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Tropical Medicine and Infectious Disease

MDPI AG

All preprints, ranked by how well they match Tropical Medicine and Infectious Disease's content profile, based on 12 papers previously published here. The average preprint has a 0.01% match score for this journal, so anything above that is already an above-average fit. Older preprints may already have been published elsewhere.

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Performance of an evidence-based risk algorithm to diagnose chlamydia and gonorrhea among pregnant Rwandan women

Sharkey, T.; Nyombayire, J.; Parker, R.; Ingabire, R.; Umuhoza, C.; Bizimana, J.; Mukamuyango, J.; Unyuzimana, M. A.; Mazzei, A.; Tichacek, A.; Allen, S.; Karita, E.; Wall, K. M.

2026-05-21 public and global health 10.64898/2026.05.18.26353484 medRxiv
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Reproductive tract infections (RTI) are associated with adverse outcomes in pregnant African women. However, many diagnostic strategies are unaffordable or perform poorly. Here, we assess RTI prevalence and predictors of chlamydia/gonorrhea (CT/NG) in pregnant women reporting vaginal discharge and the performance of our previously published CT/NG risk algorithm in this population versus Rwandan National Guidelines (RNG). From 2017-2020, free sexually transmitted infections (STI) services were provided to residents in Kigali, Rwanda. Medical history and gynecologic examination were done. Laboratory assessments included HIV; syphilis; microscopy for trichomoniasis, bacterial vaginosis (BV), and candida; and PCR for CT/NG. Eighty-seven pregnant women received STI services. Prevalence was 28% for CT/NG, 15% for trichomoniasis, 24% for BV, 39% for candida, and 79% for any RTI. Predictors of CT/NG were age <=25 (adjusted prevalence odds ratio [aPOR]=4.92; 95% confidence interval [CI]: 1.52-15.90; p=0.008), inconsistent condom use (aPOR=4.86; 95%CI: 0.98-24.10; p=0.053), absence of candida (aPOR=4.23; 95%CI: 1.13-15.82; p=0.032), and endocervical inflammation/discharge (aPOR=4.91; 95%CI: 1.40-17.20; p=0.013). Our algorithm outperformed the 2019 and 2024 RNG (sensitivity: 92% versus 46% and 35% respectively). Pregnant women seeking STI services had high RTI prevalence. Our algorithm performed well. Algorithms tailored for pregnant women and including male partner risk factors should be explored.

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Spatial heterogeneity in Onchocerca volvulus IgG4 seroprevalence around a blackfly (Simulium damnosum s.l.) breeding site in Ghana and its implications for onchocerciasis serosurveillance

Kyomuhangi, I.; Otabil, K. B.; Acheampong, A.; Ofori, D. K.; Kudzordzi, P.-C.; Nyarko, P.; Fronterre, C.; Cheke, R. A.; Basanez, M.-G.; Hawkes, F.

2026-05-06 public and global health 10.64898/2026.05.05.26352446 medRxiv
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Progress towards elimination of onchocerciasis transmission is evaluated using entomological and serological indicators. The latter assesses anti-Ov16 IgG4 seroprevalence in children aged <10 years. A seroprevalence of <0.1% suggests that ivermectin Mass Drug Administration (MDA) can be stopped and post-treatment surveillance initiated, according to World Health Organization (WHO) guidelines. Surveillance of populations living in close proximity to vector breeding sites and first-line villages may mask spatial transmission heterogeneity. We mapped anti-Ov16 seroprevalence within a 25-km radius around a known Simulium damnosum s.l. breeding site in Asubende, Ghana, to assess its spatial patterns and their implications for serosurveillance. A cross-sectional survey was conducted in September-November 2024 in 30 settlements. Individuals aged [&ge;]3 years were recruited through convenience sampling. The Ov16 rapid diagnostic test (RDT) using dry blood spots was used to estimate overall and site-level seroprevalence. Generalized additive models were used to assess seroprevalence trends versus distance from the breeding site. Among 2,479 participants with valid RDT results, overall seroprevalence was 10.0% (95% CI: 8.9%, 11.3%) and increased with age. Seroprevalence varied across sites (0-24.4%) and declined with increasing distance from the breeding site. Among 584 children <10 years old, seroprevalence was 1.5% (95% CI: 0.7%, 2.9%). Adjusting for RDT sensitivity and specificity, seroprevalence in this age-group was 0.7%, (95% CI: 0%, 2.4%). Seropositive children were detected up to 18 km from the breeding site, but none were identified at it. The distance-related decrease in overall seroprevalence is consistent with spatial patterns in vector abundance at Asubende and implies higher cumulative exposure near the breeding site. The small number of children tested limited inference in this WHO target age-group. Detection of seropositive children away from, but not at, the breeding site highlights limitations of surveillance focused on first-line villages and supports broader spatial sampling to strengthen evidence for stop-MDA decisions. Author summaryAfter decades of onchocerciasis control using ivermectin, many countries hope to demonstrate that they have interrupted transmission of this vector-borne parasitic disease using serological surveys. It is unclear whether exposure to infection is spatially clustered around the riverine breeding sites of the blackfly vectors and therefore whether this is where serosurveillance should focus. To address this, we collected dried blood spots from 2,480 consenting participants aged 3-96 years old from 29 communities within a 25-km radius of a known blackfly breeding site in Asubende, Ghana. A rapid diagnostic test was used to test the blood spots for antibodies to the Onchocerca volvulus parasite. We found that overall seropositivity declined with increasing distance from the breeding site, which suggests that cumulative exposure is higher near the breeding site, where vector population is also high. However, seropositivity in children (3-10-year-olds, n= 584), which is indicative of recent transmission, was spatially distributed across the study area and found up to 18 km from the breeding site. These findings are relevant to serosurveillance sampling strategies intended to detect low levels of transmission, which could miss peripheral evidence of ongoing transmission if they are focussed at breeding sites and those villages closest to them.

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Nearly half of adults with symptoms of sexually transmitted infections (STIs) did not seek clinical care: A population-based study of treatment-seeking behavior among adults in Rakai, Uganda

Ogale, Y. P.; Kennedy, C. E.; Nalugoda, F.; Mpagazi, J.; Jackson, J. C.; Galiwango, R.; Ssekubugu, R.; Kigozi, G.; Denison, J. A.; Gaydos, C. A.; Kagaayi, J.; Grabowski, M. K.

