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As the second largest international donor, the UK has been at the forefront of efforts to reduce the number of cases for many years by investing in treatment, prevention and research, including the fight against the threat of drug resistance. The UK has announced further support for the fight against malaria to save more than 120,000 lives ahead of a Malaria Summit tomorrow with Commonwealth leaders.
Detection of Mycoplasma pneumoniae in hospitalized children with pneumonia in Laos
Mycoplasma pneumoniae has been described worldwide as an important cause of community-acquired pneumonia. From December 2013 to December 2014, 461 children admitted to Mahosot Hospital, Vientiane, Laos, with acute respiratory infection were investigated for upper respiratory microorganisms using probe-based real-time polymerase chain reaction (PCR) (FTD33). M. pneumoniae was detected by FTD33 in the upper respiratory tract of three patients, two girls and one boy, 5.7 and 3.9 years old and 13.6 years old, respectively. They presented with clinical features compatible with M. pneumoniae infection. The two girls were also positive for other potential pathogens. The boy had abnormal pulmonary auscultation, and one of the girls had significant anaemia. These results suggest that enhancement of diagnostic systems for M. pneumoniae detection and analysis of its antibiotic resistance profile is needed to raise awareness and improve understanding of the epidemiology of M. pneumoniae infection in Laos, enable targeted therapy, and inform treatment guidelines.
Diagnosis of human leptospirosis: systematic review and meta-analysis of the diagnostic accuracy of the Leptospira microscopic agglutination test, PCR targeting Lfb1, and IgM ELISA to Leptospira fainei serovar Hurstbridge.
BackgroundLeptospirosis is an underdiagnosed infectious disease with non-specific clinical presentation that requires laboratory confirmation for diagnosis. The serologic reference standard remains the microscopic agglutination test (MAT) on paired serum samples. However, reported estimates of MAT's sensitivity vary. We evaluated the accuracy of four index tests, MAT on paired samples as well as alternative standards for leptospirosis diagnosis: MAT on single acute-phase samples, polymerase chain reaction (PCR) with the target gene Lfb1, and ELISA IgM with Leptospira fainei serovar Hurstbridge as an antigen.MethodsWe performed a systematic review of studies reporting results of leptospirosis diagnostic tests. We searched eight electronic databases and selected studies that tested human blood samples and compared index tests with blood culture and/or PCR and/or MAT (comparator tests). For MAT selection criteria we defined a threshold for single acute-phase samples according to a national classification of leptospirosis endemicity. We used a Bayesian random-effect meta-analysis to estimate the sensitivity and specificity of MAT in single acute-phase and paired samples separately, and assessed risk of bias using the Quality Assessment of Studies of Diagnostic Accuracy Approach- 2 (QUADAS-2) tool.ResultsFor the MAT accuracy evaluation, 15 studies were included, 11 with single acute-phase serum, and 12 with paired sera. Two included studies used PCR targeting the Lfb1 gene, and one included study used IgM ELISA with Leptospira fainei serovar Hurstbridge as antigen. For MAT in single acute-phase samples, the pooled sensitivity and specificity were 14% (95% credible interval [CrI] 3-38%) and 86% (95% CrI 59-96%), respectively, and the predicted sensitivity and specificity were 14% (95% CrI 0-90%) and 86% (95% CrI 9-100%). Among paired MAT samples, the pooled sensitivity and specificity were 68% (95% CrI 32-92%) and 75% (95% CrI 45-93%) respectively, and the predicted sensitivity and specificity were 69% (95% CrI 2-100%) and 75% (2-100%).ConclusionsBased on our analysis, the accuracy of MAT in paired samples was not high, but it remains the reference standard until a more accurate diagnostic test is developed. Future studies that include larger numbers of participants with paired samples will improve the certainty of accuracy estimates.
