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Understanding the global burden of enterotoxigenic E. coli (ETEC) and Shigella diarrhea as well as estimating the cost effectiveness of vaccines to control these two significant pathogens have been hindered by the lack of a diagnostic test that is rapid, simple, sensitive, and can be applied to the endemic countries. We previously developed a simple and rapid assay, Rapid Loop mediated isothermal amplification based Diagnostic Test (RLDT) for the detection of ETEC and Shigella spp. (Shigella). In this study, the RLDT assay was evaluated in comparison with quantitative PCR (qPCR), culture and conventional PCR for the detection of ETEC and Shigella. This validation was performed using previously collected stool samples from endemic countries, from the travelers to the endemic countries, as well as samples from a controlled human infection model study of ETEC. The performance of RLDT from dried stool spots was also validated. RLDT resulted in excellent sensitivity and specificity compared to qPCR (99% and 99.2% respectively) ranging from 92.3 to 100% for the individual toxin genes of ETEC and 100% for Shigella. Culture was less sensitive compared to RLDT. No significant differences were noted in the performance of RLDT using samples from various sources or stool samples from moderate to severe diarrhea or asymptomatic infections. RLDT performed equally well in detection of ETEC and Shigella from the dried stool samples on filter papers. This study established that RLDT is sufficiently sensitive and specific to be used as a simple and rapid diagnostic assay to detect ETEC and Shigella in endemic countries to determine disease burden of these pathogens in the national and subnational levels. This information will be important to guide public health and policy makers to prioritize resources for accelerating the development and introduction of effective preventative and/or treatment interventions against these enteric infections. Author summary: Enterotoxigenic E. coli (ETEC) and Shigella spp (Shigella) causes significant global morbidity and mortality, especially in low-and middle-income countries (LMICs). Since culture methods to detect Shigella are not sensitive, and the methods used to detect ETEC have not been feasible outside of specialized, well-equipped laboratories, the true burden of these pathogens at national and sub-national levels are mostly not available. Morbidity and mortality estimates, for these two pathogens are crucial to assess their relative public health importance in LMICs. We developed a simple and rapid diagnostic assay called the RLDT (Rapid Loop-mediated isothermal amplification based Diagnostic Test) for detection of ETEC and Shigella. In this study we evaluated RLDT compared to other currently available assays using previously collected stool samples. Our data showed that the RLDT assay exhibited high sensitivity and specificity for detection of ETEC and Shigella, with its result available within 50 minutes. The sensitivity of RLDT was higher than culture for these pathogens. We conclude that RLDT could be used as a rapid and simple diagnostic test to determine the burden of ETEC and Shigella in LMICs as well as in clinical vaccine trials of these pathogens. [ABSTRACT FROM AUTHOR]

Objectives: Recently, improvements have been made to diagnostics for gambiense sleeping sickness control but their performance remains poorly documented and may depend on specimen processing prior to examination. In a prospective study in the Democratic Republic of the Congo, we compared the diagnostic performance of several parasite detection techniques, immune trypanolysis and of m18S PCR on whole blood stored in a stabilisation buffer or dried on filter paper. Methods: Individuals with CATT whole blood (WB) titer ≥1∶4 or with clinical signs indicative for sleeping sickness were examined for presence of trypanosomes in lymph node aspirate (LNA) and/or in blood. Blood was examined with Capillary Centrifugation Technique (CTC), mini-Anion Exchange Centrifugation Technique (mAECT) and mAECT on buffy coat (BC). PCR was performed on whole blood (i) stored in guanidine hydrochloride EDTA (GE) stabilisation buffer and (ii) dried on filter paper, and repeatability and reproducibility were assessed. Immune trypanolysis (TL) was performed on plasma. Results: A total of 237 persons were included. Among 143 parasitologically confirmed cases, 85.3% had a CATT-WB titre of ≥1/8, 39.2% were positive in LNA, 47.5% in CTC, 80.4% in mAECT-WB, 90.9% in mAECT-BC, 95.1% in TL and up to 89.5% in PCR on GE-stabilised blood. PCR on GE-stabilised blood showed highest repeatability (87.8%) and inter-laboratory reproducibility (86.9%). Of the 94 non-confirmed suspects, respectively 39.4% and 23.4% were TL or PCR positive. Suboptimal specificity of PCR and TL was also suggested by latent class analysis. Conclusion: The combination of LNA examination with mAECT-BC offered excellent diagnostic sensitivity. For PCR, storage of blood in stabilisation buffer is to be preferred over filter paper. TL as well as PCR are useful for remote diagnosis but are not more sensitive than mAECT-BC. For TL and PCR, the specificity, and thus usefulness for management of non-confirmed suspects remain to be determined. [ABSTRACT FROM AUTHOR]

Background: Urogenital schistosomiasis and HIV/AIDS infections are widespread in sub-Saharan Africa (SSA) leading to substantial morbidity and mortality. The co-occurrence of both diseases has led to the possible hypothesis that urogenital schistosomiasis leads to increased risk of acquiring HIV infection. However, the available evidence concerning this association is inconsistent. The aim of this study was to systematically review and quantitatively synthesize studies that investigated the association between urogenital schistosomiasis and HIV/AIDS infection. Methods: A systematic review basing on PRISMA guidelines was conducted. It is registered with PROSPERO, number CRD42018116648. We searched four databases, MEDLINE, EMBASE, Global Health and Global Index Medicus for studies investigating the association between urogenital schistosomiasis and HIV infection. Only studies published in English were considered. Results of the association were summarised by gender. A meta-analysis was performed for studies on females using random-effects model and a pooled OR with 95% confidence interval was reported. Results: Of the 993 studies screened, only eight observational studies met the inclusion criteria. Across all studies, the reported unadjusted OR ranged from 0.78 to 3.76. The pooled estimate of unadjusted OR among females was 1.31 (95% CI: 0.87–1.99). Only four of the eight studies reported an adjusted OR. A separate meta-analysis done in the three studies among females that reported an adjusted OR showed that the pooled estimate was 1.85 (95% CI: 1.17–2.92). There were insufficient data to pool results for association between urogenital schistosomiasis and HIV infection in the males. Conclusion: Our investigation supports the hypothesis of an association between urogenital schistosomiasis with HIV/AIDS infection in females. Due to insufficient evidence, no conclusion could be drawn in males with urogenital schistosomiasis. Large-scale prospective studies are needed in future. Author summary: Urogenital schistosomiasis, caused by parasitic trematode Schistosoma haematobium is a significant source of morbidity in sub Saharan Africa. HIV infection caused by a retrovirus is of two subtypes HIV 1 and HIV 2, with subtype HIV 1 being found worldwide and more aggressive, leading to HIV/AIDS. Research on both of these diseases in the same settings, has shown that these diseases cross paths. This has led to the suggestion that there could be a possible association between the two. Here we describe a systematic review that was carried out to determine if there is an association between UGS and HIV/AIDS infections. We searched all published articles available in MEDLINE, EMBASE, Global Health (CABI), and Global Index Medicus before 28th January 2020. We found eight observational studies eligible to be included in the systematic review and no intervention study. Six of these studies were included in the meta-analysis. A summarized meta-analysis of the study findings with adjusted OR showed that there was a likely association between urogenital schistosomiasis and HIV/AIDS infections in females. However, due to limited papers in males, no conclusion could be drawn. [ABSTRACT FROM AUTHOR]

At the height of the Ebola epidemic in Sierra Leone in November 2014, a new decentralized approach to ending infection chains was adopted. This approach was based on building local, small-scale Community Care Centres (CCC) intended to serve as triage units for safe handling of patients waiting for test results, with subsequent transfer to Ebola Treatment Centers (ETC) for those who tested positive for Ebola. This paper deals with local response to the CCC, and explains, through qualitative analysis of focus group data sets, why this development was seen, locally, in a positive light. The responses of 562 focus group participants in seven villages with CCC and seven neighbouring control villages without CCC are assessed. These data confirm that CCC are compatible with community values concerning access to, and family care for, the sick. Mixed reactions are reported in the case of "safe burial", a process that directly challenged ritual activity seen as vital to maintaining good relations between socially-enclaved rural families. Land acquisitions to build CCC prompted divided responses. This reflects problems about land ownership unresolved since colonial times between communities and government. The study provides insights into how gaps in understanding between international Ebola responders and local communities can be bridged. Author summary: Control of Ebola Virus Disease requires facilities where patients can be isolated and treated safely, without risk to medical personnel or family members. In the 2014–15 Ebola epidemic in Sierra Leone emphasis was at first placed on large field hospitals known as Ebola Treatment Centers (ETC). These were often located far from areas where new cases were being discovered. Patients were distrustful of their purpose and slow to report, and the disease continued to spread. Six months into the epidemic a new approach was tried, based on much smaller and more rapidly constructed centres (Community Care Centres (CCC) located where new cases were occurring. This paper examines community reactions to the CCC. There was a much greater sense of community ownership of these small, localised centres, and reporting times improved. Families were able easily to visit and observe activities, even though restricted from crossing red lines. The staff were often local and provided trustworthy information on the progress of patients. Families were able to prepare home food for patients, and this was thought to improve their morale and chances of survival. CCC were also appreciated for treating other disease, and not only Ebola. Referral of patients to ETC was easier to accept when the outcome of an Ebola blood test was known. There were some differences of opinion over "safe burial" procedures and acquisition of sites for the CCC, but on balance CCC were well accepted by communities, and were seen locally as a positive development in Ebola control. [ABSTRACT FROM AUTHOR]

Background: In Bangladesh, pharmacy-purchased oral rehydration solution (ORS) is often used to treat diarrhea, including cholera. Over-the-counter sales have been used for epidemiologic surveillance in the past, but rarely, if ever, in low-income countries. With few early indicators for cholera outbreaks in endemic areas, diarrhea-related product sales may serve as a useful surveillance tool. Methodology/Principal Findings: We tracked daily ORS sales at 50 pharmacies and drug-sellers in an urban Bangladesh community of 129,000 for 6-months while simultaneously conducting surveillance for diarrhea hospitalizations among residents. We developed a mobile phone based system to track the sales of ORS and deployed it in parallel with a paper-based system. Our objectives were to determine if the mobile phone system was practical and acceptable to pharmacists and drug sellers, whether data were reported accurately compared to a paper-based system, and whether ORS sales were associated with future incidence of cholera hospitalizations within the community. We recorded 47,215 customers purchasing ORS, and 315 hospitalized diarrhea cases, 22% of which had culture-confirmed cholera. ORS sales and diarrhea incidence were independently associated with the mean daily temperature; therefore both unadjusted and adjusted models were explored. Through unadjusted cross-correlation statistics and generalized linear models, we found increases in ORS sales were significantly associated with increases in hospitalized diarrhea cases up to 9-days later and hospitalized cholera cases up to one day later. After adjusting for mean daily temperature, ORS was significantly associated with hospitalized diarrhea two days later and hospitalized cholera one day later. Conclusions/Significance: Pharmacy sales data may serve as a feasible and useful surveillance tool. Given the relatively short lagged correlation between ORS sales and diarrhea, rapid and accurate sales data are key. More work is needed in creating actionable algorithms that make use of this data and in understanding the generalizability of our findings to other settings. [ABSTRACT FROM AUTHOR]

Introduction: Pure Neural Leprosy (PNL) is a rare clinical form of leprosy in which patients do not present with the classical skin lesions but have a high burden of the disability associated with the disease. Clinical characteristics and follow up of patients in PNL are still poorly described in the literature. Objective: This paper aims to describe the clinical, electrophysiological and histopathological characteristics of PNL patients, as well as their evolution after multidrug therapy (MDT). Methods: Fifty-two PNL patients were selected. Clinical, nerve conduction studies (NCS), histopathological and anti-PGL-1serology were evaluated. Patients were also assessed monthly during the MDT. At the end of the MDT, all of the patients had a new neurological examination and 44 were submitted to another NCS. Results: Paresthesia was the complaint most frequently reported by patients, and in the neurological examination the most common pattern observed was impairment in sensory and motor examination and a mononeuropathy multiplex. Painful nerve enlargement, a classical symptom of leprosy neuropathy, was observed in a minority of patients and in the motor NCS axonal injuries, alone or in combination with demyelinating features, were the most commonly observed. 88% of the patients did not present any leprosy reaction during MDT. There was no statistically significant difference between the neurological examinations, nor the NCS pattern, performed before and after the MDT. Discussion: The classical hallmarks of leprosy neuropathy are not always present in PNL making the diagnosis even more challenging. Nerve biopsy is an important tool for PNL diagnosis as it may guide therapeutic decisions. This paper highlights unique characteristics of PNL in the spectrum of leprosy in an attempt to facilitate the diagnosis and management of these patients. Author summary: Neuropathy is responsible for most of the disability associated with leprosy disease. The pure neural leprosy (PNL), in spite of being a rare clinical presentation of that, has some singular characteristics that are still poorly studied. In this study, we selected 52 patients at the diagnosis to describe their clinical, neurophysiological and histopathological presentation patterns as well as their evolution during the multidrug therapy (MDT). We confirmed that sensitive symptoms were the most commonly described by PNL patients but neural pain is rare. Also confirmed that mononeuropathy mutiplex was the most common pattern observed at neurological examination and at the nerve conduction studies at the moment of the diagnosis. However we showed that painful nerve enlargement other cardinal signs of leprosy, besides the skin lesions, is not common in this group of patients, There was no statistically significant difference between the neurological examination and NCS performed before and after the MDT.During the MDT88.4% of the patients did not have any leprosy reaction. This may suggest that that MDT was effective in stopping disease progression. Our results highlight the difficulties in the diagnosis of PNL and the progression following MDT in an attempt to prevent further disability in PNL patients. [ABSTRACT FROM AUTHOR]

