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Scientific Reports Nov 2023African animal trypanosomiasis (AAT) is one of the major constraints to animal health and production in sub-Saharan Africa. To inform AAT control in Uganda and help...
African animal trypanosomiasis (AAT) is one of the major constraints to animal health and production in sub-Saharan Africa. To inform AAT control in Uganda and help advance along the progressive control pathway (PCP), we characterized AAT prevalence among eight host species in Uganda and explored factors that influence the prevalence variation between studies. We retrieved AAT prevalence publications (n = 2232) for Uganda (1980-2022) from five life sciences databases, focusing on studies specifying AAT detection methods, sample size, and the number of trypanosome-positive animals. Following PRISMA guidelines, we included 56 publications, and evaluated publication bias by the Luis Furuya-Kanamori (LFK) index. National AAT prevalence under DNA diagnostic methods for cattle, sheep and goats was 22.15%, 8.51% and 13.88%, respectively. Under DNA diagnostic methods, T. vivax was the most common Trypanosoma sp. in cattle (6.15%, 95% CI: 2.91-10.45) while T. brucei was most common among small ruminants (goats: 8.78%, 95% CI: 1.90-19.88, and sheep: 8.23%, 95% CI: 4.74-12.50, respectively). Northern and Eastern regions accounted for the highest AAT prevalence. Despite the limitations of this study (i.e., quality of reviewed studies, underrepresentation of districts/regions), we provide insights that could be used for better control of AAT in Uganda and identify knowledge gaps that need to be addressed to support the progressive control of AAT at country level and other regional endemic countries with similar AAT eco-epidemiology.
Topics: Animals; Cattle; Sheep; Animals, Domestic; Livestock; Prevalence; Uganda; Trypanosomiasis, African; Trypanosoma; Ruminants; Goats; DNA; Tsetse Flies
PubMed: 37990067
DOI: 10.1038/s41598-023-47141-5 -
Frontiers in Pharmacology 2022Neglected diseases (NDs) are treated with a less varied range of drugs, with high cost and toxicity, which makes the search for therapeutic alternatives important. In...
Neglected diseases (NDs) are treated with a less varied range of drugs, with high cost and toxicity, which makes the search for therapeutic alternatives important. In this context, plants, such as those from the genus , can be promising due to active substances in their composition. This study evaluates the potential of species from this genus to treat NDs. Initially, a protocol was developed to carry out a systematic review approved by Prospero (CRD42020200438). The databases PubMed, BVS, Scopus, Science Direct, and Web of Science were used with the following keywords: "zanthoxylum," "xanthoxylums," "fagaras," "leishmaniasis," "chagas disease," "malaria," and "African trypanosomiasis." Two independent evaluators analyzed the title and abstract of 166 articles, and 122 were excluded due to duplicity or for not meeting the inclusion criteria. From the 44 selected articles, results of / tests were extracted. studies showed that , through the alkaloid nitidine, was active against (IC50 <1 μg/ml) and (IC50 <8 μg/ml), and selective for both (>10 and >30, respectively). For Chagas disease, the promising species (IC50 <2 μg/ml) were and , and for sleeping sickness, the species (IC50 <4 μg/ml) stood out. In the analysis, the most promising species were and . In summary, the species , , , , and are promising sources of active molecules for the treatment of NDs.
PubMed: 36699053
DOI: 10.3389/fphar.2022.873208 -
Frontiers in Veterinary Science 2022African animal trypanocide resistance (AATr) continues to undermine global efforts to eliminate the transmission of African trypanosomiasis in endemic communities. The...
BACKGROUND
African animal trypanocide resistance (AATr) continues to undermine global efforts to eliminate the transmission of African trypanosomiasis in endemic communities. The continued lack of new trypanocides has precipitated drug misuse and overuse, thus contributing to the development of the AATr phenotype. In this study, we investigated the threat associated with AATr by using the major globally available chemotherapeutical agents.
METHODS
A total of seven electronic databases were screened for an article on trypanocide resistance in AATr by using keywords on preclinical and clinical trials with the number of animals with treatment relapse, days taken to relapse, and resistant gene markers using the PRISMA checklist. Data were cleaned using the SR deduplicator and covidence and analyzed using Cochrane RevMan®. Dichotomous outputs were presented using risk ratio (RR), while continuous data were presented using the standardized mean difference (SMD) at a 95% confidence interval.
