Aerobic glycolysis but not GLS1-dependent glutamine metabolism is critical for anti-tumor immunity and response to checkpoint inhibition.

Tumor cells undergo uncontrolled proliferation driven by enhanced anabolic metabolism including glycolysis and glutaminolysis. Targeting these pathways to inhibit cancer growth is a strategy for cancer treatment. Critically, however, tumor-responsive T cells share metabolic features with cancer cells, making them susceptible to these treatments as well. Here, we assess the impact on anti-tumor T cell immunity and T cell exhaustion by genetic ablation of lactate dehydrogenase A (LDHA) and glutaminase1 (GLS1), key enzymes in aerobic glycolysis and glutaminolysis. Loss of LDHA severely impairs expansion of T cells in response to tumors and chronic infection. In contrast, T cells lacking GLS1 can compensate for impaired glutaminolysis by engaging alternative pathways, including upregulation of asparagine synthetase, and thus efficiently respond to tumor challenge and chronic infection as well as immune checkpoint blockade. Targeting GLS1-dependent glutaminolysis, but not aerobic glycolysis, may therefore be a successful strategy in cancer treatment, particularly in combination with immunotherapy.

Could a ring treatment approach be proposed to control Taenia solium transmission in a post elimination setting? A pilot study in Zambia.

BACKGROUND: Geographically targeted Taenia solium ring approaches consisting of treating individuals within a radius of 100-meter of a cysticercosis positive pig have been trialled in Peru. This study explored if a similar approach could be proposed to control T. solium transmission in a post elimination setting in Zambia, focussing on community members' willingness to be sampled and treated. METHODOLOGY AND PRINCIPAL FINDINGS: The study was conducted in a community where elimination of active T. solium transmission was achieved. All eligible pigs and people were sampled, at 4- to 6-monthly intervals, followed by implementation of the ring treatment approach. This implied that whenever a pig was seropositive for cysticercosis during sampling, every human and pig residing in a radius of 50-meters of the seropositive pig would be treated. The results of the positive human stool samples were used to create the rings, whenever no pigs were positive. From June 2018 to October 2019, four samplings, followed by ring treatments were conducted. Between 84% and 91% of the willing people provided a stool sample, covering 46% to 59% of the total population living in the study area. Between 78% and 100% of the eligible pigs got sampled. Three ring treatments were based on porcine seropositivity and one on taeniosis results. Two to four rings were opened per sampling. During the ring treatments, between 89% and 100% of the eligible human and pig population living within a ring was treated. CONCLUSIONS: Participants were willing to participate and get treatment, once the rings were opened. However, the utility of ring treatment approaches in a post elimination setting needs further evaluation, given the lack of highly accurate diagnostic tools for porcine cysticercosis and the challenges in obtaining stool samples. The ring treatment approach adopted should be further improved before recommendations to public health authorities can be given.

Neurocysticercosis Prevalence and Characteristics in Communities of Sinda District in Zambia: A Cross-Sectional Study.

BACKGROUND: This study aimed at describing the epidemiology of (neuro)cysticercosis as well as its clinical and radiological characteristics in a Taenia solium endemic district of Zambia. METHODS: This was part of a cross-sectional community-based study conducted in Sinda district to evaluate an antibody-detecting T. solium point-of-care (TS POC) test for taeniosis and (neuro)cysticercosis. All TS POC cysticercosis positive (CC+) participants and a subset of the TS POC cysticercosis negative (CC-) received a clinical evaluation and cerebral computed tomography (CT) examination for neurocysticercosis (NCC) diagnosis and staging. RESULTS: Of the 1249 participants with a valid TS POC test result, 177 (14%) were TS POC CC+ . Cysticercosis sero-prevalence was estimated to be 20.1% (95% confidence intervals [CI] 14.6-27.0%). In total, 233 participants received a CT examination (151 TS POC CC+ , 82 TS POC CC-). Typical NCC lesions were present in 35/151 (23%) TS POC CC+ , and in 10/82 (12%) TS POC CC- participants. NCC prevalence was 13.5% (95% CI 8.4-21.1%) in the study population and 38.0% (95% CI 5.2-87.4%) among people reporting epileptic seizures. Participants with NCC were more likely to experience epileptic seizures (OR = 3.98, 95% CI 1.34-11.78, p = 0.01) than those without NCC, although only 7/45 (16%) people with NCC ever experienced epileptic seizures. The number of lesions did not differ by TS POC CC status (median: 3 [IQR 1-6] versus 2.5 [IQR 1-5.3], p = 0.64). Eight (23%) of the 35 TS POC CC+ participants with NCC had active stage lesions; in contrast none of the TS POC CC- participants was diagnosed with active NCC. CONCLUSION: NCC is common in communities in the Eastern province of Zambia, but a large proportion of people remain asymptomatic.

