Quantifying the impact of Wolbachia releases on dengue infection in Townsville, Australia.

From October 2014 to February 2019, local authorities in Townsville, North Queensland, Australia continually introduced Wolbachia-infected mosquitoes to control seasonal outbreaks of dengue infection. In this study, we develop a mathematical modelling framework to estimate the effectiveness of this intervention as well as the relative dengue transmission rates of Wolbachia-infected and wild-type mosquitoes. We find that the transmission rate of Wolbachia-infected mosquitoes is reduced approximately by a factor of 20 relative to the uninfected wild-type population. In addition, the Townsville Wolbachia release program led to a 65% reduction in predicted dengue incidence during the release period and over 95% reduction in the 24 months that followed. Finally, to investigate the potential impact of other Wolbachia release programs, we use our estimates of relative transmissibility to calculate the relationship between the reproductive number of dengue and the proportion of Wolbachia-infected mosquitoes in the vector population.

Correction: Activation of the Connective Tissue Growth Factor (CTGF)-Transforming Growth Factor ß 1 (TGF-ß 1) Axis in Hepatitis C Virus-Expressing Hepatocytes.

[This corrects the article DOI: 10.1371/journal.pone.0046526.].

A Systematic Review of Mathematical Models of Dengue Transmission and Vector Control: 2010-2020.

Vector control methods are considered effective in averting dengue transmission. However, several factors may modify their impact. Of these controls, chemical methods, in the long run, may increase mosquitoes' resistance to chemicides, thereby decreasing control efficacy. The biological methods, which may be self-sustaining and very effective, could be hampered by seasonality or heatwaves (resulting in, e.g., loss of Wolbachia infection). The environmental methods that could be more effective than the chemical methods are under-investigated. In this study, a systematic review is conducted to explore the present understanding of the effectiveness of vector control approaches via dengue transmission models.

Lassa fever cases and mortality in Nigeria: Quantile Regression vs. Machine Learning Models.

Lassa fever (LF) is caused by the Lassa fever virus (LFV). It is endemic in West Africa, of which % of the infections are ascribed to Nigeria. This disease affects mostly the productive age and hence a proper understanding of the dynamics of this disease will help in formulating policies that would help in curbing the spread of LF. The objective of this study is to compare the performance of quantile regression models with that of Machine Learning models in. Data between between 7th January 2018 2018 and 17th December, 2022 on suspected cases, confirmed cases and deaths resulting from LF were retrieved from the Nigeria Centre for Disease Control (NCDC). The data obtained were fitted to quantile regression models (QRM) at 25, 50 and 75% as well as to Machine learning models. The response variable being confirmed cases and mortality due to Lassa fever in Nigeria while the independent variables were total confirmed cases, the week, month and year. Result showed that the highest monthly mean confirmed cases (56) and mortality (9) from LF were reported in February. The first quarter of the year reported the highest cases of both confirmed cases and deaths in Nigeria. Result also revealed that for the confirmed cases, quantile regression at 50% outperformed the best of the MLM, Gaussian-matern5/2 GPR (RMSE=10.3393 vs. 11.615), while for mortality, the medium Gaussian SVM (RMSE=1.6441 vs. 1.8352) outperformed QRM. Quantile regression model at 50% better captured the dynamics of the confirmed cases of LF in Nigeria while the medium Gaussian SVM better captured the mortality of LF in Nigeria. Among the features selected, confirmed cases was found to be the most important feature that drive its mortality with the implication that as the confirmed cases of Lassa fever increases, is a significant increase in its mortality. This therefore necessitates a need for a better intervention measures that will help curb Lassa fever mortality as a result of the increase in the confirmed cases. There is also a need for promotion of good community hygiene which could include; discouraging rodents from entering homes and putting food in rodent proof containers to avoid contamination to help hart the spread of Lassa fever in Nigeria.

Modelling the ecological dynamics of mosquito populations with multiple co-circulating Wolbachia strains.

