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Development of an oral regimen of unithiol for the treatment of snakebite envenoming: a phase 1 open-label dose-escalation safety trial and pharmacokinetic analysis in healthy Kenyan adults.
Get PDFViperidae snakes are responsible for many of the 94,000 deaths caused by snakebite envenoming each year. The most pathological venom component of this globally diverse family of snakes are the zinc-dependent snake venom metalloproteinase (SVMP) enzymes, which can be inhibited by the metal chelator, unithiol. A short-course oral regimen, readily available and rapidly deployed ahead of hospital admission is needed. This open-label, phase 1 clinical trial assessed the safety of single ascending oral, multiple ascending oral, and single ascending intravenous doses of unithiol in 64 healthy adult volunteers from Kilifi County, Kenya. The multiple dose stage was informed by an interim safety and pharmacokinetic analysis, and predefined target plasma concentrations. Plasma concentrations of unithiol were measured using high-performance liquid chromatography-mass spectrometry, and safety was described by full adverse event reporting. 175 individuals were screened, and 64 (median age 30 years, IQR 25-38 years) received the study drug. There were no dose limiting toxicities or serious adverse events. There were 61 solicited adverse events, 17 related unsolicited adverse events, and 53 laboratory adverse events, all of mild or moderate severity. The maximum oral dose of 1500 mg was well tolerated and associated with the following pharmacokinetic parameters: C 14.7 μg/mL, T 2.9 h, T 18.4 h, and AUC 204.5 μg.h/mL. The phase 2 recommended dose (1500 mg loading dose, followed by 900 mg doses at 6-h and 24-h) has no safety concerns, and has promising pharmacokinetic properties for clinical use. Unithiol is affordable, stable at room temperature, and has the potential to be given orally in remote rural clinics. Its further development for snakebite indication is warranted.</p
Improved genetic screening with zygosity detection through multiplex high‐resolution melting curve analysis and biochemical characterisation for G6PD deficiency
Get PDFAccurate diagnosis of glucose-6-phosphate dehydrogenase (G6PD) deficiency is crucial for relapse malaria treatment using 8-aminoquinolines (primaquine and tafenoquine), which can trigger haemolytic anaemia in G6PD-deficient individuals. This is particularly important in regions where the prevalence of G6PD deficiency exceeds 3%–5%, including Southeast Asia and Thailand. While quantitative phenotypic tests can identify women with intermediate activity who may be at risk, they cannot unambiguously identify heterozygous females who require appropriate counselling. This study aimed to develop a genetic test for G6PD deficiency using high-resolution melting curve analysis, which enables zygosity identification of 15 G6PD alleles. In 557 samples collected from four locations in Thailand, the prevalence of G6PD deficiency based on indirect enzyme assay was 6.10%, with 8.08% exhibiting intermediate deficiency. The developed high-resolution melting assays demonstrated excellent performance, achieving 100% sensitivity and specificity in detecting G6PD alleles compared with Sanger sequencing. Genotypic variations were observed across four geographic locations, with the combination of c.1311C>T and c.1365-13T>C being the most common genotype. Compound mutations, notably G6PD Viangchan (c.871G>A, c.1311C>T and c.1365-13T>C), accounted for 15.26% of detected mutations. The high-resolution melting assays also identified the double mutation G6PD Chinese-4 + Canton and G6PD Radlowo, a variant found for the first time in Thailand. Biochemical and structural characterisation revealed that these variants significantly reduced catalytic activity by destabilising protein structure, particularly in the case of the Radlowo mutation. The refinement of these high-resolution melting assays presents a highly accurate and high-throughput platform that can improve patient care by enabling precise diagnosis, supporting genetic counselling and guiding public health efforts to manage G6PD deficiency—especially crucial in malaria-endemic regions where 8-aminoquinoline therapies pose a risk to deficient individuals.</p
Economic returns on investing in early childhood development in Vietnam: a cost-benefit analysis
