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BMJ Open Mar 2024Seasonal malaria chemoprevention (SMC) involves repeated administrations of sulfadoxine-pyrimethamine plus amodiaquine to children below the age of 5 years during the...
Understanding and maximising the community impact of seasonal malaria chemoprevention in Burkina Faso (INDIE-SMC): study protocol for a cluster randomised evaluation trial.
INTRODUCTION
Seasonal malaria chemoprevention (SMC) involves repeated administrations of sulfadoxine-pyrimethamine plus amodiaquine to children below the age of 5 years during the peak transmission season in areas of seasonal malaria transmission. While highly impactful in reducing malaria burden in controlled research settings, the impact of SMC on infection prevalence is moderate in real-life settings. It remains unclear what drives this efficacy decay. Recently, the WHO widened the scope for SMC to target all vulnerable populations. The Ministry of Health (MoH) in Burkina Faso is considering extending SMC to children below 10 years old. We aim to assess the impact of SMC on clinical incidence and parasite prevalence and quantify the human infectious reservoir for malaria in this population.
METHODS AND ANALYSIS
We will perform a cluster randomised trial in Saponé Health District, Burkina Faso, with three study arms comprising 62 clusters of three compounds: arm 1 (control): SMC in under 5-year-old children, implemented by the MoH without directly observed treatment (DOT) for the full course of SMC; arm 2 (intervention): SMC in under 5-year-old children, with DOT for the full course of SMC; arm 3 (intervention): SMC in under 10-year-old children, with DOT for the full course of SMC. The primary endpoint is parasite prevalence at the end of the malaria transmission season. Secondary endpoints include the impact of SMC on clinical incidence. Factors affecting SMC uptake, treatment adherence, drug concentrations, parasite resistance markers and transmission of parasites will be determined.
ETHICS AND DISSEMINATION
The London School of Hygiene & Tropical Medicine's Ethics Committee (29193) and the Burkina Faso National Medical Ethics Committee (Deliberation No 2023-05-104) approved this study. The findings will be presented to the community; disease occurrence data and study outcomes will also be shared with the Burkina Faso MoH. Findings will be published irrespective of their results.
TRIAL REGISTRATION NUMBER
NCT05878366.
Topics: Child, Preschool; Humans; Infant; Antimalarials; Burkina Faso; Chemoprevention; Drug Combinations; Malaria; Randomized Controlled Trials as Topic; Seasons; Child
PubMed: 38479748
DOI: 10.1136/bmjopen-2023-081682 -
Journal of Pharmaceutical Analysis Feb 2024Hepatocellular carcinoma (HCC) is one of the most common tumor types and remains a major clinical challenge. Increasing evidence has revealed that mitophagy inhibitors...
Hepatocellular carcinoma (HCC) is one of the most common tumor types and remains a major clinical challenge. Increasing evidence has revealed that mitophagy inhibitors can enhance the effect of chemotherapy on HCC. However, few mitophagy inhibitors have been approved for clinical use in humans. Pyrimethamine (Pyr) is used to treat infections caused by protozoan parasites. Recent studies have reported that Pyr may be beneficial in the treatment of various tumors. However, its mechanism of action is still not clearly defined. Here, we found that blocking mitophagy sensitized cells to Pyr-induced apoptosis. Mechanistically, Pyr potently induced the accumulation of autophagosomes by inhibiting autophagosome-lysosome fusion in human HCC cells. and studies revealed that Pyr blocked autophagosome-lysosome fusion by upregulating BNIP3 to inhibit synaptosomal-associated protein 29 (SNAP29)-vesicle-associated membrane protein 8 (VAMP8) interaction. Moreover, Pyr acted synergistically with sorafenib (Sora) to induce apoptosis and inhibit HCC proliferation and . Pyr enhances the sensitivity of HCC cells to Sora, a common chemotherapeutic, by inhibiting mitophagy. Thus, these results provide new insights into the mechanism of action of Pyr and imply that Pyr could potentially be further developed as a novel mitophagy inhibitor. Notably, Pyr and Sora combination therapy could be a promising treatment for malignant HCC.