Background: Work to control the gambiense form of human African trypanosomiasis (gHAT), or sleeping sickness, is now directed towards ending transmission of the parasite by 2030. In order to supplement gHAT case-finding and treatment, since 2011 tsetse control has been implemented using Tiny Targets in a number of gHAT foci. As this intervention is extended to new foci, it is vital to understand the costs involved. Costs have already been analysed for the foci of Arua in Uganda and Mandoul in Chad. This paper examines the costs of controlling Glossina palpalis palpalis in the focus of Bonon in Côte d'Ivoire from 2016 to 2017. Methodology/Principal findings: Some 2000 targets were placed throughout the main gHAT transmission area of 130 km2 at a density of 14.9 per km2. The average annual cost was USD 0.5 per person protected, USD 31.6 per target deployed of which 12% was the cost of the target itself, or USD 471.2 per km2 protected. Broken down by activity, 54% was for deployment and maintenance of targets, 34% for tsetse surveys/monitoring and 12% for sensitising populations. Conclusions/Significance: The cost of tsetse control per km2 of the gHAT focus protected in Bonon was more expensive than in Chad or Uganda, while the cost per km2 treated, that is the area where the targets were actually deployed, was cheaper. Per person protected, the Bonon cost fell between the two, with Uganda cheaper and Chad more expensive. In Bonon, targets were deployed throughout the protected area, because G. p. palpalis was present everywhere, whereas in Chad and Uganda G. fuscipes fuscipes was found only the riverine fringing vegetation. Thus, differences between gHAT foci, in terms of tsetse ecology and human geography, impact on the cost-effectiveness of tsetse control. It also demonstrates the need to take into account both the area treated and protected alongside other impact indicators, such as the cost per person protected. Author summary: Sleeping sickness is a fatal disease in Africa caused by trypanosomes transmitted by the bite of infected tsetse flies. The World Health Organization has set the absence of new infections as a goal for 2030. To achieve this, screening and treatment of patients is supplemented by tsetse control. Tiny Targets are small insecticide-impregnated panels of blue cloth and black netting which attract and kill tsetse. To maintain the momentum in these last stages of eliminating the disease, it is important to understand the costs of vector control. This paper presents the results of two years' cost monitoring in Bonon, an area covering 130 km2, home to 120,000 people. Since 2016, ~2,000 Tiny Targets have been deployed annually at a cost of USD 471 per km2 per year. Bonon is a degraded forested area and a relatively high number of targets was required as tsetse are present throughout. Nevertheless, the cost comes to only USD 0.5 per person protected per year. Compared to operations using Tiny Targets in Uganda and Chad, the cost was higher per km2 protected, reflecting the need to place targets throughout the area, but low per person protected compared to Chad, highlighting the need to use a range of comparators. [ABSTRACT FROM AUTHOR]

The reported cases of scrub typhus (ST) have continued to escalate, with outbreaks occurring regionally in China. These pose an increasing public health threat at a time when public health has been overwhelmed. During the period from July to August 2022, in Rongjiang County, Guizhou Province, China, 13 out of 21 fever patients were diagnosed with scrub typhus, based on epidemiological investigation and blood test analysis. The major clinical symptoms of these patients showed fever, chills, headache, eschar, fatigue and pneumonia, which were accompanied by a rise in C-reactive protein, neutrophils, alanine transaminase (ALT) and aspartate aminotransferase (AST). Furthermore, nearly half of them exhibited abnormal electrocardiogram activity. Through semi-nested PCR, Sanger sequencing and phylogenetic tree construction, the Karp strain of Orientia tsutsugamushi (O. tsutsugamushi) was confirmed as the pathogen causing ST in Rongjiang County, which shared the same evolutionary branch with O. tsutsugamushi isolated from wild mouse liver or spleen, indicating that the wild mouse plays an important role in transmitting the disease. In contrast to the sporadic cases in the past, our study is the first to disclose an epidemic and the corresponding clinical characteristics of ST in Guizhou province, which is of great significance for the prevention and treatment of regional illnesses. Author summary: In this study, 13 cases of ST were identified through clinical and laboratory diagnosis in Rongjiang County, which is the first outbreak of the disease in Guizhou province, China. It is worth noting that ST was caused by the Karp strain, which can be transmitted by wild mice, and the infected population generally had a clear history of outdoor activity. In addition to the typical clinical symptoms such as fever, chills and pneumonia, nearly half of patients with ST also exhibited abnormal electrocardiogram activity. In conclusion, our study presents a method to confirm ST through the combination of clinical and laboratory diagnosis, which provides a reference for the development of effective strategies and measures to tackle ST, and has important public health significance. [ABSTRACT FROM AUTHOR]

Simultaneous use of domestic spaces by humans and wildlife is little understood, despite global ubiquity, and can create an interface for human exposure to wildlife pathogens. Bats are a pervasive synanthropic taxon and are associated with several pathogens that can spill over and cause disease in humans. Urbanization has destroyed much natural bat habitat and, in response, many species increasingly use buildings as roosts. The purpose of this study was to characterize human interactions with bats in shared buildings to assess potential for human exposure to and spillover of bat-borne pathogens. We surveyed 102 people living and working in buildings used as bat roosts in Taita-Taveta county, Kenya between 2021 and 2023. We characterized and quantified the duration, intensity, and frequency of human-bat interactions occurring in this common domestic setting. Survey respondents reported living with bats in buildings year-round, with cohabitation occurring consistently for at least 10 years in 38% of cases. Human contact with bats occurred primarily through direct and indirect routes, including exposure to excrement (90% of respondents), and direct touching of bats (39% of respondents). Indirect contacts most often occurred daily, and direct contacts most often occurred yearly. Domestic animal consumption of bats was also reported (16% of respondents). We demonstrate that shared building use by bats and humans in rural Kenya leads to prolonged, frequent, and sometimes intense interactions between bats and humans, consistent with interfaces that can facilitate exposure to bat pathogens and subsequent spillover. Identifying and understanding the settings and practices that may lead to zoonotic pathogen spillover is of great global importance for developing countermeasures, and this study establishes bat roosts in buildings as such a setting. Author summary: Many bat species share space with people and domestic animals. Bat use of buildings, which serve as roosts where they raise young and sleep, is increasing globally with the loss of natural habitat. In such settings, interactions between bats, people, and domestic animals may occur. This may be cause for concern as bats can carry pathogens that infect people or domestic animals and interactions with bats may create opportunities for exposure to these pathogens. Until now, the characteristics of human-bat interactions in buildings, and their potential for exposing humans and domestic animals to bat-borne parasites, were unknown. In our study, people living and working in buildings used simultaneously by bats reported frequent interactions with bats and their feces, which can facilitate human exposure to bat pathogens. These interactions happened frequently and over many years. We demonstrate that shared building use by bats and people in rural Kenya leads to prolonged, frequent, and sometimes intense interactions between bats, humans, and domestic animals, consistent with exposure opportunities that can lead to pathogen spillover. Identifying the settings that may lead to human contact with pathogens is critical for developing countermeasures to mitigate public health hazards. [ABSTRACT FROM AUTHOR]

Background: In 2005, there were outbreaks of febrile polyarthritis due to Chikungunya virus (CHIKV) in the Comoros Islands. CHIKV then spread to other islands in the Indian Ocean: La Réunion, Mauritius, Seychelles and Madagascar. These outbreaks revealed the lack of surveillance and preparedness of Madagascar and other countries. Thus, it was decided in 2007 to establish a syndrome-based surveillance network to monitor dengue-like illness. Objective: This study aims to evaluate the use of capillary blood samples blotted on filter papers for molecular diagnosis of CHIKV infection. Venous blood samples can be difficult to obtain and the shipment of serum in appropriate temperature conditions is too costly for most developing countries. Methodology and principal findings: Venous blood and dried-blood blotted on filter paper (DBFP) were collected during the last CHIKV outbreak in Madagascar (2010) and as part of our routine surveillance of dengue-like illness. All samples were tested by real-time RT-PCR and results with serum and DBFP samples were compared for each patient. The sensitivity and specificity of tests performed with DBFP, relative to those with venous samples (defined as 100%) were 93.1% (95% CI:[84.7–97.7]) and 94.4% (95% CI:[88.3–97.7]), respectively. The Kappa coefficient 0.87 (95% CI:[0.80–0.94]) was excellent. Conclusion: This study shows that DBFP specimens can be used as a cost-effective alternative sampling method for the surveillance and monitoring of CHIKV circulation and emergence in developing countries, and probably also for other arboviruses. The loss of sensitivity is insignificant and involved a very small number of patients, all with low viral loads. Whether viruses can be isolated from dried blood spots remains to be determined. Author Summary: Chikungunya is a mosquito-transmitted viral disease. No treatment is currently available. The only way to prevent infection is to avoid mosquito bites. Surveillance of circulation by early diagnosis is useful to prevent or limit outbreak. CHIKV, like all RNA viruses, is heat-labile. Consequently, confirmatory diagnosis classically requires blood samples that are transported in appropriate conditions (i.e. at 4°C within 48 hours, in liquid nitrogen, or frozen at −80°C and transported on dry ice) to prevent false negative results. This is not always possible in field conditions in low income countries. Dried blood spots are already used to diagnose parasitic, bacterial and viral infection. We compared venous sample to dried blood sample to make diagnosis of Chikungunya infection. We demonstrate the usefulness of this sampling method for the molecular diagnosis of Chikungunya infection. In particular, dried blood spots were very nearly as suitable as frozen serum specimens for the diagnosis of recent infection by CHIKV. [ABSTRACT FROM AUTHOR]

In 2021, a patient died from Marburg virus (MARV) disease in Guinea and it was the first confirmed case in West Africa. The origin of the outbreak has not been identified. It was revealed that the patient didn't travel anywhere before the illness. Prior to outbreak, MARV had been found in bats in the neighboring Sierra Leone, but never in Guinea. Therefore, the origin of infection is unclear: was it an autochthonous case with spillover from a local population of bats or an imported case with spillover from fruit bats foraging/migrating from Sierra Leone? In this paper, we studied Rousettus aegyptiacus in Guinea as the possible source of MARV infection caused the patient death in 2021 in Guinea. We caught bats in 32 sites of Guéckédou prefecture, including seven caves and 25 locations of the flight path. A total of 501 fruit bats (Pteropodidae) were captured, including 66 R. aegyptiacus. The PCR screening showed three positive MARV R. aegyptiacus, roosting in two caves discovered in Guéckédou prefecture. After Sanger sequencing and phylogenetic analyses it was shown that found MARV belongs to the Angola-like lineage but it is not identical to the isolate obtained during the outbreak of 2021. Author summary: In 2020, MARV was first detected in fruit bats in Sierra Leone (West Africa). One year later, first outbreak of MARV in West Africa was registered in the neighboring Guinea after a man's death in the Temessadou M'bokét village. The source of the outbreak has not been identified. It is known, that the reservoir animal of MARV is the cave-dwelling bat Rousettus aegyptiacus, and typically, MARV disease outbreaks emerge after a visit of the index patient to a cave or mine. In our work, we studied bats in the vicinity of this village for the presence of the MARV. A cave hosting a colony of R. aegyptiacus was found close to the Temessadou M'bokét village (~4.5 km). Sampling and PCR screening of the bats from the colony identified three MARV-positive bats. The cave is inaccessible to humans; therefore, the index patient could not have been infected upon visit. We assume that the patient was infected outside the cave after direct or indirect contact with an infected bat of the same colony. These results provide the basis for preventive measures against new MARV outbreaks in Guinea. [ABSTRACT FROM AUTHOR]

Visceral leishmaniasis (VL) is a neglected tropical disease that is globally distributed and has the potential to cause very serious illness. Prior literature highlights the emergence and spread of VL is influenced by multiple factors, such as socioeconomic status, sanitation levels or animal and human reservoirs. The study aimed to retrospectively investigate the presence and infectiousness of VL in Rio Grande do Norte (RN), Brazil between 2007 and 2020. We applied a hierarchical Bayesian approach to estimate municipality-specific relative risk of VL across space and time. The results show evidence that lower socioeconomic status is connected to higher municipality-specific VL risk. Overall, estimates reveal spatially heterogeneous VL risks in RN, with a high probability that VL risk for municipalities within the West Potiguar mesoregion are more than double the expected VL risk. Additionally, given the data available, results indicate there is a high probability of increasing VL risk in the municipalities of Natal, Patu and Pau dos Ferros. These findings demonstrate opportunities for municipality-specific public health policy interventions and warrant future research on identifying epidemiological drivers in at-risk regions. Author summary: As a neglected tropical disease (NTD), Leishmaniasis contributes to poor health outcomes, suffering, and death of vulnerable populations. Leishmania infantum or Leishmania donovani is transmitted from animals to humans through the sandfly vector and can be fatal in 5% of the cases even with treatment. Visceral leishmaniasis is a severe form of Leishmaniasis. The purpose of this study was to estimate regions of high Visceral leishmaniasis risk in Rio Grande do Norte, Brazil between 2007 and 2020 to help inform public health initiatives and potential health policy interventions for this disease. Visceral leishmaniasis is a reportable disease and therefore VL cases are documented to the Brazilian Ministry of Health database through passive surveillance. Passive surveillance data can suffer from missing information; individuals may be asymptomatic, or may not seek medical care allowing for diagnosis. When modeling disease risk from passive surveillance data, assuming there is an absence of disease in regions without documented cases can underestimate disease risk. In this paper we estimate disease risk and identify areas with high-risk and increasing infection trends over time while considering data characteristics such as missing information and high correlation of risk factors. [ABSTRACT FROM AUTHOR]

Schistosomiasis is a neglected water-born parasitic disease caused by Schistosoma affecting more than 200 million people. Introgressive hybridization is common among these parasites and raises issues concerning their zoonotic transmission. Morphological identification of Schistosoma cercariae is difficult and does not permit hybrids detection. Our objective was to assess the performance of MALDI-TOF (Matrix Assistated Laser Desorption-Ionization–Time Of Flight) mass spectrometry for the specific identification of cercariae in human and non-human Schistosoma and for the detection of hybridization between S. bovis and S. haematobium. Spectra were collected from laboratory reared molluscs infested with strains of S. haematobium, S. mansoni, S. bovis, S. rodhaini and S. bovis x S. haematobium natural (Corsican hybrid) and artificial hybrids. Cluster analysis showed a clear separation between S. haematobium, S. bovis, S. mansoni and S. rodhaini. Corsican hybrids are classified with those of the parental strain of S. haematobium whereas other hybrids formed a distinct cluster. In blind test analysis the developed MALDI-TOF spectral database permits identification of Schistosoma cercariae with high accuracy (94%) and good specificity (S. bovis: 99.59%, S. haematobium 99.56%, S. mansoni and S. rodhaini: 100%). Most misidentifications were between S. haematobium and the Corsican hybrids. The use of machine learning permits to improve the discrimination between these last two taxa, with accuracy, F1 score and Sensitivity/Specificity > 97%. In multivariate analysis the factors associated with obtaining a valid identification score (> 1.7) were absence of ethanol preservation (p < 0.001) and a number of 2–3 cercariae deposited per well (p < 0.001). Also, spectra acquired from S. mansoni cercariae are more likely to obtain a valid identification score than those acquired from S. haematobium (p<0.001). MALDI-TOF is a reliable technique for high-throughput identification of Schistosoma cercariae of medical and veterinary importance and could be useful for field survey in endemic areas. Author summary: Schistosomiases are neglected tropical diseases, affecting approximately 200 million people worldwide. They are transmitted during contact with water contaminated with the infesting stage of the parasite (the cercaria stage). Species-level recognition of cercariae present in water has important implications for field campaigns aimed at eradicating schistosomiasis. In addition, Schistosomes are able to hybridize between different species. Identification of Schistosomes cercariae on microscopy is difficult because of their similarity, and it does not allow hybrids to be distinguished. Molecular biology techniques allow a reliable diagnosis but are expensive. MALDI-TOF is a recent technique that permits an inexpensive identification of micro-organisms in a few minutes. In this paper, we evaluate MALDI-TOF identification of Schistosomes cercariae. We have implemented a database of MALDI-TOF cercariae spectra obtained from parental strains and hybrids of species of medical or veterinary interest, allowing reliable identification with an accuracy of 94%. The identification errors mainly come from confusion between the natural Corsican hybrid (S. haematobium x S. bovis) and S. haematobium. The use of machine learning algorithms permits to obtain an accuracy of more than 97% in the recognition of these two parasites. In conclusion, MALDI-TOF is a promising tool for the identification of Schistosome cercariae. [ABSTRACT FROM AUTHOR]

