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The availability of a safe macrofilaricidal drug would help to accelerate onchocerciasis elimination. A trial was conducted in Cameroon to evaluate the effects of a subcutaneous injectable long-acting formulation of ivermectin (LAFI) on the microfilariae (mf) and adult stages of Onchocerca ochengi. Ten zebu cattle naturally infected with the parasite were injected subcutaneously with either 500 mg (group A, N = 4), or 1000 mg long-acting ivermectin (group B, N = 4) or the vehicle (group C, N = 2). Skin samples were collected from each animal before, and 6, 12, and 24 months after treatment to measure microfilarial densities (MFDs). Nodules excised before, and 6 and 12 months after treatment were examined histologically to assess the adult worms’ viability and reproductive status. Blood samples were collected at pre-determined time-points to obtain pharmacokinetic data. Before treatment, the average O. ochengi MFDs were similar in the three groups. Six months after treatment, all animals in groups A and B were free of skin mf, whereas those in group C still showed high MFDs (mean = 324.5 mf/g). Only one ivermectin-treated animal (belonging to group A) had skin mf 12 months after treatment (0.9 mf/g). At 24 months, another animal in group A showed skin mf (10.0 mf/g). The histologic examination of nodules at 6 and 12 months showed that LAFI was not macrofilaricidal but had a strong effect on embryogenesis. The new LAFI regimen might be an additional tool to accelerate the elimination of human onchocerciasis in specific settings.

Des données entomologiques de base ont été recueillies dans les villages de Zinga et Boali-Chutes, en République Centrafricaine (RCA) en prévision de l’évaluation de l’impact à long terme du traitement par l’ivermectine sous directives communautaires (TIDC). Les déterminations morphologiques révèlent que les simulies capturées dans les deux sites appartiennent au sous-groupe Sou/Sq. À Boali, la nuisance était assez élevée avec une moyenne de 243 piqûres/homme/jour, le taux de parturité moyen de 61,6% et le potentiel annuel de transmission (PAT) brut de 8259 larves infectantes d’onchocerques par homme et par an. En outre, le nombre moyen de larves infectantes pour 1000 pares était de 177. À Zinga, on notait une moyenne de 191 piqûres/ homme/jour, un taux de parturité moyen de 51,6% et un PAT brut de 3422; quant au nombre moyen de larves infectantes pour 1000 pares, il était de 86. En conclusion, les capacités vectrices et les indices entomologiques enregistrés sont caractéristiques de zones à forte transmission onchocerquienne. Reste que certaines des larves infectantes récoltées peuvent être d’origine animale, d’où la nécessité de leur identification pour situer le niveau réel de la transmission.

OBJECTIVE: To assess the validity of observations on eye worm and Calabar swellings for the rapid assessment of the prevalence and intensity of loiasis at the community level. METHOD: A total of 12 895 individuals over the age of 15 years living in 102 communities in Cameroon and Nigeria took part in the study. A standardized questionnaire was administered to participants from whom finger-prick blood samples were collected and examined for Loa loa microfilariae. Rapid assessments of the prevalence and intensity of loiasis were made on the basis of a history of eye worm or Calabar swellings. FINDINGS: There was a strong correlation between the indices of the rapid assessment procedures and the parasitological indices of L. loa endemicity. The rapid assessment indices were effective in diagnosing high-risk communities (sensitivity 94-100%; specificity 66-92%). The highest sensitivity (100%) and specificity (92%) were obtained with a rapid assessment procedure based on a history of eye worm lasting 1-7 days together with confirmation by the guided recognition of a photograph of adult L. loa in the eye. CONCLUSION: Rapid assessment of the prevalence and intensity of loiasis at the community level can be achieved using a procedure based on the history of eye worm lasting 1-7 days together with confirmation by the guided recognition of a photograph of an adult L. loa in the eye.