PubMed: 38464783
DOI: 10.1016/j.jpha.2023.05.014 -
Research Square Feb 2024Hard-to-reach communities represent Peru's main challenge for malaria elimination, but information about transmission in these areas is scarce. Here, we assessed (Pv)...
Hard-to-reach communities represent Peru's main challenge for malaria elimination, but information about transmission in these areas is scarce. Here, we assessed (Pv) and (Pf) transmission dynamics, resistance markers, and Pf deletions in Nueva Jerusalén (NJ), a remote, indigenous community in the Peruvian Amazon with high population mobility. We collected samples from November 2019 to May 2020 by active (ACD) and passive case detection (PCD) in NJ. Parasites were identified with microscopy and PCR. Then, we analyzed a representative set of positive-PCR samples (Pv = 68, Pf = 58) using highly-multiplexed deep sequencing assays (AmpliSeq) and compared NJ parasites with ones from other remote Peruvian areas using population genetics indexes. The ACD intervention did not reduce malaria cases in the short term, and persistent malaria transmission was observed (at least one Pv infection was detected in 96% of the study days). In Nueva Jerusalen, the Pv population had modest genetic diversity (He = 0.27). Pf population had lower diversity (He = 0.08) and presented temporal clustering, one of these clusters linked to an outbreak in February 2020. Moreover, Pv and Pf parasites from NJ exhibited variable levels of differentiation (Pv Fst = -0.52 & Pf Fst = 0.11-0.58) with parasites from other remote areas. No artemisin resistance mutations but chloroquine (57%) and sulfadoxine-pyrimethamine (35-67%) were detected in NJ's Pf parasites. Moreover, gene deletions were common (32-50% of parasites with one or both genes deleted). The persistent Pv transmission and the detection of a Pf outbreak with parasites genetically distinct from the local ones highlight the need for tailored interventions focusing on mobility patterns and imported infections in remote areas to eliminate malaria in the Peruvian Amazon.
PubMed: 38464169
DOI: 10.21203/rs.3.rs-3979991/v1 -
The American Journal of Tropical... Apr 2024Unlike praziquantel, artemisinin derivatives are effective against juvenile schistosome worms. We assessed the efficacy and safety of a single oral dose of artesunate...
Efficacy of a Single Oral Dose of Artesunate plus Sulfalene-Pyrimethamineversus Praziquantel in the Treatment of Schistosoma mansoni in Kenyan Children: An Open-Label, Randomized, Exploratory Trial.
Unlike praziquantel, artemisinin derivatives are effective against juvenile schistosome worms. We assessed the efficacy and safety of a single oral dose of artesunate plus sulfalene-pyrimethamine versus praziquantel in the treatment of Schistosoma mansoni. Seventy-three schoolchildren (aged 9-15 years) with confirmed S. mansoni infection in Rarieda, western Kenya, were randomly assigned to receive either a single oral dose of artesunate plus sulfalene-pyrimethamine (n = 39) or a single dose of praziquantel (n = 34). The cure and egg reduction rates at 4 weeks posttreatment were 69.4% (25/36) versus 80.6% (25/31) (P = 0.297) and 99.1% versus 97.5% (P = 0.607) in the artesunate plus sulfalene-pyrimethamine group versus praziquantel group, respectively. Fourteen children developed adverse events, and there were no serious adverse events. A single oral dose of artesunate plus sulfalene-pyrimethamine has efficacy comparable to that of praziquantel in the treatment of S. mansoni, but these results should be confirmed in larger randomized controlled trials.