Background: Experiencing adverse events (AEs) during mass drug administration (MDA) could affect participation in future MDAs. This study aims to understand the potential influence of AEs during a community-wide MDA (cMDA) trial for soil-transmitted helminths (STH) in India on intention to participate in future cMDAs. Methods: This study was conducted using a multi-method quantitative and qualitative approach among 74 participants who experienced an AE during STH cMDA and the 12 participants who subsequently refused cMDA treatment of the ongoing DeWorm3 trial. Path analysis and thematic analysis guided by the Theory of Planned Behaviour, was used. Principal findings: Among 74 individuals who reported an AE, 12% refused treatment in the cMDA immediately subsequent to their AE and 4% refused in all subsequent cMDAs. Of these 74 individuals, 59 (80%) completed a survey and eight participated in in-depth interviews. A positive attitude towards deworming and perceived ability to participate in cMDA (perceived behavioural control) were significant predictors of intention to participate in cMDA (p<0.05). A positive attitude towards cMDA was associated with caste (χ2 = 3.83, P = 0.05), particularly among the scheduled caste/scheduled tribe (SC/ST) (62%). Perceived behavioural control in cMDA participation was associated with occupation (χ2 = 5.02, P<0.05), with higher perceived control among those engaged in skilled occupations (78%). Intention to participate in subsequent cMDAs was associated with caste and family type (χ2 = 3.83, P = 0.05 and χ2 = 7.50, P<0.05 respectively) and was higher among SC/ST (62%) and those with extended families (67%). In-depth interviews demonstrated that perceived severe AEs may lead to treatment refusal in future, particularly if children were affected. Conclusions: Intention to participate in future STH cMDAs was associated with caste (SC/ST) and family type (extended families). Therefore, community mobilization messages about potential AEs and their management may need to intentionally target non-SC/ST households, nuclear families, and those engaged in unskilled occupations to increase cMDA participation given the possibility of AEs occurring. Trial registration: NCT03014167, ClinicalTrials.gov. Author summary: This paper sampled individuals who experienced an AE during community-wide MDA (cMDA) with albendazole for soil-transmitted helminths in the DeWorm3 trial in India to understand their intention to participate in future cMDAs. This study utilized the theory of planned behaviour, which postulates that an individual's intention to change a behaviour depends on their attitude, perceived expectations of people around them (social norms), and their perceived behavioural control to adopt the behaviour (self-efficacy). This study indicated that positive attitude towards cMDA and their perceived behavioural control in cMDA participation positively influences their intention to participate in future cMDAs. Other factors associated with intention to participate in cMDA were caste, family structure, occupation, and participation in community sensitisation activities. In-depth interviews revealed that while many individuals participate in subsequent cMDAs after an AE because of the presumed health benefits of deworming, some are likely to refuse treatment due to fear of AEs, particularly fears of AEs among children. To increase participation rates in cMDA programs where AEs undoubtably do occur, targeted counselling of groups at risk of non-participation and assuring care and support during AEs may be important strategies to improve coverage. [ABSTRACT FROM AUTHOR]

Background: Over the past decades, several viral diseases transmitted by Aedes mosquitoes—dengue, chikungunya, Zika—have spread outside of tropical areas. To limit the transmission of these viruses and preserve human health, the use of mosquito traps has been developed as a complement or alternative to other vector control techniques. The objective of this work was to perform a systematic review of the existing scientific literature to assess the efficacy of interventions based on adult mosquito trap to control Aedes population densities and the diseases they transmit worldwide. Methods and findings: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic review was conducted using the PubMed and Scopus databases. Among the 19 selected papers, lethal ovitraps were used in 16 studies, host-seeking female traps in 3 studies. Furthermore, 16 studies focused on the control of Ae. aegypti. Our review showed great heterogeneity in the indicators used to assess trap efficacy: e.g., the number of host-seeking females, the number of gravid females, the proportion of positive containers, the viral infection rate in female mosquitoes or serological studies in residents. Regardless of the type of studied traps, the results of various studies support the efficacy of mass trapping in combination with classical integrated vector control in reducing Aedes density. More studies with standardized methodology, and indicators are urgently needed to provide more accurate estimates of their efficacy. Conclusions: This review highlights gaps in the demonstration of the efficacy of mass trapping of mosquitoes in reducing viral transmission and disease. Thus, further large-scale cluster randomized controlled trials conducted in endemic areas and including epidemiological outcomes are needed to establish scientific evidence for the reduction of viral transmission risk by mass trapping targeting gravid and/or host-seeking female mosquitoes. Author summary: Over the past decades, several viral diseases transmitted by Aedes mosquitoes—dengue, chikungunya, Zika—have spread outside of tropical areas. To limit the transmission of these viruses and preserve environment and human health, the use of mosquito traps has been developed as a complement or alternative to other vector control techniques. This review support the efficacy of mass trapping in combination with classical integrated vector control on the reduction in mosquito vector populations within several weeks of deployment. However, this research highlights gaps in the demonstration of the efficacy of mass trapping of mosquitoes in reducing viral transmission and disease. Thus, further studies are needed to establish scientific evidence for the reduction of viral transmission risk by mass trapping targeting gravid and/or host-seeking female mosquitoes. [ABSTRACT FROM AUTHOR]

During infection of mammalian hosts, African trypanosomes thwart immunity using antigenic variation of the dense Variant Surface Glycoprotein (VSG) coat, accessing a large repertoire of several thousand genes and pseudogenes, and switching to antigenically distinct copies. The parasite is transferred to mammalian hosts by the tsetse fly. In the salivary glands of the fly, the pathogen adopts the metacyclic form and expresses a limited repertoire of VSG genes specific to that developmental stage. It has remained unknown whether the metacyclic VSGs possess distinct properties associated with this particular and discrete phase of the parasite life cycle. We present here three novel metacyclic form VSG N-terminal domain crystal structures (mVSG397, mVSG531, and mVSG1954) and show that they mirror closely in architecture, oligomerization, and surface diversity the known classes of bloodstream form VSGs. These data suggest that the mVSGs are unlikely to be a specialized subclass of VSG proteins, and thus could be poor candidates as the major components of prophylactic vaccines against trypanosomiasis. Author summary: The African trypanosome is a single-celled parasite causing African Sleeping Sickness in humans and related diseases in animals. It has a unique protein coat made up mostly of a single protein, called the Variant Surface Glycoprotein, or VSG. The African trypanosome possesses several thousand different VSG genes. As the immune system of an infected host learns to recognize one coat protein and kill the trypanosomes, the parasite switches to a different VSG protein that is not recognized by the immune system. This allows the parasite to keep thriving in the host as this process repeats. This paper presents molecular images of a subset of VSG proteins that are on the surface of the organism when it is transferred to hosts by the bite of the tsetse fly—the first step in infection. We show that these so-called metacyclic VSGs are neither special nor unique compared to those VSGs that take over in the bloodstream during the course of infection. These results clarify the nature of these first VSG coats the host is exposed to and have important implications for trypanosome infection and vaccine development. [ABSTRACT FROM AUTHOR]

Background: Snakebite envenoming is a neglected tropical disease affecting deprived populations, and its burden is underestimated in some regions where patients prefer using traditional medicine, case reporting systems are deficient, or health systems are inaccessible to at-risk populations. Thus, the development of strategies to optimize disease management is a major challenge. We propose a framework that can be used to estimate total snakebite incidence at a fine political scale. Methodology/Principal findings: First, we generated fine-scale snakebite risk maps based on the distribution of venomous snakes in Colombia. We then used a generalized mixed-effect model that estimates total snakebite incidence based on risk maps, poverty, and travel time to the nearest medical center. Finally, we calibrated our model with snakebite data in Colombia from 2010 to 2019 using the Markov-chain-Monte-Carlo algorithm. Our results suggest that 10.19% of total snakebite cases (532.26 yearly envenomings) are not reported and these snakebite victims and do not seek medical attention, and that populations in the Orinoco and Amazonian regions are the most at-risk and show the highest percentage of underreporting. We also found that variables such as precipitation of the driest month and mean temperature of the warmest quarter influences the suitability of environments for venomous snakes rather than absolute temperature or rainfall. Conclusions/Significance: Our framework permits snakebite underreporting to be estimated using data on snakebite incidence and surveillance, presence locations for the most medically significant venomous snake species, and openly available information on population size, poverty, climate, land cover, roads, and the locations of medical centers. Thus, our algorithm could be used in other countries to estimate total snakebite incidence and improve disease management strategies; however, this framework does not serve as a replacement for a surveillance system, which should be made a priority in countries facing similar public health challenges. Author summary: Snakebite envenoming is a neglected tropical disease that is a major challenge to manage because of incidence underreporting, which is caused by the low coverage of health centers in tropical countries and preferences for traditional medicine among snakebite victims. Several mathematical approaches have been used to explain variation in snakebite incidence via parameter adjustment, but these approximations have not been used to estimate envenomings that are not reported to medical centers. Our study proposes a statistical framework to estimate snakebite underreporting. To our knowledge, this is the first paper that provides computational estimates of the number of snakebite cases that are not receiving treatment by health care facilities; this approach is more time and labor-efficient compared with field epidemiological studies. Our modelling scheme can be used to rapidly estimate spatial heterogeneity in snakebite underreporting and identify areas where increased accessibility to health care facilities is urgently needed. Our framework can also be used to determine the expected number of snakebite cases, promote community empowerment and public health, and determine the real demand for antivenom. This tool could also be applied in various countries, but it is worth emphasizing that it should not serve as a replacement for medical surveillance system. [ABSTRACT FROM AUTHOR]

Background: Medicine quality screening devices hold great promise for post-market surveillance (PMS). However, there is little independent evidence on their field utility and usability to inform policy decisions. This pilot study in the Lao PDR tested six devices' utility and usability in detecting substandard and falsified (SF) medicines. Methodology/principal findings: Observational time and motion studies of the inspections by 16 Lao medicine inspectors of 1) the stock of an Evaluation Pharmacy (EP), constructed to resemble a Lao pharmacy, and 2) a sample set of medicines (SSM); were conducted without and with six devices: four handheld spectrometers (two near infrared: MicroPHAZIR RX, NIR-S-G1 & two Raman: Progeny, Truscan RM); one portable mid-infrared spectrometer (4500a), and single-use paper analytical devices (PAD). User experiences were documented by interviews and focus group discussions. Significantly more samples were wrongly categorised as pass/fail with the PAD compared to the other devices in EP inspections (p<0.05). The numbers of samples wrongly classified in EP inspections were significantly lower than in initial visual inspections without devices for 3/6 devices (NIR-S-G1, MicroPHAZIR RX, 4500a). The NIR-S-G1 had the fastest testing time per sample (median 93.5 sec, p<0.001). The time spent on EP visual inspection was significantly shorter when using a device than for inspections without devices, except with the 4500a, risking missing visual clues of samples being SF. The main user errors were the selection of wrong spectrometer reference libraries and wrong user interpretation of PAD results. Limitations included repeated inspections of the EP by the same inspectors with different devices and the small sample size of SF medicines. Conclusions/significance: This pilot study suggests policy makers wishing to implement portable screening devices in PMS should be aware that overconfidence in devices may cause harm by reducing inspectors' investment in visual inspection. It also provides insight into the advantages/limitations of diverse screening devices in the hands of end-users. Author summary: Substandard and falsified (SF) medicines threaten the lives of millions of people, especially where pharmaceutical legislation and regulation are limited. Screening for SF medicines in supply chains ('post-market surveillance') by medicine inspectors is crucial but currently relies only on subjective visual inspection of medicines in most countries. Many innovative portable screening technologies now exist and could be key additional assets to the current practice, but none have been extensively evaluated for medicine quality post-market surveillance. We assessed the utility and usability of six screening devices in the hands of Lao medicines inspectors in a pharmacy constructed to resemble a Lao pharmacy. Five spectrometers showed promising accuracies to identify falsified medicines, but difficulties to correctly set them up before running tests were observed. Reading and interpreting colour barcodes of the 'paper analytical cards'–a lab-on-a-chip test by inspectors were difficult, leading to lower accuracy than with spectrometers. The study suggests that overconfidence in devices may cause harm by reducing inspectors' investment in visual inspection—a crucial step to identify falsified medicines. Advantages/limitations of the devices are also documented to inform policy. [ABSTRACT FROM AUTHOR]

Background: Post-market surveillance is a key regulatory function to prevent substandard and falsified (SF) medicines from being consumed by patients. Field deployable technologies offer the potential for rapid objective screening for SF medicines. Methods and findings: We evaluated twelve devices: three near infrared spectrometers (MicroPHAZIR RX, NIR-S-G1, Neospectra 2.5), two Raman spectrometers (Progeny, TruScan RM), one mid-infrared spectrometer (4500a), one disposable colorimetric assay (Paper Analytical Devices, PAD), one disposable immunoassay (Rapid Diagnostic Test, RDT), one portable liquid chromatograph (C-Vue), one microfluidic system (PharmaChk), one mass spectrometer (QDa), and one thin layer chromatography kit (GPHF-Minilab). Each device was tested with a series of field collected medicines (FCM) along with simulated medicines (SIM) formulated in a laboratory. The FCM and SIM ranged from samples with good quality active pharmaceutical ingredient (API) concentrations, reduced concentrations of API (80% and 50% of the API), no API, and the wrong API. All the devices had high sensitivities (91.5 to 100.0%) detecting medicines with no API or the wrong API. However, the sensitivities of each device towards samples with 50% and 80% API varied greatly, from 0% to 100%. The infrared and Raman spectrometers had variable sensitivities for detecting samples with 50% and 80% API (from 5.6% to 50.0%). The devices with the ability to quantitate API (C-Vue, PharmaChk, QDa) had sensitivities ranging from 91.7% to 100% to detect all poor quality samples. The specificity was lower for the quantitative C-Vue, PharmaChk, & QDa (50.0% to 91.7%) than for all the other devices in this study (95.5% to 100%). Conclusions: The twelve devices evaluated could detect medicines with the wrong or none of the APIs, consistent with falsified medicines, with high accuracy. However, API quantitation to detect formulations similar to those commonly found in substandards proved more difficult, requiring further technological innovation. Author summary: Criminally falsified or poorly manufactured medicines can lead to patients becoming sicker and losing trust in the health system. Portable tools beyond just documentation checks and visual inspection (the current practices in many low- and middle-income countries) can help pharmacy inspectors with early detection of poor quality medicines. Currently, many tools are available to detect poor quality medicines, but their performances have not been properly assessed and compared. In this study, 12 different devices ranging from disposable single use tests to portable spectrometers were tested in a laboratory. All the tested devices could identify medicines that contained none or the wrong active ingredient(s), a common trait of falsified medicines. Disposable tests required few resources to be implemented, but had difficulties identifying medicines with reduced amounts of active ingredients. Spectrometers used 'out-of-the-box' required minimal consumables had varying degrees of success at detecting medicines with reduced amounts of active ingredients. Finally, instruments with more quantitative abilities, such as benchtop simple chromatographs or mass spectrometers, offered the best sensitivity for detecting medicines with reduced amounts of active ingredients, but required the most resources and training and were deemed to be more suitable for centralized testing. [ABSTRACT FROM AUTHOR]