Antenatal corticosteroids reduce neonatal mortality in settings without assisted ventilatory support: a retrospective cohort study of early preterm births on the Thailand-Myanmar border
Background Prematurity is the highest risk for under-five mortality globally. The aim of the study was to assess the effect of antenatal dexamethasone on neonatal mortality in early preterm in a resource-constrained setting without assisted ventilation. Methods This retrospective (2008-2013) cohort study in clinics for refugees/migrants on the Thai-Myanmar border included infants born <34 weeks gestation at home, in, or on the way to the clinic. Dexamethasone, 24 mg (three 8 mg intramuscular doses, every 8 hours), was prescribed to women at risk of preterm birth (28 to <34 weeks). Appropriate newborn care was available: including oxygen but not assisted ventilation. Mortality and maternal fever were compared by the number of doses (complete: three, incomplete (one or two), or no dose). A sub-cohort participated in neurodevelopmental testing at one year. Results Of 15,285 singleton births, 240 were included: 96 did not receive dexamethasone and 144 received one, two or three doses (56, 13 and 75, respectively). Of live-born infants followed to day 28, (n=168), early neonatal and neonatal mortality/1,000 livebirths (95%CI) with complete dosing was 217 (121–358) and 304 (190–449); compared to 394 (289–511) and 521 (407–633) with no dose. Compared to complete dosing, both incomplete and no dexamethasone were associated with elevated adjusted ORs 4.09 (1.39 to 12.00) and 3.13 (1.14 to 8.63), for early neonatal death. By contrast, for neonatal death, while there was clear evidence that no dosing was associated with higher mortality, adjusted OR 3.82 (1.42 to 10.27), the benefit of incomplete dosing was uncertain adjusted OR 1.75 (0.63 to 4.81). No adverse impact of dexamethasone on infant neurodevelopmental scores (12 months) or maternal fever was observed. Conclusions Neonatal mortality reduction is possible with complete dexamethasone dosing in pregnancies at risk of preterm birth in settings without capacity to provide assisted ventilation.
Care seeking for childhood illnesses in rural Mtwara, south-east Tanzania: a mixed methods study.
BackgroundCare seeking was assessed in preparation for a study of the health impact of novel design houses in rural Mtwara, Tanzania.MethodsA total of 578 residents of 60 villages participated in this mixed-methods study from April to August 2020. Among them, 550 participated in a healthcare-seeking survey, 17 in in-depth interviews and 28 in key informant interviews.ResultsThe decision to seek care was based on symptom severity (95.4% [370]). Caregivers first visited non-allopathic healthcare providers or were treated at home, which led to delays in seeking care at healthcare facilities. More than one-third (36.0% [140]) of respondents took >12 h seeking care at healthcare facilities. The majority (73.0% [282]) visited healthcare facilities, whereas around one-fifth (21.0% [80]) sought care at drug stores. Treatment costs deterred respondents from visiting healthcare facilities (61.4% [338]). Only 10 (3.6%) of the households surveyed reported that they were covered by health insurance.ConclusionsQuality of care, related to institutional factors, impacts timely care seeking for childhood illnesses in Mtwara, Tanzania. Ensuring accessibility of facilities is therefore not sufficient.
Identification of Falsified Chloroquine Tablets in Africa at the Time of the COVID-19 Pandemic.
Reports that chloroquine and hydroxychloroquine may be effective against COVID-19 have received worldwide attention, increasing the risk of the introduction of falsified versions of these medicines. Five different types of falsified chloroquine tablets were discovered between March 31, 2020 and April 4, 2020, in Cameroon and the Democratic Republic of Congo by locally conducted thin layer chromatographic analysis. Subsequent investigation by liquid chromatography and mass spectrometry in Germany proved the absence of detectable amounts of chloroquine and the presence of undeclared active pharmaceutical ingredients, that is, paracetamol and metronidazole, in four of the samples. The fifth sample contained chloroquine, but only 22% of the declared amount. Such products represent a serious risk to patients. Their occurrence exemplifies that once medicines or vaccines against COVID-19 may be developed, falsified products will enter the market immediately, especially in low- and middle-income countries (LMICs). Timely preparations for the detection of such products are required, including the establishment of appropriate screening technologies in LMICs.
Surveillance for substandard and falsified medicines by local faith-based organizations in 13 low- and middle-income countries using the GPHF Minilab
AbstractThis study evaluates the use of the Global Pharma Health Fund (GPHF) Minilab for medicine quality screening by 16 faith-based drug supply organizations located in 13 low- and middle-income countries. The study period included the year before the COVID-19 pandemic (2019) and the first year of the pandemic (2020). In total 1,919 medicine samples were screened using the GPHF Minilab, and samples showing serious quality deficiencies were subjected to compendial analysis in fully equipped laboratories. Thirty-four (1.8%) of the samples were found not to contain the declared active pharmaceutical ingredient (API), or less than 50% of the declared API, or undeclared APIs, and probably represented falsified products. Fifty-four (2.8%) of the samples were reported as substandard, although the true number of substandard medicines may have been higher due to the limited sensitivity of the GPHF Minilab. The number of probably falsified products increased during the COVID-19 pandemic, especially due to falsified preparations of chloroquine; chloroquine had been incorrectly advocated as treatment for COVID-19. The reports from this project resulted in four international WHO Medical Product Alerts and several national alerts. Within this project, the costs for GPHF Minilab analysis resulted as 25.85 € per sample. Medicine quality screening with the GPHF Minilab is a cost-effective way to contribute to the global surveillance for substandard and falsified medical products.