2023-02-03 public and global health 10.1101/2023.02.01.23285331 medRxiv
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Understanding treatment-seeking behavior is critical to the treatment and control of sexually transmitted infections (STIs), yet current data on STI treatment-seeking in low-resource settings is scarce. This study aims to describe STI treatment-seeking behavior and identify factors associated with seeking treatment at a clinic among adults with STI-related symptoms in rural Uganda. The STI prevalence study (STIPS) conducted a population-based survey and STI testing among all consenting adults aged 18-49 in two communities in rural south-central Uganda. Of 1,825 participants, 962 individuals self-reported STI symptoms in the past six months; we present descriptive data on treatment-seeking and STI prevalence among these individuals. We used multivariable Poisson regressions with robust variance to determine the sociodemographic and symptom-related factors independently associated with seeking STI treatment at a clinic and assessed the association with previous clinic treatment-seeking and current STI diagnosis. Forty-three percent of adults who reported STI-related symptoms in the past six months said they did not seek any treatment. Among those who did, 58% sought treatment at a private clinic, 28% at a government clinic, 9% at a pharmacy/drug store, 3% at a traditional healer, 2% at a market/shop, and 5% at another location. Among both men and women, having multiple STI related symptoms was positively associated with clinic treatment seeking (men=PRR: 1.73, 95%CI: 1.36-2.21; women=PR: 1.41, 95%CI: 1.12-1.78). Approximately one-third of men and women who reported previously seeking clinic treatment for their symptoms were diagnosed with a curable STI at the time of the survey. In this setting, nearly half of adults with STI-related symptoms are not seeking clinical care and many who report having sought treatment recent STI symptoms have curable STIs. Future studies should explore barriers to care-seeking and strategies to improve STI services.

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Risk Factors of Human Mpox (Monkeypox) Infection: A Systematic Review and Meta-Analysis

Ugwu, C. L. J.; Bragazzi, N. L.; Wu, J.; Kong, J. D.; Asgary, A.; Orbinski, J.; Woldegerima, W. A.

2024-08-20 public and global health 10.1101/2024.08.14.24311975 medRxiv
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BackgroundMpox (formerly Monkeypox) virus has affected the lives of thousands of individuals both in endemic and non-endemic countries. Before the May 2022 outbreak, Mpox infections were sporadically endemic in Central and Western Africa, still research into Mpox has been limited and lacking epidemiological data. Thus, identification of potential risk factors to better understand who is at risk of being infected is critical for future prevention and control. ObjectiveTo synthesize comprehensive evidence on risk factors associated with human Mpox transmission both in endemic and non-endemic countries from inception to March 31, 2024. MethodsThe Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed in conducting the systematic review. Electronic databases were searched. Two reviewers sifted the articles that were included in the review: firstly, by title and abstract, and secondly, by full text. We used the Newcastle-Ottawa Scale (NOS) to assess the risk of bias for included articles. Fixed or random effects meta-analysis were conducted when at least two studies reported odds ratios (OR), relative risks (RR), with 95% confidence intervals (CI). Heterogeneity was assessed using the I2 statistic and sensitivity analysis was also done. The study protocol has been registered under PROSPERO with ID: CRD42023459895. Results947 articles were identified from the database search and 31 articles were eligible to be included in the systematic review. The findings of the meta-analysis showed that interaction with infected animals (OR = 5.61, 95% CI = 2.83, 11.13), HIV (OR = 4.46, 95% CI = 3.27, 6.08), other STIs (OR = 1.76, 95% CI = 1.42, 2.91), sexual contact/activities (OR = 1.53, 95% CI = 1.13, 4.82), contact with an infected person (OR = 2.39, 95%CI = 1.87, 3.05), being identified as men who have sex with men (MSM) (OR = 2.18, 95%CI = 1.88, 2.51), and having multiple sexual partners Mpox (OR = 1.61, 95%CI = 1.24, 2.09), were associated with an increased risk of contracting Mpox. However, patients who were vaccinated against smallpox had a lower risk of Mpox infection (OR = 0.24, 95%CI = 0.11, 0.55). ConclusionThis study is the first meta-analysis on reported risk factors for Mpox. Our analysis demonstrated that certain factors were associated with increased risk of Mpox, whereas smallpox vaccination had a protective role against contracting Mpox. The study findings could facilitate future strategic public health planning and targeted intervention. Key messages of this articleO_ST_ABSWhat is already known on this topicC_ST_ABSO_LIMpox (monkeypox) is a zoonotic infectious disease of notable global public health importance due to recent outbreaks in non-endemic countries. C_LIO_LIPrior outbreaks of Mpox have been associated with travel to endemic areas in Western and Central Africa, contact with infected animals, and close contact with infectious lesions, particularly among household members. C_LI What this study addsO_LIThis study is the first meta-analysis on reported risk factors for Mpox. Our study findings add to the body of evidence on Mpox research efforts and could assist in future Mpox global strategic intervention and control. C_LIO_LIOur meta-analysis revealed a strong correlation between increased risk of Mpox infection, HVI, other STIs, physical and sexual contacts, and being identified as MSM. C_LIO_LIWhile HIV infection may be a risk factor for Mpox, Mpox lesions could also facilitate the transmission of HIV and other STIs. C_LI How this study might affect research, practice or policyO_LIThe results of this systematic review and meta-analysis provide evidence to support policymakers in future Mpox intervention and prevention in both endemic and non-endemic countries based on identified risk factors. C_LI

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Leishmaniasis in migrants crossing Central America and Mexico: An emerging epidemiological threat

Zamora-Chimal, J.; Rodriguez-Perez, M. A.; Caneda-Guzman, I. C.; Wei, L.; Ruiz-Remigio, A.; Meneses-Ruiz, G.; Garcia-Ruiz, J. P.; Salaiza, N.; Juarez-Gabriel, J.; Aguilar-Duran, J. A.; Guo, X.; Hernandez-Salinas, U.; Garrido-Lozada, E. G.; Hamer, S. A.; Hamer, G. L.; Becker, I.; Fernandez Santos, N. A.

