Multiple factors affecting Ixodes ricinus ticks and associated pathogens in European temperate ecosystems (northeastern France).

In Europe, the main vector of tick-borne zoonoses is Ixodes ricinus, which has three life stages. During their development cycle, ticks take three separate blood meals from a wide variety of vertebrate hosts, during which they can acquire and transmit human pathogens such as Borrelia burgdorferi sensu lato, the causative agent of Lyme borreliosis. In this study conducted in Northeastern France, we studied the importance of soil type, land use, forest stand type, and temporal dynamics on the abundance of ticks and their associated pathogens. Negative binomial regression modeling of the results indicated that limestone-based soils were more favorable to ticks than sandstone-based soils. The highest tick abundance was observed in forests, particularly among coniferous and mixed stands. We identified an effect of habitat time dynamics in forests and in wetlands: recent forests and current wetlands supported more ticks than stable forests and former wetlands, respectively. We observed a close association between tick abundance and the abundance of Cervidae, Leporidae, and birds. The tick-borne pathogens responsible for Lyme borreliosis, anaplasmosis, and hard tick relapsing fever showed specific habitat preferences and associations with specific animal families. Machine learning algorithms identified soil related variables as the best predictors of tick and pathogen abundance.

Feasibility and safety of integrating mass drug administration for helminth control with seasonal malaria chemoprevention among Senegalese children: a randomized controlled, observer-blind trial.

BACKGROUND: The overlap in the epidemiology of malaria and helminths has been identified as a potential area to exploit for the development of an integrated control strategy that may help to achieve elimination of malaria and helminths. A randomized, controlled, observer-blind trial was conducted to assess the feasibility and safety of combining mass drug administration (MDA) for schistosomiasis and soil transmitted helminths (STH) with seasonal malaria chemoprevention (SMC) among children living in Senegal. METHODS: Female and male children aged 1-14 years were randomized 1:1:1, to receive Vitamin A and Zinc on Day 0, followed by SMC drugs (sulfadoxine-pyrimethamine and amodiaquine) on Days 1-3 (control group); or praziquantel and Vitamin A on Day 0, followed by SMC drugs on Days 1-3 (treatment group 1); or albendazole and praziquantel on Day 0, followed by SMC drugs on Days 1-3 (treatment group 2). Safety assessment was performed by collecting adverse events from all children for six subsequent days following administration of the study drugs. Pre- and post-intervention, blood samples were collected for determination of haemoglobin concentration, malaria microscopy, and PCR assays. Stool samples were analyzed using Kato-Katz, Merthiolate-iodine-formalin and PCR methods. Urine filtration, PCR and circulating cathodic antigen tests were also performed. RESULTS: From 9 to 22 June 2022, 627 children aged 1-14 years were randomized into the three groups described above. Mild, transient vomiting was observed in 12.6% (26/206) of children in treatment group 2, in 10.6% (22/207) in group 1, and in 4.2% (9/214) in the control group (p = 0.005). Pre-intervention, the geometric mean value of Plasmodium falciparum parasite density was highest among children who received albendazole, praziquantel with SMC drugs. Post-intervention, the parasite density was highest among children who received SMC drugs only. Children who received praziquantel and SMC drugs had a lower risk of developing severe anaemia than their counterparts who received SMC drugs alone (OR = 0.81, 95% CI 0.13-5.00, p = 0.63). CONCLUSIONS: Integration of MDA for helminths with SMC drugs was safe and feasible among Senegalese children. These findings support further evaluation of the integrated control model. TRIAL REGISTRATION: The study is registered at Clinical Trial.gov NCT05354258.

Provider and User Acceptability of Integrated Treatment for the Control of Malaria and Helminths in Saraya, South-Eastern Senegal.