Topics: Adolescent; Animals; Child; Humans; Anthelmintics; Artemisinins; Artesunate; Drug Therapy, Combination; East African People; Kenya; Praziquantel; Pyrimethamine; Schistosoma mansoni; Schistosomiasis mansoni; Sulfalene; Treatment Outcome
PubMed: 38460198
DOI: 10.4269/ajtmh.23-0337 -
Frontiers in Epidemiology 2024Antimalarial drugs including artemisinin-based combination therapy (ACT) regimens and sulphadoxine-pyrimethamine (SP) are used in Ghana for malaria therapeutics and...
INTRODUCTION
Antimalarial drugs including artemisinin-based combination therapy (ACT) regimens and sulphadoxine-pyrimethamine (SP) are used in Ghana for malaria therapeutics and prophylaxis respectively. The genetic basis of development of drug resistance involves single nucleotide polymorphisms in genes encoding proteins for multiple cellular and metabolic processes. The prevalence of single nucleotide polymorphisms in nine genes linked to ACT and SP resistance in the malaria parasite population was determined.
METHODS
Archived filter paper blood blot samples from patients aged 9 years and below with uncomplicated malaria reporting at 10 sentinel sites located in three ecological zones for the Malaria Therapeutic Efficacy Studies were used. The samples used were collected from 2007-2018 malaria transmission seasons and mutations in the genes were detected using PCR and Sanger sequencing.
RESULTS
In all 1,142 samples were used for the study. For falcipain-2 gene () Sanger sequencing was successful for 872 samples and were further analysed. The prevalence of the mutants was 45% (392/872) with markers V51I and S59F occurring in 15.0% (128/872) and 3.0% (26/872) of the samples respectively. Prevalence of other gene mutations: coronin () was 44.8% (37/90); cysteine desulfurase () was 73.9% (68/92); apicoplast ribosomal protein S10 () was 36.8% (35/95); ferredoxin () was 8.8% (8/91); multidrug resistance protein-1 () was 95.2.0% (80/84); multidrug resistance protein-2 () was 91.4% (32/35); dihydrofolate reductase () was 99.0% (84/85); dihydropteroate synthase () was 72% (68/95).
DISCUSSION
The observation of numerous mutations in these genes of interest in the Ghanaian isolates, some of which have been implicated in delayed parasite clearance is of great interest. The presence of these genotypes may account for the decline in the efficacies of ACT regimens being used to treat uncomplicated malaria in the country. The need for continuous monitoring of these genetic markers to give first-hand information on parasite susceptibility to antimalarial drugs to inform policy makers and stakeholders in malaria elimination in the country is further discussed.
PubMed: 38456076
DOI: 10.3389/fepid.2024.1279835 -
PloS One 2024Accurate bike-sharing demand prediction is crucial for bike allocation rebalancing and station planning. In bike-sharing systems, the bike borrowing and returning...
Accurate bike-sharing demand prediction is crucial for bike allocation rebalancing and station planning. In bike-sharing systems, the bike borrowing and returning behavior exhibit strong spatio-temporal characteristics. Meanwhile, the bike-sharing demand is affected by the arbitrariness of user behavior, which makes the distribution of bikes unbalanced. These bring great challenges to bike-sharing demand prediction. In this study, a usage pattern similarity-based dual-network for bike-sharing demand prediction, called FF-STGCN, is proposed. Inter-station flow features and similar usage pattern features are fully considered. The model includes three modules: multi-scale spatio-temporal feature fusion module, bike usage pattern similarity learning module, and bike-sharing demand prediction module. In particular, we design a multi-scale spatio-temporal feature fusion module to address limitations in multi-scale spatio-temporal accuracy. Then, a bike usage pattern similarity learning module is constructed to capture the underlying correlated features among stations. Finally, we employ a dual network structure to integrate inter-station flow features and similar usage pattern features in the bike-sharing demand prediction module to realize the final prediction. Experiments on the Citi Bike dataset have demonstrated the effectiveness of our proposed model. The ablation experiments further confirm the indispensability of each module in the proposed model.