RESULTS
A total of eight publications in which diminazene aceturate (DA), isometamidium chloride (ISM), and homidium chloride/bromide (HB) were identified as the major trypanocides were used. In all preclinical studies, the development of resistance was in the order of HB > ISM > DA. DA vs. ISM (SMD = 0.15, 95% CI: -0.54, 0.83; = 46%, = 0.05), DA vs. HB (SMD = 0.96, 95% CI: 0.47, 1.45; = 0%, = 0.86), and HB vs. ISM (SMD = -0.41, 95% CI: -0.96, 0.14; = 5%, = 0.38) showed multiple cross-resistance. Clinical studies also showed evidence of multi-drug resistance on DA and ISM (RR = 1.01, 95% CI: 0.71-1.43; = 46%, = 0.16). To address resistance, most preclinical studies increased the dosage and the treatment time, and this failed to improve the patient's prognosis. Major markers of resistance explored include AT1, P1/P2 transporters, folate transporters, such as F-I, F-II, F-III, and polyamine biosynthesis inhibitors. In addition, immunosuppressed hosts favor the development of AATr.
CONCLUSION
AATr is a threat that requires a shift in the current disease control strategies in most developing nations due to inter-species transmission. Multi-drug cross-resistance against the only accessible trypanocides is a major public health risk, justifying the need to revise the policy in developing countries to promote control of African trypanosomiasis.
PubMed: 36686196
DOI: 10.3389/fvets.2022.950248 -
Pathogens (Basel, Switzerland) Sep 2022Background Human African trypanocide resistance (HATr) is a challenge for the eradication of Human African Trypansomiaisis (HAT) following the widespread emergence of... (Review)
Review
Background Human African trypanocide resistance (HATr) is a challenge for the eradication of Human African Trypansomiaisis (HAT) following the widespread emergence of increased monotherapy drug treatment failures against Trypanosoma brucei gambiense and T. b. rhodesiense that are associated with changes in pathogen receptors. Methods: Electronic searches of 12 databases and 3 Google search websites for human African trypanocide resistance were performed using a keyword search criterion applied to both laboratory and clinical studies. Fifty-one publications were identified and included in this study using the PRISMA checklist. Data were analyzed using RevMan and random effect sizes were computed for the statistics at the 95% confidence interval. Results: Pentamidine/melarsoprol/nifurtimox cross-resistance is associated with loss of the T. brucei adenosine transporter 1/purine 2 gene (TbAT1/P2), aquaglyceroporins (TbAQP) 2 and 3, followed by the high affinity pentamidine melarsoprol transporter (HAPT) 1. In addition, the loss of the amino acid transporter (AAT) 6 is associated with eflornithine resistance. Nifurtimox/eflornithine combination therapy resistance is associated with AAT6 and nitroreductase loss, and high resistance and parasite regrowth is responsible for treatment relapse. In clinical studies, the TbAT1 proportion of total random effects was 68% (95% CI: 38.0−91.6); I2 = 96.99% (95% CI: 94.6−98.3). Treatment failure rates were highest with melarsoprol followed by eflornithine at 41.49% (95% CI: 24.94−59.09) and 6.56% (3.06−11.25) respectively. HATr-resistant phenotypes used in most laboratory experiments demonstrated significantly higher pentamidine resistance than other trypanocides. Conclusion: The emergence of drug resistance across the spectrum of trypanocidal agents that are used to treat HAT is a major threat to the global WHO target to eliminate HAT by 2030. T. brucei strains were largely resistant to diamidines and the use of high trypanocide concentrations in clinical studies have proved fatal in humans. Studies to develop novel chemotherapeutical agents and identify alternative protein targets could help to reduce the emergence and spread of HATr.
PubMed: 36297157
DOI: 10.3390/pathogens11101100 -
Tropical Medicine and Infectious Disease Aug 2022African trypanocide resistance is an emerging public health emergency whose control requires a revisit on farmer's knowledge, attitudes, and practices in developing... (Review)
Review
BACKGROUND
African trypanocide resistance is an emerging public health emergency whose control requires a revisit on farmer's knowledge, attitudes, and practices in developing countries. African animal trypanocide resistance (AATr) is rife in an environment where drug use and policy decisions are disjointed. The objective of the study was to identify community factors responsible for the development of AATr. This was important since diminazene aceturate (DA), isometamidium chloride (ISM), and homidium bromide (HB) have existed for over 30 years and no new drugs have been provided to farmers.