Background: Spatial modelling of STH and schistosomiasis epidemiology is now commonplace. Spatial epidemiological studies help inform decisions regarding the number of people at risk as well as the geographic areas that need to be targeted with mass drug administration; however, limited attention has been given to propagated uncertainties, their interpretation, and consequences for the mapped values. Using currently published literature on the spatial epidemiology of helminth infections we identified: (1) the main uncertainty sources, their definition and quantification and (2) how uncertainty is informative for STH programme managers and scientists working in this domain. Methodology/Principal Findings: We performed a systematic literature search using the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) protocol. We searched Web of Knowledge and PubMed using a combination of uncertainty, geographic and disease terms. A total of 73 papers fulfilled the inclusion criteria for the systematic review. Only 9% of the studies did not address any element of uncertainty, while 91% of studies quantified uncertainty in the predicted morbidity indicators and 23% of studies mapped it. In addition, 57% of the studies quantified uncertainty in the regression coefficients but only 7% incorporated it in the regression response variable (morbidity indicator). Fifty percent of the studies discussed uncertainty in the covariates but did not quantify it. Uncertainty was mostly defined as precision, and quantified using credible intervals by means of Bayesian approaches. Conclusion/Significance: None of the studies considered adequately all sources of uncertainties. We highlighted the need for uncertainty in the morbidity indicator and predictor variable to be incorporated into the modelling framework. Study design and spatial support require further attention and uncertainty associated with Earth observation data should be quantified. Finally, more attention should be given to mapping and interpreting uncertainty, since they are relevant to inform decisions regarding the number of people at risk as well as the geographic areas that need to be targeted with mass drug administration. [ABSTRACT FROM AUTHOR]

The microscopic agglutination test (MAT) is the standard serological reference test for the diagnosis of leptospirosis, despite being a technically demanding and laborious procedure. The use of a locally optimised MAT panel is considered essential for proper performance and interpretation of results. This paper describes the procedure of selecting such an optimised panel for Sri Lanka, a country hyper-endemic for leptospirosis. MAT was performed using 24 strains on 1132 serum samples collected from patients presenting with acute undifferentiated fever. Of 24 strains, 15 were selected as the optimised panel, while only 11% of serum samples showed positivity. A geographical variation in predominantly reactive serovars was observed, whereas reactivity was low with the saprophytic strain Patoc. Testing with paired sera yielded a higher sensitivity but provided only a retrospective diagnosis. Serological tests based on ELISA with complimentary molecular diagnosis using PCR are a feasible and robust alternative approach to diagnose leptospirosis in countries having a higher burden of the disease. Author summary: Microscopic agglutination test is the most commonly used serological test in the diagnosis of leptospirosis. The test uses a live panel of Leptospira representing main serogroups and for proper performance of the test, an optimised panel which react well with patient samples need to be selected. This paper describes the procedure of selecting such an optimised panel for Sri Lanka which is a country hyper-endemic for leptospirosis. The test was done on serum samples collected from patients presented with acute undifferentiated fever with 24 panel of serogroups and 15 were selected as the optimised panel. The test was found to have a low sensitivity in the acute stage and ELISA based serological tests with molecular diagnosis using PCR assays would be a better way for diagnosis of leptospirosis. [ABSTRACT FROM AUTHOR]

Harris County, TX, is the third most populous county in the USA and upon detection of arboviruses Harris County Public Health applies insecticides (e.g., pyrethroid-based Permanone 31–66) against adults of Culex quinquefasciatus to prevent disease transmission. Populations of Aedes aegypti, while not yet a target of public health control, are likely affected by pyrethroid exposure. As this species is a vector of emerging arboviruses, its resistance status to Permanone and the kdr mutations in the voltage-gated sodium channel (VGSC) associated with pyrethroid resistance were investigated. We examined females of known genotype at the V1016I and F1534C sites (N = 716) for their genotype at the 410 amino acid position in the VGSC, and for the influence of their kdr genotype on survival to Permanone at three different distances from the insecticide source in field tests. Most females (81.8%) had at least one resistant L allele at the 410 position, being the first report of the V410L mutation in Ae. aegypti for Texas. When only genotypes at the 410 position were analyzed, the LL genotype exhibited higher survivorship than VL or VV. Out of 27 possible tri-locus kdr genotypes only 23 were found. Analyses of the probability of survival of tri-locus genotypes and for the V410L genotype using a multivariate logistic regression model including area, distance, and genotype found significant interactions between distance and genotype. When only the most common tri-locus genotypes were analyzed (LL/II/CC, 48.2%; VL/II/CC, 19.1%; and VV/II/CC, 10.1%) genotype had no effect on survival, but significant interactions of distance and genotype were found. This indicated that the V410L kdr allele increased survival probability at certain distances. Genotypes did not differ in survivorship at 7.62-m, but LL/II/CC had higher survivorship than VL/II/CC at 15.24- and 22.86-m. The model also identified differences in survivorship among the operational areas investigated. Author summary: Preventing Aedes aegypti populations from spreading arboviruses in highly populated areas primarily relies upon chemical control with insecticides, such as pyrethroids, applied by public health agencies to target the female mosquito vector. However, the development of insecticide resistance in mosquito populations jeopardizes these vector control strategies. The impact of the different kdr mutations conferring resistance to pyrethroids on the survival of Ae. aegypti in the field is not fully understood. We previously found that two knockdown resistance (kdr) mutations in the voltage gated sodium channel (VGSC) did not increase survivorship in field cage tests despite their widespread presence and high frequency. In this paper, we report the first detection of the V410L kdr mutation in combination with the V1016I and F1534C genotypes. Most females were detected with kdr mutations at one, two or three of these sites in the VGSC. Genotyping females after insecticide application in field cage tests showed that the V410L mutations were associated with higher survivorship only at the 15.24- and 22.86-meter distances from the source of the spray application, as we observed that the LL/II/CC genotype had higher survivorship than the VL/II/CC genotype at these distances. [ABSTRACT FROM AUTHOR]

Chagas' disease is a neglected tropical disease caused by the kinetoplastid protozoan Trypanosoma cruzi. The only therapies are the nitroheterocyclic chemicals nifurtimox and benznidazole that cause various adverse effects. The need to create safe and effective medications to improve medical care remains critical. The lack of verified T. cruzi therapeutic targets hinders medication research for Chagas' disease. In this respect, cytochrome bc1 has been identified as a promising therapeutic target candidate for antibacterial medicines of medical and agricultural interest. Cytochrome bc1 belongs to the mitochondrial electron transport chain and transfers electrons from ubiquinol to cytochrome c1 by the action of two catalytic sites named Qi and Qo. The two binding sites are highly selective, and specific inhibitors exist for each site. Recent studies identified the Qi site of the cytochrome bc1 as a promising drug target against T. cruzi. However, a lack of knowledge of the drug mechanism of action unfortunately hinders the development of new therapies. In this context, knowing the cause of binding site selectivity and the mechanism of action of inhibitors and substrates is crucial for drug discovery and optimization processes. In this paper, we provide a detailed computational investigation of the Qi site of T. cruzi cytochrome b to shed light on the molecular mechanism of action of known inhibitors and substrates. Our study emphasizes the action of inhibitors at the Qi site on a highly unstructured portion of cytochrome b that could be related to the biological function of the electron transport chain complex. Author summary: Chagas' disease is caused by the parasite Trypanosoma cruzi, which is prevalent in low-income African, Asian, and American countries and spread through the rest of the world through migrations infecting about 8 million people and causing 10 000 deaths per year. Currently, the only drugs approved for treating Chagas' disease have various side effects. Identifying proteins of the parasite that can limit its activity can help the development of new and more effective drugs. In this context, the cytochrome bc1 of Trypanosoma cruzi has been identified as a promising drug target. However, it is unclear how certain drugs affect cytochrome bc1 biological activity. Molecular dynamics simulations have been used to analyze the impact of specific small molecules on protein conformational changes that may be related to cytochrome bc1's biological function. This manuscript presents a computational approach that could identify small-molecule lead compounds and distinguish between true and false cytochrome b inhibitors. [ABSTRACT FROM AUTHOR]

HEV study protocol: design of a cluster-randomised, blinded trial to assess the safety, immunogenicity and effectiveness of the hepatitis E vaccine HEV 239 (Hecolin) in women of childbearing age in rural Bangladesh. Barriers to use Use of vaccine in an outbreak Although the 2015 WHO position paper acknowledged that there may be special situations where HEV vaccine should be used, including outbreaks of hepatitis E, decisions regarding use of vaccine were deferred to local/national authorities. Hepatitis E vaccine - Illuminating the barriers to use HEV study protocol: design of a cluster-randomised, blinded trial to assess the safety, immunogenicity and effectiveness of the hepatitis E vaccine HEV 239 (Hecolin) in women of childbearing age in rural Bangladesh. [Extracted from the article]

Anthrax is a serious zoonosis caused by Bacillus anthracis, which primarily affects wild herbivorous animals with spillover into humans. The disease occurs nearly worldwide but is poorly reported in Southeast Asian countries. In Vietnam, anthrax is underreported, and little is known about its temporal and spatial distributions. This paper examines the spatio-temporal distribution and epidemiological characteristics of human and livestock anthrax from Dien Bien province, Vietnam from 2010 to 2019. We also aim to define the role of livestock vaccination in reducing human cases. Historical anthrax data were collected by local human and animal health sectors in the province. Spatial rate smoothing and spatial clustering analysis, using Local Moran's I in GeoDa and space-time scan statistic in SaTScan, were employed to address these objectives. We found temporal and spatial overlap of anthrax incidence in humans and livestock with hotspots of human anthrax in the east. We identified three significant space-time clusters of human anthrax persisting from 2010 to 2014 in the east and southeast, each with high relative risk. Most of the human cases were male (69%), aged 15–59 years (80%), involved in processing, slaughtering, or eating meat of sick or dead livestock (96.9%) but environmental and unknown exposure were reported. Animal reports were limited compared to humans and at coarser spatial scale, but in areas with human case clusters. In years when livestock vaccination was high (>~25%), human incidence was reduced, with the opposite effect when vaccine rates dropped. This indicates livestock vaccination campaigns reduce anthrax burden in both humans and livestock in Vietnam, though livestock surveillance needs immediate improvement. These findings suggest further investigation and measures to strengthen the surveillance of human and animal anthrax for other provinces of Vietnam, as well as in other countries with similar disease context. Author summary: Anthrax is a bacterial disease, cause by Bacillus anthracis, that can transmit from herbivorous animals to humans through close contact, eating meat of infected animals, or through environmental contamination. Anthrax can be a severe disease requiring early diagnosis and treatment to avoid fatal outcomes, disability, or financial burden to patients and their families. The disease also affects human well-being when livestock is their livelihood and an important part in agricultural practice. Anthrax is preventable by vaccine but effective strategy for vaccine distribution should be built on the characteristics of the disease in both human communities and the local animal populations. This study provides evidence on the space-time distribution and other characteristics of anthrax applying a One Health approach and geographical information analysis techniques. We show that hotspots of human disease correspond to areas of animal case reporting. We also show human incidence is reduced with livestock vaccination rates are relatively high. The study results are useful for researchers to foster investigation on other aspects of the disease and control efforts. It also provides scientific evidence for advocacy and communication on the importance of anthrax vaccination and strategic planning on vaccine production and distribution in Vietnam and other countries with similar context. [ABSTRACT FROM AUTHOR]

Members of Cryptococcus gattii/neoformans species complex are the etiological agents of the potentially fatal human fungal infection cryptococcosis. C. gattii and its sister species cause disease in both immunocompetent and immunocompromised hosts, while the closely related species C. neoformans and C. deneoformans predominantly infect immunocompromised hosts. To date, most studies have focused on similarities in pathogenesis between these two groups, but over recent years, important differences have become apparent. In this review paper, we highlight some of the major phenotypic differences between the C. gattii and neoformans species complexes and justify the need to study the virulence and pathogenicity of the C. gattii species complex as a distinct cryptococcal group. [ABSTRACT FROM AUTHOR]

Rift Valley fever (RVF) is a zoonotic arbovirosis which has been reported across Africa including the northernmost edge, South West Indian Ocean islands, and the Arabian Peninsula. The virus is responsible for high abortion rates and mortality in young ruminants, with economic impacts in affected countries. To date, RVF epidemiological mechanisms are not fully understood, due to the multiplicity of implicated vertebrate hosts, vectors, and ecosystems. In this context, mathematical models are useful tools to develop our understanding of complex systems, and mechanistic models are particularly suited to data-scarce settings. Here, we performed a systematic review of mechanistic models studying RVF, to explore their diversity and their contribution to the understanding of this disease epidemiology. Researching Pubmed and Scopus databases (October 2021), we eventually selected 48 papers, presenting overall 49 different models with numerical application to RVF. We categorized models as theoretical, applied, or grey, depending on whether they represented a specific geographical context or not, and whether they relied on an extensive use of data. We discussed their contributions to the understanding of RVF epidemiology, and highlighted that theoretical and applied models are used differently yet meet common objectives. Through the examination of model features, we identified research questions left unexplored across scales, such as the role of animal mobility, as well as the relative contributions of host and vector species to transmission. Importantly, we noted a substantial lack of justification when choosing a functional form for the force of infection. Overall, we showed a great diversity in RVF models, leading to important progress in our comprehension of epidemiological mechanisms. To go further, data gaps must be filled, and modelers need to improve their code accessibility. Author summary: Rift Valley fever (RVF) affects humans and livestock across Africa, South West Indian Ocean islands, and the Arabian Peninsula. This disease is one of the World Health Organization priorities and is caused by a virus which is transmitted by mosquitoes (mainly of Aedes and Culex spp. genera), but also by direct contact from livestock to humans. Mathematical models have been used in the last 20 years to disentangle RVF virus transmission dynamics. These models can further improve our understanding of processes driving outbreaks, test the efficiency of control strategies, or even anticipate possible emergence. Provided with detailed datasets, models can tailor their conclusions to specific geographical contexts and aid in decision-making in the field. This review provides a general overview of mathematical models developed to study RVF virus transmission dynamics. We describe their main results and methodological choices, and identify hurdles to be lifted. To offer innovative animal and public health value, we recommend that future models focus on the relative contribution of host species to transmission, and the role of animal mobility. [ABSTRACT FROM AUTHOR]