Topics: Bicycling; Transportation; Learning; Pyrimethamine
PubMed: 38451911
DOI: 10.1371/journal.pone.0298684 -
Tropical Parasitology 2024Resistance to antimalarial drugs is one of the major challenges for malaria elimination. In India, artemisinin combination therapy (artesunate-sulfadoxin pyrimethamine)...
Prevalence of polymorphisms in marker genes associated with antimalarial drug resistance in following 10 years of artemisinin-based combination therapy implementation in urban Kolkata.
CONTEXT
Resistance to antimalarial drugs is one of the major challenges for malaria elimination. In India, artemisinin combination therapy (artesunate-sulfadoxin pyrimethamine) was introduced in place of chloroquine (CQ) for the treatment of uncomplicated falciparum malaria in 2010. Periodical monitoring of polymorphisms in antimalarial drug resistance marker genes will be useful for assessing drug pressure, mapping and monitoring of drug resistance status; and will be helpful for searching alternative treatments.
OBJECTIVES
This study was conducted to study the polymorphisms in antimalarial drug resistance marker genes among clinical isolates collected from Kolkata after 10 years of artemisinin-based combination therapie (ACT) implementation.
MATERIALS AND METHODS
Blood samples were collected from mono-infected patients and polymorphisms in CQ resistance transporter , multidrug resistance , dihydrofolate reductase , dihydropteroate synthetase , and propeller genes were analysed by polymerase chain reaction and DNA sequencing.
RESULTS
In gene, C72S, and K76T mutation was recorded in 100% isolates and no mutations was detected in any of the targeted codons of gene. A double mutant haplotype SVMNT and wildtype haplotype NYD in were prevalent in 100% of study isolates. Triple mutant haplotype ANRNI-SGKAA was recorded. No polymorphism in gene was documented in any of the isolates.
CONCLUSIONS
Observed wild codon N86 along with Y184 and D1246 of gene might be an indication of the reappearance of CQ sensitivity. The absence of quadruple and quintuple haplotypes in gene along with the wild haplotype of pfK13 is evidence of ACT effectivity. Hence, similar studies with large sample size are highly suggested for monitoring the drug resistance status of .
PubMed: 38444799
DOI: 10.4103/tp.tp_43_23 -
Ocular Immunology and Inflammation Mar 2024To describe the effect of long-term, low-dose pyrimethamine for the prevention of ocular toxoplasmosis (OT) recurrences.
PURPOSE
To describe the effect of long-term, low-dose pyrimethamine for the prevention of ocular toxoplasmosis (OT) recurrences.
METHODS
Sixty-three consecutive patients with inactive ocular toxoplasmosis and positive toxoplasma IgG serology were included. Pyrimethamine (25 mg) + folinic acid (15 mg) were administered every other day (three times weekly) for 12 months. Eighteen patients received the treatment for an additional six months as part of an extension study.
RESULTS
Thirty-eight patients (60.3%, = 63) were female; 38 (60.3%) had a previous history of recurrence and 37 (58.7%) had active OT within the preceding 12 months. Three (4.8%) patients had unilateral recurrences at 8, 12 and 18 months after starting intermittent pyrimethamine treatment. Five patients (7.9%) were discontinued due to hematological, renal and hepatic changes. Treatment was considered successful in 42 patients (84%).
CONCLUSION
Long-term, low-dose pyrimethamine can be considered as a treatment option for the prevention of ocular toxoplasmosis recurrence in selected patients, with only a few, mild and reversible systemic adverse events.
PubMed: 38441575
DOI: 10.1080/09273948.2024.2321270 -
Experimental Parasitology Apr 2024Toxoplasmosis is a zoonosis that is a worldwide health problem, commonly affecting fetal development and immunodeficient patients. Treatment is carried out with a...
