 concerns. In each of the remaining nine health districts, two to five villages were randomly selected.
In each village, 10 to 30 households were randomly selected. In total, 144 households were visited.
In each household, all members present on the survey date (aged one year and older) were invited 225 to participate.
The chosen villages (communities) in 2016 and 2017 belong to specific health areas and in 227 each health area there is a health centre that meets the criteria of geographical accessibility.
In both studies, unique reference codes were assigned to each study participant. Assuming 229 a mean schistosomiasis prevalence of 50.0% in this population, we calculated that 100 to 150 230 individuals should be included per health district, for each study.
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In 2016, study participants provided one stool sample from which S. mansoni could be diagnosed 234 using a duplicate Kato-Katz test (2 smears per stool) [44] . One hour after collection, stool 235 specimens were transported to the local laboratory for examination. The smears were allowed to 236 clear for half an hour before being read. The number of eggs detected on the smear was recorded 237 for each helminth species separately.
Uurine samples were requested from 20.0% randomly selected participants of each village.
The centrifugation pellets of these urine samples were microscopically examined (40X magnifier (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint this version posted August 13, 2020 . . https://doi.org/10.1101 /2020 For quality control, about 10-30% randomly selected Kato-Katz slides were re-read by the 255 principal investigator. Urine POC-CCA test trace and weakly positive results were discussed by 256 the laboratory team and the principal investigator. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint this version posted August 13, 2020. . https://doi.org/10.1101/2020.08.10.20171090 doi: medRxiv preprint well as young adults, adults, and older people. Body mass index (BMI) was calculated and four 276 BMI categories were established: underweight (<18.5 kg/m²), normal weight (18.5-24.9 kg/m²), proportions. An univariable logistic regression analysis was performed to associate S. mansoni 288 infection (outcome) with potential risk factors (predictors), such as demographic, geographical, 289 behavioural, and socioeconomic variables. Co-variables exhibiting an association at a significance 290 level of at least 20%, as determined by the likelihood ratio test (LRT), were included in the 291 multivariable logistic regression models. Odds ratios (OR) and 95% confidence intervals (95% CI) 292 were calculated. To visualize prevalence rates at health district and village levels, a twoway scatter 293 bar command, which displays numeric (y, x) data as histogram-like bars, was performed using the 294 vertical bar plot option in STATA. Bars were drawn at the specified xvar values (health districts 295 and villages) and extended up from 0 according to the corresponding yvar values (prevalence). To 296 explore the relationship between S. mansoni infection risk and age, age-and sex-prevalence curves 297 were produced using the twoway quadratic fitted values. This command calculates the prediction 298 for yvar (prevalence or intensity) from a linear regression of yvar on xvar and xvar^2 and plots the 299 All rights reserved. No reuse allowed without permission.
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The copyright holder for this preprint this version posted August 13, 2020. . https://doi.org/10.1101/2020.08.10.20171090 doi: medRxiv preprint resulting curve. An S. mansoni distribution map was made as follows: village prevalence (resulting 300 from the Kato-Katz tests in 2016 and 2017) and geographic decimal coordinates (latitude and 301 longitude) were entered in two adjoining columns in Excel and then plotted. A non-uniform spline 302 interpolation was performed with MATLAB®, revealing shadows, the intensity of which were 303 proportional to prevalence levels. Dark coloured shadows indicate high prevalence and lighter 304 shadows (high transparency) indicate low prevalence. P-values below 5% were considered 305 statistically significant.
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The copyright holder for this preprint this version posted August 13, 2020. (Table S1d ). Table 1 shows the demographic characteristics of 313 participants in the S. mansoni geographical distribution study. There were slightly more female 314 (51.0%) than male participants. The mean age of participants was 22.2 years, with little difference 315 between men and women. Children under 15 years made up almost half of all study participants.
Nearly two thirds of participants (58.0%) had a normal BMI, one third (33.0%) were underweight 317 and nine percent were overweight or obese. More than three quarters of the overweight/obese group 318 were female.
Of the 1,044 individuals enrolled in the 2017 study, 707 completed all procedures ( Figure 3 ).
Participants lived in one of 12 villages (144 households), with at least 23 participants present in 321 each village (Table S2a) . Table 2 shows the demographic characteristics of participants in the in-322 depth study carried out in 2017.
Female participants (56.3%) outnumbered male participants. More than half of the participants 324 (51.4%) were younger than 15 years. Almost half of the participants (49.4%) were underweight, 325 38.3% had a normal weight, and 12.3% were overweight or obese. More than 80% of the 326 overweight/obese group were female. 327 328 All rights reserved. No reuse allowed without permission.