Abstract Background Anti-Wolbachia treatment with doxycycline is effective in sterilising and killing adult Onchocerca volvulus nematodes, proving superior to ivermectin and of great potential as an alternative approach for the treatment and control of onchocerciasis, particularly in areas of Loa loa co-endemicity. Nevertheless, the length of the required treatment poses potential logistical problems and risk of poor compliance, raising a barrier to the use of doxycycline in Mass Drug Administration (MDA) strategies. In 2007 and 2008 a feasibility trial of community-directed treatment with doxycycline was carried out in two health districts in Cameroon, co-endemic for O. volvulus and L. loa. With 17,519 eligible subjects, the therapeutic coverage was 73.8% with 97.5% compliance, encouraging the feasibility of using doxycycline community-directed delivery in restricted populations of this size. The current study evaluated the effectiveness of this community-directed delivery of doxycycline four years after delivery. Findings Infection with O. volvulus was evaluated by skin biopsy and nodule palpation. Of the 507 subjects recruited, 375 had completed the treatment with doxycycline followed by one or two rounds of annual ivermectin MDA and 132 received one or two rounds of annual ivermectin MDA alone. Statistically significant lower microfilarial prevalence (17.0% [doxycycline plus ivermectin group], 27.0% [ivermectin only group], p = 0.014) and load (p = 0.012) were found in people that had received doxycycline followed by ivermectin compared to those who received ivermectin only. Conclusions This study demonstrates the long-term effectiveness of doxycycline treatment delivered with a community-directed strategy even when evaluated four years after delivery in an area of ongoing transmission. This finding shows that a multi-week course of treatment is not a barrier to community-delivery of MDA in restricted populations of this size and supports its implementation to compliment existing control strategies for onchocerciasis, where needed.

Abstract Background Immunological mechanisms involved in the survival and development of human filarial species in the vertebrate host are poorly known due to the lack of suitable experimental models. In order to understand the role of cytokines in the survival and development of filarial larvae in the vertebrate host, we infected different strains of BALB/c mice deficient in a number of cytokine or cytokine receptor genes with Loa loa. The survival and development of larvae were monitored. Methods BALB/c mice genetically deficient in IL-4R, IFN-γ, IFN-γ/IL-5, IL-5, and IL-4R/IL-5 cytokine or cytokine receptor genes were infected with a human strain of L. loa and necropsies were performed at different time intervals up to 70 days post infection to monitor the survival and development of L. loa larvae. The larvae were teased out of the skin, muscles, peritoneal and pleural cavities, heart and lung tissues. The length and width of the recovered larvae were measured to assess their growth. Results In mice deficient for IL-4R, IFN-γ, IFN-γ/IL-5, IL-5 and IL-4R/IL-5, the larvae survived up to 5, 20, 40, 50 and 70 days respectively. Worms recovered 70 days post infection in IL-4R/IL-5 DKO mice were young adults and measured 10.12 mm in length and 0.1 mm in width. Overall, 47% of larvae were recovered from subcutaneous tissues, 40% from muscles, 6% from the peritoneal cavity and 4% from the pleural cavity, lungs and heart. Conclusion L. loa exhibits a differential survival and development in different strains of cytokine or cytokine receptor gene knockout mice with IL-4R and IL-5 playing critical roles in the host resistance to L. loa infection. The knock out BALB/c mouse therefore represents a useful tool to explore the key effectors of adaptive immunity involved in the killing of the L. loa parasite in a mammal host.

Abstract Background The human parasite Onchocerca volvulus harbours Wolbachia endosymbionts essential for worm embryogenesis, larval development and adult survival. In this study, the development of Wolbachia-depleted microfilariae (first stage larvae) to infective third stage larvae (L3) in the insect vector Simulium damnosum was analysed. Methods Infected volunteers in Cameroon were randomly and blindly allocated into doxycycline (200 mg/day for 6 weeks) or placebo treatment groups. After treatment, blackflies were allowed to take a blood meal on the volunteers, captured and dissected for larval counting and DNA extraction for quantitative real-time PCR analysis. Results PCR results showed a clear reduction in Wolbachia DNA after doxycycline treatment in microfilariae from human skin biopsies with > 50% reduction at one month post-treatment, eventually reaching a reduction of > 80%. Larval stages recovered from the insect vector had similar levels of reduction of endosymbiotic bacteria. Larval recoveries were analysed longitudinally after treatment to follow the kinetics of larval development. Beginning at three months post-treatment, significantly fewer L3 were seen in the blackflies that had fed on doxycycline treated volunteers. Concomitant with this, the proportion of second stage larvae (L2) was significantly increased in this group. Conclusions Doxycycline treatment and the resulting decline of Wolbachia endobacteria from the microfilaria resulted in retarded development of larvae in the insect vector. Thus, anti-wolbachial treatment could have an additive effect for interrupting transmission by reducing the number of L3 that can be transmitted by blackflies.