Quality of oxytocin and misoprostol in health facilities of Rwanda
Sustainable Development Goal 3.1 calls for a reduction of the maternal mortality ratio to less than 70 per 100,000 live births by 2030. The most important cause of maternal mortality is post-partum haemorrhage (PPH). Oxytocin injections and misoprostol tablets are medicines of first choice for the management of PPH in low- and middle-income countries (LMICs). Unfortunately, both substances are chemically unstable, and previous studies have revealed serious quality problems of these medicines in LMICs. The present study is the first report on their quality in Rwanda. From 40 randomly selected health facilities (hospitals, health centers, retail pharmacies and private clinics) in different parts of Rwanda, as well as from six wholesalers and government stores, oxytocin injections and misoprostol tablets were collected. Oxytocin storage temperatures in the health facilities were monitored for six months using temperature data loggers, and found to correctly follow the storage requirements stated by the manufacturers (2–8°C, or room temperature) with few minor deviations. Oxytocin injections (57 samples, representing seven batches of four brands) were tested for their oxytocin content and pH value according to the United States Pharmacopeia. Twenty-four samples from three European manufacturers passed all tests. However, all nine samples of one batch of a Chinese manufacturer showed an excessive content of oxytocin (range 117.2–121.5% of the declared amount). Another batch of the same manufacturer showed extreme variations of the concentration of the preservative benzyl alcohol. Misoprostol tablets (25 samples, representing ten batches of six brands) were tested for content and dissolution according to the International Pharmacopoeia. Fifteen samples passed, but all 10 samples of two brands from India failed with extreme deviations, containing only 42.5–48.7% of the stated amount of misoprostol. In conclusion, oxytocin quality in Rwanda was better than reported from other African countries. However, two extremely substandard brands of misoprostol tablets were found. The Rwandan authorities reacted quickly and efficiently, and recalled these substandard medicines from the market. For oxytocin and misoprostol, with their well-known problems of quality and stability, procurement should possibly be restricted to medicines which are WHO-prequalified or which have been manufactured in countries with stringent regulatory authorities.
An open-source smartphone app for the quantitative evaluation of thin-layer chromatographic analyses in medicine quality screening.
Substandard and falsified medicines present a serious threat to public health. Simple, low-cost screening tools are important in the identification of such products in low- and middle-income countries. In the present study, a smartphone-based imaging software was developed for the quantification of thin-layer chromatographic (TLC) analyses. A performance evaluation of this tool in the TLC analysis of 14 active pharmaceutical ingredients according to the procedures of the Global Pharma Health Fund (GPHF) Minilab was carried out, following international guidelines and assessing accuracy, repeatability, intermediate precision, specificity, linearity, range and robustness of the method. Relative standard deviations of 2.79% and 4.46% between individual measurements were observed in the assessments of repeatability and intermediate precision, respectively. Small deliberate variations of the conditions hardly affected the results. A locally producible wooden box was designed which ensures TLC photography under standardized conditions and shielding from ambient light. Photography and image analysis were carried out with a low-cost Android-based smartphone. The app allows to share TLC photos and quantification results using messaging apps, e-mail, cable or Bluetooth connections, or to upload them to a cloud. The app is available free of charge as General Public License (GPL) open-source software, and interested individuals or organizations are welcome to use and/or to further improve this software.
Substandard and Falsified Antibiotics and Medicines against Noncommunicable Diseases in Western Cameroon and Northeastern Democratic Republic of Congo.