2026-01-22 public and global health 10.64898/2026.01.20.26344417 medRxiv
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BackgroundIrregular migration across Central America and Mexico has increased in recent years, exposing migrants to various health risks, including vector-borne diseases such as leishmaniasis. The migration corridor from South America, through the Darien Gap, to northern Mexico traverses multiple leishmaniasis-endemic regions with active Leishmania spp. transmission, where environmental exposure during migrants transit may increase the risk of infection. Methodology / Principal FindingsFrom 2023 to 2025, clinical and epidemiological data were collected from 365 migrants transiting through Mexico, including a subset of individuals with clinical suspicion of cutaneous leishmaniasis (CL). Migrants were evaluated at two shelters in northern Mexico and at the Centro de Medicina Tropical (CMT) of the Universidad Nacional Autonoma de Mexico (UNAM). Diagnostic testing included serology and polymerase chain reaction (PCR) for species identification. Sociodemographic data, country of origin, and migration routes were documented. A complementary literature review was conducted to map the geographic distribution of sand fly vectors along migratory pathways. A total of 26 leishmaniasis clinical cases were identified, namely a 7.1% prevalence (95%-CI = 4.6-9.9%). Most individuals originated from Venezuela (n = 12), Honduras (n = 3), and Mexico (n = 3), with additional cases from Haiti and the Czech Republic. Six participants did not disclose their country of origin but reported traveling from South America. Polymerase chain reaction confirmed active infections with Leishmania (Viannia) panamensis (7 cases) and Leishmania (Viannia) braziliensis (1 case), both detected among Venezuelan migrants. Additional PCR-positive cases were classified within the Viannia subgenus. Conclusions/SignificanceThese findings underscore the urgent need for tailored surveillance strategies and integrated cross-border healthcare interventions to address migrant populations, who may also contribute to the introduction of Leishmania species into Mexico, including those belonging to the Viannia subgenus. The presence of competent sand fly vectors along migration routes heightens the risk of transmission to both migrants and local resident communities. Author SummaryLeishmaniasis is a neglected tropical disease transmitted by sand flies which remains a major public health concern in many parts of Mexico, Central, and South America. In recent years, irregular migration from South America to northern Mexico has increased, exposing migrants to endemic disease risks. Here, clinical and epidemiological data from migrants transiting Mexico between 2023 and 2025 were examined, and 26 cases of cutaneous leishmaniasis were identified. Species-level identification confirmed infections with L. (V.) panamensis and L. (V.) braziliensis, underscoring the importance of precise diagnosis to help guide treatment and clinical follow-up of migrants. The presence of competent sand fly vectors along migration routes further highlights the vulnerability of the migrant population. These findings emphasize the urgent need for active surveillance and integrated healthcare strategies to protect both migrant and local populations, while also considering social and ecological factors. Addressing leishmaniasis in an integrated context requires coordinated medical and educational interventions to prevent transmission, reduce disease burden, and support vulnerable communities.

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Understanding the association between immune modulating helminths and HPV or cervical cancer: a scoping review

Frank, A.; Correa-Mendez, M.; Livinski, A. A.; Duncan, K.; Gravitt, P. G.; Clark, E. H.

2025-08-05 public and global health 10.1101/2025.08.05.25330736 medRxiv
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BackgroundCervical cancer disproportionately affects people living in low- and middle-income countries (LMICs). While access to effective preventive interventions explains some of the disparity, biological causes cannot be ruled out as important contributors to the observed disparities in cervical cancer outcomes. Because chronic infection with helminths which cause immune dysregulation and suppress anti-viral responses is common in LMICs, we sought to review the available epidemiologic evidence evaluating associations between helminth infection and HPV infection and/or cervical cancer. MethodsWe searched five databases of scientific publications using search terms targeted towards journal articles published between 1990-2022 evaluating an epidemiologic association between helminth infection and HPV prevalence, persistence, or cervical cancer progression. We identified eight relevant studies and describe them in this scoping review. ResultsAll eight studies showed a positive population-level relationship between helminth infection and HPV or cervical cancer. Six studies found a positive association between schistosomiasis and cervical neoplasia; two studies found a positive association between hookworm infection and HPV prevalence; and 1 study found a positive association between Ascaris, Trichuris, and Strongyloides and HPV prevalence. ConclusionsThese data suggest a positive association between helminth infection and cervical neoplasia. Given the high burden of helminth and HPV co-infection in LMICs, further evaluation of helminth infection as a potential risk factor for cervical cancer development is warranted. Author SummaryThe high prevalence of helminth and HPV co-infections in LMICs significantly impacts quality of life, necessitating studies to expand our knowledge of their epidemiological and health impacts. Understanding the interaction between helminth infection, persistence of high-risk HPV, and cervical cancer is then crucial for developing evidence-based public health programs to improve health outcomes in affected populations. Chronic helminth infections, such as schistosomiasis and hookworm, induce immune responses that can impair antiviral responses critical for HPV clearance. Eight studies included in this scoping review suggest a positive association between helminth infection and cervical pre-cancerous and cancerous lesions, warranting further evaluation of this interaction given the high burden of co-infection. Findings expand the evidence-base to support the need to incorporate schistosomiasis screening into gynecological examinations and/or cervical cancer screening efforts to enhance the accuracy of diagnosing and treating pre- and cancerous cervical lesions in endemic regions.

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How does treatment coverage and proportion never treated influence the success of Schistosoma mansoni elimination as a public health problem by 2030?

KURA, K.; Nyamai, M.; Basanez, M.-G.; Coffeng, L. E.; Thumbi, S. M.; Anderson, R.

2023-10-21 public and global health Community evaluation 10.1101/2023.10.20.23297322 medRxiv
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BackgroundThe 2030 target for schistosomiasis is elimination as a public health problem (EPHP), achieved when the prevalence of heavy intensity infection among school-aged children (SAC) reduces to <1%. To achieve this, the new World Health Organization (WHO) guidelines recommend a broader target of population to include pre-school (pre-SAC) and adults. However, the probability of achieving EPHP should be expected to depend on patterns in repeated uptake of mass drug administration (MDA) by individuals. MethodsWe employed two individual-based stochastic models to evaluate the impact of school-based and community-wide treatment and calculated the number of rounds required to achieve EPHP for Schistosoma. mansoni by considering various levels of the population never treated (NT). We also considered two age intensity profiles, corresponding to a low and high burden of infection in adults. ResultsThe number of rounds needed to achieve this target depends on the baseline prevalence and the coverage used. For low and moderate transmission areas, EPHP can be achieved within seven years if NT [&le;]10% and NT <5%, respectively. In high transmission areas, community wide treatment with NT<1% is required to achieve EPHP. ConclusionsThe higher the intensity of transmission, and the lower the treatment coverage, the lower the acceptable value of NT becomes. Using more efficacious treatment regimens would permit NT values to be marginally higher. A balance between target treatment coverage and NT values may be an adequate treatment strategy depending on the epidemiological setting, but striving to increase coverage and/or minimise NT can shorten programme duration.