Abstract Background Onchocerca volvulus, the causative agent of river blindness, is transmitted through the black fly Simulium damnosum s.l., which breeds in turbulent river waters. To date, the number of flies attacking humans has only been determined by standard fly collectors near the river or the village. In our study, we counted the actual number of attacking and successfully feeding S. damnosum s.l. flies landing on individual villagers during their routine day-time activities in two villages of the Sudan-savannah and rainforest of Cameroon. We compared these numbers to the number of flies caught by a standard vector-collector, one positioned near the particular villager during his/her daily activity and the other sitting at the nearest Simulium breeding site. Results Using these data obtained by the two vector-collectors, we were able to calculate the Actual Index of Exposure (AIE). While the AIE in the savannah was on average 6,3%, it was 34% in the rainforest. The Effective Annual Transmission Potential (EATP) for individual villagers was about 20 fold higher in the rainforest compared to the savannah. Conclusions Here we show for the first time that it is possible to determine the EATP. Further studies with more subjects are needed in the future. These data are important for the development of future treatment strategies.

Abstract Background Severe side effects following ivermectin treatment of onchocerciasis in areas of co-endemicity with loaisis have been an impediment for the work of the African Programme for Onchocerciasis Control (APOC) in forested regions of several countries. Doxycycline has been shown to be effective in the treatment of onchocerciasis and has the added advantages of killing adult Onchocerca volvulus but neither adult Loa loa nor their microfilariae. This drug therefore offers great potential for the treatment of onchocerciasis in areas of co-endemicity with loiasis. The limitation of use of this drug is the duration of treatment that may pose a potential problem with therapeutic coverage and compliance with treatment. To benefit from the advantages that doxycycline offers in the treatment of onchocerciasis, it will be necessary to establish an effective distribution system that can access remote communities. This study assessed the feasibility of a large-scale distribution of doxycycline for the treatment of onchocerciasis in areas of co-endemicity with loiasis using a community-directed approach. Methods The study was carried out in 5 health areas co-endemic for Onchocerca volvulus and Loa loa which had no prior experience of the Community Directed Treatment with Ivermectin (CDTI). The community-directed delivery process was introduced using a cascade mechanism from the central health system that passed through the regional health delegation, health district and the health areas. Community health implementers (CHIs) were trained to deliver doxycycline to community members and, under the supervision of the health system, to monitor and document drug intake and side effects. Results The community members adhered massively to the process. Of the 21355 individuals counted, 17519 were eligible for treatment and 12936 were treated with doxycycline; giving a therapeutic coverage of eligible population of 73.8%. Of the 12936 who started the treatment, 97.5% complied by the end of six weeks. No serious side effect was registered during the six week treatment. Conclusion This study indicates that when empowered the community health implementers can successfully deliver doxycycline for six weeks for the treatment of onchocerciasis in areas of co-endemicity with loiasis. The therapeutic coverage and the compliance treatment rate achieved in this study coupled to the known efficacy of doxycycline on O. volvulus, are indicators that the strategy involving the mass administration of doxycycline can be used to control onchocerciasis in those areas of co-endemicity with loiasis where ivermectin may be contraindicated.

Energy management strategies with prediction message show great potential in optimizing control objectives for fuel cell hybrid vehicles. This paper presents a novelty model-predictive-control based energy management framework for fuel cell commercial vehicle, in which the vehicle mass is firstly introduced as a variable parameter for controller. A vehicle mass identification model is established and embed in the framework based on recursive least square algorithm, and the influence of variable algorithm parameters on estimator is evaluated. Then the effects of mass varying on vehicle performance is talked about in detail. In addition, the performance for different drive cycles on different loaded is also given. The simulation results show that the fuel consumption is positively correlated with the mass identification error, and the designed controller can reduce the additional fuel consumption to around 0.1%, which is much batter to the deterministic parameters scheme. Finally, the shortcomings of the designed controller are given. This paper provides a reliable theoretical basis to address varying-mass vehicle energy management problems.

Abstract Aims Right ventricular pacing (RVP) dependence could impair left ventricular ejection fraction (LVEF). This study aimed to illuminate the relationship between RVP proportion and LVEF, as well as disclosing independent predictors of RVP dependence. Methods and results Patients indicated for permanent pacemaker implantation were included (2016–2020). The ventricular pacing lead was placed in right ventricular apex or septum. Pacing mode programming followed universal standard. Electrocardiographic, echocardiographic, and serological parameters were collected. RVP dependence was defined according to its influence on LVEF. This study was of case–control design. Included patients were matched by potentially confounding factors through propensity score matching. A total of 1183 patients were included, and the mean duration of follow‐up was 24 months. Percentage of RVP 120 ms (OR = 2.46, 95% CI: 1.42–4.27), QTc interval > 470 ms (OR = 2.01, 95% CI: 1.33–3.05), and pulmonary artery systolic pressure (PASP) > 40 mmHg (OR = 1.93, 95% CI: 1.46–2.56) were proved to predict RVP dependence. Conclusions High RVP percentage (>80%) indicating RVP dependence significantly correlates with poor prognosis of cardiac function. High degree/complete AVB, AF, ischaemic aetiology, PCI history, HRmax 120 ms, QTc interval > 470 ms, and PASP > 40 mmHg were verified as independent risk factors of RVP dependence.