Wolbachia intracellular bacteria successfully reduce the transmissibility of arthropod-borne viruses (arboviruses) when introduced into virus-carrying vectors such as mosquitoes. Despite the progress made by introducing Wolbachia bacteria into the Aedes aegypti wild-type population to control arboviral infections, reports suggest that heat-induced loss-of-Wolbachia-infection as a result of climate change may reverse these gains. Novel, supplemental Wolbachia strains that are more resilient to increased temperatures may circumvent these concerns, and could potentially act synergistically with existing variants. In this article, we model the ecological dynamics among three distinct mosquito (sub)populations: a wild-type population free of any Wolbachia infection; an invading population infected with a particular Wolbachia strain; and a second invading population infected with a distinct Wolbachia strain from that of the first invader. We explore how the range of possible characteristics of each Wolbachia strain impacts mosquito prevalence. Further, we analyse the differential system governing the mosquito populations and the Wolbachia infection dynamics by computing the full set of basic and invasive reproduction numbers and use these to establish stability of identified equilibria. Our results show that releasing mosquitoes with two different strains of Wolbachia did not increase their prevalence, compared with a single-strain Wolbachia-infected mosquito introduction and only delayed Wolbachia dominance.

Modelling and forecasting new cases of Covid-19 in Nigeria: Comparison of regression, ARIMA and machine learning models.

Covid-19 remains a global pandemic threatening hundreds of countries in the world. The impact of Covid-19 has been felt in almost every aspect of life and it has introduced globally, a new normal of livelihood. This global pandemic has triggered unparalleled global health and economic crisis. Therefore, modelling and forecasting the dynamics of this pandemic is very crucial as it will help in decision making and strategic planning. Nigeria as the most populous country in Africa and most populous black nation in the world has been adversely affected by Covid-19 pandemic. This study models and compares forecasting performance of regression, ARIMA and Machine Learning models in predicting new cases of Covid-19 in Nigeria. The study obtained data on daily new cases of Covid-19 in Nigeria between 27th February, 2020 and 30th November, 2021. Graphical analysis showed that Nigeria had witnessed three waves of Covid-19 with the first wave between 27th February, 2020 and 23rd October, 2020, the second wave between 24th October, 2020 and 20th June, 2021 and the third wave between 21st June, 2021 and 30th November, 2021.The second wave recorded the highest spikes in new cases compared to the first wave and third wave. Result reveals that in terms of forecasting performance, inverse regression model outperformed other regression models considered as it shows lowest RMSE of 0.4130 compared with other regression models. Also, the ARIMA (4, 1, 4) outperformed other ARIMA models as it reveals the highest R2 of 0.856 (85.6%), least RMSE (0.6364), AIC (-8.6024) and BIC (-8.5299). Result reveals that Fine tree which is one of the Machine Learning models is more reliable in forecasting new cases of Covid-19 in Nigeria compared to other models as Fine tree gave the highest R2 of 0.90 (90.0%) and least RMSE of 0.22165. Result of 15 days forecasting indicates that Covid-19 pandemic is not over yet in Nigeria as new cases of Covid-19 is projected to increase on 15/12/2021 with predicted new cases of 988 compared with that of 14/12/2021, where only 729 new cases was predicted. This therefore emphasizes the need to strengthen and maintain the existing Covid-19 preventive measures in Nigeria.

Modelling direct and herd protection effects of vaccination against the SARS-CoV-2 Delta variant in Australia.

OBJECTIVES: To analyse the outcomes of COVID-19 vaccination by vaccine type, age group eligibility, vaccination strategy, and population coverage. DESIGN: Epidemiologic modelling to assess the final size of a COVID-19 epidemic in Australia, with vaccination program (Pfizer, AstraZeneca, mixed), vaccination strategy (vulnerable first, transmitters first, untargeted), age group eligibility threshold (5 or 15 years), population coverage, and pre-vaccination effective reproduction number ( Reffv¯ ) for the SARS-CoV-2 Delta variant as factors. MAIN OUTCOME MEASURES: Numbers of SARS-CoV-2 infections; cumulative hospitalisations, deaths, and years of life lost. RESULTS: Assuming Reffv¯ = 5, the current mixed vaccination program (vaccinating people aged 60 or more with the AstraZeneca vaccine and people under 60 with the Pfizer vaccine) will not achieve herd protection unless population vaccination coverage reaches 85% by lowering the vaccination eligibility age to 5 years. At Reffv¯ = 3, the mixed program could achieve herd protection at 60-70% population coverage and without vaccinating 5-15-year-old children. At Reffv¯ = 7, herd protection is unlikely to be achieved with currently available vaccines, but they would still reduce the number of COVID-19-related deaths by 85%. CONCLUSION: Vaccinating vulnerable people first is the optimal policy when population vaccination coverage is low, but vaccinating more socially active people becomes more important as the Reffv¯ declines and vaccination coverage increases. Assuming the most plausible Reffv¯ of 5, vaccinating more than 85% of the population, including children, would be needed to achieve herd protection. Even without herd protection, vaccines are highly effective in reducing the number of deaths.