Falsified and substandard medicines may undermine the progress toward the Sustainable Development Goals. The present study investigated the quality of 13 essential medicines in Cameroon and the Democratic Republic of Congo (DR Congo). Five hundred six medicine samples were collected from the government and faith-based health facilities, private pharmacies, and informal vendors (total 60 facilities). Collected samples were analyzed according to the U.S. Pharmacopeia (USP) for identity, content, and dissolution of their active pharmaceutical ingredients (APIs) and for uniformity of dosage units. Three samples (0.6%) were identified as falsified. Overall, 8.5% of the samples failed USP specifications for the content of the API and 11.7% failed dissolution testing. Medicines from informal vendors showed a higher out-of-specification rate (28.2%) than other types of drug outlets (12.3%; P < 0.0001). All three falsified medicines had been sold by informal vendors. The failure rate of medicines stated to be produced in Europe (5.1%) was lower than that for medicines from Asia (17.7%; P = 0.0049) and Africa (22.2%; P = 0.0042). Medicines against noncommunicable diseases showed a higher failure rate than antibiotics (25.3% versus 12.1%; P = 0.0004). Four hundred fifty-one of the samples were analyzed in Cameroon and the DR Congo with the Global Pharma Health Fund Minilab (thin-layer chromatography and disintegration testing). The three falsified medicines were readily detected in Minilab analysis. However, substandard samples were detected with low sensitivity. A well-enforced ban of medicine sales by informal vendors and increased attention to supplier qualification in the procurement process may reduce the prevalence of substandard and falsified medicines.
Identification of Substandard and Falsified Medicines: Influence of Different Tolerance Limits and Use of Authenticity Inquiries.
Substandard and falsified medicines have severe public health and socioeconomic effects, especially in low- and middle-income countries. The WHO has emphasized the need for reliable estimates of the prevalence of such medicines to efficiently respond to this problem. In the present study, we used 601 medicine samples collected in Cameroon, the DR Congo, and Malawi to assess the rates of substandard and falsified medicines based on different criteria. Based on the specifications of the U.S. Pharmacopoeia for the amount of the active pharmaceutical ingredients, the rate of out-of-specification medicines was 9.3%. By contrast, this rate ranged from 3.3% up to 35.0% if the tolerance limits of other pharmacopoeias or recently published medicine quality studies were used. This shows an urgent need for harmonization. Principal methods to assess the rate of falsified medicines are packaging analysis, chemical analysis, and authenticity inquiries. In the present study, we carried out an authenticity inquiry for the aforementioned medicine samples, contacting 126 manufacturers and 42 distributors. Response rates were higher for samples stated to be manufactured in Asia (52.4%) or Europe (53.8%) than for samples manufactured in Africa (27.4%; P < 0.001). One sample had been identified as falsified by packaging analysis by the local researchers and two additional ones by chemical analysis. Notably, seven additional falsified samples were identified by the authenticity inquiries. The total rate of falsified medicines resulted as 1.7%. Considerations are discussed for assessing the rates of "substandard" and "falsified" medicines in future medicine quality studies.
Quality assurance in anti-tuberculosis drug procurement by the Stop TB Partnership-Global Drug Facility: Procedures, costs, time requirements, and comparison of assay and dissolution results by manufacturers and by external analysis.
BackgroundQuality-assured medicines are a principal means of achieving health-related Sustainable Development Goals. An example of quality assurance/quality control (QA/QC) procedures in drug procurement is provided by the operation of the Global Drug Facility (GDF) of the Stop TB Partnership, the largest provider of tuberculosis (TB) medicines to the public sector worldwide.MethodsProcedures and results of GDF's quality assurance/quality control (QA/QC) over the five-year period 2013-2017 were analysed retrospectively. 13,999 batches of 51 different medicines had been procured and reviewed within this period. 1,388 of these batches had been analysed in the laboratories of GDF's external quality control agent (QCA). Assay and dissolution results determined by the manufacturers and by the external QCA were compared using Bland-Altman analysis.ResultsAll investigated batches of medicines were in specifications at the time of shipment. The costs for QA/QC were 0.8% of purchase costs. The median time required for chemical analysis was 10 working days. Comparison of the medicine quality analysis results showed for the poorly water-soluble compound rifampicin a bias of 4.4%, with the manufacturers reporting higher values than the external QCA, most likely due to different methods employed for the analysis. Overall 95% limits of agreement (LOAs) were -6.7 to +8.0% for assay, and -10.1 to +11.8% for dissolution. In case of kanamycin injections, 95% LOAs for assay reached -14.5 to +13.2%, largely attributable to samples from one manufacturer who had used a microbiological assay while the external QCA had used an HPLC assay.ConclusionsGDF's procedures represent a useful benchmark when evaluating QA/QC procedures of other medicine procurement operations. Inter-laboratory comparison using Bland-Altman plots allows to investigate bias and variability in medicine quality control and should be considered as a routine procedure by drug procurement agencies, to identify priorities for further improvements.