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Doxycycline prophylaxis for sexually transmitted infection prevention in Vietnam: Awareness, attitudes, and willingness to use among men who have sex with men using HIV-PrEP

Bui, H. T. M.; Adamson, P. C.; Klausner, J. D.; Le, G. M.; Gorbach, P. M.

2024-12-05 public and global health 10.1101/2024.12.02.24318296 medRxiv
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ObjectivesDoxycycline prophylaxis shows promise for sexually transmitted infection (STI) prevention, but data primarily come from high-income countries. This study assessed awareness, willingness and factors associated with willingness to use doxycycline for STI prevention among men who have sex with men (MSM) using HIV-PrEP in Vietnam. MethodsBetween January 25 and February 4, 2024, a cross-sectional study recruited males aged [&ge;]18 years who reported sex with men in the past 12 months from 11 PrEP clinics in Hanoi and Ho Chi Minh City. Self -administered surveys were conducted, and multivariable logistic regression was applied to identify factors associated with willingness to use doxyPEP/PrEP. ResultsAmong 350 participants (45.7% Hanoi, 54.3% Ho Chi Minh City), the median age was 25 (interquartile range [IQR]: 21-30), and 10.6% self-reported an STI diagnosis in the past 12 months. In the previous 6 months, the median number of sex partners was 2 (IQR: 1-4), 53.1% reported condomless anal sex. Awareness of doxycycline was low (20.2%; 65/322), however, 75.4% (264/350) expressed willingness to use it, with 63.6% (168/264) preferring doxyPrEP. Participants who disclosed HIV-PrEP use to all sex partners (adjusted odds ratio [aOR]: 4.17; 95% confidence interval [95%CI] 1.84, 9.46), and those with higher perceived STI risk (aOR: 1.12; 95% CI 1.03, 1.22) were more likely to report willingness to use doxycycline prophylaxis. Concerns about daily medication (aOR: 0.43; 95% CI 0.24, 0.81) and fear of judgement from peers (aOR: 0.41; 95% CI: 0.21, 0.81) were associated with lower willingness. ConclusionsKnowledge of doxyPEP/PrEP among MSM on HIV-PrEP in Vietnam was low. However, most expressed willingness to use doxycycline prophylaxis, with two-thirds preferring doxyPrEP. Findings highlight the need to disseminate information on doxyPEP/PrEP for STI prevention strategy, evaluating the usage and comparative effectiveness of doxyPEP and doxyPrEP to guide implementation efforts in Vietnam. 1. What is already known on this topicMen who have sex with men (MSM) experience a disproportionate burden of HIV and bacterial sexually transmitted infections (STIs) worldwide, including in Vietnam. Despite the successful expansion of HIV Pre-Exposure Prophylaxis (PrEP) programs in Vietnam, bacterial STI rates remain persistently high among PrEP users, highlighting gaps in prevention efforts. Evidence from high-income countries (HICs) suggests that doxycycline prophylaxis can significantly reduce the incidence of bacterial STIs such as syphilis and chlamydia. However, little is known about the awareness, acceptability, and feasibility of doxycycline prophylaxis in Vietnam and other low-and middle-income countries (LMICs). 2. What this study addsThis study is the first to assess awareness, attitudes, and willingness to use doxycycline prophylaxis for STI prevention among MSM in Vietnam, a LMIC setting. Despite low prior awareness, the study found high willingness (75.4%) to use doxycycline, with most participants preferring daily doxyPrEP over doxyPEP. It also identified critical facilitators, such as perceived high STI risk and disclosure of HIV-PrEP use to sex partners, as well as barriers, including stigma, cost, and concerns about daily medication. These findings provide insights into the feasibility of introducing doxycycline prophylaxis in Vietnam, distinguishing it from contexts in HICs where different preferences and barriers may exist. 3. How this study might affect research, practice, or policyThis study provides a foundation for further research on doxycycline prophylaxis in LMICs, emphasizing the need to evaluate its real-world effectiveness and implementation in settings with high AMR prevalence. Policymakers can use these findings to develop tailored guidelines and subsidies for doxycycline prophylaxis in Vietnam, ensuring affordability and accessibility.

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A geospatial approach to understanding transmission patterns of onchocerciasis in Ghana

Opoku, M.; Deane, D. C.; Shrestha, H.; Frempong, K. K.; Pi-Bansa, S.; Nyarko Osei, J. H.; Opare, J. K. L.; Mensah, E.; Aseidu, O. D.; de Souza, D. K.; Boakye, D. A.; Hedtke, S. M.

2026-07-28 public and global health 10.64898/2026.07.27.26359079 medRxiv
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Background Onchocerciasis (river blindness), caused by the filarial nematode Onchocerca volvulus and transmitted by Simulium blackflies, remains a public health challenge in sub-Saharan Africa. Following the transition from vector control to large-scale ivermectin distribution, microfilariae (mf) prevalence has declined substantially across Ghana. The World Health Organization targets onchocerciasis elimination, defined as sustained mf prevalence below 1%. This requires identifying areas of persistent or resurgent transmission to guide targeted mapping surveys and interventions. Methods A Bayesian spatiotemporal, multilevel, generalized additive model with a zero-inflated beta-binomial outcome was fitted to mf prevalence data from 1353 surveys across 671 villages and environmental and socio-economic predictors. Temporal prevalence trends for ecozones within operational transmission zones (OTZ) were modelled using a 2D spatial smooth to account for residual spatial autocorrelation. Temporal autocorrelation in prevalence was accounted for using a random effect for village nested within ecozone. Results Runoff probability and surface wetness were positively associated with prevalence, consistent with Simulium breeding in fast-flowing water. Despite high initial mf prevalence, by 2015 the median prevalence across all OTZs in Ghana was estimated to be between 0.43 and 1.97%. The probability that prevalence was <1% in 2015 ranged from 0.15 to 0.87. Assuming testing rates and mass drug administration have remained consistent (twice a year and >80% coverage), linear extrapolation predicted that the three OTZs have some probability of exceeding the elimination threshold by 2030, while two were predicted to have near-zero prevalence. The Tano-Ankobra OTZ, which includes both savanna and forest agro-ecological zones, was a persistent hotspot. Conclusions This first comprehensive spatio-temporal analysis of onchocerciasis in Ghana reflects the well-documented challenge of onchocerciasis control in forested riverine environments. Persistent transmission foci in eastern and southern Ghana, particularly in forest zones with sustained vector habitat, warrant targeted investigation and intensified intervention to meet WHO elimination thresholds.