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The copyright holder for this preprint this version posted August 13, 2020. (Table S1b ) and in both sexes (Table S1c) was highly significant (p<0.001). The prevalence 430 in the youngest age group (1-4 years) was a quite low (7.7%), being 8.3% and 7.1% in girls and 431 boys, respectively. This figure rose clearly in subsequent age groups to reach a maximum of 50.2% 432 in the 15-19 years, being 45.8% in females and 54.5% in males. Then, the prevalence declined 433 slightly after this peak but remained generally high throughout. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint this version posted August 13, 2020. . https://doi.org/10.1101/2020.08.10.20171090 doi: medRxiv preprint and Laybo), the overall prevalence was less than 10.0%. The difference in the prevalence of 440 infection across the twelve health districts was highly significant (p<0.001) (Table S1d and Figure   441 4). The difference in the prevalence of infection according to the altitude above the sea levelhigh 442 (>1,800 m), middle (1,000-1,800 m), and low (<1,000 m)was highly significant in both sexes 443 (p<0.001) (Table S1b and Figure 8 ). However, the difference between rural areas (40.5%) and 444 urban area (33.9%) (p=0.081), and both among females (p=0.568) and males (p=0.060), was not 445 significant. At the village level, infection prevalence varied widely but was mostly consistent with 446 the health district mean value. In three of the 46 villages, no S. mansoni infection was detected.
These villages were Upepeni and Ombanya, in the Adi and Laybo health districts, respectively 448 (northern Ituri province), and Fundi, in the Rethy health district (located in the hills at about 1,920 449 m above sea level). Villages along the shore of Lake Albert had prevalence rates over 70%, with 450 the highest prevalence rate reaching 90.2% in Kolokoto (at the Ugandan border), in the Nyarambe 451 health district (Table S1d and Figure 5 ).
As for the ethnic groups, the prevalence of S, mansoni infection was highest in Pygmies 453 (50.3%), followed by Bantu (48.0%), Nilotic (47.4%), and Nilo-Hamite (47.2%). The Sudanese 454 ethnic group had the lowest (18.4%) (Table S1b) , and all these differences were consistent with 455 sex (Table S1c ) and were statistically significant (p<0.001).
In 2017, the overall S. mansoni prevalence was 38.5% with one stool sample 55.0% with 457 two stool samples examined by Kato-Katz test alone. The prevalence rose to 62.5% with one POC-458 CCA test alone and to 73.1% after combining the Kato-Katz results of two stool samples with one 459 POC-CCA test findings. All the results were consistent in both sexes (Tables S2b-S2e, and S2g-460 S2i). In this section, we only took in account results from the combining diagnostic approach 461 (2KK+POC-CCA) which appeared more relevant in our viewpoint (Table S2g ). Herein also, 462 All rights reserved. No reuse allowed without permission.
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The copyright holder for this preprint this version posted August 13, 2020. . https://doi.org/10.1101/2020.08.10.20171090 doi: medRxiv preprint and Nilo-Hamite (68.8%). The differences were not statistically significant (p=0.068) and were 486 consistent with sex (p=0.208) and (p<0.350) among females and males, respectively (Table S2g) .
Comparing the prevalence of S. mansoni infection at the health district level (Figure 4) (Table S2b ) and 104.1 epg using 2KK (Table S2d) Table S1d ). The proportion 504 of males with heavy infection intensity (13.8%) was higher compared to that of females (9.7%) 505 (p=0.013) ( Table S1b ). The age distribution of S. mansoni infection prevalence and intensity is 506 shown in Figure 6 . In fact, the highest egg counts were found among boys of the age groups of 10-507 All rights reserved. No reuse allowed without permission.
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The copyright holder for this preprint this version posted August 13, 2020. . https://doi.org/10.1101/2020.08.10.20171090 doi: medRxiv preprint 14 years (14,424 epg), 15-19 years (13,248 epg), whereas girls of the age groups of 5-9 years 508 (10,680 epg) and 10-14 years (8,376 epg) bore the heaviest S. mansoni infection intensities. The 509 difference in the intensity of infection across the eight age groups was highly significant in both 510 sexes (p<0.001). The figure of infection intensity follows that of the prevalence, rising sharply to 511 peak in 10-19 years age group and declining with the increasing age, but remaining high into the 512 older age. As for the ethnic groups, the heaviest mean intensities in males and females were as S1b and S1c).