Quality of medicines in southern Togo: Investigation of antibiotics and of medicines for non-communicable diseases from pharmacies and informal vendors.
Substandard and falsified medicines represent a serious threat for public health and patient safety. Especially in low and middle-income countries, the prevalence of substandard and falsified medicines is reportedly high. However, reliable information on the prevalence of poor-quality medicines is scarce. In this study, 12 essential medicines, including antibiotics, antidiabetics, cardiac drugs and antiasthmatic drugs, were collected from six informal vendors and six licensed pharmacies in the southern part of Togo (regions Maritime and Plateaux). A mystery shopper approach was used in both types of outlets. In total, 64 samples were collected from licensed pharmacies and 30 from informal vendors. Both availability of medicines and prices of medicines were higher in licensed pharmacies than in informal vendors. 92 medicine samples were analyzed by visual examination, followed by chemical analysis for the content and for the dissolution of the active pharmaceutical ingredients according to the respective monographs of the United States Pharmacopoeia. 7 samples (8%) did not comply with the pharmacopoeial specifications, and one sample (1%) showed even extreme deviations. None of the samples was obviously falsified. However, one sample of amoxicillin capsules contained only 47% of the declared content of the active pharmaceutical ingredient, indicating that it may represent amoxicillin capsules 250 mg, rather than 500mg as declared on the label. Medicines stated to originate from Asia (i.e. mainly from India and China) showed a significantly higher proportion (24%) of non-compliant samples than those from Africa and Europe (4%, p = 0.007). High failure rates were observed in medicines both from informal vendors (13%) and from licensed pharmacies (5%), but the difference between both groups was not statistically significant (p = 0.152). The observed high prevalence of substandard medicines requires action from regulatory authorities and health care providers. Testing of selected samples for related substances indicated that inappropriate transport and storage conditions may have been an important cause for substandard quality.
Determinants of the uptake of intermittent preventive treatment of malaria in pregnancy with sulphadoxine pyrimethamine in Sabatia Sub County, Western Kenya
Abstract Background Annually, 125.2 million pregnant women worldwide risk contracting malaria, including 30.3 million and 1.5 million in Sub-Saharan Africa and Kenya respectively. At least three doses of sulphadoxine pyrimethamine for intermittent preventive treatment of malaria in pregnancy (IPTp-SP) is recommended for optimal benefit. Kenya recorded low IPTp-SP optimal uptake in 2015. This study investigated the prevalence of and factors influencing IPTp-SP optimal uptake in Sabatia Sub County, Western Kenya. Methods A cross-sectional study was conducted in Sabatia Sub County from April to October 2020. Using a validated semi-structured questionnaire, data were obtained from 372 randomly sampled post-delivery women aged 15–49 years with live birth within one year preceding the study. Women on cotrimoxazole prophylaxis during pregnancy were excluded. Pearson Chi-square and Fisher’s Exact test were measures of association used. Binary logistic regression analysed predictors of optimal IPTp-SP uptake. Results Optimal IPTp-SP uptake was 79.6%, 95% CI 75.5%–83.7%. Predictors of IPTp-SP optimization were gestational age at first antenatal care (ANC) visit (P = 0.04), frequency of ANC visits (P < 0.001), maternal knowledge of IPTp-SP benefits (P < 0.001), maternal knowledge of optimal sulphadoxine pyrimethamine (SP) dose (P = 0.03) and SP administration at ANC clinic (P = 0.03). Late ANC initiators were less likely to receive optimal IPTp-SP (aOR = 0.4, 95% CI 0.2–0.9). Odds of optimizing IPTp-SP increased among women with ≥ 4 ANC visits (aOR = 16.7, 95% CI 7.9–35.3), good knowledge of IPTp-SP benefits (aOR = 2.4, 95% CI 1.3–4.5) and good knowledge of optimal SP dose (aOR = 1.9, 95% CI 1.1–3.4). Women who never missed being administered SP were highly likely to receive optimal IPTp-SP (aOR = 2.9, 95% CI 1.1–7.2) Conclusions This study has found high IPTp-SP optimal uptake in the study area. Efforts should be directed towards early and more frequent ANC visits. Intensive and targeted health education is required. It’s fundamental to adequately stock and consistently administer SP. Future studies considering larger samples and health workers’ perspectives of the health system delivery factors are recommended. Graphical abstract