Towards an actionable One Health approach.

BACKGROUND: Despite the increasing focus on strengthening One Health capacity building on global level, challenges remain in devising and implementing real-world interventions particularly in the Asia-Pacific region. Recognizing these gaps, the One Health Action Commission (OHAC) was established as an academic community for One Health action with an emphasis on research agenda setting to identify actions for highest impact. MAIN TEXT: This viewpoint describes the agenda of, and motivation for, the recently formed OHAC. Recognizing the urgent need for evidence to support the formulation of necessary action plans, OHAC advocates the adoption of both bottom-up and top-down approaches to identify the current gaps in combating zoonoses, antimicrobial resistance, addressing food safety, and to enhance capacity building for context-sensitive One Health implementation. CONCLUSIONS: By promoting broader engagement and connection of multidisciplinary stakeholders, OHAC envisions a collaborative global platform for the generation of innovative One Health knowledge, distilled practical experience and actionable policy advice, guided by strong ethical principles of One Health.

Gaps in treatment of epileptic seizures in a Zambian rural area.

BACKGROUND: Epilepsy is a multifactorial neurological disorder, including parasitic infections of the brain such as neurocysticercosis (NCC). People with epileptic seizures (PWES) in low and middle-income countries often do not receive appropriate treatment, which besides epileptic seizures, may also lead to reduced quality of life and possibly death. The objective of this study was to describe gaps in treatment of epileptic seizures in a Zambian rural area. METHODS: A cross-sectional study was conducted in Sinda district of Zambia between August and October 2018. PWES identified from clinic records and with the help of community healthcare workers were recruited. Two questionnaires, one to PWES and the other to local healthcare workers, were administered to describe the treatment gap. RESULTS: A total of 146 PWES and 43 healthcare workers were interviewed. Of the 146 PWES, 131 had taken anti-seizure medication (ASM) at some point since their seizure onset, of which 49.6% were on current treatment. Only 18.3% were on continuous ASM, an overall treatment gap of 83.6%. Over 55% of healthcare workers did not know the relationship between epilepsy and NCC. The risk factors associated with lack of appropriate treatment were stock-outs of ASMs, lack of diagnostic equipment, poor patient follow-up, and PWES opting for traditional medicine. CONCLUSION: The treatment gap is substantial in Sinda district. The causes are multifactorial, involving shortcomings at the level of healthcare facilities, communities, and individuals. Directed training of healthcare workers and significant improvements in the supply and dispensing of ASMs will be key in substantially reducing the gap.

Evaluation of a point-of-care test for the diagnosis of Taenia solium neurocysticercosis in rural southern Tanzania: a diagnostic accuracy study.