Mutations in Pfcrt and Pfmdr1 genes of Plasmodium falciparum isolates from two sites in Northcentral and Southwest Nigeria.

The ability of malaria parasites to develop resistance to antimalarial drugs has made it necessary to continuously survey malaria parasite populations for resistance markers. Mutations in specific malaria parasite genes confer resistance to antimalarial drugs. The study compared mutations in Pfcrt and Pfmdr1 genes of P. falciparum from two ecologically different areas of Nigeria. Plasmodium falciparum dried blood spots collected from New Bussa (Northcentral Nigeria) and Ijede (Southwest Nigeria) were analysed by PCR-RFLP for Pfcrt, K76 T, Pfmdr1, N86Y and Y184F mutations. Pfmdr1 copy number was determined by quantitative-PCR. A total of 145 blood spots [Ijede = 55; New Bussa = 90 blood spots] were analysed, but Pfcrt gene was successfully amplified in 144 samples while Pfmdr1 was amplified in 132 samples. Overall, prevalence of mutant forms of Pfcrt 76 T,Pfmdr1 86Y and 184F were 74.3% (95% CI: 66.4-81.2%), 18.2% (95% CI: 12.0-25.8%) and 35.6% (95% CI: 27.5-44.4%). The frequency of Pfcrt 76 T was similar in both study sites [Ijede: 81.8% (95%CI: 69.1-90.9%); New Bussa: 69.7% (95%CI: 59.0-79.0), p = 0.105]. However, the frequencies of Pfmdr1 86Y and 184F were significantly higher in Ijede (28.3% and 62.3%) than in New Bussa (11.4% and 17.7%), respectively (P < 0.05). Eight parasite genotypes based on three codons of the two genes were identified. The most frequent genotype was TNY 53(40.5%) while the least was KYF 1 (0.8%). The most frequent genotype in Ijede and New Bussa were TNF 18(34.0%) and TNY 40 (51.3%) respectively. The frequency of wild strain KNF in Ijede and New Bussa were 3 (5.7%) and 18 (23.1%), respectively. The distribution of the genotypes differed significantly by location. The genotypes with more than two or more mutations were more in Ijede 32 (60.4%) than in New Bussa 16 (20.5%) (p < 0.001). Amplification of Pfmdr1 copy number was not observed in the two study sites. The prevalence of Pfcrt 76 T was similar in both locations while Pfmdr1 86Y and 184F differed in both locations. Single nucleotide polymorphisms in the three codons assessed were more in Ijede than in New Bussa.

Community Knowledge, Attitude and Practices on Malaria Vector Control Strategies in Lagos State, South-West Nigeria.

Malaria is a leading public health challenge causing mortality and morbidity in sub-Saharan Africa. Prominent malaria vector control methods employed in sub-Saharan Africa include Long Lasting Insecticide Nets (LLINs) and Indoor Residual spraying (IRS). This study investigated knowledge, attitude and practices (KAP) of malaria vector control methods in Lagos, South-West Nigeria. Structured questionnaires were employed for the cross-sectional survey which was carried out between May and August 2018. Multi-stage sampling technique was used to select Lagos Mainland, Kosofe, and Ojo local government areas (LGAs). Five hundred and twenty questionnaires were used for the study. Data were analyzed for descriptive statistics, whereas χ 2 was used to determine influence of respondents' LGA, level of education and type of dwelling on respondents' attitude and practice. Respondents' LGAs have no significant impact on attitude and practice to malaria vector control methods. However, 'level of education' as well as 'type of dwelling structure' impacted significantly on some practices and attitude. Basically, IRS is the major tool employed in malaria vector control, but sometimes it is used in combination with other methods. A good number of residents also use LLINs. 'Choice of method' employed is mainly based on the effectiveness of method. General perception about LLINs and IRS is that they are effective, cheap and safer. Considering the widespread use of IRS and LLINs for malaria vector control in Lagos, implementation of malaria control programs should consider KAP to these two strategies.