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Antimalarial Drug Resistance in Plasmodium falciparum from Tak Province, Thailand (1998-2001): A TaqMan Array Card Study.

Thaloengsok, S.; Chaisatit, C.; Saingam, P.; Lertsethakarn, P.; Spring, M.; Sriwichai, S.; Pholwat, S.; Guler, J. L.; Houpt, E.; Vesely, B. A.

2024-05-31 public and global health 10.1101/2024.05.29.24308164 medRxiv
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Despite declining malaria cases in Thailand, surveillance in endemic areas is crucial. Retrospectively analyzing samples from Tak province, Thailand, we found prevalent drugresistant Plasmodium falciparum, particularly to mefloquine and sulfadoxine/pyrimethamine. Notably, mutations indicating resistance to artemisinin were detected at low frequencies, suggesting evolving resistance. These findings stress the need for continuous surveillance to guide control strategies and prevent outbreaks, even with decreasing cases, to sustain malaria elimination efforts.

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Time-to-Tuberculosis disease diagnosis after completion of Tuberculosis preventive therapy among people living with HIV on Antiretroviral Therapy in Eastern Uganda: A retrospective cohort study

Esele, B. A.; Oryokot, B.; Ssentongo, S. M.; Mulongo, M.; Akanyo, J.; Bongomin, F.

2026-04-13 hiv aids 10.64898/2026.04.08.26350451 medRxiv
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BackgroundTuberculosis (TB) remains a leading cause of morbidity and mortality among people living with HIV (PLHIV), who face a 12-fold higher risk of active TB reactivation than HIV-negative individuals. TB preventive therapy (TPT) is an effective intervention, yet TB/HIV co-infection persists at 40-45%, raising questions about the durability of a single course of TPT. This study assessed the time from TPT completion to TB diagnosis and predictors of early TB reactivation. MethodsWe conducted a retrospective case-only cohort study using routine data from Ugandas electronic medical record system, TB registers, and patient files at three TASO Centres of Excellence (Soroti, Mbale, Tororo). PLHIV on antiretroviral therapy (ART) diagnosed with TB after completing TPT between 2022-2024 were included. Participant characteristics and time to TB diagnosis were summarised descriptively; predictors of early TB were identified using logistic regression. ResultsAmong 670 participants, most were female (464, 69.3%) with mean age 51.6 years (SD 14.5). Newly diagnosed TB accounted for 638 (95.2%), including bacteriologically confirmed pulmonary TB (535, 79.9%), clinically diagnosed TB (123, 18.4%), and extrapulmonary TB (12, 1.8%). Overall, 548 (82.8%) participants were virally suppressed, with most on Dolutegravir-based regimens (641, 95.7%). Early TB occurred in 144 (21.5%), with average time to diagnosis 2.6 years. Multivariable analysis showed care at TASO Soroti was protective (aOR = 0.104, p < 0.001), while clinically diagnosed TB (aOR = 1.91, p = 0.007), shorter ART duration (<5 years: aOR = 3.07, p = 0.001; 5-10 years: aOR = 1.74, p = 0.018), and viral suppression (aOR = 1.87, p = 0.014) increased odds of early TB. ConclusionsTB can occur soon after TPT completion, with one in five PLHIV developing early disease particularly those with shorter ART duration despite viral suppression. Strengthening TB screening, continuous monitoring, and repeat TPT for high-risk groups may improve prevention.

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First Detection of Oropouche Virus in Culicoides insignis in the Ucayali Region, Peru: Evidence of a Possible New Vector

Requena-Zuniga, E.; Palomino-Salcedo, M.; Garcia-Mendoza, M.-P.; Figueroa-Romero, M.; Merino-Sarmiento, N.; Escalante-Maldonado, O.; Cornelio-Santos, A.; Cardenas-Garcia, P.; Jimenez, C.-A.; Cabezas Sanchez, C. A.

2024-12-08 infectious diseases 10.1101/2024.12.06.24318268 medRxiv
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This report details the first detection of the Oropouche virus (OROV) in Culicoides insignis in the Ucayali region (Peruvian Amazon) during an outbreak study in 2024. Captures conducted in peri-urban and rural areas showed that C. insignis accounted for 96.7% of the collected Culicoides specimens. RT-qPCR testing confirmed the presence of the virus in two C. insignis pools, establishing this species as a potential OROV vector in the study area, thereby contributing to the understanding of the viruss epidemiology in the Amazon region.

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Assessment of Awareness and Willingness to Use Pre-Exposure Prophylaxis for HIV Prevention among Female Sex Workers in Rwanda.

Munyaneza, A.; Nzungize, A.

2024-12-13 public and global health 10.1101/2024.12.12.24318894 medRxiv
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BackgroundFemale sex workers (FSWs) in sub Saharan Africa bear a disproportionate burden of HIV infection. While pre exposure prophylaxis (PrEP) is increasingly accessible in the region, limited data exist on FSWs awareness of and willingness to use PrEP. This study aimed to assess PrEP awareness and willingness to use it, along with associated factors, among FSWs in Kigali, Rwanda. MethodsThis cross sectional study, conducted from April to September 2024, evaluated PrEP awareness and willingness to use it among 333 FSWs recruited through community based FSW associations. Data were analyzed using SPSS, with logistic regression employed to explore associations between participant characteristics and PrEP awareness and willingness. Ethical approval was obtained from the Rwanda National Ethics Committee. ResultsThe mean age of participants was 30 years (SD: 7.26), with 47% aged between 25 and 34. Most were single (67%) and unemployed (66%), with nearly half (49.5%) reporting only primary education. A significant proportion (81%) had undergone HIV testing in the past six months, and 50% had been involved in sex work for 2 to 5 years. The median number of sexual partners in the past week was 7. Awareness of PrEP was high (81%), however, consistent condom users were less likely to be aware of PrEP (adjusted odds ratio (aOR): 0.40, 95% confidence interval (CI): 0.19, 0.83), as were those not screened for sexually transmitted infections (STIs) compared to those who were screened (aOR: 0.43, 95% CI: 0.22, 0.85). Willingness to use PrEP was reported by 80% of participants. Those with a primary education were more willing to use PrEP compared to those with no formal education (aOR: 4.09, 95% CI: 1.62, 10.33). Conversely, participants screened for STIs were less likely to report willingness compared to those not screened (aOR: 0.28, 95% CI: 0.12, 0.62). ConclusionThis study demonstrates high awareness and willingness to use PrEP among FSWs in Kigali. However, consistent condom users and those unscreened for STIs were less aware of PrEP, and willingness to use it varied based on education and STI screening status. These findings underscore the need for targeted health education and STI screening initiatives to enhance PrEP uptake and strengthen HIV prevention efforts in this vulnerable population.

