21367 research outputs found
Sort by
Hemostatic hellfire: Rhabdophis helleri (Red-necked Keelback) snake venom pathophysiologically activates Factor VII and Factor X through novel uses of the clotting cofactors calcium, phospholipid, and Factor Va
Get PDFRhabdophis helleri envenomations may cause lethal coagulopathy, yet the venom mechanisms are poorly characterized. This study investigated the procoagulant mechanisms of R. helleri venom, with particular focus on coagulation factor activation and cofactor dependencies. We demonstrate that R. helleri venom potently activates Factor VII (FVII) and Factor X (FX) in a highly cofactor-dependent manner. FVII activation was minimal with venom alone but increased dramatically with the addition of the cofactor protein Factor V (FV) and reached maximal activity with the addition of the cofactor Factor Va (FVa). In addition to using endogenous thrombin produced FVa, the itself is able to convert FV into a useable FVa product. Similarly, FX activation was greatly amplified in the presence of FV or FVa, and showed similar cofactor dependence and the ability to use venom-activated FVa. Under comparable FV or FVa cofactor conditions, FX was activated at substantially lower magnitude than Factor VII, suggesting that Factor VII is the primary pathophysiological target. Systematic calcium and phospholipid requirement analysis revealed extremely high levels of dependence upon both cofactors. This is the first time for any venom that such a high level of phospholipid dependence has been noted. These results represent the first documentation of Factor Va-dependent zymogen activation in a non-front-fanged species, indicating convergent evolution of this mechanism across Natricidae, Elapidae, and Viperidae snake families. The determination of the biochemistry underpinning the rapid plasma clotting induced by the venom provides mechanistic insight into the consumption coagulopathy observed clinically in human envenomations and the stroke-inducing effect in prey. These toxicological findings advance understanding of rear-fanged snake venom evolution and inform development of treatment strategies for this understudied but medically important species.</p
Susceptibility of Anopheles stephensi SDA500 strain to common insecticides and efficacy of glazed tile bioassay for resistance characterization
Get PDFResearch on the urban malaria vector Anopheles stephensi has intensified in recent years following its rapid spread throughout the Horn of Africa and beyond. In addition to behavioural and ecological traits which may limit the efficacy of control efforts, insecticide resistance is a notable problem in invasive An. stephensi populations. The most frequently used laboratory reference strain for An. stephensi is SDA500 originally colonized from Pakistan; though considered insecticide susceptible, quantitative demonstration of this crucial assumption is lacking. We characterized the susceptibility status of SDA500 against multiple insecticide classes used for adult and larval control using the standard WHO techniques for larval bioassays and two alternatives for adults: bottle bioassays and glazed tile bioassays. SDA500 showed full susceptibility against all insecticides tested, and via dose-response assays, we provide the first comprehensive LC50 dataset for a strain of An. stephensi, filling a key knowledge gap and providing an important resource for all future studies of resistance in this important malaria vector. Whilst tile and bottle adult bioassays produced broadly comparable results for both SDA500 and additional laboratory strains, differences were found when testing neonicotinoids and butenolides, which require the addition of the compound MERO® for effectiveness. Nevertheless, the glazed tile bioassay represents a much higher throughput and less resource-intensive technique than bottle bioassays for simultaneous screening of multiple insecticides.</p
Association between care by hypertension specialists and major adverse cardiovascular events in patients with uncontrolled hypertension
Get PDFBackground: The impact of medical care by hypertension specialists on the risk of subsequent major adverse cardiovascular events (MACE) among uncontrolled hypertensive patients remains unclear. We aimed to investigate the association between care by hypertension specialists and the risk of MACE among patients with uncontrolled hypertension. Methods: Using the Urumqi Hypertension Database (UHDATA), we studied a retrospective cohort of patients aged 45–79 years who were admitted for uncontrolled hypertension at People's Hospital of Xinjiang Uygur Autonomous Region, China, between 2015 and 2019. Based on hospitalization departments, we identified patients who had been exposed to medical care by hypertension specialists at least once and divided patients into a hypertension specialists group and a non-specialists group. Cox proportional hazards modeling was used to estimate the risk for MACE (a four-component outcome of cardiovascular death, non-fatal stroke, non-fatal myocardial infarction, and coronary revascularization) in the cohort using the propensity score method of stabilized inverse probability of treatment weighting (sIPTW). Results: A total of 10,680 patients with uncontrolled hypertension were analyzed, with a median follow-up of 4.0 years. Of these, 5,646 (52.9%) patients received medical care by hypertension specialists and experienced fewer MACE than the non-specialists group [21.5 vs. 39.7 per 1,000-person-year, adjusted hazard ratio (HR) 0.67, 95% confidence interval (CI) 0.57–0.79] after sIPTW. Results persisted for the MACE component, non-fatal stroke (HR 0.62, 95% CI 0.49–0.79), non-fatal myocardial infarction (HR 0.48, 95% CI 0.33–0.69), and coronary revascularization (HR 0.71, 95% CI 0.55–0.93). In subgroup analyses, no significant interaction effect was observed between medical care by hypertension specialists and key subgroup factors on MACE. Conclusions: This study demonstrated a significant association between medical care by hypertension specialists and a reduced risk of MACE in patients with uncontrolled hypertension. Our results suggest that medical care by hypertension specialists may play an essential role in improving cardiovascular outcomes among this high cardiovascular disease risk population.</p
