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Detection of Anopheles stephensi Mosquitoes by Molecular Surveillance, Kenya.
The Anopheles stephensi mosquito is an invasive malaria vector recently reported in Djibouti, Ethiopia, Sudan, Somalia, Nigeria, and Ghana. The World Health Organization has called on countries in Africa to increase surveillance efforts to detect and report this vector and institute appropriate and effective control mechanisms. In Kenya, the Division of National Malaria Program conducted entomological surveillance in counties at risk for An. stephensi mosquito invasion. In addition, the Kenya Medical Research Institute conducted molecular surveillance of all sampled Anopheles mosquitoes from other studies to identify An. stephensi mosquitoes. We report the detection and confirmation of An. stephensi mosquitoes in Marsabit and Turkana Counties by using endpoint PCR and morphological and sequence identification. We demonstrate the urgent need for intensified entomological surveillance in all areas at risk for An. stephensi mosquito invasion, to clarify its occurrence and distribution and develop tailored approaches to prevent further spread.
A field bioassay for assessing ivermectin bio-efficacy in wild malaria vectors.
BACKGROUND: Ivermectin (IVM) mass drug administration is a candidate complementary malaria vector control tool. Ingestion of blood from IVM treated hosts results in reduced survival in mosquitoes. Estimating bio-efficacy of IVM on wild-caught mosquitoes requires they ingest the drug in a blood meal either through a membrane or direct feeding on a treated host. The latter, has ethical implications, and the former results in low feeding rates. Therefore, there is a need to develop a safe and effective method for IVM bio-efficacy monitoring in wild mosquitoes. METHODS: Insectary-reared Anopheles gambiae s.s. were exposed to four IVM doses: 85, 64, 43, 21 ng/ml, and control group (0 ng/ml) in three different solutions: (i) blood, (ii) 10% glucose, (iii) four ratios (1:1, 1:2, 1:4, 1:8) of blood in 10% glucose, and fed through filter paper. Wild-caught An. gambiae s.l. were exposed to 85, 43 and 21 ng/ml IVM in blood and 1:4 ratio of blood-10% glucose mixture. Survival was monitored for 28 days and a pool of mosquitoes from each cohort sacrificed immediately after feeding and weighed to determine mean weight of each meal type. RESULTS: When administered in glucose solution, mosquitocidal effect of IVM was not comparable to the observed effects when similar concentrations were administered in blood. Equal concentrations of IVM administered in blood resulted in pronounced reductions in mosquito survival compared to glucose solution only. However, by adding small amounts of blood to glucose solution, mosquito mortality rates increased resulting in similar effects to what was observed during blood feeding. CONCLUSION: Bio-efficacy of ivermectin is strongly dependent on mode of drug delivery to the mosquito and likely influenced by digestive processes. The assay developed in this study is a good candidate for field-based bio-efficacy monitoring: wild mosquitoes readily feed on the solution, the assay can be standardized using pre-selected concentrations and by not involving treated blood hosts (human or animal) variation in individual pharmacokinetic profiles as well as ethical issues are bypassed. Meal volumes did not explain the difference in the lethality of IVM across the different meal types necessitating further research on the underlying mechanisms.
Sugar and blood: the nutritional priorities of the dengue vector, Aedes aegypti.