A Review: Aedes-Borne Arboviral Infections, Controls and Wolbachia-Based Strategies.

Arthropod-borne viruses (Arboviruses) continue to generate significant health and economic burdens for people living in endemic regions. Of these viruses, some of the most important (e.g., dengue, Zika, chikungunya, and yellow fever virus), are transmitted mainly by Aedes mosquitoes. Over the years, viral infection control has targeted vector population reduction and inhibition of arboviral replication and transmission. This control includes the vector control methods which are classified into chemical, environmental, and biological methods. Some of these control methods may be largely experimental (both field and laboratory investigations) or widely practised. Perceptively, one of the biological methods of vector control, in particular, Wolbachia-based control, shows a promising control strategy for eradicating Aedes-borne arboviruses. This can either be through the artificial introduction of Wolbachia, a naturally present bacterium that impedes viral growth in mosquitoes into heterologous Aedes aegypti mosquito vectors (vectors that are not natural hosts of Wolbachia) thereby limiting arboviral transmission or via Aedes albopictus mosquitoes, which naturally harbour Wolbachia infection. These strategies are potentially undermined by the tendency of mosquitoes to lose Wolbachia infection in unfavourable weather conditions (e.g., high temperature) and the inhibitory competitive dynamics among co-circulating Wolbachia strains. The main objective of this review was to critically appraise published articles on vector control strategies and specifically highlight the use of Wolbachia-based control to suppress vector population growth or disrupt viral transmission. We retrieved studies on the control strategies for arboviral transmissions via arthropod vectors and discussed the use of Wolbachia control strategies for eradicating arboviral diseases to identify literature gaps that will be instrumental in developing models to estimate the impact of these control strategies and, in essence, the use of different Wolbachia strains and features.

Cost-Effectiveness of PBO versus Conventional Long-Lasting Insecticidal Bed Nets in Preventing Symptomatic Malaria in Nigeria: Results of a Pragmatic Randomized Trial.

Insecticide treated nets (ITNs) have been the major tool in halving malaria's burden since 2000, but pyrethroid insecticide resistance threatens their ongoing effectiveness. In 2017, the WHO concluded that long-lasting ITNs (LLINs) with a synergist, piperonyl butoxide (PBO), provided additional public health benefit over conventional (pyrethroid-only) LLINs alone in areas of moderate insecticide resistance and endorsed them as a new class of vector control products. We performed an economic appraisal of PBO nets compared with conventional LLINs in 2019 US$ from prevention and health systems perspectives (including treatment cost offsets). We used data from a pragmatic randomized 2012-2014 trial in Nigeria with epidemiological outcomes in an area with confirmed pyrethroid resistance. Each village had 50 months of epidemiologic data, analyzed by village by month, using negative binomial regression. Compared with LLINs, although adding $0.90 per net delivered, PBO nets reduced symptomatic malaria cases by 33.4% (95% CI 10.2-50.6%). From a prevention perspective, the incremental cost-effectiveness ratio was $11 (95% CI $8-$37) per disability-adjusted life year averted. From the health systems perspective, PBO nets were significantly cost-saving relative to conventional LLINs. The benefit-cost analysis found that the added economic benefits of PBO nets over LLINs were $201 (95% CI $61-$304) for every $1 in incremental costs. Growing pyrethroid resistance is likely to strengthen the economic value of PBO nets over LLINs. Beyond their contribution to reducing malaria, PBO nets deliver outstanding economic returns for a small additional cost above conventional LLINs in locations with insecticide resistance.

Socio-economic behavioural indicators of falciparum malaria parasitaemia and moderate to severe anaemia among pregnant women attending antenatal clinics in Lagos, Southwest Nigeria.