Navigating the trials of a trial: lessons from ProRIDE on recruitment, retention, and follow-up in rural Africa
Get PDFThe ProRIDE randomized clinical trial (RCT) started participant recruitment in February 2022, successfully enrolling 2,000 infants within an 11-month period and achieving a follow-up rate of 97% at six months of age. This narrative article describes critical components of the research protocol, the composition of the research team, community sensitization efforts, and the local performance of the study. The research initiative was conceptualized by a collaborative group of scientists from both high- and low-income countries, and its successful implementation was contingent upon the active involvement and participation of a rural, low-income community. Based on previous study findings in Tanzania, which consistently indicated a high prevalence of severe infections related to multidrug-resistant bacteria, the research team recognized the urgent need for preventive strategies aimed at reducing the incidence of sepsis and severe bacterial infections. Given the scarcity of data from rural areas and the imperative for inclusivity, the rationale for conducting this RCT in a rural context was compelling. We believe that a key factor in the successful completion of this trial was the intentional design of a simple, straightforward, and practical intervention, and study framework. Caregivers administered the study medication at home, thereby mirroring real-world therapeutic practices and enhancing the generalizability of the findings. To ensure adherence to the one-month intervention regimen, the research team conducted a day-seven home visit to confirm proper administration of the investigational product and address any associated early challenges. During this interaction, the field workers reiterated the instructions for the proper application of the product, thereby serving as a reminder to the caretaker regarding its correct usage. Additionally, a thorough planning phase was undertaken prior to the study's commencement, involving extensive collaboration between the researchers from Norway, Muhimbili University of Health and Allied Sciences, Tanzania, and the leadership at Haydom Lutheran Hospital. Through a series of meetings and discussions, the research team in Norway and Tanzania identified specific areas requiring enhancement, particularly in laboratory infrastructure and the training of personnel in blood culture techniques and antimicrobial susceptibility testing. Despite facing numerous challenges both prior to and during the trial, this RCT successfully recruited 2,000 participants within 11 months. This accomplishment can be attributed to the strong collaboration and teamwork exhibited throughout the process. The insights gained from this study may be of particular interest to researchers and scientists aiming to conduct investigations involving infants and children in low-income settings. Trial registrations This trial is registered with ClinicalTrials.gov, NCT04172012. November 21, 2019.</p
PoolSeq Genome-Wide Association Studies and Microbial Signature Analyses Identify Novel Candidates Associated With Pyrethroid Resistance Evolution in Anopheles funestus in Cameroon
Get PDFIntensification of insecticide resistance in malaria vectors is undermining efforts to sustain control strategies. The evolutionary features underlying such exacerbation in major vector such as Anopheles funestus are only partially understood. PoolSeq whole genome analysis of Anopheles funestus from Mibellon (Cameroon), (alive and dead at 1×, 5× and 10× concentrations), failed to identify hits associated with resistance escalation. However, stronger signals emerge at the rp1 and CYP9 loci when comparing these phenotypes to the susceptible reference strain FANG, with genomic analysis using F3 crosses implicating these regions in resistance evolution. Temporal genomic between 2014 and control unexposed 2021 populations confirmed substantial genomic changes largely confined to these two regions with evidence of selective sweeps linked to the presence of multiple novel replacement polymorphisms and signatures of complex genomic evolution emerging from major cytochrome P450 genes within the CYP9 and rp1 regions at increasing allelic frequencies in field individuals and alive genetic crosses, indicating that those variants are potentially driving resistance evolution. Combined genotyping of the rp1-based 4.3 kb SV and CYP9K1 (G454A) in alive and dead genetic crosses underscores their significant contribution to super-resistant phenotype in Anopheles funestus population in Mibellon. On the other hand, microbial composition changes, notably Elizabethkingia anophelis was associated with resistance evolution, suggesting their potential role in shaping the resistance phenotype while Serratia marcescens and Asaia bongorensis correlate with susceptibility. Genetic events and microbial symbionts associated with resistance evolution offer promising avenues for developing molecular markers to manage insecticide resistance.</p
Correction:Intersecting injustices: child marriage and the law in conflict-affected Sudan (International Journal for Equity in Health, (2025), 24, 1, (357), 10.1186/s12939-025-02706-w)