During the course of the 2015–2017 outbreak of Zika virus (ZIKV) in the Americas, the emerging virus was recognized as a congenital infection that could damage the developing brain. As the Latin American ZIKV outbreak advanced, the scientific and public health community questioned if this newly recognized neurotropic flavivirus could affect the developing brain of infants and young children infected after birth. We report here the study design, methods and the challenges and lessons learned from the rapid operationalization of a prospective natural history cohort study aimed at evaluating the potential neurological and neurodevelopmental effects of postnatal ZIKV infection in infants and young children, which had become epidemic in Central America. This study enrolled a cohort of 500 mothers and their infants, along with nearly 400 children 1.5–3.5 years of age who were born during the initial phase of the ZIKV epidemic in a rural area of Guatemala. Our solutions and lessons learned while tackling real-life challenges may serve as a guide to other researchers carrying out studies of emerging infectious diseases of public health priority in resource-constrained settings. Author summary: During the 2015–17 Zika outbreak in the Americas, many research sites struggled to rapidly establish cohorts to study the neurodevelopmental outcomes of exposed infants and children, due to both logistical difficulties and a lack of appropriately adapted/validated neurodevelopmental tools. During this time period, we conducted a study evaluating the neurodevelopmental outcomes of post-natal ZIKV and dengue virus (DENV) infection among of infants (<3 months at enrollment) and children (1.5–3.5 years at enrollment) at a site in rural, southwest Guatemala. The study, which enrolled a cohort of 500 mother-infant pairs and 400 children, was a collaborative effort that leveraged expertise at multiple institutions to rapidly implement a study protocol in a resource-limited region of Guatemala. In this Methods paper, we describe the study methodology, how we implemented our research protocol in this rural, resource-limited community, and challenges and lessons learned during its operationalization. Specifically, we address how we adapted neurodevelopmental testing tools to the local language and cultural context, trained and managed a research team recruited from the local community, maintained competency and quality control in this workforce, developed critical laboratory infrastructure, and engaged with local community stakeholders. Our approach may serve as a guide to other researchers carrying out future studies focusing on child neurodevelopment as well as clinical evaluation of ZIKV and other emerging infectious diseases of public health priority. [ABSTRACT FROM AUTHOR]

Intestinal parasitic infections, caused by helminths and protozoa, are globally distributed and major causes of worldwide morbidity. The gut microbiota may modulate parasite virulence and host response upon infection. The complex interplay between parasites and the gut microbiota is poorly understood, partly due to sampling difficulties in remote areas with high parasite burden. In a large study of children in Guinea-Bissau, we found high prevalence of intestinal parasites. By sequencing of the 16S rRNA genes of fecal samples stored on filter paper from a total of 1,204 children, we demonstrate that the bacterial microbiota is not significantly altered by helminth infections, whereas it is shaped by the presence of both pathogenic and nonpathogenic protozoa, including Entamoeba (E.) spp. and Giardia (G.) lamblia. Within-sample diversity remains largely unaffected, whereas overall community composition is significantly affected by infection with both nonpathogenic E. coli (R2 = 0.0131, P = 0.0001) and Endolimax nana (R2 = 0.00902, P = 0.0001), and by pathogenic E. histolytica (R2 = 0.0164, P = 0.0001) and G. lamblia (R2 = 0.00676, P = 0.0001). Infections with multiple parasite species induces more pronounced shifts in microbiota community than mild ones. A total of 31 bacterial genera across all four major bacterial phyla were differentially abundant in protozoan infection as compared to noninfected individuals, including increased abundance of Prevotella, Campylobacter and two Clostridium clades, and decreased abundance of Collinsella, Lactobacillus, Ruminococcus, Veillonella and one Clostridium clade. In the present study, we demonstrate that the fecal bacterial microbiota is shaped by intestinal parasitic infection, with most pronounced associations for protozoan species. Our results provide insights into the interplay between the microbiota and intestinal parasites, which are valuable to understand infection biology and design further studies aimed at optimizing treatment strategies. Author summary: Infections with enteric parasites, including helminths and protozoa, are among the most common infections in poor countries. These infections continue to have enormous impact on both mortality and morbidity worldwide. Enteric parasites inhabit the gut of the infected host, but how infections with these parasites may change the composition of bacteria within the gut remains more or less unclear. Here, we explore how the bacterial composition in stool from children from Guinea-Bissau (Western Africa) is altered by infection with different enteric parasite species. We find that infections with multiple parasite species induces more pronounced changes in the bacterial composition, and that certain parasite species significantly changes the diversity of bacteria. Furthermore, we demonstrate that fecal samples stored at room temperature on filter papers for months can be used in field studies of gut bacteria composition. Our study provides new insights into the complex relationship between enteric parasites and fecal bacteria composition, and may pave the way for new treatment options and help explain why some people are more susceptible to infection compared to others. [ABSTRACT FROM AUTHOR]

Background: Schistosomiasis is a parasitic disease caused by trematode worms of the genus Schistosoma and belongs to the neglected tropical diseases. The disease has been reported in 78 countries, with around 290.8 million people in need of treatment in 2018. Schistosomiasis is predominantly considered a rural disease with a subsequent focus of research and control activities in rural settings. Over the past decades, occurrence and even expansion of schistosomiasis foci in peri-urban and urban settings have increasingly been observed. Rural–urban migration in low- and middle-income countries and subsequent rapid and unplanned urbanization are thought to explain these observations. Fifty-five percent (55%) of the world population is already estimated to live in urban areas, with a projected increase to 68% by 2050. In light of rapid urbanization and the efforts to control morbidity and ultimately achieve elimination of schistosomiasis, it is important to deepen our understanding of the occurrence, prevalence, and transmission of schistosomiasis in urban and peri-urban settings. A systematic literature review looking at urban and peri-urban schistosomiasis was therefore carried out as a first step to address the research and mapping gap. Methodology: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic computer-aided literature review was carried out using PubMed, ScienceDirect, and the World Health Organization Database in November 2019, which was updated in March 2020. Only papers for which at least the abstract was available in English were used. Relevant publications were screened, duplicates were removed, guidelines for eligibility were applied, and eligible studies were reviewed. Studies looking at human Schistosoma infections, prevalence, and intensity of infection in urban and peri-urban settings were included as well as those focusing on the intermediate host snails. Principal findings: A total of 248 publications met the inclusion criteria. The selected studies confirm that schistosomiasis is prevalent in peri-urban and urban areas in the countries assessed. Earlier studies report higher prevalence levels in urban settings compared to data extracted from more recent publications, yet the challenge of migration, rapid uncontrolled urbanization, and resulting poor living conditions highlight the potential for continuous or even newly established transmission to take place. Conclusions: The review indicates that schistosomiasis has long existed in urban and peri-urban areas and remains a public health problem. There is, however, a challenge of comparability of settings due to the lack of a clear definition of what constitutes urban and peri-urban. There is a pressing need for improved monitoring of schistosomiasis in urban communities and consideration of treatment strategies. Author summary: Schistosomiasis is an infectious parasitic disease and one of the 20 diseases considered by the World Health Organization as a neglected tropical disease. It is typically associated with poor environmental and sanitary conditions, primarily affecting rural communities. However, with the currently observed rapid urbanization and predicted two-thirds of the world population living in urban areas by 2050, concerns are raised about a spread of schistosomiasis to urban and peri-urban areas. At the same time, there seems to be little knowledge of the extent of schistososomiasis in urban areas. In light of the efforts to control morbidity and ultimately achieve elimination of schistosomiasis as well as reaching Sustainable Development Goals 3 "achieve health for all" and 11 "make human settlements inclusive, safe, resilient, and sustainable," this systematic literature review was conducted to address the existing research and mapping gaps and to contribute to the understanding of the burden of schistosomiasis in areas that have not, as yet, been the focus of control efforts and mass drug administration programs. The review suggests that rapid and unorganized urbanization and resulting poor living conditions in urban and peri-urban areas may lead to new disease foci and thereby increase the overall disease burden. Research and policy implications are discussed. [ABSTRACT FROM AUTHOR]

Neglected Tropical Diseases (NTDs) remain endemic to many regions of sub-Saharan Africa (SSA) left behind by socioeconomic progress. As such, these diseases are markers of extreme poverty and inequity that are propagated by the political, economic, social, and cultural systems that affect health and wellbeing. As countries embrace and work towards achieving the Sustainable Development Goals (SDGs), the needs of such vulnerable populations need to be addressed in local and global arenas. The research uses primary qualitative data collected from five NTD endemic counties of Kenya: interviews key informants (n = 21) involved in NTD implementation programs and focus groups (n = 5) of affected individuals. Informed by theories of political ecology of health, the research focuses on post-devolution Kenya and identifies the political, economic, social, and cultural factors that propagate NTDs and their effects on health and wellbeing. Our findings indicate that structural factors such as competing political interests, health worker strikes, inadequate budgetary allocations, economic opportunity, marginalization, illiteracy, entrenched cultural norms and practices, poor access to water, sanitation and housing, all serve to propagate NTD transmission and subsequently affect the health and wellbeing of populations. As such, we recommend that post-devolution Kenya ensures local political, economic and socio-cultural structures are equitable, sensitive and responsive to the needs of all people. We also propose poverty alleviation through capacity building and empowerment as a means of tackling NTDs for sustained economic opportunity and productivity at the local and national level. Author summary: Wellbeing is currently seen as an avenue that shapes, happiness, productivity, environmental awareness, social inclusion, and justice; however, most countries presently adopting wellbeing measures are in the global north. Neglected Tropical Diseases (NTDs) significantly compromise populations' health and well-being in the global south, causing undesirable effects on the personal, social, and economic capabilities of communities living in endemic regions. As countries work towards achieving the Sustainable Development Goals (SDGs), it is paramount that countries in the global south adopt wellbeing measures and, in doing so, capture the lived experiences of individuals experiencing inequities, particularly as these are shaped by NTDs. In sub-Saharan Africa (SSA), political and economic power manifests across different scales, determining human-environmental interaction, distribution of resources, and the transmission of infectious agents. This paper uses a political ecology of health approach to identify the political, economic, social and cultural factors that contribute to NTDs, which are among the world's greatest global health problems. The vast majority of people bearing the burden of NTDs reside in low-income countries. Surprisingly, as the economies of the low-income countries improve to middle-income status, NTDs continue to thrive among sub-populations of low socioeconomic status because of the unequal distribution of economic gains. As a result, NTDs are found in environments characterized by poverty and income inequality, and other inequalities in access to health services, housing, safe water, and sanitation. This paper uses political ecology of health in the primarily biomedical field of NTDs to demonstrate that inequities are embedded within the broad political, socio-cultural, and economic systems that exacerbate NTD infection. The study recommends that NTD endemic countries in SSA formulate policies that enhance equity through capacity building and empowerment in order to enhance population wellbeing. [ABSTRACT FROM AUTHOR]

Background: Adult T-cell leukemia/lymphoma (ATLL), a peripheral T-cell leukemia/lymphoma associated with the human T-cell lymphotropic virus type-1 (HTLV-1), has been classified following the clinical forms defined by Shimoyama in 1991. A suggestion to modify Shimoyama's classification was proposed in 2007 to differentiate within the smoldering patients those who presented nodules or tumors in the skin without lung involvement, which was named the primary cutaneous tumoral (PCT) form of ATLL. In the present study, according to their clinicopathological characteristics, we estimated the mortality rates of 143 ATLL patients from Bahia, Brazil. We also evaluated the importance of classifying PCT/ATLL separately from the smoldering type on disease prognosis. Methodology/Principal findings: Diagnosis of ATLL was established based on a positive serology for HTLV-1, histopathological and/or cytological diagnosis of peripheral T-cell leukemia/lymphoma. Patients were clinically grouped according to Shimoyama's classification, considering PCT variants separately from the smoldering cases. Bivariate and multivariable survival analyses were applied to identify factors associated with disease prognosis. Significant differences in the median survival time were observed between the clinical types, with the smoldering type presenting the longest median survival (109 months) compared to the other forms (<50 months); the median survival for PCT/ATLL was 20 months. Multivariable analysis confirmed that ATLL clinical types were associated with survival, with a better prognosis for patients with the smoldering and chronic types. Furthermore, skin involvement was related to a worse outcome in the multivariable analysis, regardless of the clinical form and presence of lymphadenopathy. Conclusions/Significance: Our results reinforce the importance of considering the PCT/ATLL separately from the smoldering type when classifying ATLL to better define prognosis and treatment, given the significant difference in the survival of patients between the smoldering form and PCT/ATLL. Skin involvement should also be considered an independent prognostic factor in patients with ATLL. Author summary: The human T-cell lymphotropic virus type-1 (HTLV-1) may cause serious diseases, such as adult T-cell leukemia/lymphoma (ATLL), which can manifest itself in different clinical forms. In this paper, we investigated the survival of 143 Brazilian ATLL patients, according to the clinical form and other clinicopathological characteristics using bivariate and multivariable analyses. The original clinical classification of ATLL was employed; however, we considered the primary cutaneous tumoral (PCT) ATLL and the smoldering type separately. We found statistically significant differences in the mortality rates by clinical types and highlighted the better prognosis of patients with the smoldering type (mortality rate: 0.6 per 100 person-years) compared to those with PCT (mortality rate: 5.3 per 100 person-years). This finding emphasizes the importance of considering the PCT/ATLL separately from the smoldering type when using the ATLL classification to determine prognosis and treatment. PCT/ATLL should be treated with more aggressive ATLL protocols than the smoldering type without skin nodules or tumors. [ABSTRACT FROM AUTHOR]

T cells recognize their ligand, the peptide major histocompatibility complex (MHC), via the T-cell receptor (TCR), which is composed of covalently linked α and β or γ and δ chains. This recognition is critical for T-cell ontogeny and controls the selection, activation, and function of T lymphocytes. Specific TCR αβ variable regions have been associated with immunopathogenesis of Chagas disease. Here, we present a systematic review that compiles experimental in vivo and human data regarding the preferential expression of variable alpha (Vα) and variable beta (Vβ) chain regions in Trypanosoma cruzi infection. The original studies indexed in PubMed/Medline, Scopus, and Web of Science databases were screened according to the PRISMA strategy. The analysis showed that expression of TCR Vα subfamilies were evaluated in one human study, and, unlike TCR Vβ, TCR Vα presented a more restricted usage. Despite the great variability in the usage of TCR Vβ regions in human Chagas disease, a down-regulation of TCR Vβ5 expression by T cells from patients in the acute phase of the disease was shown. Opposingly, this TCR region was found overly expressed in CD4+ T cells from chronic Chagas patients. It was also demonstrated that murine Vβ9+ T cells derived from nonlymphoid organs of T. cruzi-infected animals had a modulatory profile, while splenic Vβ9+ T cells produced inflammatory cytokines, indicating that although they display the same TCR Vβ region usage, these cells are functionally distinct. Despite the limitations of few papers and year of publication of the studies, compiling the data derived from them reveals that further investigation of TCR usage will point to their potential role in protective or pathogenic responses, as biomarkers of disease progression, and in the search for dominant peptides potentially useful for the development of vaccines or therapies. Author summary: Chagas disease is a neglected tropical disease, caused by infection with Trypanosoma cruzi. Differential expression of certain T-cell receptor (TCR) variable regions has been associated with the immunopathogenesis of Chagas disease. Here, we present a systematic review that compiled experimental in vivo and human data regarding the preferential expression of TCR alpha and beta chain variable regions in Chagas disease. The original studies indexed in the PubMed/Medline, Scopus, and Web of Science databases were screened according to the PRISMA strategy. Despite the great variability in the use of TCR Vβ in T. cruzi infection, the outcomes indicate that there is a down-regulation of TCR Vβ5 expression in T cells from patients in the acute phase of Chagas disease. However, this region is preferentially expressed by CD4+ T cells from chronic Chagas patients. Additionally, it has been demonstrated that murine Vβ9+ T cells derived from nonlymphoid organs displayed a modulatory profile, while splenic Vβ9+ T cells produced inflammatory cytokines, indicating that although they express the same TCR Vβ region, these cells are functionally distinct. Information on TCR expression, specificity and function have critical impact on vaccine design. [ABSTRACT FROM AUTHOR]