METHODS
An electronic keyword search across 12 databases was conducted using a search criterion from 1806 to June 2022. This generated a total of 24 publications, but after removing duplicates, review articles, and nonrelated articles, a total of eight papers were included in the analysis by following the PRISMA checklist. A meta-analysis was conducted on the data extracted and the risk ratio and inverse variance at 95% confidence interval were calculated using RevMan.
RESULTS
All the eight articles in the study showed that DA was the most preferred trypanocide in both West and Eastern Africa. Poor farmer knowledge of AATr and limited drug options were major drivers for trypanocide resistance. In addition, farmer treatments, use of untrained personnel, poor administration, poor dosing, and preparation of trypanocides were major drivers for the development of AATr and similarities were identified in DA and ISM practices (P = 0.13).
CONCLUSIONS
AATr is spread in developing countries due to a lack of community knowledge, attitudes, and drug-use practices. This situation could be reversed through interdisciplinary collaborations in endemic communities by promoting effective treatments and responsible drug handling.
PubMed: 36136616
DOI: 10.3390/tropicalmed7090205 -
Journal of Medical Entomology Jul 2022African animal trypanosomiasis (AAT) a parasitic disease of livestock in sub-Saharan Africa causing tremendous loses. Sub-Saharan continental estimation of mean... (Meta-Analysis)
Meta-Analysis
African animal trypanosomiasis (AAT) a parasitic disease of livestock in sub-Saharan Africa causing tremendous loses. Sub-Saharan continental estimation of mean prevalence in both large and small domestic animals, risk factors, tsetse and non-tsetse prevalence and drug resistance is lacking. A review and meta-analysis was done to better comprehend changes in AAT prevalence and drug resistance. Publish/Perish software was used to search and extract peer-reviewed articles in Google scholar, PubMed and CrossRef. In addition, ResearchGate and African Journals Online (AJOL) were used. Screening and selection of articles from 2000-2021 was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Articles 304 were retrieved; on domestic animals 192, tsetse and non-tsetse vectors 44, risk factors 49 and trypanocidal drug resistance 30. Prevalence varied by, host animals in different countries, diagnostic methods and species of Trypanosoma. Cattle had the highest prevalence with Ethiopia and Nigeria leading, T. congolense (11.80-13.40%) and T. vivax (10.50-18.80%) being detected most. This was followed by camels and pigs. Common diagnostic method used was buffy coat microscopy. However; polymerase chain reaction (PCR), CATT and ELISA had higher detection rates. G. pallidipes caused most infections in Eastern regions while G. palpalis followed by G. mortisans in Western Africa. Eastern Africa reported more non-tsetse biting flies with Stomoxys leading. Common risk factors were, body conditions, breed type, age, sex and seasons. Ethiopia and Nigeria had the highest trypanocidal resistance 30.00-35.00% and highest AAT prevalence. Isometamidium and diminazene showed more resistance with T. congolense being most resistant species 11.00-83.00%.
Topics: Animals; Cattle; Cattle Diseases; Drug Resistance; Ethiopia; Prevalence; Risk Factors; Swine; Swine Diseases; Trypanosoma; Trypanosomiasis, African; Tsetse Flies
PubMed: 35579072
DOI: 10.1093/jme/tjac018 -
Scientific Reports Dec 2021Human African trypanosomiasis (HAT) is endemic in Africa; hence, the possibility of co-infection with malaria among patients with HAT exists. The present study... (Meta-Analysis)
Meta-Analysis
Human African trypanosomiasis (HAT) is endemic in Africa; hence, the possibility of co-infection with malaria among patients with HAT exists. The present study investigated co-infection with malaria among patients with HAT to provide current evidence and characteristics to support further studies. Potentially relevant studies that reported Plasmodium spp. infection in patients with HAT was searched in PubMed, Web of Science, and Scopus. The risk of bias among the included studies was assessed using the checklist for analytical cross-sectional studies developed by the Joanna Briggs Institute. The pooled prevalence of Plasmodium spp. infection in patients with HAT was quantitatively synthesized using a random-effects model. Subgroup analyses of study sites and stages of HAT were performed to identify heterogeneity regarding prevalence among the included studies. The heterogeneity of the outcome among the included studies was assessed using Cochran's Q and I statistics for consistency. Publication bias was assessed if the number of included studies was 10 or more. For qualitative synthesis, a narrative synthesis of the impact of Plasmodium spp. infection on the clinical and outcome characteristics of HAT was performed when the included studies provided qualitative data. Among 327 studies identified from three databases, nine studies were included in the systematic review and meta-analysis. The prevalence of Plasmodium spp. co-infection (692 cases) among patients with HAT (1523 cases) was 50% (95% confidence interval [CI] = 28-72%, I = 98.1%, seven studies). Subgroup analysis by type of HAT (gambiense or rhodesiense HAT) revealed that among patients with gambiense HAT, the pooled prevalence of Plasmodium spp. infection was 46% (95% CI = 14-78%, I = 96.62%, four studies), whereas that among patients with rhodesiense HAT was 44% (95% CI = 40-49%, I = 98.3%, three studies). Qualitative syntheses demonstrated that Plasmodium spp. infection in individuals with HAT might influence the risk of encephalopathy syndrome, drug toxicity, and significantly longer corrected QT time. Moreover, longer hospital stays and higher treatment costs were recorded among co-infected individuals. Because of the high prevalence of malaria among patients with HAT, some patients were positive for malaria parasites despite being asymptomatic. Therefore, it is suggested to test every patient with HAT for malaria before HAT treatment. If malaria is present, then antimalarial treatment is recommended before HAT treatment. Antimalarial treatment in patients with HAT might decrease the probability of poor clinical outcomes and case fatality in HAT.