Integration of vertical programs for the control of malaria, schistosomiasis, and soil-transmitted helminthiasis has been recommended to achieve elimination of malaria and neglected tropical diseases (NTD) by 2030. This qualitative study was conducted within the context of a randomized controlled trial to explore the perceptions and views of parents/caregivers of at-risk children and healthcare providers to determine their acceptability of the integrated malaria-helminth treatment approach. Randomly selected parents/caregivers of children enrolled in the trial, healthcare providers, trial staff, malaria, and NTD program managers were interviewed using purpose-designed topic guides. Transcripts obtained from the interviews were coded and common themes identified using content analysis were triangulated. Fifty-seven study participants comprising 26 parents/caregivers, 10 study children aged ≥ 10 years, 15 trial staff, four healthcare providers, and two managers from the Senegal Ministry of Health were interviewed. Thirty-eight of the participants (66.7%) were males, and their ages ranged from 10 to 65 years. Overall, the integrated malaria-helminth treatment approach was considered acceptable, but the study participants expressed concerns about the taste, smell, and side effects associated with amodiaquine and praziquantel in the combination package. Reluctance to accept the medications was also observed among children aged 10 to 14 years due to peer influence and gender-sensitive cultural beliefs. Addressing concerns about the taste and smell of amodiaquine and praziquantel is needed to optimize the uptake of the integrated treatment program. Also, culturally appropriate strategies need to be put in place to cater for the inclusion of children aged 10 to 14 years in this approach.

Prevalence of malaria-helminth co-infections among children living in a setting of high coverage of standard interventions for malaria and helminths: Two population-based studies in Senegal.

Background: Concurrent infections of Plasmodium falciparum with Soil Transmitted Helminths (STH) and Schistosoma spp are still a major public health problem among children living in Sub-Saharan Africa. We conducted two prospective studies among children living in urban and rural settings of Senegal, where control programmes for malaria, STH and schistosomiasis have been sustained, to determine the prevalence of malaria-helminth co-infection. Methods: We enrolled 910 children aged 1-14 years from Saraya and Diourbel districts of Senegal in June and November 2021, respectively. We collected finger-prick blood samples from the children for malaria parasite detection using microscopy and PCR methods. Stool samples were also collected and Kato-Katz and PCR methods were used to detect STH and S. mansoni; and Merthiolate-iodine-formalin (MIF) test for other intestinal protozoans. Urine samples were analyzed using a filtration test, Point of Care Circulating Cathodic Antigens (POC-CCA) and PCR methods for detection of S. haematobium. Statistical analyses were performed to compare the continuous and categorical variables across the two study sites and age groups, as well as using the adjusted Odds ratios (aOR) to explore risk factors for malaria-helminth co-infections. Results: The overall prevalence of polyparasitism with P. falciparum, STH, S. haematobium and S. mansoni among children in the two study sites was 2.2% (20/910) while prevalence of P. falciparum-S. haematobium co-infection was 1.1% (10/910); P. falciparum-S. mansoni 0.7% (6/910) and P. falciparum with any intestinal protozoan 2.4% (22/910). Co-infection was slightly higher among 5-14 year old children (17/629, 2.7%; 95% CI: 1.43-3.97) than 1-4 years (3/281, 1.1%; 95% CI: -0.12-2.32) and, in boys (13/567, 2.3%; 95% CI: 1.27-3.96) than girls (7/343, 2.1%; 95% CI: 0.52-3.48). Children aged 5-14 years (aOR = 3.37; 95% CI: 0.82-13.77, p = 0.09), who were boys (aOR = 1.44; 95% CI: 0.48-4.36, p = 0.51) and lived in Saraya (aOR = 1.27; 95% CI: 0.24-6.69, p = 0.77) had a higher risk of malaria-helminth co-infection than other age group, in girls and those who lived in Diourbel. Living in houses with spaces between the walls and roofs as well as frequent contacts with water during swimming were statistically significant risk factors for malaria-helminth co-infection. Conclusions: The prevalence of malaria-helminth co-infection is low in two districts in Senegal, possibly due to sustained implementation of effective control measures for malaria and NTDs. These findings could help to develop and implement strategies that would lead to elimination of malaria and helminths in the study areas.

Computation of the conditions for anti-angiogenesis and gene therapy synergistic effects: Sensitivity analysis and robustness of target solutions.