BACKGROUND: Neurocysticercosis is a common cause of epilepsy in Taenia solium-endemic areas in sub-Saharan Africa but is often undiagnosed because of an absence of affordable diagnostic tools. This study evaluated the diagnostic accuracy of a T solium cysticercosis antibody-detecting lateral-flow point-of-care assay (TS POC test) for the neuroimaging-based diagnosis of neurocysticercosis. METHODS: Patients with epileptic seizures or severe progressive headache were recruited consecutively from three hospitals in southern Tanzania. All patients were tested with the TS POC test. All patients positive for cysticercosis on the TS POC test and every tenth patient who was negative for cysticercosis received a brain CT examination and underwent reference testing for T solium cysticercosis (ie, rT24H-EITB, LLGP-EITB, and antigen ELISA). The primary outcome of the study was the sensitivity of the TS POC test for the diagnosis of neurocysticercosis. FINDINGS: Of the 601 recruited participants, 102 (17%) tested positive for cysticercosis with the TS POC test. Overall, 48 (62%) of the 77 patients positive for cysticercosis and five (17%) of the 29 patients negative for cysticercosis on the TS POC test had CT-confirmed neurocysticercosis. The TS POC test yielded a sensitivity of 49% (uncertainty interval [UI] 41-58) for neurocysticercosis. Sensitivity was similar to that of the rT24H-EITB (44%, UI 37-51) and the antigen ELISA (50%, 43-56). For the subset of neurocysticercosis cases with at least one active (ie, vesicular) lesion, sensitivity was above 98% for the TS POC test, the rT24H-ETIB, and the antigen ELISA. INTERPRETATION: The TS POC test showed promising results for the diagnosis of neurocysticercosis in patients with vesicular lesions, which need to be confirmed in a larger study. This test could be considered to support policies on screening patients with suspected neurocysticercosis in clinical settings, which would allow appropriate referral for neuroimaging and early treatment. FUNDING: German Federal Ministry of Education and Research and the European & Developing Countries Clinical Trials Partnership. TRANSLATION: For the Swahili translation of the abstract see Supplementary Materials section.

Performance evaluation of protocols for Taenia saginata and Ascaris suum egg recovery from the house fly's gastrointestinal tract and exoskeleton.

BACKGROUND: The synanthropic house fly (Musca domestica) can potentially contribute to the mechanical spread of eggs of Taenia and Ascaris spp. in the environment and between hosts. However, the absence of validated protocols to recover eggs hampers an in-depth analysis of the house fly's role in parasite egg transmission. METHODS: The gastrointestinal tract and exoskeleton of euthanized house flies were spiked with Taenia saginata eggs. The performance of several recovery protocols, in terms of both the recovery rate and ease-of-use, was (microscopically) evaluated and compared. These protocols employed steps such as washing, maceration, filtration, flotation and both passive and centrifugal sedimentation. The final validated protocols were subsequently evaluated for the recovery of Ascaris suum eggs. RESULTS: The final protocol validated for the recovery of T. saginata eggs from the house fly's gastrointestinal tract involved homogenization in phosphate-buffered saline and centrifugation at 2000 g for 2 min, yielding a recovery rate of 79.7%. This protocol required 6.5 min to perform (which included 1.5 min of hands-on time) and removed large debris particles that could hinder the differentiation of eggs from debris. Similarly, the final protocol validated for the recovery of T. saginata eggs from the fly's exoskeleton involved washing by vortexing for 2 min in Tween 80 (0.05%), 15 min of passive sedimentation and centrifugation at 2000 g for 2 min, yielding a recovery rate of 77.4%. This protocol required 20.5 min to perform (which included 3.5 min of hands-on time) and successfully removed debris. The same protocols yielded recovery rates of 74.2% and 91.5% for the recovery of A. suum eggs from the fly's gastrointestinal tract and exoskeleton, respectively. CONCLUSIONS: Effective, simple and easy-to-use protocols were developed and validated for the recovery of T. saginata and A. suum eggs from the house fly's gastrointestinal tract and exoskeleton. These protocols can be applied to investigate the importance of flies as parasite egg transmitters in laboratory and field settings.

Spatial transferability of an agent-based model to simulate Taenia solium control interventions.