BACKGROUND: Incidence of malaria and anaemia are of public health importance especially in pregnant women in endemic regions, due to the negative health consequences to the mother and fetus. This study aimed to assess the pattern of falciparum malaria infection and anaemia, based on malaria prevention methods practiced by participants. METHODS: A semi-structured tool was used to capture information on demographic, socio-economic and malaria prevention practices from 113 pregnant women attending antenatal clinics in 2 peri-urban health facilities in Lagos, southwest Nigeria. Malaria microscopy was conducted and haematocrit was measured. Logistic regression analysis was performed on the data collated from the survey. RESULTS: The prevalence of anaemia among pregnant women was 87.2%. The mean (± sd) packed cell volume (PCV) (%) of the 22 (19.5%) infected subjects (26.8 ± 6.6), was significantly lower (t = -2.60, P value = 0.007) than that of the 91 (80.5%) uninfected subjects (30.8 ± 6.0). The prevalence of infection was highest in the 3rd trimester (n = 40, 35.4%) at 27.5% (11/40) and among those in their first pregnancy (n = 32, 28.3%) at 25.0% (8/32). There was a significant difference (t = -2.23, P-value = 0.01) in the mean PCV % of pregnant women who consumed herbal teas in pregnancy (28.2 ± 5.2) compared to those who did not (30.8 ± 6.6). Regression analysis showed that first pregnancy, anti-malarial use and insecticide-treated nets use the night before study had increased odds of malaria infection in participants (OR = 1.35, P = 0.006, 95% CI 0.52-2.49; OR = 2.3, P = 0.005, 95% CI 0.14-0.41; OR = 1.92, P = 0.001, 95% CI 0.62-5.98) while intermittent preventive treatment (IPT) participation and formal education were strongly and significantly associated with lower risk of parasitaemia (OR = 0.95, P = 0.025, 95% CI 0.41-2.26; OR = 0.44, P = 0.005, 95% CI 0.34-10.50). CONCLUSION: Interventions that will reduce malaria and moderate to severe anaemia, especially in a first pregnancy, should include education on the correct use of long-lasting insecticide-treated bed nets (LLIN), IPT and the dangers of herbal teas in pregnancy.

Modeling the potential of wAu-Wolbachia strain invasion in mosquitoes to control Aedes-borne arboviral infections.

Arboviral infections such as dengue, Zika and chikungunya are fast spreading diseases that pose significant health problems globally. In order to control these infections, an intracellular bacterium called Wolbachia has been introduced into wild-type mosquito populations in the hopes of replacing the vector transmitting agent, Aedes aegypti with one that is incapable of transmission. In this study, we developed a Wolbachia transmission model for the novel wAu strain which possesses several favourable traits (e.g., enhanced viral blockage and maintenance at higher temperature) but not cyctoplasmic incompatibility (CI)-when a Wolbachia-infected male mosquito mates with an uninfected female mosquito, producing no viable offspring. This model describes the competitive dynamics between wAu-Wolbachia-infected and uninfected mosquitoes and the role of imperfect maternal transmission. By analysing the system via computing the basic reproduction number(s) and stability properties, the potential of the wAu strain as a viable strategy to control arboviral infections is established. The results of this work show that enhanced maintenance of Wolbachia infection at higher temperatures can overcome the lack of CI induction to support wAu-Wolbachia infected mosquito invasion. This study will support future arboviral control programs, that rely on the introduction of new Wolbachia variants.

Transcriptomics-Based Drug Repurposing Approach Identifies Novel Drugs against Sorafenib-Resistant Hepatocellular Carcinoma.

Objective: Hepatocellular carcinoma (HCC) is frequently diagnosed in patients with late-stage disease who are ineligible for curative surgical therapies. The majority of patients become resistant to sorafenib, the only approved first-line therapy for advanced cancer, underscoring the need for newer, more effective drugs. The purpose of this study is to expedite identification of novel drugs against sorafenib resistant (SR)-HCC. Methods: We employed a transcriptomics-based drug repurposing method termed connectivity mapping using gene signatures from in vitro-derived SR Huh7 HCC cells. For proof of concept validation, we focused on drugs that were FDA-approved or under clinical investigation and prioritized two anti-neoplastic agents (dasatinib and fostamatinib) with targets associated with HCC. We also prospectively validated predicted gene expression changes in drug-treated SR Huh7 cells as well as identified and validated the targets of Fostamatinib in HCC. Results: Dasatinib specifically reduced the viability of SR-HCC cells that correlated with up-regulated activity of SRC family kinases, its targets, in our SR-HCC model. However, fostamatinib was able to inhibit both parental and SR HCC cells in vitro and in xenograft models. Ingenuity pathway analysis of fostamatinib gene expression signature from LINCS predicted JAK/STAT, PI3K/AKT, ERK/MAPK pathways as potential targets of fostamatinib that were validated by Western blot analysis. Fostamatinib treatment reversed the expression of genes that were deregulated in SR HCC. Conclusion: We provide proof of concept evidence for the validity of this drug repurposing approach for SR-HCC with implications for personalized medicine.