Toxoplasmosis is a zoonosis that is a worldwide health problem, commonly affecting fetal development and immunodeficient patients. Treatment is carried out with a combination of pyrimethamine and sulfadiazine, which can cause cytopenia and intolerance and does not lead to a parasitological cure of the infection. Lysine deacetylases (KDACs), which remove an acetyl group from lysine residues in histone and non-histone proteins are found in the Toxoplasma gondii genome. Previous work showed the hydroxamate-type KDAC inhibitors Tubastatin A (TST) and Vorinostat (Suberoylanilide Hydroxamic Acid, SAHA) were effective against T. gondii. In the present study, the effects of three hydroxamates (KV-24, KV-30, KV-46), which were originally designed to inhibit human KDAC6, showed different effects against T. gondii. These compounds contain a heterocyclic cap group and a benzyl linker bearing the hydroxamic acid group in para-position. All compounds showed selective activity against T. gondii proliferation, inhibiting tachyzoite proliferation with IC values in a nanomolar range after 48h treatment. Microscopy analyses showed that after treatment, tachyzoites presented mislocalization of the apicoplast, disorganization of the inner membrane complex, and arrest in the completion of new daughter cells. The number of dividing cells with incomplete endodyogeny increased significantly after treatment, indicating the compounds can interfere in the late steps of cell division. The results obtained in this work that these new hydroxamates should be considered for future in vivo tests and the development of new compounds for treating toxoplasmosis.
Topics: Humans; Toxoplasma; Lysine; Toxoplasmosis; Pyrimethamine; Hydroxamic Acids; Vorinostat
PubMed: 38431113
DOI: 10.1016/j.exppara.2024.108727 -
Compliance With Guidelines on Seasonal Malaria Chemoprevention in Kwara State, Northcentral Nigeria.West African Journal of Medicine Jan 2024Seasonal malaria chemoprevention (SMC) is an effective strategy for reducing malaria morbidity and mortality in children aged 3-59 months in areas with seasonal malaria...
BACKGROUND
Seasonal malaria chemoprevention (SMC) is an effective strategy for reducing malaria morbidity and mortality in children aged 3-59 months in areas with seasonal malaria transmission. Sulphadoxine-pyrimethamine plus amodiaquine is given to an eligible child at monthly intervals during the peak malaria transmission season. The aim of this study was to determine the level of compliance with SMC guidelines by community drug distributors during SMC implementation in Kwara State.
METHOD
Caregivers of eligible children from six Local Government Areas were interviewed using a structured questionnaire on the KoboCollect app downloaded on hand-held android devices. The questionnaire was composed of questions on caregiver's demographics, SMC drug administration, and adherence to SMC protocol.
RESULTS
A total of 1,314 caregivers were interviewed, most of them were female 1076 (81.9%), married 1200 (91.3%) and literate 795 (60.5%). The mean SMC coverage for the 4 cycles was 1183(88.5%). SMC information was received by 1166 (88.7%) of caregivers. Most of the caregivers 1166 (88.7%) heard about SMC. Overall, SPAQ administration was directly observed in most cases 1169 (91.5%), second dose was given 1226 (96.0%) and drugs were fully ingested 1140(89.3%). Poor compliance was observed in home visits by lead mothers 988 (77.4%). The report of adverse drug reactions was low 132 (10.3% [95% CI: 8.8-12.3%]), the commonest being severe vomiting 50 (37.9%). There were significant (P<0.05) variations in SMC implementation across the 6 LGAs in virtually all the performance indicators. SPAQ administration to over-age children was low 128 (10.0%).
CONCLUSION
Overall, the compliance with SMC implementation guidelines in Kwara state was good though significant differences in performance were observed across the six LGAs. Home visits by lead mothers were generally poor. The self-reported coverage of SMC by caregivers was commendable.
Topics: Child; Female; Humans; Infant; Male; Antimalarials; Seasons; Nigeria; Malaria; Chemoprevention
PubMed: 38412205
DOI: No ID Found