BACKGROUND: Models can be used to study and predict the impact of interventions aimed at controlling the spread of infectious agents, such as Taenia solium, a zoonotic parasite whose larval stage causes epilepsy and economic loss in many rural areas of the developing nations. To enhance the credibility of model estimates, calibration against observed data is necessary. However, this process may lead to a paradoxical dependence of model parameters on location-specific data, thus limiting the model's geographic transferability. METHODS: In this study, we adopted a non-local model calibration approach to assess whether it can improve the spatial transferability of CystiAgent, our agent-based model of local-scale T. solium transmission. The calibration dataset for CystiAgent consisted of cross-sectional data on human taeniasis, pig cysticercosis and pig serology collected in eight villages in Northwest Peru. After calibration, the model was transferred to a second group of 21 destination villages in the same area without recalibrating its parameters. Model outputs were compared to pig serology data collected over a period of 2 years in the destination villages during a trial of T. solium control interventions, based on mass and spatially targeted human and pig treatments. RESULTS: Considering the uncertainties associated with empirical data, the model produced simulated pre-intervention pig seroprevalences that were successfully validated against data collected in 81% of destination villages. Furthermore, the model outputs were able to reproduce validated pig seroincidence values in 76% of destination villages when compared to the data obtained after the interventions. The results demonstrate that the CystiAgent model, when calibrated using a non-local approach, can be successfully transferred without requiring additional calibration. CONCLUSIONS: This feature allows the model to simulate both baseline pre-intervention transmission conditions and the outcomes of control interventions across villages that form geographically homogeneous regions, providing a basis for developing large-scale models representing T. solium transmission at a regional level.

The global burden of neglected zoonotic diseases: Current state of evidence.

The majority of emerging infectious diseases are zoonoses, most of which are classified as "neglected". By affecting both humans and animals, zoonoses pose a dual burden. The disability-adjusted life year (DALY) metric quantifies human health burden since it combines mortality and morbidity. This review aims to describe and analyze the current state of evidence on neglected zoonotic diseases (NZDs) burden and start a discussion on the current understanding of the global burden of NZDs. We identified 26 priority NZDs through consulting three international repositories for national prioritization exercises. A systematic review of global and national burden of disease (BoD) studies was conducted using pre-selected databases. Data on diseases, location and DALYs were extracted for each eligible study. A total of 1887 records were screened, resulting in 74 eligible studies. The highest number of BoD was found for non-typhoidal salmonellosis (23), whereas no estimates were found for West Nile, Marburg and Lassa fever. Geographically, the highest number of studies was performed in the Netherlands (11), China (5) and Iran (4). The number of BoD retrieved mismatched the perceived importance in national prioritization exercises. For example, anthrax was considered a priority NZD in 65 countries; however, only one national study estimating BoD was retrieved. By summing the available global estimates, the selected NZDs caused at least 21 million DALYs per year, a similar order of magnitude to (but less than) the burden due to foodborne disease (included in the Foodborne Disease Burden Epidemiology Reference Group). The global burden of disease landscape of NZDs remains scattered. There are several priority NZDs for which no burden estimates exist, and the number of BoD studies does not reflect national disease priorities. To have complete and consistent estimates of the global burden of NZDs, these diseases should be integrated in larger global burden of disease initiatives.

CD4+ T cell calibration of antigen-presenting cells optimizes antiviral CD8+ T cell immunity.

Antiviral CD8+ T cell immunity depends on the integration of various contextual cues, but how antigen-presenting cells (APCs) consolidate these signals for decoding by T cells remains unclear. Here, we describe gradual interferon-α/interferon-ß (IFNα/ß)-induced transcriptional adaptations that endow APCs with the capacity to rapidly activate the transcriptional regulators p65, IRF1 and FOS after CD4+ T cell-mediated CD40 stimulation. While these responses operate through broadly used signaling components, they induce a unique set of co-stimulatory molecules and soluble mediators that cannot be elicited by IFNα/ß or CD40 alone. These responses are critical for the acquisition of antiviral CD8+ T cell effector function, and their activity in APCs from individuals infected with severe acute respiratory syndrome coronavirus 2 correlates with milder disease. These observations uncover a sequential integration process whereby APCs rely on CD4+ T cells to select the innate circuits that guide antiviral CD8+ T cell responses.