BACKGROUND: Sugar-feeding behaviour is essential for mosquito survival and reproduction, and has been exploited to develop new control strategies, such as the attractive targeted sugar baits (ATSB). This study examined the sugar-feeding habits of the dengue vector, Aedes aegypti, in semi-field conditions to determine the optimal timing (age) of sugar meals and whether the availability of sugar sources could affect blood-feeding by these mosquitoes. METHODS: A series of paired-choice assays were conducted in which mosquitoes were allowed to choose between a sugar meal or a blood meal directly from a rabbit. Female 1-day-old mosquitoes were given meal choices in cages I-V and observed for feeding choice in only one cage every day for 5 days starting with cages I to V. The preference of Ae. aegypti to feed on sugar or blood and the effect of sugar source availability on blood-feeding was assessed at different chronological and physiological ages. RESULTS: In the first 5 days post-emergence, there was no significant difference in mosquito preference for sugar or blood meals. However, after the first gonotrophic cycle, they had a greater preference for blood over sugar (odds ratio, OR [95% confidence interval, CI] = 9.4 [6.7-13.0]; P
Effectiveness of Rotarix® vaccine in Africa in the first decade of progressive introduction, 2009-2019: systematic review and meta-analysis
Background: Randomized controlled trials of licensed oral rotavirus group A (RVA) vaccines, indicated lower efficacy in developing countries compared to developed countries. We investigated the pooled effectiveness of Rotarix® in Africa in 2019, a decade since progressive introduction began in 2009. Methods: A systematic search was conducted in PubMed to identify studies that investigated the effectiveness of routine RVA vaccination in an African country between 2009 and 2019. A meta-analysis was undertaken to estimate pooled effectiveness of the full-dose versus partial-dose of Rotarix® (RV1) vaccine and in different age groups. Pooled odds ratios were estimated using random effects model and the risk of bias assessed using Newcastle-Ottawa scale. The quality of the evidence was assessed using GRADE. Results: By December 2019, 39 (72%) countries in Africa had introduced RVA vaccination, of which 34 were using RV1. Thirteen eligible studies from eight countries were included in meta-analysis for vaccine effectiveness (VE) of RVA by vaccine dosage (full or partial) and age categories. Pooled RV1 VE against RVA associated hospitalizations was 44% (95% confidence interval (CI) 28-57%) for partial dose versus 58% (95% CI 50-65%) for full dose. VE was 61% (95% CI 50-69%), 55% (95% CI 32-71%), 56% (95% CI 43-67%), and 61% (95% CI 42-73%) for children aged <12 months, 12-23 months, <24 months and 12-59 months, respectively. Conclusion: RV1 vaccine use has resulted in a significant reduction in severe diarrhoea in African children and its VE is close to the efficacy findings observed in clinical trials. RV1 VE point estimate was higher for children who received full dose than those who received partial dose, and its protection lasted beyond the first year of life.
Investigating the spatiotemporal patterns and clustering of attendances for mental health services to inform policy and resource allocation in Thailand.
BACKGROUND: Mental illness poses a substantial global public health challenge, including in Thailand, where exploration of access to mental health services is limited. The spatial and temporal dimensions of mental illness in the country are not extensively studied, despite the recognized association between poor mental health and socioeconomic inequalities. Gaining insights into these dimensions is crucial for effective public health interventions and resource allocation. METHODS: This retrospective study analyzed mental health service utilization data in Thailand from 2015 to 2023. Temporal trends in annual numbers of individuals visiting mental health services by diagnosis were examined, while spatial pattern analysis employed Moran's I statistics to assess autocorrelation, identify small-area clustering, and hotspots. The implications of our findings for mental health resource allocation and policy were discussed. RESULTS: Between 2015 and 2023, mental health facilities documented a total of 13,793,884 visits. The study found anxiety, schizophrenia, and depression emerged as the top three illnesses for mental health visits, with an increase in patient attendance following the onset of the COVID-19 outbreak. Spatial analysis identified areas of significance for various disorders across different regions of Thailand. Positive correlations between certain disorder pairs were found in specific regions, suggesting shared risk factors or comorbidities. CONCLUSIONS: This study highlights spatial and temporal variations in individuals visiting services for different mental disorders in Thailand, shedding light on service gaps and socioeconomic issues. Addressing these disparities requires increased attention to mental health, the development of appropriate interventions, and overcoming barriers to accessibility. The findings provide a baseline for policymakers and stakeholders to allocate resources and implement culturally responsive interventions to improve mental health outcomes.
Identifying proteomic risk factors for cancer using prospective and exome analyses of 1463 circulating proteins and risk of 19 cancers in the UK Biobank.
The availability of protein measurements and whole exome sequence data in the UK Biobank enables investigation of potential observational and genetic protein-cancer risk associations. We investigated associations of 1463 plasma proteins with incidence of 19 cancers and 9 cancer subsites in UK Biobank participants (average 12 years follow-up). Emerging protein-cancer associations were further explored using two genetic approaches, cis-pQTL and exome-wide protein genetic scores (exGS). We identify 618 protein-cancer associations, of which 107 persist for cases diagnosed more than seven years after blood draw, 29 of 618 were associated in genetic analyses, and four had support from long time-to-diagnosis ( > 7 years) and both cis-pQTL and exGS analyses: CD74 and TNFRSF1B with NHL, ADAM8 with leukemia, and SFTPA2 with lung cancer. We present multiple blood protein-cancer risk associations, including many detectable more than seven years before cancer diagnosis and that had concordant evidence from genetic analyses, suggesting a possible role in cancer development.