Both anti-angiogenesis and gene therapy involve complex processes depending on non-point parameters belonging to a space of values. To successfully overcome the challenges involved in their therapeutic approaches, there is a need to analyze the sensitivity of these parameters. In this paper, a new mathematical model that combines immune system stimulations, inflammatory processes associated with tumor development, and gene therapy aimed at enhancing the efficacy of both treatments are explored. Using the global sensitivity methods of Sobol and Morris, the most important parameters are estimated. Estimation of the sensitivity variance revealed a strong interdependence between the parameters. Also, determinations of the conditions for effective therapy lead to a target of reducing the cancer cell numbers by at least 50%. This opened the way for delimiting the parameter spaces making it possible to reach the treatment target in addition to enhancing the estimation of the minimum time of remission. The combination of therapies and sensitivity analysis have demonstrated the robustness of therapy success.

Microplastics enhance Daphnia magna sensitivity to the pyrethroid insecticide deltamethrin: Effects on life history traits.

The aim of the study was to investigate the influence of microplastics (MPs) on the ecotoxicity of common contaminants of aquatic ecosystems. As a model contaminant, the hydrophobic pesticide deltamethrin (DM) was chosen, and its effects on life history traits of Daphnia magna were studied in the presence or absence of polyethylene MPs. Commercialized DM and MPs obtained as dry powder were used in the experiment. According the manufacturer (Cospheric, Santa Barbara, CA, USA) MPs were spherical (1-4 µm in diameter), had a density of 0.96 g/cm-3 and were without any solvent. Three concentrations of polyethylene MPs were tested (0, 1, 10 mg/L) with two realistic concentrations of DM (0 and 40 ng/L) and a solvent control (acetone). During the 21 d experiment, D. magna neonates were individually exposed to the treatments, and the effects of MPs and DM alone and together were evaluated by assessing survival, number of cumulative molts, days to first brood, number of broods, number of neonates per surviving adult, and body length. Significant detrimental effects on survival were only observed for the two mixture treatments. DM alone (40 ng/L) delayed the days to first brood and reduced the number of neonates per surviving adult, whereas MPs alone (10 mg/L) induced significant reduction in the number of juveniles by surviving adults. The combined exposure to DM and MPs clearly had a synergistic effect on survival, brood number, and number of neonates per surviving female. For example, compared to exposure to 40 ng/L of DM alone, the addition of 1 mg/L of MPs resulted in a 51.1% reduction in number of neonates per surviving female and a 46% reduction in brood number. These results suggest the potential drastic effects of this kind of mixed exposure on daphnid populations, which are key components of freshwater food webs.

Combined acute ecotoxicity of malathion and deltamethrin to Daphnia magna (Crustacea, Cladocera): comparison of different data analysis approaches.

We studied the combined acute effect (i.e., after 48 h) of deltamethrin (a pyrethroid insecticide) and malathion (an organophosphate insecticide) on Daphnia magna. Two approaches were used to examine the potential interaction effects of eight mixtures of deltamethrin and malathion: (i) calculation of mixture toxicity index (MTI) and safety factor index (SFI) and (ii) response surface methodology coupled with isobole-based statistical model (using generalized linear model). According to the calculation of MTI and SFI, one tested mixture was found additive while the two other tested mixtures were found no additive (MTI) or antagonistic (SFI), but these differences between index responses are only due to differences in terminology related to these two indexes. Through the surface response approach and isobologram analysis, we concluded that there was a significant antagonistic effect of the binary mixtures of deltamethrin and malathion that occurs on D. magna immobilization, after 48 h of exposure. Index approaches and surface response approach with isobologram analysis are complementary. Calculation of mixture toxicity index and safety factor index allows identifying punctually the type of interaction for several tested mixtures, while the surface response approach with isobologram analysis integrates all the data providing a global outcome about the type of interactive effect. Only the surface response approach and isobologram analysis allowed the statistical assessment of the ecotoxicological interaction. Nevertheless, we recommend the use of both approaches (i) to identify the combined effects of contaminants and (ii) to improve risk assessment and environmental management.

Mathematical modeling of bone marrow--peripheral blood dynamics in the disease state based on current emerging paradigms, part I.