Clinical characteristics and management of neurocysticercosis patients: a retrospective assessment of case reports from Europe.

OBJECTIVES: Neurocysticercosis (NCC) is a parasitic disease caused by the larval stage of the tapeworm Taenia solium. NCC mainly occurs in Africa, Latin America and South-East Asia and can cause a variety of clinical signs/symptoms. Although it is a rare disease in Europe, it should nonetheless be considered as a differential diagnosis. The aim of this study was to describe clinical characteristics and management of patients with NCC diagnosed and treated in Europe. METHODS: We conducted a systematic search of published and unpublished data on patients diagnosed with NCC in Europe (2000-2019) and extracted demographic, clinical and radiological information on each case, if available. RESULTS: Out of 293 identified NCC cases, 59% of patients presented initially with epileptic seizures (21% focal onset); 52% presented with headache and 54% had other neurological signs/symptoms. The majority of patients had a travel or migration history (76%), mostly from/to Latin America (38%), Africa (32%) or Asia (30%). Treatment varied largely depending on cyst location and number. The outcome was favorable in 90% of the cases. CONCLUSIONS: Management of NCC in Europe varied considerably but often had a good outcome. Travel and migration to and from areas endemic for T. solium will likely result in continued low prevalence of NCC in Europe. Therefore, training and guidance of clinicians is recommended for optimal patient management.

Urinary neopterin reflects immunological variation associated with age, helminth parasitism, and the microbiome in a wild primate.

Neopterin, a product of activated white blood cells, is a marker of nonspecific inflammation that can capture variation in immune investment or disease-related immune activity and can be collected noninvasively in urine. Mounting studies in wildlife point to lifetime patterns in neopterin related to immune development, aging, and certain diseases, but rarely are studies able to assess whether neopterin can capture multiple concurrent dimensions of health and disease in a single system. We assessed the relationship between urinary neopterin stored on filter paper and multiple metrics of health and disease in wild geladas (Theropithecus gelada), primates endemic to the Ethiopian highlands. We tested whether neopterin captures age-related variation in inflammation arising from developing immunity in infancy and chronic inflammation in old age, inflammation related to intramuscular tapeworm infection, helminth-induced anti-inflammatory immunomodulation, and perturbations in the gastrointestinal microbiome. We found that neopterin had a U-shaped relationship with age, no association with larval tapeworm infection, a negative relationship with metrics related to gastrointestinal helminth infection, and a negative relationship with microbial diversity. Together with growing research on neopterin and specific diseases, our results demonstrate that urinary neopterin can be a powerful tool for assessing multiple dimensions of health and disease in wildlife.

A Systematic Review and Meta-Analysis on the Occurrence of Toxoplasmosis in Animals Slaughtered in Brazilian Abattoirs.

Toxoplasmosis is mainly transmitted to human beings through the consumption of contaminated food, and several outbreaks caused by infected meat consumption have been reported in Brazil. We performed a systematic literature review on the prevalence and risk factors for toxoplasmosis in slaughtered animals and performed a meta-analysis of its prevalence for different species and regions. Furthermore, we also discussed the infectivity of seropositive animals, risk factors, and preventive strategies. In the meta-analysis, the overall prevalence estimates for poultry, ostrich, goats, swine, equids, sheep, and bovines were 42.4, 40.4, 23.0, 19.9, 19.1, 17.3, and 16.2%, respectively. Regarding the Brazilian regions, the highest prevalence values were detected for bovines and equids in the South (32.3 and 34.4%, respectively) and swine, goats, sheep, and poultry in the Northeast (29.3, 23.0, 22.9, and 69.8%%, respectively). High proportions of Toxoplasma gondii viability in bioassay conducted on seropositive animals were seen for sheep (34/40 = 85%) and swine (12/15 = 80%). Toxoplasma gondii infections are widespread on Brazilian farms, and the summarized data allow the establishment of high-priority areas and/or species for the adoption of preventive strategies to control this parasite at different levels of the food chain.

Epidemiological, clinical and radiological characteristics of people with neurocysticercosis in Tanzania-A cross-sectional study.