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Assessing mpox knowledge and sexual behaviours within high-risk populations in the Democratic Republic of the Congo

Lemaille, C.; Halbrook, M.; Merritt, S.; Anta, Y.; Lunyanga, L.; Mukadi, P.; Hasivirwe Vakaniaki, E. V.; Kalonji, T.; Kenye, M.; Kacita, C.; Linsuke, S.; Bogoch, I.; Cevik, M.; Gonsalves, G. S.; Hunter, M.; Liesenborghs, L.; Shaw, S. Y.; Shongo, R.; Hensley, L. E.; Hoff, N. A.; Rimoin, A. W.; Mbala-Kingebeni, P.; Kindrachuk, J.

2025-04-21 infectious diseases 10.1101/2025.04.20.25326123 medRxiv
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BackgroundHistorically, the Democratic Republic of the Congo (DRC) has faced the greatest public health burden from mpox, including more than 70,000 probable cases from 01 January 2024 to 02 February 2025. However, there has been a relative paucity of investigation focused on mpox community engagement in DRC, including assessments of disease knowledge and risk perception. MethodsGiven the ongoing Clade I mpox public health emergency of international concern, and the linkage between sustained human-to-human transmission and dense sexual networks, we sought to investigate mpox knowledge and sexual behaviours among key populations. Between March 20, 2024, and August 25, 2024, we recruited 2794 participants distributed across Kinshasa, Kwango and North Kivu provinces, with a focus in urban centers where mpox risk was considered high. ResultsMost participants were considered other at-risk populations (1035; 37.0%), followed by men who have sex with men (MSM, 831; 29.7%) and sex workers (810; 29.0%). Mpox knowledge, including transmission routes, as well as sexual and health-seeking behaviours were evaluated through questionnaires led by peer educators. Overall, only 6.1% of all participants reported prior mpox knowledge. Among this participant subset, zoonosis ("direct contact with infected animals") and "people living in high-risk areas" were the most frequently selected options in regard to mpox transmission and populations at risk, respectively. When considering at-risk behaviors for mpox, those that identified as sex workers reported significantly higher risk sexual activities including multiple sexual partners (80.3% of sex work participants), engaging in transactional sex (84.7.0%), and anonymous sex (80.8%) compared to MSM. However, both sex workers (44.8%) and MSM (56.7%) reported the highest health seeking behaviors for a suspected sexually transmitted infection. ConclusionOur results highlight that community engagement which incorporates both mpox knowledge and risk perception activities and is inclusive of at-risk populations are needed for ongoing mpox containment and mitigation efforts.

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Lymphatic Filariasis Transmission at Spot-Check Sites in Six Endemic Districts of Nepal After Two IDA Mass Drug Administration Rounds

Mahato, R. K.; Dahal, G.; Kandel, S.; Chaudhary, A.; Paudel, S. R.; Khaniya, R.; Shakya, P.; Devkota, B. P.; Sapkota, B. P.; Poudel, K. P.; Bajracharya, B.; Shrestha, D.; Jha, C. B.; Neupane, R.; Dhakal, K. B.; Bennani, K.

2026-04-23 infectious diseases 10.64898/2026.04.22.26351459 medRxiv
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BackgroundNepal has set a goal to eliminate lymphatic filariasis (LF) by 2030. As of 2024, Nepal has stopped the mass drug administration (MDA) in 56 of the 64 endemic districts and completed two rounds of MDA in six districts with persistent LF ([&ge;]2% antigen prevalence) using the three-drug regimen of Ivermectin, Diethylcarbamazine, and Albendazole (IDA), exceeding 65% coverage. We subsequently conducted an Epidemiological Monitoring Survey (EMS) to assess the impact of the MDA in reduction of LF infection prevalence below the transmission threshold and examine the factors associated with it. MethodsWe conducted a cross-sectional EMS nine months after MDA in 12 evaluation units (EUs) across six districts, with two sites per EU. We recruited a total of 7,343 individuals aged [&ge;]20 years, sampled using multi-stage sampling, ensuring at least 300 blood samples collected per site. We collected data on demographics and MDA participation. We performed the LF antigen testing for all participants, followed by night blood microfilariae testing in antigen-positive individuals. Statistical analyses included non-parametric tests, Chi-square and Fishers Exact tests, and multivariable logistic regression to assess outcomes after adjusting for potential confounders. ResultsNine of 12 evaluation units (EUs) recorded <1% microfilaremia, meeting the WHO threshold for passing EMS, while three EUs failed with [&ge;]1% prevalence in at least one site. Antigen and MF prevalence were 4.47% and 0.34%, respectively (ratio 13:1). Both Antigen and MF prevalences were significantly associated with female sex (AOR= 0.564, 95% CI: 0.441-0.721 and AOR = 0.326, 95% CI: 0.129-0.826 respectively) and participation in the most recent MDA round (AOR = 0.477; 95% CI: 0.385-0.591 and AOR = 0.089; 95% CI: 0.017-0.464 respectively). MDA uptake was influenced by age (<40 years, AOR = 0.72; 95% CI: 0.653- 0.793), sex (female, AOR = 1.438; 95% CI: 1.29-1.603), cross-border residence (AOR = 0.616; 95% CI: 0.558-0.681), and occupation (agriculture and housewife, AOR = 1.144; 95% CI: 1.008-1.298). MF prevalence was also associated with younger age (<40 years, AOR = 0.211; 95% CI: 0.071-0.626). ConclusionThe survey indicates progress toward LF elimination, with nine of twelve EUs achieving WHOs <1% microfilaremia threshold after two rounds of IDA-MDA. However, transmission persists in three sites, likely linked to poor MDA participation among specific subgroups-- particularly males, younger adults, and cross-border populations. Strengthening MDA coverage and compliance across all demographic and occupational groups, with special focus on border areas, is essential to achieve LF elimination in Nepal.