Background: In new leprosy cases, grade 2 disability (G2D) is still a public health burden worldwide. It is often associated with the delayed leprosy diagnoses that healthcare systems should play a crucial role in preventing. The aim of this systematic review was to identify healthcare factors related to delays in case detection in leprosy. Methods: PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) was used as a guideline in this research. The study protocol was registered in the PROSPERO (International Prospective Register of Systematic Reviews) with reference code CRD42020189274. Data was collected from five electronic databases: Embase.com, Medline All Ovid, Web of Science, Cochrane CENTRAL, and the WHO Global Health Library. Results: After applying the selection criteria for original empirical studies, and after removing duplicates, we included 20 papers from 4313 records. They had been conducted in ten countries and published between January 1, 2000, and January 31, 2021. We identified three categories of healthcare factors related to delayed case. 1) Structural factors, such as i) financial and logistic issues, and geographical circumstances (which we classified as barriers); ii) Health service organization and management including the level of decentralization (classified as facilitators). 2) Health service factors, such as problems or shortages involving referral centers, healthcare personnel, and case-detection methods. 3) Intermediate factors, such as misdiagnosis, higher numbers of consultations before diagnosis, and inappropriate healthcare services visited by people with leprosy. Conclusions: Delays in leprosy case detection are due mainly to misdiagnosis. It is crucial to improve the training and capacity of healthcare staff. To avoid misdiagnosis and reduce detection delays, national leprosy control programs should ensure the sustainability of leprosy control within integrated health services. Author summary: New leprosy patients diagnosed with visible physical deformities represent a significant disease burden that also poses an important public health challenge. The physical deformities often result from long delays in case detection. Greater insight into the healthcare factors that contribute to such delays will support the development of effective prevention programs. We therefore reviewed all studies on the healthcare factors related to case-detection delay that had been published between January 1, 2000, and January 31, 2021. Twenty studies were included in our analysis. We found that misdiagnosis was a core healthcare factor related to delays. Other common factors included inappropriate health services, a high number of consultations before diagnosis; and a lack of referral centers, healthcare personnel, and case-detection methods. Detection delay was further influenced by geographical circumstances, financial and logistic issues, and health-service organization and management including the level of the decentralization of healthcare programs. Because delays in leprosy case detection are due mainly to misdiagnosis, we recommend to improve the training and capacity of healthcare staff. To avoid misdiagnosis and reduce detection delays, national leprosy control programs should ensure the sustainability of leprosy control within integrated health services. [ABSTRACT FROM AUTHOR]

Introduction: Mexico was the first country in the Americas and the third in the world to eliminate trachoma as a public health problem, as validated by the WHO in 2017. Objective: To describe the critical elements that favored the elimination of trachoma as a public health problem in Mexico and the public health impact of this success. Methodology: A revision and compilation of data and information contained in the dossier presented by the country to PAHO/WHO to obtain the validation of trachoma elimination as a public health problem was conducted by a group of delegates from the national and local trachoma prevention and control program. Data from the national and local surveillance systems and reports of actions conducted after achieving the elimination goal were also included. Critical elements that favored the achievement of the elimination goal from 1896 to 2019 were extracted. Results: Mexico reached the elimination of trachoma in 2016 obtaining the validation in 2017. 264 communities were no longer endemic and 151,744 people were no longer at risk of visual impairment or possible blindness due to trachoma. The key to the success of this elimination process was primarily the local leadership of health authorities with sustained funding for brigades, increased access to potable water and sanitation, and key alliances with indigenous authorities, health authorities, and government institutions that contributed to the achievement of the goal. The SAFE strategy started implementation in Mexico in 2004 as a comprehensive package of interventions. SAFE stands for surgery, antibiotics, facial cleanliness, and improvement of the environmental conditions. These actions impacted drastically on the number of new cases trachmatous trichiasis (TT) and trachomatous inflammation-follicular (TF), which decreased from 1,794 in 2004 to zero in 2016. Conclusions: The elimination of trachoma as a public health problem in Mexico is a true success story that may serve as a model example for the elimination of other neglected infectious diseases in the Americas. Author summary: Trachoma is an eye disease caused by an infection with Chlamydia trachomatis. It is the principal infectious cause of irreversible blindness worldwide and is one of the 20 neglected tropical diseases which is present in 1,338 districts worldwide with an estimated 154.5 million people living in endemic areas. Globally, the disease was earmarked for elimination as a public health problem by the year 2020 and later extended to the year 2030. The WHO elimination strategy SAFE includes Surgery, Antibiotics, Facial cleanliness, and Environmental improvement. This paper describes the SAFE activities implemented and actions taken for Mexico to achieve the elimination of trachoma as a public health problem. From the compilation of national and local data and information, it was possible to identify that local and federal political commitment and leadership, effective coordination across health institutions and critical sectors such as water and sanitation agencies, and consistent communication and health promotion activities that supported the implementation of SAFE strategies were determinant in driving trachoma elimination. The model of coordinated work and collaboration serves as a model example for the elimination of trachoma and other Neglected Infectious Diseases in Latin America. [ABSTRACT FROM AUTHOR]

A high burden of Salmonella enterica subspecies enterica serovar Typhi (S. Typhi) bacteremia has been reported from urban informal settlements in sub-Saharan Africa, yet little is known about the introduction of these strains to the region. Understanding regional differences in the predominant strains of S. Typhi can provide insight into the genomic epidemiology. We genetically characterized 310 S. Typhi isolates from typhoid fever surveillance conducted over a 12-year period (2007–2019) in Kibera, an urban informal settlement in Nairobi, Kenya, to assess the circulating strains, their antimicrobial resistance attributes, and how they relate to global S. Typhi isolates. Whole genome multi-locus sequence typing (wgMLST) identified 4 clades, with up to 303 pairwise allelic differences. The identified genotypes correlated with wgMLST clades. The predominant clade contained 290 (93.5%) isolates with a median of 14 allele differences (range 0–52) and consisted entirely of genotypes 4.3.1.1 and 4.3.1.2. Resistance determinants were identified exclusively in the predominant clade. Determinants associated with resistance to aminoglycosides were observed in 245 isolates (79.0%), sulphonamide in 243 isolates (78.4%), trimethoprim in 247 isolates (79.7%), tetracycline in 224 isolates (72.3%), chloramphenicol in 247 isolates (79.6%), β-lactams in 239 isolates (77.1%) and quinolones in 62 isolates (20.0%). Multidrug resistance (MDR) determinants (defined as determinants conferring resistance to ampicillin, chloramphenicol and cotrimoxazole) were found in 235 (75.8%) isolates. The prevalence of MDR associated genes was similar throughout the study period (2007–2012: 203, 76.3% vs 2013–2019: 32, 72.7%; Fisher's Exact Test: P = 0.5478, while the proportion of isolates harboring quinolone resistance determinants increased (2007–2012: 42, 15.8% and 2013–2019: 20, 45.5%; Fisher's Exact Test: P<0.0001) following a decline in S. Typhi in Kibera. Some isolates (49, 15.8%) harbored both MDR and quinolone resistance determinants. There were no determinants associated with resistance to cephalosporins or azithromycin detected among the isolates sequenced in this study. Plasmid markers were only identified in the main clade including IncHI1A and IncHI1B(R27) in 226 (72.9%) isolates, and IncQ1 in 238 (76.8%) isolates. Molecular clock analysis of global typhoid isolates and isolates from Kibera suggests that genotype 4.3.1 has been introduced multiple times in Kibera. Several genomes from Kibera formed a clade with genomes from Kenya, Malawi, South Africa, and Tanzania. The most recent common ancestor (MRCA) for these isolates was from around 1997. Another isolate from Kibera grouped with several isolates from Uganda, sharing a common ancestor from around 2009. In summary, S. Typhi in Kibera belong to four wgMLST clades one of which is frequently associated with MDR genes and this poses a challenge in treatment and control. Author summary: Typhoid fever is a major public health concern in endemic regions. Understanding the circulating strains of S. Typhi, could provide insight into the genomic epidemiology and guide in the choice of appropriate antibiotics. In this paper, our aim was to characterize S. Typhi strains causing invasive disease in Kibera, where a high typhoid burden has been described. We also aim to understand the evolutionary history of these strains and how antimicrobial resistance determinants have changed over time. We found that there was low diversity of S. Typhi observed in Kibera isolates with isolates grouping into 4 wgMLST clades and five genotypes. The majority (93.5%) of the isolates belonged to genotype 4.3.1; phylodynamic analysis suggest isolates of this genotype from Kibera are related to other 4.3.1 isolates from Africa and this genotype has been introduced multiple times in Kibera. This genotype in particular warrants close monitoring to inform antibiotic strategy in this population. Furthermore, concurrent detection of gene markers for MDR and quinolone resistance in some isolates raise concern about the potential emergence of extensive drug resistant (XDR) strains. Additional surveillance is needed in Kibera to monitor changing trends in resistance that may require altering clinical treatment, and to inform other preventive measures such as typhoid-conjugate vaccine introduction. [ABSTRACT FROM AUTHOR]

BackgroundAccuracy of molecular tools for the identification of parasites that cause human cutaneous leishmaniasis (CL) could largely depend on the sampling method. Non-invasive or less-invasive sampling methods such as filter paper imprints and cotton swabs are preferred over punch biopsies and lancet scrapings for detection methods of Leishmania based on polymerase chain reaction (PCR) because they are painless, simple, and inexpensive, and of benefit to military and civilian patients to ensure timely treatment. However, different types of samples can generate false negatives and there is a clear need to demonstrate which sample is more proper for molecular assays.MethodologyHere, we compared the sensitivity of molecular identification of different Leishmania (Viannia) species from Peru, using three types of sampling: punch biopsy, filter paper imprint and lancet scraping. Different composite reference standards and latent class models allowed to evaluate the accuracy of the molecular tools. Additionally, a quantitative PCR assessed variations in the results and parasite load in each type of sample.Principal findingsDifferent composite reference standards and latent class models determined higher sensitivity when lancet scrapings were used for sampling in the identification and determination of Leishmania (Viannia) species through PCR-based assays. This was consistent for genus identification through kinetoplastid DNA-PCR and for the determination of species using FRET probes-based Nested Real-Time PCR. Lack of species identification in some samples correlated with the low intensity of the PCR electrophoretic band, which reflects the low parasite load in samples.ConclusionsThe type of clinical sample can directly influence the detection and identification of Leishmania (Viannia) species. Here, we demonstrated that lancet scraping samples consistently allowed the identification of more leishmaniasis cases compared to filter paper imprints or biopsies. This procedure is inexpensive, painless, and easy to implement at the point of care and avoids the need for anesthesia, surgery, and hospitalization and therefore could be used in resource limited settings for both military and civilian populations.

Domestic dogs are responsible for 99% of all cases of human rabies and thus, mass dog vaccination has been demonstrated to be the most effective approach towards the elimination of dog-mediated human rabies. Namibia demonstrated the feasibility of this approach by applying government-led strategic rabies vaccination campaigns to reduce both human and dog rabies incidences in the Northern Communal Areas of Namibia since 2016. The lessons learnt using paper-based form for data capturing and management of mass dog vaccination campaign during the pilot and roll out phase of the project (2016–2018) led to the implementation of a simple and accurate data collection tool in the second phase (2019–2022) of the rabies elimination program. In this paper, we describe the implementation of such custom-developed vaccination tracking device, i.e. the Global Alliance for Rabies Control (GARC) Data Logger (GDL), and the integration of the collected data into a website-based rabies surveillance system (Rabies Epidemiological Bulletin—REB) during 2019 and 2020 campaigns. A total of 10,037 dogs and 520 cats were vaccinated during the 2019 campaign and 13,219 dogs and 1,044 cats during the 2020 campaign. The vaccination data were recorded with the GDL and visualized via REB. Subsequent GIS-analysis using gridded population data revealed a suboptimal vaccination coverage in the great majority of grid cells (82%) with a vaccination coverage below 50%. Spatial regression analysis identified the number of schools, estimated human density, and adult dog population were associated with the vaccination performance. However, there was an inverse correlation to human densities. Nonetheless, the use of the GDL improved data capturing and monitoring capacity of the campaign, enabling the Namibian government to improve strategies for the vaccination of at-risk areas towards achieving adequate vaccination coverage which would effectively break the transmission of rabies. Author summary: We used a custom-developed vaccination tracking device—the Global Alliance for Rabies Control (GARC) Data Logger—to capture dog rabies vaccination data during the 2019 and 2020 mass vaccination campaign in the Northern Communal Areas of Namibia, and then integrated the collected data into the web-based Rabies Epidemiological Bulletin, a rabies-specific disease surveillance platform for rabies-endemic countries. This approach allowed automatic collation, analysis and, visualization of data and drastically improved the data capturing and monitoring capacity of the Namibian government led campaign. Additionally, subsequent GIS analysis enabled a better estimation of vaccination coverage at a much higher spatial resolution, thus identifying areas where improvements in the vaccination strategy are needed to ensure long-term success of the project. [ABSTRACT FROM AUTHOR]