BACKGROUND: Neurocysticercosis (NCC) is common among people with epilepsy in low-resource settings. Prevalence of NCC and radiological characteristics of patients with NCC vary considerably even within small areas but differences have been poorly characterized so far. METHODS: We conducted a cross-sectional study between August 2018 and April 2020 in three district hospitals in southern Tanzania (Ifisi, Tukuyu and Vwawa). Patients with and without epileptic seizures were included in this study. All patients were tested with a novel antibody-detecting point-of-care test for the diagnosis of Taenia solium cysticercosis. All test positives and a subset of test negatives had a further clinical work-up including medical examination and computed tomography of the brain. NCC was defined according to the Del Brutto criteria. We assessed epidemiological, clinical and radiological characteristics of patients with NCC by presence of epileptic seizures and by serology status. RESULTS: In all three district hospitals, more than 30% of all people with epileptic seizures (PWE) had NCC lesions in their brain (38% in Vwawa, 32% in Tukuyu and 31% in Ifisi). Most PWE with NCC had multiple lesions and mostly parenchymal lesions (at least 85%). If patients were serologically positive, they had in the median more lesions than serologically negative patients (15 [interquartile range 8-29] versus 5 [1.8-11]), and only serologically positive patients had active stage lesions. Furthermore, serologically positive PWE had more lesions than serologically positive people without epileptic seizures (10.5 [7-23]), and more often had active lesions. PWE diagnosed with NCC (n = 53) were older, and more commonly had focal onset seizures (68% versus 44%, p = 0.03) and headache episodes (34% versus 14%, p = 0.06), which were also stronger than in PWE without NCC (p = 0.04). CONCLUSION: NCC is common among PWE. A combination of clinical and serological factors could help to establish an algorithm to identify patients potentially suffering from active NCC, who benefit from further clinical investigation including neuroimaging.

Assessing the burden of Taenia solium cysticercosis in Burundi, 2020.

BACKGROUND: Taenia solium cysticercosis is a zoonotic disease that is endemic in many low- and middle-income countries where risk factors for disease transmission are present. The economic impact of cysticercosis on public health and on the pig production sector is not well known in many of those countries, including Burundi. This study aimed at estimating the burden of T. solium cysticercosis in Burundi including data on humans and pigs. METHODS: Epidemiological and economic data were collected from literature up to July 30, 2021 and governmental and non-governmental agencies. Direct and indirect costs for neurocysticercosis (NCC)-associated epilepsy and losses due to porcine cysticercosis were estimated to assess the economic burden, while the health burden was estimated using zoonotic disability-adjusted life years (zDALYs). Different probability distributions (Uniform, Beta, Dirichlet and Gamma) were applied depending on the type of epidemiological parameter. Monte Carlo simulations and 100,000 iterations were used to calculate the 95% uncertainty interval (UI) for each parameter and perform sensitivity analyses. RESULTS: In Burundi, 4.26 million USD (95% UI, 1,858,308-8,190,951) were estimated as economic impact due to T. solium cysticercosis in humans and pigs, of which 40.2% (95% UI, 10.3-75.1) of the total costs were due to NCC-associated epilepsy and 59.8% (95% UI, 24.9-89.7) of the losses due to porcine cysticercosis. The cost per NCC-associated epilepsy case was 72 USD (95% UI, 25-168), representing 30.8% of the GDP per capita in 2020. The probable incident cases and deaths for NCC-associated epilepsy were 9065 (95% UI, 2370-16,716) and 61 (95% UI, 16-114), respectively. More than 2 zDALYs (95% UI, 1.1-3.4) per thousand person-years was estimated, of which an average of 1.3 DALYs [0;0] (95% UI, 0.3-2.6) was due to NCC- associated epilepsy and 0.8 animal loss equivalents (ALEs) (95% UI, 0.3-1.5) due to porcine cysticercosis. CONCLUSIONS: This study provides evidence of a significant burden of T. solium cysticercosis for Burundi's population. We urge policy makers to use these evidence-based results and put T. solium cysticercosis on the public health agenda of the country. This study recommends urgent action to find solutions for integrated control strategies for T. solium cysticercosis in Burundi.