Role of B Cell Lymphoma 2 in the Regulation of Liver Fibrosis in miR-122 Knockout Mice.

MicroRNA-122 (miR-122) has been identified as a marker of various liver injuries, including hepatitis- virus-infection-, alcoholic-, and non-alcoholic steatohepatitis (NASH)-induced liver fibrosis. Here, we report that the extracellular miR-122 from hepatic cells can be delivered to hepatic stellate cells (HSCs) to modulate their proliferation and gene expression. Our published Argonaute crosslinking immunoprecipitation (Ago-CLIP) data identified several pro-fibrotic genes, including Ctgf, as miR-122 targets in mice livers. However, treating Ctgf as a therapeutic target failed to rescue the fibrosis developed in the miR-122 knockout livers. Alternatively, we compared the published datasets of human cirrhotic livers and miR-122 KO livers, which revealed upregulation of BCL2, suggesting its potential role in regulating fibrosis. Notably, ectopic miR-122 expression inhibited BCL2 expression in human HSC (LX-2) cells). Publicly available ChIP-seq data in human hepatocellular cancer (HepG2) cells and mice livers suggested miR-122 could regulate BCL2 expression indirectly through c-MYC, which was confirmed by siRNA-mediated depletion of c-MYC in Hepatocellular Carcinoma (HCC) cell lines. Importantly, Venetoclax, a potent BCL2 inhibitor approved for the treatment of leukemia, showed promising anti-fibrotic effects in miR-122 knockout mice. Collectively, our data demonstrate that miR-122 suppresses liver fibrosis and implicates anti-fibrotic potential of Venetoclax.

Ibrutinib Potentiates Antihepatocarcinogenic Efficacy of Sorafenib by Targeting EGFR in Tumor Cells and BTK in Immune Cells in the Stroma.

Hepatocellular carcinoma (HCC), the most prevalent primary liver cancer, is a leading cause of cancer-related death worldwide because of rising incidence and limited therapy. Although treatment with sorafenib or lenvatinib is the standard of care in patients with advanced-stage HCC, the survival benefit from sorafenib is limited due to low response rate and drug resistance. Ibrutinib, an irreversible tyrosine kinase inhibitor (TKI) of the TEC (e.g., BTK) and ErbB (e.g., EGFR) families, is an approved treatment for B-cell malignancies. Here, we demonstrate that ibrutinib inhibits proliferation, spheroid formation, and clonogenic survival of HCC cells, including sorafenib-resistant cells. Mechanistically, ibrutinib inactivated EGFR and its downstream Akt and ERK signaling in HCC cells, and downregulated a set of critical genes involved in cell proliferation, migration, survival, and stemness, and upregulated genes promoting differentiation. Moreover, ibrutinib showed synergy with sorafenib or regorafenib, a sorafenib congener, by inducing apoptosis of HCC cells. In vivo, this TKI combination significantly inhibited HCC growth and prolonged survival of immune-deficient mice bearing human HCCLM3 xenograft tumors and immune-competent mice bearing orthotopic mouse Hepa tumors at a dose that did not exhibit systemic toxicity. In immune-competent mice, the ibrutinib-sorafenib combination reduced the numbers of BTK+ immune cells in the tumor microenvironment. Importantly, we found that the BTK+ immune cells were also enriched in the tumor microenvironment in a subset of primary human HCCs. Collectively, our findings implicate BTK signaling in hepatocarcinogenesis and support clinical trials of the sorafenib-ibrutinib combination for this deadly disease.