No full textFollowing the publication of the original article [1], it was noted that in the sentence beginning ‘Despite high enrolment rates…’ the age range of ‘(15–24)’ was incorrectly denoted as references. In addition, in the Authors’ contributions statement, the initials ‘AKAE’ were incorrectly given as ‘AA’ in the sentence ‘AKAE provided key input and conducted a detailed review’. The original article [1] has been corrected.</p
Correction:Intersecting injustices: child marriage and the law in conflict-affected Sudan (International Journal for Equity in Health, (2025), 24, 1, (357), 10.1186/s12939-025-02706-w)
No full textFollowing the publication of the original article [1], it was noted that in the sentence beginning ‘Despite high enrolment rates…’ the age range of ‘(15–24)’ was incorrectly denoted as references. In addition, in the Authors’ contributions statement, the initials ‘AKAE’ were incorrectly given as ‘AA’ in the sentence ‘AKAE provided key input and conducted a detailed review’. The original article [1] has been corrected.</p
The impact of the termination of Lymphatic Filariasis mass drug administration on Soil-transmitted Helminth prevalence in school children in Malawi
Get PDFBACKGROUND: Soil-transmitted helminths (STH) have been passively targeted through the implementation of mass drug administration (MDA), with the drugs ivermectin and albendazole, against the parasitic disease, lymphatic filariasis (LF). In Malawi, LF MDA was administered to communities between 2008 and 2014. The aim of this analysis was to estimate the impact of LF MDA and its termination on STH prevalence in school aged children (SAC). METHODOLOGY: School survey data of STH prevalence in Malawi were obtained through the ESPEN website. The surveys spanned the periods before (1998-2004), during (2012-2014) and after LF MDA (2015-2019). Bayesian mixed-effects models were fitted to estimate the impact of LF MDA termination, and other STH risk factors, on the odds of infection, as well as generate predictions of nationwide STH prevalence during and after LF MDA. PRINCIPAL FINDINGS: SAC after the termination of LF MDA had 1.8 times greater odds of A. lumbricoides infection compared to SAC during the implementation of LF MDA (95% credible interval (CI): 1.03 - 3.35), despite ongoing STH preventive chemotherapy (PC) targeting SAC. Predictions indicate majority of districts increased in their probability of exceeding 2% A. lumbricoides prevalence in SAC after the termination of LF MDA, with Chitipa, Mulanje and Nsanje districts estimated to have > 80% probability of exceeding 2% prevalence. CONCLUSIONS/SIGNIFICANCE: An overall resurgence in A. lumbricoides infections after LF MDA was estimated in SAC, despite ongoing annual STH PC. This suggests STH PC could not sustain the prevalence levels achieved in SAC under community-wide LF MDA. The potential role of drug resistance in this resurgence calls for urgent investigation. Understanding how this resurgence corresponds to prevalence of moderate and heavy infections should be a priority for future research.</p
Infant HIV transmission despite maternal viral suppression: a case of post-weaning seroconversion
Get PDFDespite widespread availability of antiretroviral therapy (ART) and comprehensive prevention of vertical transmission (PVT) programmes, rare cases of postnatal HIV transmission continue to occur. Maternal viral suppression during pregnancy and breastfeeding has dramatically reduced transmission risk, with global guidelines now recommending maternal ART as the cornerstone of prevention.1 Current evidence estimates the overall risk of pregnancy and postnatal HIV transmission to be less than 1% in mothers who are fully suppressed on ART.2 However, we report a case that illustrates a complex diagnostic and clinical challenge: infant HIV seroconversion following cessation of breastfeeding, despite sustained maternal virological suppression and adherence to all PVT interventions
Exploring the importance and preference of sugar feeding behaviour of malaria vectors in sugar plantations of southern Malawi
Get PDFBackground Reliable tools are needed to control opportunistic outdoor biting and resting malaria vectors that remain beyond the reach of indoor targeted interventions. The attractive targeted sugar baits (ATSBs) have demonstrated effectiveness in some settings but have shown limited impact in other areas, in part due to differences in mosquito species’ preferences and the presence of competing natural sugar sources. We evaluated the sugar-feeding preferences of Anopheles gambiae in Chikwawa, southern Malawi, to inform context specific sugar-based vector control interventions. Methods Using three collection tools, CDC Light traps; Prokopack aspirator and the barrier screen, we collected 187 adult anophelines from the Illovo sugar plantations. Collected mosquitoes were subjected to cold anthrone tests in the laboratory to assess the presence of plant sugars in their gut. Additionally, 810 adult Anopheles gambiae s.l., reared in the insectary from wild caught larvae, were exposed in an olfactory-driven choice experiment to identify the most attractive available sugar source in the area. Sugar sources included guavas, melon, bananas, mango, marula and sugarcane. Results Over 40% (n = 74) of the collected Anopheles mosquitoes- including An. gambiae s.l., An. funestus, An. coustani and An. tenebrous were found to have fed on natural sugar sources. For the sugar attractiveness tests for An. gambiae s.l., guava was found to be twice as attractive (IRR = 1.97, 95% CI: 1.49–2.62, p < 0.001) as sugarcane (our reference fruit), followed by banana (IRR = 1.68, 95% CI: 1.26–2.24, P < 0.001), then mango, and melon (IRR = 1.49, 95% CI: 1.11–2.01, P = 0.008) and (IRR = 1.45, 95% CI: 1.08–1.96, P = 0.014) respectively. Conclusion Sugar feeding is a key activity for Anopheles mosquitoes and presents a potential target for control. Understanding local sugar source preferences will help tailor novel mosquito control intervention strategies such as the ATSBs to specific ecological contexts.</p