Epidemiology of COVID-19 infections on routine polymerase chain reaction (PCR) and serology testing in Coastal Kenya
Background: There are limited studies in Africa describing the epidemiology, clinical characteristics and serostatus of individuals tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We tested routine samples from the Coastal part of Kenya between 17th March 2020 and 30th June 2021. Methods: SARS-CoV-2 infections identified using reverse transcription polymerase chain reaction (RT-PCR) and clinical surveillance data at the point of sample collection were used to classify as either symptomatic or asymptomatic. IgG antibodies were measured in sera samples, using a well validated in-house enzyme-linked immunosorbent assay (ELISA). Results: Mombasa accounted for 56.2% of all the 99,694 naso-pharyngeal/oro-pharyngeal swabs tested, and males constituted the majority tested (73.4%). A total of 7737 (7.7%) individuals were SARS-CoV-2 positive by RT-PCR. The majority (i.e., 92.4%) of the RT-PCR positive individuals were asymptomatic. Testing was dominated by mass screening and travellers, and even at health facility level 91.6% of tests were from individuals without symptoms. Out of the 97,124 tests from asymptomatic individuals 7,149 (7%) were positive and of the 2,568 symptomatic individuals 588 (23%) were positive. In total, 2458 serum samples were submitted with paired naso-pharyngeal/oro-pharyngeal samples and 45% of the RT-PCR positive samples and 20% of the RT-PCR negative samples were paired with positive serum samples. Symptomatic individuals had significantly higher antibody levels than asymptomatic individuals and become RT-PCR negative on repeat testing earlier than asymptomatic individuals. Conclusions: In conclusion, the majority of SARS-CoV-2 infections identified by routine testing in Coastal Kenya were asymptomatic. This reflects the testing practice of health services in Kenya, but also implies that asymptomatic infection is very common in the population. Symptomatic infection may be less common, or it may be that individuals do not present for testing when they have symptoms.
Effects of larval exposure to sublethal doses of ivermectin on adult fitness and susceptibility to ivermectin in Anopheles gambiae s.s.
Abstract Background The effects of ivermectin (endectocide) on mosquito survival make it a potential new malaria vector control tool. The drug can be administered to mosquito disease vectors through blood hosts that include humans and livestock. Its increased use may cause contamination of larval habitats, either directly through livestock excreta or indirectly through leaching or run-off from contaminated soil, albeit in sublethal doses. However, the effects of such exposure on immature stages and the subsequent adults that emerge are poorly understood. This study was undertaken to evaluate the impact of ivermectin exposure on Anopheles gambiae s.s. larvae and its effects on fitness and susceptibility to ivermectin in the emerging adults. Methods Laboratory-reared An. gambiae s.s. (Kilifi strain) larvae were exposed to five different ivermectin concentrations; 0, 0.00001, 0.0001, 0.001, and 0.01 ppm, and larval survival was monitored to determine the appropriate sub-lethal dose. Concentrations with survival > 50% (0.00001 and 0.0001 ppm) were selected and used as the sub-lethal doses. The fecundity, fertility, and susceptibility to ivermectin of adults emerging after larval exposure to the sub-lethal doses were examined. Results Overall, exposure of An. gambiae s.s. aquatic stages to ivermectin caused a dose-dependent reduction in larval survival irrespective of the stage at which the larvae were exposed. Exposure to ivermectin in the larval stage did not have an effect on either the number of eggs laid or the hatch rate. However, exposure of first/second-instar larvae to 0.0001 ppm and third/fourth-instar larvae to 0.001 ppm of ivermectin reduced the time taken to oviposition. Additionally, exposure to ivermectin in the larval stage did not affect susceptibility of the emerging adults to the drug. Conclusions This study shows that contamination of larval habitats with ivermectin affects An. gambiae s.s. larval survival and could potentially have an impact on public health. However, there are no carry-over effects on the fecundity, fertility, and susceptibility of the emerging adults to ivermectin. In addition, this study shows that environmental exposure to ivermectin in the larval habitats is unlikely to compromise the efficacy of ivermectin in the emerging adults. Graphical Abstract
Malaria vector bionomics in Taita-Taveta County, coastal Kenya