Prognostic accuracy of screening tools for clinical deterioration in adults with suspected sepsis in northeastern Thailand: a cohort validation study
Abstract Background We sought to assess the performance of commonly used clinical scoring systems to predict imminent clinical deterioration in patients hospitalized with suspected infection in rural Thailand. Methods Patients with suspected infection were prospectively enrolled within 24 hours of admission to a referral hospital in northeastern Thailand between 2013 and 2017. In patients not requiring intensive medical interventions, multiple enrollment scores were calculated including the National Early Warning Score (NEWS), the Modified Early Warning Score (MEWS), Between the Flags (BTF) and the quick Sequential Organ Failure Assessment (qSOFA) score. Scores were tested for predictive accuracy of clinical deterioration, defined as a new requirement of mechanical ventilation, vasoactive medications, ICU admission, and/or death approximately 1 day after enrollment. The association of each score with clinical deterioration was evaluated by logistic regression and discrimination was assessed by generating areas under the receiver operating characteristic curve (AUROC). Results 2680/4989 enrolled patients met criteria for secondary analysis and 100/2680 (4%) experienced clinical deterioration within 1 day following enrollment. NEWS had the highest discrimination for predicting clinical deterioration (AUROC 0.78, 95% confidence interval (CI) 0.74-0.83) compared to MEWS (AUROC 0.67, 95% CI 0.63-0.73, p<0.0001), qSOFA (AUROC 0.65, 95% CI 0.60-0.70, p<0.0001), and BTF (AUROC 0.69, 95% CI 0.64-0.75, p<0.001). NEWS ≥ 5 yielded optimal sensitivity and specificity for clinical deterioration prediction. Conclusion In patients hospitalized with suspected infection in a resource-limited setting in Southeast Asia, NEWS can identify patients at risk of imminent clinical deterioration with greater accuracy than other clinical scoring systems.
Safety, pharmacokinetics, and potential neurological interactions of ivermectin, tafenoquine, and chloroquine in Rhesus macaques.
Ivermectin (IVM) could be used for malaria control as treated individuals are lethal to blood-feeding Anopheles, resulting in reduced transmission. Tafenoquine (TQ) is used to clear the liver reservoir of Plasmodium vivax and as a prophylactic treatment in high-risk populations. It has been suggested to use ivermectin and tafenoquine in combination, but the safety of these drugs in combination has not been evaluated. Early derivatives of 8-aminoquinolones (8-AQ) were neurotoxic, and ivermectin is an inhibitor of the P-glycoprotein (P-gp) blood brain barrier (BBB) transporter. Thus, there is concern that co-administration of these drugs could be neurotoxic. This study aimed to evaluate the safety and pharmacokinetic interaction of tafenoquine, ivermectin, and chloroquine (CQ) in Rhesus macaques. No clinical, biochemistry, or hematological outcomes of concern were observed. The Cambridge Neuropsychological Test Automated Battery (CANTAB) was employed to assess potential neurological deficits following drug administration. Some impairment was observed with tafenoquine alone and in the same monkeys with subsequent co-administrations. Co-administration of chloroquine and tafenoquine resulted in increased plasma exposure to tafenoquine. Urine concentrations of the 5,6 orthoquinone TQ metabolite were increased with co-administration of tafenoquine and ivermectin. There was an increase in ivermectin plasma exposure when co-administered with chloroquine. No interaction of tafenoquine on ivermectin was observed in vitro. Chloroquine and trace levels of ivermectin, but not tafenoquine, were observed in the cerebrospinal fluid. The 3''-O-demethyl ivermectin metabolite was observed in macaque plasma but not in urine or cerebrospinal fluid. Overall, the combination of ivermectin, tafenoquine, and chloroquine did not have clinical, neurological, or pharmacological interactions of concern in macaques; therefore, this combination could be considered for evaluation in human trials.