Topics: Africa; Coinfection; Geography, Medical; Humans; Malaria; Patient Outcome Assessment; Prevalence; Public Health Surveillance; Publication Bias; Registries; Trypanosomiasis, African
PubMed: 34893680
DOI: 10.1038/s41598-021-03295-8 -
The Cochrane Database of Systematic... Dec 2021Human African trypanosomiasis, or sleeping sickness, is a severe disease affecting people in the poorest parts of Africa. It is usually fatal without... (Review)
Review
BACKGROUND
Human African trypanosomiasis, or sleeping sickness, is a severe disease affecting people in the poorest parts of Africa. It is usually fatal without treatment. Conventional treatments require days of intravenous infusion, but a recently developed drug, fexinidazole, can be given orally. Another oral drug candidate, acoziborole, is undergoing clinical development and will be considered in subsequent editions. OBJECTIVES: To evaluate the effectiveness and safety of currently used drugs for treating second-stage Trypanosoma brucei gambiense trypanosomiasis (gambiense human African trypanosomiasis, g-HAT).
SEARCH METHODS
On 14 May 2021, we searched the Cochrane Infectious Diseases Group Specialized Register, the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, Latin American and Caribbean Health Science Information database, BIOSIS, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform. We also searched reference lists of included studies, contacted researchers working in the field, and contacted relevant organizations.
SELECTION CRITERIA
Eligible studies were randomized controlled trials that included adults and children with second-stage g-HAT, treated with anti-trypanosomal drugs currently in use.
DATA COLLECTION AND ANALYSIS
Two review authors extracted data and assessed risk of bias; a third review author acted as an arbitrator if needed. The included trial only reported dichotomous outcomes, which we presented as risk ratio (RR) or risk difference (RD) with 95% confidence intervals (CI). MAIN RESULTS: We included one trial comparing fexinidazole to nifurtimox combined with eflornithine (NECT). This trial was conducted between October 2012 and November 2016 in the Democratic Republic of the Congo and the Central African Republic, and included 394 participants. The study reported on efficacy and safety, with up to 24 months' follow-up. We judged the study to be at low risk of bias in all domains except blinding; as the route of administration and dosing regimens differed between treatment groups, participants and personnel were not blinded, resulting in a high risk of performance bias. Mortality with fexinidazole may be higher at 24 months compared to NECT. There were 9/264 deaths in the fexinidazole group and 2/130 deaths in the NECT group (RR 2.22, 95% CI 0.49 to 10.11; 394 participants; low-certainty evidence). None of the deaths were related to treatment. Fexinidazole likely results in an increase in the number of people relapsing during follow-up, with 14 participants in the fexinidazole group (14/264) and none in the NECT group (0/130) relapsing at 24 months (RD 0.05, 95% CI 0.02 to 0.08; 394 participants; moderate-certainty evidence). We are uncertain whether there is any difference between the drugs regarding the incidence of serious adverse events at 24 months. (31/264 with fexinidazole and 13/130 with NECT group at 24 months). Adverse events were common with both drugs (247/264 with fexinidazole versus 121/130 with NECT), with no difference between groups (RR 1.01, 95% CI 0.95 to 1.06; 394 participants; moderate-certainty evidence). AUTHORS' CONCLUSIONS: Oral treatment with fexinidazole is much easier to administer than conventional treatment, but deaths and relapse appear to be more common. However, the advantages or an oral option are considerable, in terms of convenience, avoiding hospitalisation and multiple intravenous infusions, thus increasing adherence.