Abstract Background Estimation of the composition and densities of mosquito species populations is crucial for monitoring the epidemiology of mosquito-borne diseases and provide information on local vectors to public health officials and policy-makers. The aim of this study was to evaluate malaria vector bionomics in ecologically distinct sites in Taita-Taveta County, Kenya. Methods Adult mosquitoes were collected using backpack aspirators and paired indoor/outdoor CDC light traps in 10 randomly selected households in six villages with distinct ecologies over a study period of 3 years. All Anopheles mosquitoes were morphotyped, and sibling species of Anopheles gambiae sensu lato (An. gambiae s.l.) were identified and separated by PCR analysis of extracted ribosomal DNA. All female anophelines were tested for sporozoite infectivity, with engorged females screened for blood-meal sources using the enzyme-linked immunosorbent assay technique. A subsample of those testing positive and those testing negative for Plasmodium in the ELISA were subjected to PCR assay. Results A total of eight different Anopheles species were collected both indoors and outdoors. Anopheles gambiae s.l. (82.6%, n = 5252) was the predominant species sensu lato, followed by Anopheles coustani sensu lato (An. coustani s.l.; (10.5%, n = 666) and Anopheles funestus sensu lato (An. funestus s.l.; 5.6%, n = 357). A subset of 683 mosquito samples representing An. gambiae s.l. (n = 580, approx. 11.0%) and An. funestus s.l. (n = 103, approx. 28.9%) were identified by molecular diagnostic assays into sibling species. The An. gambiae s.l. complex was composed of Anopheles arabiensis (62.5%, n = 363/580), An. gambiae sensu stricto (An. gambiae s.s.; 0.7%, n = 4/580), Anopheles merus (0.7%, n = 4/580) and Anopheles quadriannulatus (0.2%, n = 1/580), with the remaining samples (35.5%, n = 206/580) unamplified. Anopheles funestus s.l. was composed of An. rivulorum (14.6%, n = 15/103) and An. leesoni (11.6%, n = 12/103); the remaining samples were unamplified (73.8%, n = 76/103). A total of 981 samples were subjected to PCR analysis for malaria parasite detection; of these 16 (1.6%) were confirmed to be positive for Plasmodium falciparum. The overall human blood index was 0.13 (32/238). Conclusions Anopheles gambiae, An. funestus and An. coustani are key malaria vectors in the Taveta region of Kenya, showing concurrent indoor and outdoor transmission. All of the vectors tested showed a higher propensity for bovine and goat blood than for human blood. Graphical Abstract
TRUE-1: Trial of Repurposed Unithiol for snakebite Envenoming phase 1 (safety, tolerability, pharmacokinetics and pharmacodynamics in healthy Kenyan adults)
Background: Snakebites affect over 5 million people each year, and over 100,000 per year die as a result. The only available treatment is antivenom, which has many shortcomings including high cost, intravenous administration, and high risk of adverse events. One of the most abundant and harmful components of viper venoms are the zinc-dependent snake venom metalloproteinases (SVMPs). Unithiol is a chelating agent which is routinely used to treat heavy metal poisoning. In vivo experiments in small animal models have demonstrated that unithiol can prevent local tissue damage and death caused by a certain viper species. This phase I clinical trial will assess the safety of ascending doses of unithiol with a view for repurposing for snakebite indication. Methods: This open label, single agent, phase I clinical trial of a repurposed drug has a primary objective to evaluate the safety of escalating doses of unithiol, and a secondary objective to describe its pharmacokinetics. In total, 64 healthy Kenyan volunteers from Kilifi County will be dosed in consecutive groups of eight, with dose escalation decisions dependent on review of safety data by an independent data safety monitoring board. Four groups will receive ascending single oral doses, two will receive multiple oral doses, and two will receive single intravenous doses. Follow-up will be for 6-months and includes full adverse event reporting. Pharmacokinetic analysis will define the Cmax, Tmax, half-life and renal elimination. Conclusions: This clinical trial will assess the safety and tolerability of a promising oral therapeutic in a relevant setting where snakebites are prevalent. Unithiol is likely to be safer than antivenom, is easier to manufacture, has activity against diverse snake species, and can be administered orally, and thus shows promise for repurposing for tropical snakebite. Pan African Clinical Trials Registry: PACTR202103718625048 (3/3/2021)