In 2017, the health districts of Lolwa (420.5 epg), of Mandima (131.4 epg) in the south-western 518 forest-covered areas, and that of Tchomia (109.2 epg) in the shore of Lake Albert, were leading 519 with heaviest infection intensities. They are followed by health districts of Angumu (83.9 epg) and 520 Bunia (48.6 epg). The lowest infection intensity was found in Nia-Nia health district (5.8 epg).
Overall, the proportion of males with heavy infection intensity (5.8%) was insignificantly lower 522 compared to that of females (6.5%) (p=0.564) ( Table S2b ). The age distribution of S. mansoni 523 infection prevalence and intensity is shown in Figure 6 . In fact, the highest egg counts were found (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint this version posted August 13, 2020. . https://doi.org/10.1101/2020.08.10.20171090 doi: medRxiv preprint Among Nilotic and Nilo-Hamite ethnic groups, males had 63.7 and 26.1 epg, and females 84.1 and 532 72.0 epg, respectively (Table S2d) . The relationship between the risk of S. mansoni infection and age is displayed in Figure 6 . (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint this version posted August 13, 2020. . https://doi.org/10.1101/2020.08.10.20171090 doi: medRxiv preprint infection intensity was higher among males than among females in 2016, it was similar among 558 males and females in 2017. The trends for different age groups, in terms of prevalence and intensity, 559 are almost the same. However, a slight difference is observed in 2017: while infection intensity 560 decreased abruptly for males, it remained a plateau for females. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint this version posted August 13, 2020. . https://doi.org/10.1101/2020.08.10.20171090 doi: medRxiv preprint Knowledge about the use of praziquantel was found to be a protective factor against S. mansoni 597 infection.
Predictive variables with a significance level of less than 20% in the univariate model were 599 retained in the multivariate risk factor model. Gender was also included in the multivariable logistic 600 regression model (see Table S4 ). (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint this version posted August 13, 2020. . https://doi.org/10.1101/2020.08.10.20171090 doi: medRxiv preprint (p=0.014) and washing clothes in streams (p=0.018) were also associated with a significant risk 608 increase. Furthermore, infection risk increased significantly with a longer residence period (≥10 609 years vs shorter period) and closer proximity to water bodies (p=0.005). Finally, participants who 
Risk analysis performed for participants from 12 villages in Ituri province (n=707). Odds ratios 615 (OR), large red diamond and 95% confidence interval (CI), range indicated by horizontal blue lines.
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To the best of our knowledge, this study is the first comprehensive, province-wide 619 assessment of S. mansoni infection prevalence, intensity, and risk factors in Ituri since colonial 620 times. In two studies, encompassing 14 (38.9%) of the 36 health districts in Ituri province ( Figure   621 S2b), including 56 villages and more than 2,800 participants, we firstly used Kato-Katz test alone Second, considerable variability in infection prevalence was observed at the health district 639 level, ranging from 3.9% in Adi to 80.2% in Nyarambe. Three villages were found free of S. 640 All rights reserved. No reuse allowed without permission.
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The copyright holder for this preprint this version posted August 13, 2020 . . https://doi.org/10.1101 /2020 mansoni infection, two in the northern side and one in the high hill region. For the two first villages, 641 we did not find an evident reason since these villages are all built near streams that are currently 642 used for washing and bathing. However, our results are consistent with the low S. mansoni infection 643 rate in colonial times, when Aru territory prevalence was reportedly below 3.0% [8, 48] .
Concerning the village of Fundi, the high altitude with generally cold temperature and water 645 velocity would not be suitable for snails reproduction. Due to the same reason, people may also 646 have fewer contacts with water, thereby reducing the probability to become infected [49, 50] . In We observed that prevalence was slightly higher in rural areas (75.1%) compared to urban 661 areas (70.9%). Schistosomiasis particularly affects poor communities [1, 55-57] without the means 662 to protect themselves from risky water contacts. Hence, rural communities are especially affected 663 All rights reserved. No reuse allowed without permission.
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The copyright holder for this preprint this version posted August 13, 2020. . https://doi.org/10.1101/2020.08.10.20171090 doi: medRxiv preprint The infection prevalence ranged from 52.7% to 95.0% at health district level and from 32.3% to 683 96.2% at village level. 684 All rights reserved. No reuse allowed without permission.
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The Kato-Katz technique remains the standard method for diagnosing S. mansoni, however 685 it has some shortcomings. It has a low sensitivity; it is time consuming and it requires skilled and 686 trained technicians to identify the S. mansoni eggs microscopically. In addition, its sensitivity (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint this version posted August 13, 2020. . https://doi.org/10. 1101 /2020 In our study, gender was not a risk factor for infection as females and males had similar 708 levels of infection prevalence in both studies, with a difference <2.0% in 2017 and >5.0% in 2016.