Soil-transmitted helminth (STH) infections are the most widespread of the neglected tropical diseases, primarily affecting marginalized populations in low- and middle-income countries. More than one billion people are currently infected with STHs. For the control of these infections, the World Health Organization (WHO) recommends an integrated approach, which includes access to appropriate sanitation, hygiene education, and preventive chemotherapy (i.e., large-scale, periodic distribution of anthelmintic drugs). Since 2010, WHO has coordinated two large donations of benzimidazoles to endemic countries. Thus far, more than 3.3 billion benzimidazole tablets have been distributed in schools for the control of STH infections, resulting in an important reduction in STH-attributable morbidity in children, while additional tablets have been distributed for the control of lymphatic filariasis. This paper (i) summarizes the progress of global STH control between 2008 to 2018 (based on over 690 reports submitted by endemic countries to WHO); (ii) provides regional and country details on preventive chemotherapy coverage; and (iii) indicates the targets identified by WHO for the next decade and the tools that should be developed to attain these targets. The main message is that STH-attributable morbidity can be averted with evidence-informed program planning, implementation, and monitoring. Caution will still need to be exercised in stopping control programs to avoid any rebound of prevalence and loss of accrued morbidity gains. Over the next decade, with increased country leadership and multi-sector engagement, the goal of eliminating STH infections as a public health problem can be achieved. Author summary: Intestinal worm infections are extremely frequent in areas where sanitation, access to clean water, and hygiene measures are poor. These infections negatively affect the nutritional status and development of children and women. The World Health Organization (WHO) recommends the periodic administration of anthelmintic drugs as one of the components of a control strategy to eliminate these infections. Since 2010, WHO has managed two donations of anthelmintics (i.e., albendazole and mebendazole) that are provided to ministries of health in endemic countries. The present paper summarizes anthelmintic treatment coverage data over a 10-year period (2008–2018) from over 690 reports (and more than 3.3 billion tablets) submitted to WHO by ministries of health. It also reports on the results of surveys, which have been conducted in several countries to evaluate the impact of the drug distribution. Lastly, it presents global objectives for the control of intestinal worm infections, to be achieved by 2030, as identified by a panel of WHO experts and collaborators. In conclusion, the program for the control of intestinal worm infections has steadily progressed between 2008 and 2018 and achieving a coverage level of over 60% in school-age children. The health consequences of these infections have also been significantly reduced. With sustained program implementation, the elimination of these worm infections as a public health problem might be achieved by 2030. [ABSTRACT FROM AUTHOR]

Background: Mycetoma is an important neglected tropical disease associated with debilitation, disfigurement and death if not diagnosed and treated adequately. In Pakistan, mycetoma cases have frequently been diagnosed in histopathology and microbiology laboratories. However, there is scarcity of published data from this country. Therefore, the objectives of this study were to evaluate the frequency and type of mycetoma reported in skin and soft tissue biopsies from a single center over 10 years and review of published literature from Pakistan. Method: This descriptive observational retrospective study was conducted at the Aga Khan University Hospital laboratory, Karachi, Pakistan. Laboratory data from 2009–2018 of skin and soft tissue biopsies with positive findings of mycetoma were retrieved from hospital information system. The variables for statistical analysis were age and gender of patient, anatomical site of lesion, residence of patient (geographical location) in the country, etiologic agents of mycetoma and significant gross and microscopic histopathological findings. The data was entered, and descriptive epidemiologic assessment was carried out using MS excel 2013. Geographical information system was used for mapping the location. Literature review of mycetoma cases reported from Pakistan was done on PubMed, Google search and PakMediNet from 1980 till April 2019. Result: During ten years of study period, 89 skin and soft tissue biopsies were reported as mycetoma, majority were eumycetoma [n = 66/89 (74%)] followed by actinomycetoma [n = 23/89 (26%)]. Involvement of lower limb was predominantly observed [n = 74/89 (83%)] in which foot had significant contribution [n = 65/74 (88%)]. Only 18 specimens were submitted for microbiological assessment and six grew agents of mycetoma, with Madurella mycetomatis reported in only three. Well-formed granuloma formation was observed in only 26%[n = 23/89] of cases. Specific geographical location was not identified, and cases were reported from across the country. From Pakistan, only two original papers and 7 case reports were available in published literature. Conclusion: This single center study reports a handful of cases of mycetoma from Pakistan. We conclude that the index of suspicion should remain high among treating surgeons and physicians and clinical laboratories should improve their diagnostic capacity and skills. This will have a great impact on disease outcome and patient's life. Author summary: World Health Organization (WHO) has included Mycetoma in the neglected tropical diseases. Epidemiological data of mycetoma cases from Pakistan is not available. Although physicians and surgeons frequently see cases of mycetoma in their clinical practice, but poor socioeconomic conditions of patients restrict laboratory diagnosis such as histopathological and microbiological confirmation of disease. This leads to disability, disfigurement and at times limb loss or mortality. Through this study we are documenting the diagnosed cases of mycetoma from specimens submitted to our laboratory. The diagnosis was mainly made by histopathological examination of samples. It is disappointing to note that mycetoma was not included in the differential diagnosis list of clinicians. Probably, that is the reason that very few samples were submitted to the microbiology laboratory for the culture to find out etiologic agents of eumycetoma and actinomycetoma. Overall, this study has highlighted the gaps in the clinical as well as laboratory diagnosis of this disease and case management. [ABSTRACT FROM AUTHOR]

Preventive chemotherapy interventions for the control of soil-transmitted helminthiases (STH) and schistosomiasis scaled up from a global coverage level of around 5% in the year 2000 to a coverage that surpassed 60% in the year 2019. The present paper analyses the concomitant reduction in the number of disability-adjusted life years (DALYs) lost due to STH and schistosomiasis during the same period, from 6.3 to 3.5 million DALYs. The cumulative gain during the 19-year period was estimated at over 26 million DALYs. Given the low cost of the intervention, our study suggests that deworming for STH and schistosomiasis is one of the most cost-effective public health interventions. Author summary: Schistosomiasis and intestinal parasites cause significant morbidity and, in endemic countries, WHO recommends the implementation of periodical large scale distribution of anthelminthic drugs (deworming) for the control of the morbidity due to these infections. Deworming significantly scaled up from the year 2000 to 2019 reaching the majority of children at risk, as a consequence the number of infected individuals and the severity of the infections has been significantly reduced. This is reflected on the significant reduction of number of DALYs lost in the last two decades for these two infections. [ABSTRACT FROM AUTHOR]

Soil-transmitted helminth (STH) infections cause significant morbidity in children and women of reproductive age. The World Health Organization (WHO) recommends preventive chemotherapy (PC) of at-risk populations with anthelminthics to control these infections. Historically, STH are very intensively transmitted in Pemba Island (Zanzibar). A survey conducted in 1994 in 12 schools estimated a STH prevalence near to 100%. This extremely high prevalence induced the introduction of PC in the island; initially, however, PC was not regularly administered because of difficulties linked to drug procurement. A second STH survey, conducted in 2011, in 24 schools estimated a prevalence of STH of 89%; after this survey, PC was regularly administered until 2018. We conducted a survey in 2021 using the same method as that used in 2011. The prevalence of STH was evaluated at 80% (95% CI 78.1–81.5) and most of the STH cases were due to Trichuris trichiura. More than 32% (95% CI 30.3–34.0) of the children investigated had infections of moderate or heavy intensity. PC has been conducted for over 25 years in Pemba Island. However, despite its beneficial impact, both the prevalence and the intensity of STH infections remain high, and the intervention has been insufficient in controlling STH morbidity. This is probably due to a combination of irregular PC, climatic conditions favourable to STH transmission, the low sensitivity of T. trichiura to benzimidazoles, high population density and poor sanitation. Improvement of sanitation coverage remains a key measure to permanently reduce the prevalence and intensity of STH. Possible changes to the present PC approaches to better control STH in Pemba would be (i) to assure high coverage in all schools, (ii) to use mebendazole instead of albendazole given its better activity on T. trichiura and (iii) to use a combination of ivermectin and mebendazole to further increase anthelminthic efficacy on T. trichiura. Author summary: A survey conducted in 1994 in school aged children showed that soil-transmitted helminth were very intensively transmitted in Pemba Island (Zanzibar) with prevalence near to 100%. Between 1994 and 2011 several rounds of administration of anthelminthic were organized and a second survey was conducted in 2011 showing a decrease of prevalence and intensity of infection. The present paper reports the results of a third survey conducted in 2021 showing a further decline of the prevalence and a persistence of T. trichiura as the more prevalent parasite (in 1994 hookworms were the most transmitted STH). The interventions conducted until now where not sufficient to eliminate the morbidity caused by these parasites and it is suggested to include ivermectin in the anthelminthic distributed periodically. [ABSTRACT FROM AUTHOR]

Background: Japanese Encephalitis (JE) is known for its high case fatality ratio (CFR) and long-term neurological sequelae. Over the years, efforts in JE treatment and control might change the JE fatality risk. However, previous estimates were from 10 years ago, using data from cases in the 10 years before this. Estimating JE disease severity is challenging because data come from countries with different JE surveillance systems, diagnostic methods, and study designs. Without precise and timely JE disease severity estimates, there is continued uncertainty about the JE disease burden and the effect of JE vaccination. Methodology: We performed a systematic review to collate age-stratified JE fatality and morbidity data. We used a stepwise model selection with BIC as the selection criteria to identify JE CFR drivers. We used stacked regression, to predict country-specific JE CFR from 1961 to 2030. JE morbidity estimates were grouped from similar study designs to estimate the proportion of JE survivors with long-term neurological sequelae. Principal findings: We included 82 and 50 peer-reviewed journal articles published as of March 06 2021 for JE fatality and morbidity with 22 articles in both analyses. Results suggested overall JE CFR estimates of 26% (95% CI 22, 30) in 1961–1979, 20% (95% CI 17, 24) in 1980–1999, 14% (95% CI 11, 17) in 2000–2018, and 14% (95% CI 11, 17) in 2019–2030. Holding other variables constant, we found that JE fatality risk decreased over time (OR: 0.965; 95% CI: 0.947–0.983). Younger JE cases had a slightly higher JE fatality risk (OR: 1.012; 95% CI: 1.003–1.021). The odds of JE fatality in countries with JE vaccination is 0.802 (90% CI: 0.653–0.994; 95% CI: 0.62–1.033) times lower than the odds in countries without JE vaccination. Ten percentage increase in the percentage of rural population to the total population was associated with 15.35% (95% CI: 7.71, 22.57) decrease in JE fatality odds. Ten percentage increase in population growth rate is associated with 3.71% (90% CI: 0.23, 7.18; 95% CI: -0.4, 8.15) increase in JE fatality odds. Adjusting for the effect of year, rural population percent, age of JE cases, and population growth rate, we estimated that there was a higher odds of JE fatality in India compared to China. (OR: 5.46, 95% CI: 3.61–8.31). Using the prediction model we found that, in 2000–2018, Brunei, Pakistan, and Timor-Leste were predicted to have the highest JE CFR of 20%. Bangladesh, Guam, Pakistan, Philippines, and Vietnam had projected JE CFR over 20% for after 2018, whereas the projected JE CFRs were below 10% in China, Indonesia, Cambodia, Myanmar, Malaysia, and Thailand. For disability, we estimated that 36% (min-max 0–85) JE patients recovered fully at hospital discharge. One year after hospital discharge, 46% (min-max 0%-97%) JE survivors were estimated to live normally but 49% (min-max 3% - 86%)till had neurological sequelae. Conclusion: JE CFR estimates were lower than 20% after 2000. Our study provides an updated estimation of CFR and proportion of JE cases with long-term neurological sequelae that could help to refine cost-benefit assessment for JE control and elimination programs. Author summary: Japanese Encephalitis (JE) is known for its high case fatality ratio (CFR) and long-term neurological sequelae. Although JE fatality and morbidity risk might change as the characteristics of the population change with the strengthened surveillance scales, expanded immunization coverage, and healthcare improvements, there have not been any updates in the estimates for JE mortality and morbidity estimates for 10 years. In this paper, we made updated estimates of the JE CFR and the proportion of JE survivors with long-term neurological sequelae by performing a systematic review and developing statistical and machine learning models. We estimated JE CFR decreased over time, with estimates of 26% (95% CI 22, 30) in 1961–1979, 20% (95% CI 17, 24) in 1980–1999, 14% (95% CI 11, 17) in 2000–2018, and 14% (95% CI 11, 17) in 2019–2030. countries without JE vaccination, younger JE cases, higher population growth rate, and lower rural population percentage were associated with higher JE CFR. We estimated that 36% (min-max 0–85) JE patients recovered fully at hospital discharge. One year after hospital discharge, 46% (min-max 0%-97%) JE survivors were estimated to live normally but 49% (min-max 3% - 86%) JE patients still had neurological sequelae. The insights gained will be important in evaluating and updating current JE disease burden among all endemic areas and effectively channeling resources to most needed areas. [ABSTRACT FROM AUTHOR]

Background: Lymphatic filariasis (LF) is a neglected tropical disease caused by the filarial nematodes Wuchereria bancrofti, Brugia malayi and Brugia timori. The Global Program to Eliminate LF uses mass drug administration (MDA) of anti-filarial drugs that clear microfilariae (Mf) from blood to interrupt transmission by mosquitos. New diagnostic tools are needed to assess the impact of MDA on bancroftian filariasis, because available serologic tests can remain positive after successful treatment. Methodology/Principal findings: We identified Wb-bhp-1, which encodes a W. bancrofti homologue of BmR1, the B. malayi protein used in the Brugia Rapid antibody test for brugian filariasis. Wb-bhp-1 has a single exon that encodes a 16.3 kD protein (Wb-Bhp-1) with 45% amino acid identity to BmR1. Immunohistology shows that anti-Wb-Bhp-1 antibodies primarily bind to Mf. Plasma from 124 of 224 (55%) microfilaremic individuals had IgG4 antibodies to Wb-Bhp-1 by ELISA. Serologic reactivity to Wb-Bhp-1 varied widely with samples from different regions (sensitivity range 32–92%), with 77% sensitivity for 116 samples collected from microfilaremic individuals outside of sub-Saharan Africa. This variable sensitivity highlights the importance of validating new diagnostic tests for parasitic diseases with samples from different geographical regions. Individuals with higher Mf counts were more likely to have anti-Wb-Bhp-1 antibodies. Cross-reactivity was observed with a minority of plasma samples from people with onchocerciasis (17%) or loiasis (10%). We also identified, cloned and characterized BmR1 homologues from O. volvulus and L. loa that have 41% and 38% identity to BmR1, respectively. However, antibody assays with these antigens were not sensitive for onchocerciasis or loiasis. Conclusions: Wb-Bhp-1 is a novel antigen that is useful for serologic diagnosis of bancroftian filariasis. Additional studies are needed to assess the value of this antigen for monitoring the success of filariasis elimination programs. Author summary: Lymphatic filariasis (LF) is a highly disabling and stigmatizing disease caused by parasitic worms that are transmitted by mosquitoes. There is a coordinated global effort to eliminate LF based on mass drug administration (MDA) of donated anti-filarial medications. Improved methods are needed to determine when transmission of the infection has been interrupted in previously endemic areas so that MDA can be safely stopped. This paper reports the discovery and characterization of a novel W. bancrofti antigen, Wb-Bhp-1, which is a homologue of the Brugia malayi protein used in antibody tests to monitor filariasis elimination in areas of Asia where LF is caused by Brugia species. We show that a test for IgG4 antibodies to Wb-Bhp-1 was fairly specific for W. bancrofti infection. However, the sensitivity of this test varied by the geographic origin of the samples. Sensitivity was highest for samples collected in the Indo-Pacific region and lowest for samples collected in Côte d'Ivoire. Geographic differences in the parasite or the human immune responses to infection may account for this variability. This range in sensitivity highlights the importance of validating new diagnostic tests for parasitic diseases with samples from different geographical regions. [ABSTRACT FROM AUTHOR]