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Triple-drug therapy with ivermectin, diethylcarbamazine and albendazole for the acceleration of lymphatic filariasis elimination in Kenya: Programmatic implementation and results of the first impact surveillance

Njenga, S. M.; Kanyi, H.; Okoyo, C.; Githinji, E.; Mwatele, C.; Matendechero, H. S.; Omondi, W. P.; Gitahi, P. N.; Owaga, C.; Onsongo, J. K.; Gass, K.

2024-01-30 public and global health 10.1101/2024.01.30.24301765 medRxiv
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The World Health Organization (WHO) endorsed the use of triple-drug mass drug administration (MDA) regimen with ivermectin, diethylcarbamazine (DEC) and albendazole (commonly abbreviated as IDA) to accelerate the elimination of lymphatic filariasis (LF) as a public health problem in settings where onchocerciasis is not co-endemic. The National Programme for Elimination of LF (NPELF) in Kenya was among the first adopters of the IDA-MDA and two annual rounds were provided in 2018 and 2019 to the residents of Lamu County and Jomvu sub-County in the coast region. There is a need to determine efficient sampling strategies, indicators, and the appropriate population groups that could be used for the monitoring and evaluation of LF programs using IDA-MDA for the elimination of the disease as a public health problem. Two cross-sectional surveys were conducted at baseline in 2018 before IDA-MDA and an impact assessment 17 months after the second round of IDA-MDA. The reported epidemiological treatment coverage was at least 80% in all implementation units during each round of IDA-MDA. Blood samples were tested for circulating filarial antigens using commercial Filariasis Test Strips (FTS) and any individual that was found to be positive was tested again at night for the presence of microfilariae in finger prick blood smears using microscopy. The overall prevalence of LF infection was relatively low at the baseline survey with Jomvu having 1.39% (95% CI: 0.91, 2.11) and Lamu having 0.48% (95% CI: 0.21, 1.13). Significant reductions in LF prevalence were observed during the impact assessment after two annual rounds of treatment. The overall relative risk reduction (%) in LF prevalence following the two rounds of MDA with IDA was significant in both Jomvu (52.45%, Z = -2.46, P < 0.02) and Lamu (52.71%, Z = -1.97, P < 0.05). Heterogeneity, however, was observed in the LF prevalence reduction between random and purposive clusters, as well as between adult and child populations. The results of the endline impact survey offered strong evidence that it was safe to stop the IDA-MDA in the two EUs because transmission appears to have been interrupted. It is also important to implement a post-treatment surveillance system which would enable efficient detection of any recrudescence of LF infection transmission at a sub-evaluation unit level. Our findings show that IDA-MDA may be considered for acceleration of LF elimination in other settings where onchocerciasis is not co-endemic. Author summaryPreventive chemotherapy with antifilarial drugs is currently the mainstay public health intervention recommended for the elimination of lymphatic filariasis in endemic countries. Two-drug regimen mass drug administration of albendazole plus either diethylcarbamazine or ivermectin has been used widely in most countries since the launch of the Global Programme to Eliminate Lymphatic Filariasis by the World Health Organization in 2000. Safety and efficacy clinical studies conducted in Papua New Guinea have shown that co-administration of three antifilarial drugs namely, ivermectin, diethylcarbamazine and albendazole is superior than the two-drug regimen diethylcarbamazine and albendazole in clearance of microfilariae from the bloodstream. Consequently, the triple-drug regimen was endorsed for accelerating efforts to eliminate lymphatic filariasis as a public health problem in areas where onchocerciasis is not co-endemic. The aim of this study was to assess the feasibility of delivering mass treatment with the triple-drug regimen under programmatic conditions. An operational research study was conducted to determine the optimal sampling strategies, indicator (or set of indicators), and study populations for monitoring and evaluation of lymphatic filariasis programs using the triple-drug regimen mass drug administration. Two rounds of mass treatment with the triple-drug regimen were given to the residents of Lamu County (comprising of Lamu East and Lamu West sub-counties) and Jomvu sub-County (in Mombasa) in November 2018 and November 2019. The programme epidemiological treatment coverage was at least 80% in each implementation unit during the two treatment rounds. The preventive treatment resulted in significant reductions in the prevalence of the disease with the number of positive cases being fewer than the threshold recommended for areas where transmission is likely to be no longer sustainable.

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Does the Pareto Principle describe parasite counts in humans? The case of hookworm in pregnant women

Orobio, Y.; Alexander, N.

2021-01-04 infectious diseases 10.1101/2020.12.30.20249036 medRxiv
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The Pareto Principle (PP) -- that 80% of an attribute are found in 20% of individuals -- is one way to characterize heterogeneity in infectious diseases. An alternative is the dispersion parameter (k) of the negative binomial distribution (NBD). The NBD has two parameters, while the PP is a single property which may hold for any distribution family. The objectives of the current work are: a) to obtain a relation between the PP and NBD, i.e. to specify which combinations of NBD parameters comply with the PP; b) for hookworm, a soil-transmitted intestinal parasite of humans, to identify whether the PP or the NBD is a more parsimonious description of heterogeneity of infection load. For objective a), an empirical relation is found in the form of a saw-toothed line on a plot of k against the mean, reaching an asymptote of approximately 0.24. For objective b), we estimate k and the mean from nine studies from a systematic review of hookworm in pregnant women. Seven studies had higher heterogeneity than the PP, ranging from 83:20 to 100:20: we call these super-Pareto. One study was sub-Pareto (74:20), and one was Pareto (80:20). This suggests that at least two parameters, as supplied by the NBD, are necessary to describe the heterogeneity of hookworm. The probability of reaching a target reduction in prevalence is less when there is greater aggregation, which suggests that estimating aggregation via a subsample could be worthwhile, in order to set a target coverage threshold before starting mass drug administration.

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Prevalence of HIV history and associated factors in people affected by mpox in Colombia, 2022

MUNOZ LOZADA, C. M.; MADERO REALES, J. A.; CHAPARRO NARVAEZ, P. E.; PRIETO ALVARADO, F. E.