These results are consistent with those of other authors [74, 75] . In Ituri province, men and women 710 have different types of water contact activities, but contact intensities are comparable.
Age was an important risk factor. S. mansoni infection prevalence and intensity follow a 712 typical age peak curve. In both studies, the prevalence and intensity increased with age until it 713 peaked among the groups aged 10-19 years. Interestingly, the infection prevalence peak was higher (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint this version posted August 13, 2020 . . https://doi.org/10.1101 /2020 Some positive associations were likely linked to both behavioural and environmental 731 covariates, such as swimming and washing clothes in streams, which are widely practiced in the 732 province and result in exposure to safe water.
Our study has some limitations. First, the sampling techniques during the two studies were (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint this version posted August 13, 2020 . . https://doi.org/10.1101 /2020 that work toward eliminating schistosomiasis as a public health problem by 2025, following the were not investigated, the best times for treatment could be during the two annual dry periods,
December to February and June to July. During these periods, the weather is warm, and water 771 becomes more and more scarce. People, especially children, make greater use of water courses for 772 play, domestic, recreational, and occupational activities which expose them to infection. Our data 773 will be of practical value to help improve control interventions, especially as COVID-19 became 774 currently a huge global problem. COVID-19. Just to emphasize that this virus will surely make the 775 work to be done even more complicated, not to mention all the people that will get ill and die. 776 All rights reserved. No reuse allowed without permission.
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The copyright holder for this preprint this version posted August 13, 2020. . https://doi.org/10. 1101 /2020 The results of this study are important in several respects. They show that (i) S. mansoni is 777 highly prevalent in Ituri province. The infection rates observed are beyond those reported in the 778 1960s [52] and those described in other parts of the country [13, 15, 20, 23, 24] . The observed 779 infection levels are comparable with those in Ugandan fishing villages [74, 75] . The results also 780 show that (ii) the age distribution of infection prevalence and intensity follows the typical pattern 781 of an S. mansoni endemic area, where control measures are insufficiently implemented; and that 782 (iii) preschool children bear a high infection burden and, therefore deserve special attention in the 783 control programme.
In conclusion, our results provide comprehensive baseline data showing that S. mansoni is 785 highly endemic and is a major health concern in Ituri province, DRC. Infection prevalence and 786 intensity, and its relationship with the prevailing socioeconomic, environmental, and behavioural 787 risk factors reflect intense exposure and alarming transmission rates. Our findings call for more pandemic that will make the work to be done even more complicated, not to mention all the people 797 that will get ill and die. Altogether, these efforts are likely to yield appreciable and sustainable 798 gains in improving health and welfare of the population of Ituri province. 799 All rights reserved. No reuse allowed without permission.
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The copyright holder for this preprint this version posted August 13, 2020. Nyankunde staff for their support, as well as the local authorities for their support during fieldwork.
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The copyright holder for this preprint this version posted August 13, 2020. Schistosoma mansoni among participants from 12 villages in Ituri province (n=707).
1093 Table S4 .
of the multivariable analysis of risk groups for infection with Schistosoma mansoni 1095 among participants from 12 villages in Ituri province (n=707).
1096 All rights reserved. No reuse allowed without permission.
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The copyright holder for this preprint this version posted August 13, 2020. . Orange bars: 2017 study (12 study villages across 6 health districts), Kato-Katz test of two stool samples (four smears) and one POC-CCA urine test.
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The copyright holder for this preprint this version posted August 13, 2020. . https://doi.org/10.1101/2020.08.10.20171090 doi: medRxiv preprint Figure 5 . Map of Ituri province with estimated S. mansoni prevalence. Estimated S. mansoni prevalence using non-uniform spline interpolation. Intensity of red shadows is proportional to prevalence levels. Dots indicate studied villages. Areas outside of the red shadow were inaccessible, dense tropical forest and sparsely populated.
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The copyright holder for this preprint this version posted August 13, 2020. . https://doi.org/10.1101/2020.08.10.20171090 doi: medRxiv preprint Figure 8 . Correlation of S. mansoni infection prevalence and intensity with altitude (meters above sea level) in the 2016 distribution study. The figure above shows the influence of altitude on S. mansoni infection prevalence (top) and intensity expressed as an arithmetic mean (bottom) as observed in 2016. The higher the altitude, the lower the infection prevalence and intensity. All rights reserved. No reuse allowed without permission.
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint this version posted August 13, 2020. . https://doi.org/10.1101/2020.08.10.20171090 doi: medRxiv preprint