Stemming from current emerging paradigms related to the cancer stem cell hypothesis, an existing mathematical model is expanded and used to study cell interaction dynamics in the bone marrow and peripheral blood. The proposed mathematical model is described by a system of nonlinear differential equations with delay, to quantify the dynamics in abnormal hematopoiesis. The steady states of the model are analytically and numerically obtained. Some conditions for the local asymptotic stability of such states are investigated. Model analyses suggest that malignancy may be irreversible once it evolves from a nonmalignant state into a malignant one and no intervention takes place. This leads to the proposition that a great deal of emphasis be placed on cancer prevention. Nevertheless, should malignancy arise, treatment programs for its containment or curtailment may have to include a maximum and extensive level of effort to protect normal cells from eventual destruction. Further model analyses and simulations predict that in the untreated disease state, there is an evolution towards a situation in which malignant cells dominate the entire bone marrow - peripheral blood system. Arguments are then advanced regarding requirements for quantitatively understanding cancer stem cell behavior. Among the suggested requirements are, mathematical frameworks for describing the dynamics of cancer initiation and progression, the response to treatment, the evolution of resistance, and malignancy prevention dynamics within the bone marrow - peripheral blood architecture.

Investigation of differences in sensitivity between 3 strains of Daphnia magna (crustacean Cladocera) exposed to malathion (organophosphorous pesticide).

Acute and chronic ecotoxic effects of organophosphorous insecticide malathion (Fyfanon 50 EC 500 g L(-1)) were investigated on three strains of Daphnia magna. The nominal effective concentrations immobilizing 50% (EC50) of Daphnia after 24 and 48 h were 0.53 and 0.36 µg L(-1), 0.70 and 0.44 µg L(-1), and 0.75 and 0.46 µg L(-1) for the strains 1, 2, and 3 respectively. There was an increase in malathion ecotoxicity with time of exposure as confirmed by chronic studies. In fact, after 21 days of exposure, significant effects on survival (lowest observed effect concentration or LOECs) were recorded at malathion concentrations of 22, 220 and 230 ng L(-1) for strains 1, 2 and 3 respectively. Other endpoints were also examined, including reproduction (with different parameters), body length and embryo toxicity. ICs10 and ICs20 were calculated for these different parameters. ICs10 ranged from 4.7 to more than 220 ng L(-1) for the three tested strains. The most sensitive parameter was the number of neonates per adult (ICs10 = 4.7 and 10.8 ng L(-1) for strains 1 and 2 respectively) or the number of broods (IC10 = 10 ng L(-1) for strain 3). Moreover, an increase in embryo development abnormalities was observed at the two highest tested malathion concentrations. Abnormalities comprised undeveloped second antennae, curved or unextended shell spines, and curved post-abdomen spines in live neonates. Results suggest that malathion could act as an endocrine disruptor in D. magna as it interferes with development. It also induces a significant decrease in acetylcholinesterase (AChE) activities for the three strains. Both strains 2 and 3 seemed more sensitive (LOECs = 60 ng L(-1)) than strain 1 (LOEC = 120 ng L(-1)). Our results suggest that the AChE activity response can also be used as a biomarker of inter-strain (or inter-clonal) susceptibility (i.e. strain (or clone)-specific response).

Mathematical modeling of glioma therapy using oncolytic viruses.

Diffuse infiltrative gliomas are adjudged to be the most common primary brain tumors in adults and they tend to blend in extensively in the brain micro-environment. This makes it difficult for medical practitioners to successfully plan effective treatments. In attempts to prolong the lengths of survival times for patients with malignant brain tumors, novel therapeutic alternatives such as gene therapy with oncolytic viruses are currently being explored. Based on such approaches and existing work, a spatio-temporal model that describes interaction between tumor cells and oncolytic viruses is developed. Conditions that lead to optimal therapy in minimizing cancer cell proliferation and otherwise are analytically demonstrated. Numerical simulations are conducted with the aim of showing the impact of virotherapy on proliferation or invasion of cancer cells and of estimating survival times.