2025-02-08 public and global health 10.1101/2025.02.05.25321718 medRxiv
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The 2022 mpox outbreak disproportionately affected men who have sex with men (MSM) and individuals with history of HIV. This study investigated the prevalence of HIV infection and associated factors among mpox cases in Colombia. A cross-sectional analysis of 4,046 confirmed mpox cases reported to the Public Health Surveillance System between June 25 and December 31, 2022, was conducted. The prevalence of a history of HIV infection in mpox cases was determined, and associated factors were assessed using bivariate and multivariate logistic regression. Most mpox patients were male (97%), with a median age of 31 years (IQR = 27, 37). The most affected age group was 25 to 34 years (52%), and 83.7% were MSM. The prevalence of HIV history was 60%, with the highest rates in Manizales, Medellin, and Itagui. Common symptoms included genital lesions (59.6%) and fever (67.6%). Factors associated with HIV history in mpox patients were male sex [OR = 9.6, 95% CI = 4.35, 21.31], having sexually transmitted infections: hepatitis B [OR = 2.9, 95% CI = 1.91, 4.40], hepatitis C [OR = 7.0, 95% CI = 3.50, 13.97], syphilis [OR = 2.1, 95% CI = 1.46-3.12], hospitalization [OR = 2.2, 95% CI = 1.65, 2.93], Colombian nationality [OR = 2.5, 95% CI = 1.86, 3.48] and being homosexual [OR = 2.5, 95% CI = 2.09, 3.06]. A high prevalence of HIV infection (60%) was found among mpox patients in Colombia, predominantly among MSM. This highlights the need for targeted interventions, such as priority care for people with HIV, active surveillance, and education for timely diagnosis and prevention of complications.

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The role of molecular xenomonitoring in the assessment of the impact of Ivermectin, Diethylcarbamazine Citrate and Albendazole triple-drug therapy treatment to the lymphatic filariasis infection levels in the Kenyan coast.

Kanyi, H.; Odongo, D.; Jaoko, W.; Gass, K.; Chieng, B.; Araka, S.; Okoyo, C.; Njenga, S. M.

2025-06-18 public and global health 10.1101/2025.06.17.25329747 medRxiv
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Lymphatic Filariasis (LF) is a mosquito-borne disease primarily caused by the filarial parasite Wuchereria bancrofti. The triple-drug therapy of Ivermectin, Diethylcarbamazine (DEC), and Albendazole (IDA) has been adopted to accelerate LF elimination, particularly in areas where onchocerciasis is not co-endemic. In Kenya, IDA was administered to endemic communities in Jomvu sub-County (Mombasa) and Lamu County in 2018 and 2019. The impact of IDA was assessed using Molecular Xenomonitoring (MX), which involves detecting W. bancrofti DNA in mosquito pools via quantitative PCR (qPCR). MX surveys were conducted at baseline (2018) and at IDA impact survey 1 (IIS-1) in 2021 after two treatment rounds. Mosquitoes were collected from 30 randomly and 5-9 purposively selected villages per area. Traps used included CDC light, Gravid, and BioGents(R) (BG) traps at baseline, and only CDC light and Gravid traps at IIS-1. Mosquitoes were sorted by genus and pooled in up to 25 per pool. DNA was extracted and analyzed by qPCR. Filarial DNA prevalence was estimated using PoolTools v0.1.4. Concurrently, human infection was assessed using filariasis test strips (FTS) to detect circulating filarial antigen (CFA). At baseline, 37,732 mosquitoes were collected: 0.07% Anopheles, 2.3% Aedes, and 97.6% Culex. Of 486 pools tested, 30 (0.26%) were positive for W. bancrofti DNA. At IIS-1, 71,634 mosquitoes were collected: 0.46% Anopheles and 99.5% Culex. Of 1,695 pools tested, 22 (0.06%) were positive. Significant reductions were observed in filarial DNA in mosquitoes (76.9%, p < 0.001) and human antigenemia (52.1%, p = 0.004) after two treatment rounds. This study demonstrates a substantial decline in LF infection following two rounds of IDA. It also highlights molecular xenomonitoring as a sensitive, non-invasive tool for monitoring LF elimination progress. We recommend its integration into national LF control programs as a complementary surveillance method post-MDA

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LLIN Evaluation in Uganda Project (LLINEUP) - Plasmodium infection prevalence and genotypic markers of insecticide resistance in Anopheles vectors from 48 districts of Uganda

Lynd, A. R.; Gonahasa, S.; Staedke, S. G.; Oruni, A.; Maiteki-Sebuguzi, C.; Hancock, P. A.; Knight, E.; Dorsey, G.; Opigo, J.; Yeka, A.; Katureebe, A.; Kyohere, M.; Hemingway, J.; Kamya, M. R.; McDermott, D.; Lucas, E. R.; Donnelly, M. J.

2023-08-05 public and global health 10.1101/2023.07.31.23293323 medRxiv
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BackgroundIn 2017-2019, we conducted a large-scale, cluster-randomised trial (LLINEUP) to evaluate long-lasting insecticidal nets (LLINs) treated with a pyrethroid insecticide plus the synergist piperonyl butoxide (PBO LLINs), as compared to conventional, pyrethroid-only LLINs across 104 health sub-districts (HSDs) in Uganda. In LLINEUP, and similar trials in Tanzania, PBO LLINs were found to provide greater protection against malaria than conventional LLINs, reducing parasitaemia and vector density. In the LLINEUP trial, cross-sectional entomological surveys were carried out at baseline and then every 6 months for two years. In each survey, ten households per HSD were randomly selected for indoor household entomological collections. ResultsOverall, 5395 female Anopheles mosquitoes were collected from 5046 households. The proportion of mosquitoes infected with Plasmodium falciparum did not change significantly over time, while infection with non-falciparum malaria decreased in An. gambiae s.s, but not An. funestus. The frequency of genetic markers associated with pyrethroid resistance increased significantly over time, but the rate of change was not different between the two LLIN types. The knock-down resistance (kdr) mutation Vgsc-995S declined over time as Vgsc-995F, the alternative resistance mutation at this codon, increased. Vgsc-995F appears to be spreading into Uganda. ConclusionsDistribution of LLINs in Uganda was associated with reductions in parasite prevalence and vector density, but the proportion of infective mosquitoes remained stable, suggesting that the potential for transmission persisted. The increased frequency of markers of pyrethroid resistance indicates that LLIN distribution favoured the evolution of resistance within local vectors and highlights the potential benefits of resistance management strategies. Trial registration: This study is registered with ISRCTN, ISRCTN17516395. Registered 14 February 2017, http://www.isrctn.com/ISRCTN17516395