Neutralization of SARS-CoV-2 by destruction of the prefusion Spike
SummaryThere are as yet no licenced therapeutics for the COVID-19 pandemic. The causal coronavirus (SARS-CoV-2) binds host cells via a trimeric Spike whose receptor binding domain (RBD) recognizes angiotensin-converting enzyme 2 (ACE2), initiating conformational changes that drive membrane fusion. We find that monoclonal antibody CR3022 binds the RBD tightly, neutralising SARS-CoV-2 and report the crystal structure at 2.4 Å of the Fab/RBD complex. Some crystals are suitable for screening for entry-blocking inhibitors. The highly conserved, structure-stabilising, CR3022 epitope is inaccessible in the prefusion Spike, suggesting that CR3022 binding would facilitate conversion to the fusion-incompetent post-fusion state. Cryo-EM analysis confirms that incubation of Spike with CR3022 Fab leads to destruction of the prefusion trimer. Presentation of this cryptic epitope in an RBD-based vaccine might advantageously focus immune responses. Binders at this epitope may be useful therapeutically, possibly in synergy with an antibody blocking receptor attachment.HighlightsCR3022 neutralises SARS-CoV-2Neutralisation is by destroying the prefusion SPIKE conformationThis antibody may have therapeutic potential alone or with one blocking receptor attachment
David Sackett Fellowship 2022: CEBM Report to the McCall MacBain Foundation
We are delighted to report on the success of the inaugural David Sackett Fellowship, building on the success of the 2019 Doug Altman Scholarship, with generous funding and support from the McCall MacBain Foundation (MMF). We used the funding for nine forward-thinking future leaders in Evidence-Based Medicine (EBM) to attend the 2022 EBMLive Conference in Oxford. The nine Fellows brought provocative, bold, and constructive contributions on the theme of making research relevant, replicable, and accessible to end-users. From a highly competitive field, we selected the scholars because of their forward-thinking solutions to address the issue of making research evidence relevant, replicable, and accessible to end-users, as set out in the EBM manifesto, building on the legacy of David Sackett. After an unanticipated delay in hosting EBMLive in 2020 due to the COVID-19 pandemic, the return to an in-person meeting in Oxford, where David Sackett first founded the Centre for Evidence-Based Medicine, re-invigorated the EBM movement with their ideas, enthusiasm, and perspectives. This report highlights the contributions of the awardees, their outputs and the work of the CEBM that supports early-mid career researchers and builds capacity in EBM globally.
Comparative analysis of SARS-CoV-2 neutralization titers reveals consistency between human and animal model serum and across assays.
The evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires ongoing monitoring to judge the ability of newly arising variants to escape the immune response. A surveillance system necessitates an understanding of differences in neutralization titers measured in different assays and using human and animal serum samples. We compared 18 datasets generated using human, hamster, and mouse serum and six different neutralization assays. Datasets using animal model serum samples showed higher titer magnitudes than datasets using human serum samples in this comparison. Fold change in neutralization of variants compared to ancestral SARS-CoV-2, immunodominance patterns, and antigenic maps were similar among serum samples and assays. Most assays yielded consistent results, except for differences in fold change in cytopathic effect assays. Hamster serum samples were a consistent surrogate for human first-infection serum samples. These results inform the transition of surveillance of SARS-CoV-2 antigenic variation from dependence on human first-infection serum samples to the utilization of serum samples from animal models.
The alteration of NK cells phenotypes related to the functions and dengue disease outcomes.
Natural killer cells (NK cells) are the front line of immune cells to combat pathogens and able to influence the subsequent adaptive immune responses. One of the factors contributing to pathogenesis in dengue hemorrhagic fever (DHF) disease is aberrant immune activation during early phase of infection. This study explored the profile of NK cells in dengue infected pediatric patients with different degrees of disease severity. DHF patients contained higher frequency of activated NK cells but lower ratio of CD56dim:CD56bright NK subsets. Activated NK cells exhibited alterations in several NK receptors. Interestingly, the frequencies of NKp30 expressing activated NK cells were more pronounced in dengue fever (DF) than in DHF pediatric patients. In vitro functional analysis indicated that degranulation of NK cells in responding to dengue infected dendritic cells (DCs) required cell-cell contact and type I IFNs. Meanwhile, Interferon gamma (IFN-γ) production initially required cell-cell contact and type I IFNs followed by Interleukin-12 (IL-12), Interleukin-15 (IL-15) and Interleukin-18 (IL-18) resulting in the amplification of IFN-γ producing NK cells over time. This study highlighted the complexity and the factors influencing NK cells responses to dengue virus. Degree of activation, phenotypes of activated cells and the crosstalk between NK cells and other immune cells, could modulate the outcome of NK cells function in the dengue disease.