The role of cooking practices in the transmission of the foodborne parasite Taenia solium: A qualitative study in an endemic area of Southern Tanzania.

The pork tapeworm Taenia solium is a zoonotic food-borne parasite endemic in many developing countries causing human cysticercosis and taeniosis as well as porcine cysticercosis. It mainly affects the health of rural smallholder pig farmers and their communities, resulting in lower health status, reduced pork quality, and economic loss due to condemnation of pigs or low pricing of pork. This qualitative study aimed to identify key food related practices linked to consumption of pork at village level, of importance for transmission of taeniosis. We used an interpretivist-constructivist paradigm in a multiple case study of exploratory qualitative research design. Data was acquired through guided and probing interviews with 64 pork cooks, and 14 direct observations in four villages in a T. solium endemic area of Mbeya Region in the Southern Highlands of Tanzania. The study showed that the informants were members of communities of practice through their pork cooking practices, one community of practice for the restaurant cooks and one for the home cooks, learning, sharing, and distributing their cooking skills. Furthermore, the analysis showed that the pork cooks generally had some awareness of there being something undesirable in raw pork, but they had very diverse understandings of what it was, or of its potential harm. Major potential transmission points were identified in restaurants and in home kitchens. It appears that the pork cooks act according to socio-cultural and economic factors guiding them in their actions, including pressure from customers in restaurants, the family values of tradition in the home kitchens, and the culturally guided risk perception and appraisal. These practices might generate potential transmission points. Future research on interventions aimed at preventing the spread of T. solium taeniosis should recognise the importance of tradition and culture in risky food practices.

Non-local validated parametrization of an agent-based model of local-scale Taenia solium transmission in North-West Peru.

The pork tapeworm, Taenia solium, is the cause of a preventable zoonotic disease, cysticercosis, affecting both pigs and humans. Continued endemic transmission of T. solium is a major contributor of epilepsy and other neurologic morbidity, and the source of important economic losses, in many rural areas of developing countries. Simulation modelling can play an important role in aiding the design and evaluation of strategies to control or even eliminate transmission of the parasite. In this paper, we present a new agent based model of local-scale T. solium transmission and a new, non-local, approach to the model calibration to fit model outputs to observed human taeniasis and pig cysticercosis prevalence simultaneously for several endemic villages. The model fully describes all relevant aspects of T. solium transmission, including the processes of pig and human infection, the spatial distribution of human and pig populations, the production of pork for human consumption, and the movement of humans and pigs in and out in several endemic villages of the northwest of Peru. Despite the high level of uncertainty associated with the empirical measurements of epidemiological data associated with T. solium, the non-local calibrated model parametrization reproduces the observed prevalences with an acceptable precision. It does so not only for the villages used to calibrate the model, but also for villages not included in the calibration process. This important finding demonstrates that the model, including its calibrated parametrization, can be successfully transferred within an endemic region. This will enable future studies to inform the design and optimization of T. solium control interventions in villages where the calibration may be prevented by the limited amount of empirical data, expanding the possible applications to a wider range of settings compared to previous models.

MYB orchestrates T cell exhaustion and response to checkpoint inhibition.

CD8+ T cells that respond to chronic viral infections or cancer are characterized by the expression of inhibitory receptors such as programmed cell death protein 1 (PD-1) and by the impaired production of cytokines. This state of restrained functionality-which is referred to as T cell exhaustion1,2-is maintained by precursors of exhausted T (TPEX) cells that express the transcription factor T cell factor 1 (TCF1), self-renew and give rise to TCF1- exhausted effector T cells3-6. Here we show that the long-term proliferative potential, multipotency and repopulation capacity of exhausted T cells during chronic infection are selectively preserved in a small population of transcriptionally distinct CD62L+ TPEX cells. The transcription factor MYB is not only essential for the development of CD62L+ TPEX cells and maintenance of the antiviral CD8+ T cell response, but also induces functional exhaustion and thereby prevents lethal immunopathology. Furthermore, the proliferative burst in response to PD-1 checkpoint inhibition originates exclusively from CD62L+ TPEX cells and depends on MYB. Our findings identify CD62L+ TPEX cells as a stem-like population that is central to the maintenance of long-term antiviral immunity and responsiveness to immunotherapy. Moreover, they show that MYB is a transcriptional orchestrator of two fundamental aspects of exhausted T cell responses: the downregulation of effector function and the long-term preservation of self-renewal capacity.