Context and objective. The time spent by young people at the university is generally marked by a profound transition in lifestyle and eating habits, which exposes them to several risk factors for diseases that will develop later such as chronic diseases related to diet. The objective of this study was to assess malnutrition and identify the particular risk factors for malnutrition among students at the University of Maroua. Methods. Three hundred and thirty students of both sexes, aged between 17 and 35 years old, were recruited from January to February 2018. Anthropometric parameters (weight, height, waist and hip circumference, and BMI) were measured, and an eating and lifestyle questionnaire was administered to each participant, as well as a 24-hour dietary recall. Results. The mean age of participants was 23.95 ± 3.67 years and BMI was 22.19 ± 2.78 kg/m2. Approximately 6.1% were underweight, 12.1% overweight, and 0.9% obese, and all age groups were affected. Concerning eating habits, low protein, fruit, and vegetable consumption were recorded among students. Cereals were the main source of carbohydrates consumed. Besides, 6% of them had a low dietary intake, 21% had a poorly diversified diet, and 2% were highly food insecure. The students’ daily macronutrient intake was within the recommended reference values, except for carbohydrates, which exceeded and represented 62.69± 13.84% of daily energy intake. Also, only 32.2% of respondents had adequate energy intake. A poorly diversified diet was associated with a high incidence of overweight. Conclusions. Both forms of malnutrition are indeed present among the students of the University of Maroua, and nutritional education for this young segment of the population will be essential to prevent complications associated with malnutrition in the working life.

Abstract Cancer vaccines and oncolytic immunotherapy are promising treatment strategies with potential to provide greater clinical benefit to patients with advanced-stage cancer. In particular, recombinant vaccinia viruses (VV) hold great promise as interventional agents. In this article, we first summarize the current understanding of virus biology and viral genes involved in host-virus interactions to further improve the utility of these agents in therapeutic applications. We then discuss recent findings from basic and clinical studies using VV as cancer vaccines and oncolytic immunotherapies. Despite encouraging results gleaned from translational studies in animal models, clinical trials implementing VV vectors alone as cancer vaccines have yielded largely disappointing results. However, the combination of VV vaccines with alternate forms of standard therapies has resulted in superior clinical efficacy. For instance, combination regimens using TG4010 (MVA-MUC1-IL2) with first-line chemotherapy in advanced-stage non-small cell lung cancer or combining PANVAC with docetaxel in the setting of metastatic breast cancer have clearly provided enhanced clinical benefits to patients. Another novel cancer vaccine approach is to stimulate anti-tumor immunity via STING activation in Batf3-dependent dendritic cells (DC) through the use of replication-attenuated VV vectors. Oncolytic VVs have now been engineered for improved safety and superior therapeutic efficacy by arming them with immune-stimulatory genes or pro-apoptotic molecules to facilitate tumor immunogenic cell death, leading to enhanced DC-mediated cross-priming of T cells recognizing tumor antigens, including neoantigens. Encouraging translational and early phase clinical results with Pexa-Vec have matured into an ongoing global phase III trial for patients with hepatocellular carcinoma. Combinatorial approaches, most notably those using immune checkpoint blockade, have produced exciting pre-clinical results and warrant the development of innovative clinical studies. Finally, we discuss major hurdles that remain in the field and offer some perspectives regarding the development of next generation VV vectors for use as cancer therapeutics.

Infrared target detection is often disrupted by a complex background, resulting in a high false alarm and low target recognition. This paper proposes a robust principal component decomposition model with joint spatial and temporal filtering and L1 norm regularization to effectively suppress the complex backgrounds. The model establishes a new anisotropic Gaussian kernel diffusion function, which exploits the difference between the target and the background in the spatial domain to suppress the edge contours. Furthermore, in order to suppress the dynamically changing background, we construct an inversion model that combines temporal domain information and L1 norm regularization to globally constrain the low rank characteristics of the background, and characterize the target sparse component with L1 norm. Finally, the overlapping multiplier method is used for decomposition and reconstruction to complete the target detection.Through relevant experiments, the proposed background modeling method in this paper has a better background suppression effect in different scenes. The average values of the three evaluation indexes, SSIM, BSF and IC, are 0.986, 88.357 and 18.967, respectively. Meanwhile, the proposed detection method obtains a higher detection rate compared with other algorithms under the same false alarm rate.