Topics: Animals; Antiprotozoal Agents; Humans; Nifurtimox; Pharmaceutical Preparations; Randomized Controlled Trials as Topic; Trypanosoma brucei gambiense; Trypanosomiasis, African
PubMed: 34882307
DOI: 10.1002/14651858.CD015374 -
Cureus Aug 2021Human African trypanosomiasis (HAT), or sleeping sickness disease, is an infection caused mainly by human African trypanosomiasis (g-HAT) and is transmitted by tsetse... (Review)
Review
Human African trypanosomiasis (HAT), or sleeping sickness disease, is an infection caused mainly by human African trypanosomiasis (g-HAT) and is transmitted by tsetse flies. The disease goes through two stages: hemolymphatic and meningo-encephalic phases. The treatment for the second stage has changed from melarsoprol or eflornithine to nifurtimox-eflornithine combination therapy (NECT) and fexinidazole. We aimed to systematically review the literature on the efficacy and toxicity of fexinidazole and NECT. We used PubMed advanced strategy and Google Scholar databases, including clinical trials and observational studies on humans in the last 20 years in the English literature. Applying the inclusion/exclusion criteria, we reviewed eight studies. We used Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) and Meta-analysis of Observational Studies in Epidemiology (MOOSE) protocol. For assessing bias, we used the Cochrane Collaboration's tool for risk assessment of the clinical trials and the Robins-I tool for the observational studies. Overall, the clinical trials showed that NECT was non-inferior to eflornithine. The proportion of patients discharged alive is higher in patients treated with NECT vs. patients treated with eflornithine. Gastrointestinal complaints are a common side effect of NECT therapy, while fearful but relatively rare convulsions can also occur. The main limitation among the studies of NECT was the lack of blinding because most of them were open-label. Fexinidazole, the new oral medication showed is effective and safe for the treatment of g-HAT infection. Because of their convenience, fexinidazole is preferred over NECT therapy, oral vs. IV infusion in the first and second stages of the disease. Compared to older therapies, fexinidazole and NECT are more effective and safer than eflornithine and melarsoprol monotherapy.
PubMed: 34513456
DOI: 10.7759/cureus.16881 -
Environmental Pollution (Barking, Essex... Sep 2021This systematic review and meta-analysis aimed to investigate the association between air pollution and DNA methylation in adults from published observational studies.... (Meta-Analysis)
Meta-Analysis
This systematic review and meta-analysis aimed to investigate the association between air pollution and DNA methylation in adults from published observational studies. PubMed, Web of Science and Embase databases were systematically searched for available studies on the association between air pollution and DNA methylation published up to March 9, 2021. Three DNA methylation approaches were considered: global methylation, candidate-gene, and epigenome-wide association studies (EWAS). Meta-analysis was used to summarize the combined estimates for the association between air pollutants and global DNA methylation levels. Heterogeneity was assessed with the Cochran Q test and quantified with the I statistic. In total, 38 articles were included in this study: 16 using global methylation, 18 using candidate genes, and 11 using EWAS, with 7 studies using more than one approach. Meta-analysis revealed an imprecise but inverse association between exposure to PM and global DNA methylation (for each 10-μg/m PM, combined estimate: 0.39; 95% confidence interval: 0.97 - 0.19). The candidate-gene results were consistent for the ERCC3 and SOX2 genes, suggesting hypermethylation in ERCC3 associated with benzene and that in SOX2 associated with PM exposure. EWAS identified 201 CpG sites and 148 differentially methylated regions that showed differential methylation associated with air pollution. Among the 307 genes investigated in 11 EWAS, a locus in nucleoredoxin gene was found to be positively associated with PM in two studies. Current meta-analysis indicates that PM is imprecisely and inversely associated with DNA methylation. The candidate-gene results consistently suggest hypermethylation in ERCC3 associated with benzene exposure and that in SOX2 associated with PM exposure. The Kyoto Encyclopedia of Genes and Genomes (KEGG) network analyses revealed that these genes were associated with African trypanosomiasis, Malaria, Antifolate resistance, Graft-versus-host disease, and so on. More evidence is needed to clarify the association between air pollution and DNA methylation.
Topics: Air Pollutants; Air Pollution; DNA Methylation; Environmental Exposure; Observational Studies as Topic; Particulate Matter
PubMed: 33895575
DOI: 10.1016/j.envpol.2021.117152