Global efforts to control Aedes mosquito-transmitted pathogens still rely heavily on insecticides. However, available information on vector resistance is mainly restricted to mosquito populations located in residential and public areas, whereas commercial settings, such as hotels are overlooked. This may obscure the real magnitude of the insecticide resistance problem and lead to ineffective vector control and resistance management. We investigated the profile of insecticide susceptibility of Aedes aegypti mosquitoes occurring at selected hotel compounds on Zanzibar Island. At least 100 adults Ae. aegypti females from larvae collected at four hotel compounds were exposed to papers impregnated with discriminant concentrations of DDT (4%), permethrin (0.75%), 0.05 deltamethrin (0.05%), propoxur (0.1%) and bendiocarb (0.1%) to determine their susceptibility profile. Allele-specific qPCR and sequencing analysis were applied to determine the possible association between observed resistance and presence of single nucleotide polymorphisms (SNPs) in the voltage-gated sodium channel gene (VGSC) linked to DDT/pyrethroid cross-resistance. Additionally, we explored the possible involvement of Glutathione-S-Transferase gene (GSTe2) mutations for the observed resistance profile. In vivo resistance bioassay indicated that Ae. aegypti at studied sites were highly resistant to DDT, mortality rate ranged from 26.3% to 55.3% and, moderately resistant to deltamethrin with a mortality rate between 79% to and 100%. However, genotyping of kdr mutations affecting the voltage-gated sodium channel only showed a low frequency of the V1016G mutation (n = 5; 0.97%). Moreover, for GSTe2, seven non-synonymous SNPs were detected (L111S, C115F, P117S, E132A, I150V, E178A and A198E) across two distinct haplotypes, but none of these were significantly associated with the observed resistance to DDT. Our findings suggest that cross-resistance to DDT/deltamethrin at hotel compounds in Zanzibar is not primarily mediated by mutations in VGSC. Moreover, the role of identified GSTe2 mutations in the resistance against DDT remains inconclusive. We encourage further studies to investigate the role of other potential insecticide resistance markers. Author summary: Available information on mosquito resistance to insecticides is mainly restricted to residential and public areas, whereas commercial settings, such as hotels are overlooked. This may hide the real size of an insecticide resistance problem and lead to ineffective mosquito control. We investigated insecticide susceptibility of Aedes aegypti mosquitoes occurring at selected hotel compounds on Zanzibar Island. We also looked at whether resistance occurred in mosquitoes with gene mutations for two proteins (voltage-gated sodium channels and glutathione-S-transferase) that are known to cause resistance to insecticides in other parts of the world. The Ae. aegypti mosquitoes collected from hotels were highly resistant to DDT, and moderately and possibly resistant to deltamethrin and propoxur, respectively. However, resistance to these insecticides was not linked to mutations in either of the studied genes. The presence of insecticide resistance in Ae. aegypti in hotel compounds on Zanzibar is concerning and shows that these areas can act as sources of resistant mosquitoes. More needs to be done to establish the underlying causes for insecticide resistance in hotel Ae. aegypti populations, and this information can then be used to design measures that prevent resistance from becoming more widespread on Zanzibar. [ABSTRACT FROM AUTHOR]

Background: Wolbachia is an endosymbiont bacterium generally found in about 40% of insects, including mosquitoes, but it is absent in Aedes aegypti which is an important vector of several arboviral diseasesdengue, chikungunya, zika, and yellow fever. The evidence that Wolbachia trans-infected Ae. aegypti mosquitoes lost their vectorial competence and became less capable of transmitting arboviruses to human hosts highlights the potential of using Wolbachia-based approaches for prevention and control of arboviral diseases. Recently, release of Wolbachia trans-infected Ae. aegypti has been deployed widely in many countries for the control of mosquito-borne viral diseases. Field surveillance and monitoring of Wolbachia presence in released mosquitoes is important for the success of these control programs. So far, a number of studies have reported the development of loop mediated isothermal amplification (LAMP) assays to detect Wolbachia in mosquitoes, but the methods still have some specificity and cost issues. Methodology/Principal findings: We describe here the development of a LAMP assay combined with the DNA strand displacement-based electrochemical sensor (BIOSENSOR) method to detect wAlbB Wolbachia in trans-infected Ae. aegypti. Our developed LAMP primers used a low-cost dye detecting system and 4 oligo nucleotide primers which can reduce the cost of analysis while the specificity is comparable to the previous methods. The detection capacity of our LAMP technique was 1.4 nM and the detection limit reduced to 2.2 fM when combined with the BIOSENSOR. Our study demonstrates that a BIOSENSOR can also be applied as a stand-alone method for detecting Wolbachia; and it showed high sensitivity when used with the crude DNA extracts of macerated mosquito samples without DNA purification. Conclusions/Significance: Our results suggest that both LAMP and BIOSENSOR, either used in combination or stand-alone, are robust and sensitive. The methods have good potential for routine detection of Wolbachia in mosquitoes during field surveillance and monitoring of Wolbachia-based release programs, especially in countries with limited resources. Author summary: Mosquito-borne diseases such as dengue, chikungunya, zika, and yellow fever are transmitted to humans mainly by the bites of Aedes aegypti mosquitoes. Controlling the vectors of these diseases relies mostly on the use of insecticides. However, the efficiency has been reduced through the development of insecticide resistance in mosquitoes. Wolbachia is an endosymbiotic bacterium that is naturally found in 40% of insects, including mosquitoes. The bacterium can protect its insect hosts from viral infections and can also cause sterility in insect host populations, therefore, providing an opportunity to use it for human disease control. Application of a Wolbachia trans-infected mosquitoes needs simple, rapid and sensitive methods for detecting the bacteria in released mosquitoes. In this paper, we develop the methods of LAMP and BIOSENSORS for detecting wAlbB Wolbachia in mosquitoes. Our positive LAMP reaction can be visualized by color change from violet to blue at a sensitivity of ≥ 10 pg of genomic DNA. When used in combination with the BIOSENSOR method, the sensitivity increases a millionfold without losing specificity. Our study suggests that both developed methods, either used in combination or stand-alone, are efficient and cost-effective, hence, they could be applied for routine surveys of Wolbachia in mosquito control programs that use Wolbachia-based approaches. [ABSTRACT FROM AUTHOR]

Background: Onchocerciasis elimination currently relies on repeated ivermectin-based preventive chemotherapy. Current World Health Organization's guidelines strongly recommend, though with low evidence of certainty, the use of Ov16 serology testing in children younger than 10 years old to assess whether mass drugs administration can be safely stopped. Therefore, more evidences are needed to support the use of this marker as sero-evaluation tool. This study aimed at determining the relationship between microfilaridermia and anti-Ov16 IgG4, and their variation according to age, gender and ivermectin intake history. Methodology: A cross-sectional survey was conducted in an area where ivermectin-based MDA has been implemented since more than 20 years. A questionnaire was used to record ivermectin intake history for the last 5 years. All volunteers aged ≥2 years were tested for microfilaridermia. IgG4 antibodies against Ov16 antigen were determined using the Standard Diagnostic Ov16 IgG4 ELISA kits and the recombinant anti-Ov16 AbD19432 antibodies. Prevalences, microfilaridermia counts and IgG4 concentrations were compared with regards to age, gender and history of ivermectin intake. Principal findings: The prevalence of skin microfilariae was 23.4% (95% CI: 23.4–30.8), whereas Ov16 seroprevalence was 53.2% (95% CI: 47.9–58.4). A moderate positive percentage agreement (50.4%) and a high negative percentage agreement (69.2%) was found between skin snip and Ov16 serology in the whole population, while in children aged <10 years, the agreements were higher (positive percentage agreement: 62.6%; negative percentage agreement: 83.5%). In addition, no associations were found between ivermectin intake, Mf counts and estimated IgG4 concentration of participants. Anti-Ov16 IgG4 were higher in individuals harboring microfilariae than their negative counterparts (p<0.0001), though a negative correlation was found between skin microfilarial counts and anti-Ov16 IgG4 levels (r = -0.2400; p = 0.03). No variation in microfilarial counts according to age and gender was observed. Though positively correlated with age (r = 0.4020; p<0.0001), IgG4 was significantly different between the different age classes (p<0.0001). Conclusion/Significance: Our results revealed moderate positive and negative agreements between parasitological and immunological parameters of onchocerciasis infection after several rounds MDA. Anti-Ov16 IgG4 levels increased with age but decreased with microfilarial counts, suggesting a variation of anti-Ov16 IgG4 as a result of constant exposure and accumulation of infection. This brings evidence sustaining the use of Ov16 serology in children as evaluation tool. However, additional investigations are needed to further reshape the appropriate age range among children aged <10 years old. Author summary: The elimination of onchocerciasis places high demands on monitoring and evaluation. The current WHO's guidelines recommend the use of serological test (ELISA) to determine the presence of IgG4 antibodies to the O. volvulus specific antigen Ov16 among children aged <10 years old, thought with low evidence of certainty. In this paper, we explored the relationship between anti-Ov16 IgG4 antibodies and microfilaridermia counts, and assessed their variation according to age, gender and history of ivermectin intake. Our findings revealed no variation of Mf count and IgG4 with ivermectin intake. However, we observed that anti-Ov16 IgG4 decrease with microfilaridermia counts, but an increasing trend was observed with age. This brings evidence sustaining the use of Ov16 serology testing as exposition marker in children younger than 10 years. However, children age 2 to 4 years seem to have a very low anti-Ov16 IgG4 concentration, this finding should be considered when defining the age class for seroprevalence evaluation. [ABSTRACT FROM AUTHOR]

Owing to the increased reports in Aedes-borne diseases in the Caribbean and Latin America, the United States Agency for International Development assisted the Jamaican Ministry of Health and Wellness in conducting insecticide susceptibility tests on Aedes aegypti populations. Sentinel sites were established in seven parishes of Jamaica (St. Catherine, Kingston and St. Andrew, St. Thomas, Portland, St. Mary and St. Ann) and Aedes aegypti eggs were collected, reared to adults per collected population and their susceptibility to varying pyrethroids and organophosphates were tested using the World Health Organization paper bioassays for these insecticides. The Centers for Disease Control and Prevention bottle bioassay was used to assess susceptibility to the carbamate, bendiocarb. The voltage gated sodium channel gene mutations V1016I and I1011V, normally associated with pyrethroid resistance, were also analysed. The results showed that Aedes aegypti collected from all parishes exhibited resistance to pyrethroids at the following concentrations, permethrin 0.25–2.5%; deltamethrin 0.03–0.15%; lambda-cyhalothrin 0.03–0.3%; and etofenprox 0.5–2.5%. The insecticide deltamethrin at concentration 0.3% was the only pyrethroid tested that resulted in high mortality, 94.9 ± 0.34% knockdown within 1 hour of exposure and 98.95 ± 0.01% mortality (p <0.01) at 24 hours post exposure. The frequency of the voltage gated sodium channel gene mutation V1016I was high in the tested population, possibly accounting for the reduced sensitivity to pyrethroids. Organophosphate resistance was also observed in all populations tested. Mortality rates for 0.8% Malathion was 0.8 ± 0.02–60.68 ± 0.01% after 24 hour and 0.00–47.10 ± 0.09%, for pirimiphos-methyl 0.21%. Bendiocarb applied as 12.5 μg/ bottle resulted in mortality rates of 76.25 ± 4.30–100 ± 0.00% after 30 minutes of exposure. The results showed that Ae. aegypti from the seven parishes analysed demonstrated resistance to the insecticides tested. Deltamethrin and bendiocarb at concentrations 0.3% and 12.5μg respectively, were considered most effective, causing high mortality in the local populations. Routine monitoring and evaluations of Ae. aegypti populations from the included parishes are recommended. Additionally, the study results represent the most comprehensive testing to date with local Aedes aegypti populations distributed across different parishes of Jamaica and should be useful to guide national and sub national strategies for vector control and surveillance. Author summary: The recent outbreaks of chikungunya, Zika and dengue viruses in the Caribbean and Latin America during 2013–2018, have motivated local health authorities in individual countries to seek international assistance from multiple agencies and adjust their vector management strategies in order to contain the transmission of Aedes-borne diseases. Countries within the region rely mainly on the use of commercially available insecticides to manage the mosquito populations and by extension, reduce the transmission of vector-borne diseases. However, this practice is stymied by the ability of these insects to develop resistance mechanisms to insecticides of frequent use. Many countries in the Caribbean and Latin America regions lack the facilities and supplies to conduct routine insecticide susceptibility testing. In an effort to ascertain knowledge on the presence of insecticide resistance in Aedes aegypti populations, and to determine which insecticide is more effective to reduce vector populations of Jamaica, we conducted an array of bioassays with three different types of insecticides (pyrethroid, organophosphate, carbamate) to use local evidence and inform public health authorities on vector control status and alternatives. [ABSTRACT FROM AUTHOR]

Approximately 300,000 persons in the United States (US) are infected with Trypanosoma cruzi, the protozoan that causes Chagas disease, but less than 1% are estimated to have received antiparasitic treatment. Benznidazole was approved by the US Food and Drug Administration (FDA) for treatment of T. cruzi infection in 2017 and commercialized in May 2018. This paper analyzes factors that affect access to benznidazole following commercialization and suggests directions for future actions to expand access. We applied an access framework to identify barriers, facilitators, and key actors that influence the ability of people with Chagas disease to receive appropriate treatment with benznidazole. Data were collected from the published literature, key informants, and commercial databases. We found that the mean number of persons who obtained benznidazole increased from just under 5 when distributed by the CDC to 13 per month after the commercial launch (from May 2018 to February 2019). Nine key barriers to access were identified: lack of multi-sector coordination, failure of health care providers to use a specific order form, lack of an emergency delivery system, high medical costs for uninsured patients, narrow indications for use of benznidazole, lack of treatment guidelines, limited number of qualified treaters, difficulties for patients to make medical appointments, and inadequate evaluation by providers to determine eligibility for treatment. Our analysis shows that access to benznidazole is still limited after FDA approval. We suggest six areas for strategic action for the pharmaceutical company that markets benznidazole and its allied private foundation to expand access to benznidazole in the US. In addition, we recommend expanding the existing researcher-clinician network by including government agencies, companies and others. This paper's approach could be applied to access programs for benznidazole in other countries or for other health products that target neglected populations throughout the world. Author summary: Less than 1% of persons in the United States with Trypanosoma cruzi infection, the cause of Chagas disease, have received antiparasitic treatment. In this paper, we examine the status of access to benznidazole in the United States following its approval by the FDA for treatment of Chagas disease treatment in 2017 and its commercialization in 2018. We found that the average number of patients who received benznidazole from the manufacturer increased after commercialization from just under 5 (when distributed by the CDC) to 13 patients (when sold in commercial channels) per month. We identified various barriers to access to treatment such as problems in the drug ordering process, low demand from health care providers, inadequate clinical assessment of patient eligibility for treatment, obstacles for patients to make medical appointments or to pay medical costs, and weak coordination among key actors in the health system. To overcome these access barriers, we propose strategic actions that can be taken by the pharmaceutical producer in collaboration with other key actors. Our work contributes to expanding access to Chagas disease treatment in the United States, and our approach could be applied to efforts to expand access to health products for other neglected diseases. [ABSTRACT FROM AUTHOR]