Preliminary evaluation of different methods to detect and quantify Taenia eggs in sludge and water samples: A spiking experiment to assess recovery efficiency.

An improved understanding of the environmental transmission of Taenia spp. is key to control of the parasite. Methods to detect and quantify Taenia eggs in different environmental matrices, including sludge and water, currently lack performance validation with regard to the recovery efficiency and process ease of use. Therefore, this study aimed to assess the recovery efficiency and process duration of commonly used methods for the detection of Taenia eggs in sludge and water samples. Ten detection methods for Taenia spp. eggs were selected from a systematic review. Sludge and water samples were spiked with a high dose of Taenia saginata eggs, i.e., around 200 eggs/g sludge and 50 eggs/ml water, and were tested using five methods each. The two methods with the highest egg recovery efficiencies were selected per matrix for assessment with a lower spiking dose, i.e., 4 eggs/g sludge and 1 egg/ml water. Each time five replicates were used. Recovery efficiency was defined as the proportion of the number of eggs recovered to the total number of eggs spiked. Using the high spiking dose, all samples tested positive for all the methods. The mean egg recovery efficiency varied from 4% to 69% for sludge samples and from 3% to 68% for water samples. Using the lower spiking dose, one of the methods performed on sludge samples was able to detect all replicates, whereas only one replicate was positive using the other method. For water, all low dose samples tested positive using both methods. In conclusion, most methods performed inadequately in recovering Taenia eggs from sludge and water, with half of the methods performed on the high dose samples having a mean egg recovery efficiency of approximately 10% or less. The assessed recovery methods were generally time-consuming and labourious. A more thorough validation of existing recovery methods and improvement of method protocols to increase recovery efficiency is thus urgently needed.

CystiHuman: A model of human neurocysticercosis.

INTRODUCTION: The Taenia solium tapeworm is responsible for cysticercosis, a neglected tropical disease presenting as larvae in the body of a host following taenia egg ingestion. Neurocysticercosis (NCC), the name of the disease when it affects the human central nervous system, is a major cause of epilepsy in developing countries, and can also cause intracranial hypertension, hydrocephalus and death. Simulation models can help identify the most cost-effective interventions before their implementation. Modelling NCC should enable the comparison of a broad range of interventions, from treatment of human taeniasis (presence of an adult taenia worm in the human intestine) to NCC mitigation. It also allows a focus on the actual impact of the disease, rather than using proxies as is the case for other models. METHODS: This agent-based model is the first model that simulates human NCC and associated pathologies. It uses the output of another model, CystiAgent, which simulates the evolution of pig cysticercosis and human taeniasis, adding human and cyst agents, including a model of cyst location and stage, human symptoms, and treatment. CystiHuman also accounts for delays in the appearance of NCC-related symptoms. It comprises three modules detailing cyst development, seizure probability and timing, and intracranial hypertension/hydrocephalus, respectively. It has been implemented in Java MASON and calibrated in three endemic villages in Peru, then applied to another village (Rica Playa) to compare simulation results with field data in that village. RESULTS AND DISCUSSION: Despite limitations in available field data, parameter values found through calibration are plausible and simulated outcomes in Rica Playa are close to actual values for NCC prevalence and the way it increases with age and cases with single lesions. Initial simulations further suggest that short-term interventions followed by a rapid increase in taeniasis prevalence back to original levels may have limited impacts on NCC prevalence.