Get PDFBackgroundEconomic evidence on the long-term benefits of investing in early childhood development is limited. This study aimed to estimate the potential long-term economic benefits of an early childhood development intervention ‘Learning Clubs’ in Vietnam.MethodsWe conducted a cost-benefit analysis to estimate the costs and benefits of the intervention compared to the standard of care from a limited societal perspective. The intervention cost and child cognitive development outcome were derived from the published ‘Learning Clubs’ trial-based cost-effectiveness analysis. Benefits were monetised based on the gains in wages associated with improved cognitive development over a lifetime at the population level, using a life-table model. The benefit-cost ratio was estimated as the benefits in wages divided by the intervention cost with a 3% discount rate, assuming nationwide scale up to a hypothetical national birth cohort. Sensitivity, scenario, and threshold analyses were conducted to examine the uncertainty around the model.ResultsThe benefit-cost ratio was 5.52, indicating that the expected benefit for each US5.52. The intervention would generate economic benefits of US2.28 billion per national annual birth cohort. Probabilistic sensitivity analyses estimated the benefit-cost ratio to be 5.90 (95%CI 2.66 to 11.12). The findings were relatively robust as the benefit-cost ratios remained above 1 in all sensitivity and scenario analyses.ConclusionsOur findings support greater investments in early childhood development. The Excel-based model is available for further use and adaption to other settings.</p
Developing an intervention to improve early infant HIV diagnosis service uptake among postpartum women in Malawi’s primary healthcare using a co-designing approach with stakeholders
Get PDFLow health service use by women and infants after birth limits early infant HIV diagnosis (EID). From August 2021 to December 2022, we collaborated with 44 healthcare workers (HCW), service users, and non-governmental organisation stakeholders from seven public facilities and five non-governmental organisations in Blantyre, building on a previous study. We analysed context-specific problems in EID services and co-designed a context-appropriate enhanced health system intervention to improve the uptake of six weeks’ EID services in primary health facilities in Blantyre, Malawi, using qualitative methods and co-designing workshops. The Behaviour Change Wheel, Theoretical Domain Framework and Consolidated Framework for sustainability constructs in healthcare guided the workshops. Reflexive thematic analysis of the data showed that stakeholders found that EID services were sub-optimal and identified challenges to service provision in 5 key areas: (1) client identification, (2) context-appropriate client-centred service integration, (3) HCW coordination and accountability, (4) HCW capacity building for optimal service delivery, and (5) intervention sustainability. Specifically, client and HCW stigma perceptions, referral gaps, resource challenges, HCW lack of time and poor documentation affected client identification; HCW clustered work shifts to extend off-duty periods, failure to synchronise client appointments, and lack of resources were barriers to client-centred integrated services; dysfunctional teams, minimal supervision and misconduct among HCW impacted coordination and accountability; and lack of information sharing and limited training reduced HCW capacity for service delivery. Context-appropriate stakeholder informed co-design initiatives to address identified challenges included: clients’ unique identifiers, booking systems, strengthening leadership, data validation, care pathways, and facility-based training. We recommend evaluating these initiatives in low resource settings as they have potential to address the identified EID service implementation gaps and significantly improve the EID of HIV in contexts of greatest need.</p
Advancing Global Health Security through Rapid Operational Research on Diagnostics during Outbreaks
Get PDFGlobal health security (GHS) relies on accurate and timely diagnosis of pathogens with epidemic and pandemic potential, as well as effective and timely interventions.1 Operational research (OR), defined as “research into strategies, interventions, and tools or knowledge that can enhance the quality, coverage, and effectiveness or performance of the health system or program in which the research is being conducted,” plays a crucial role in advancing GHS worldwide.2 Operational research conducted in low-and middle-income countries (LMICs) helps bolster GHS by ensuring that global health policy and programmatic recommendations, strategies, and interventions, which are often developed based on insights and findings from high-income countries, are appropriately adapted and relevant to LMICs</p
Adverse maternal outcomes among women who gave birth at public hospitals in eastern Ethiopia: a cross-sectional study
Get PDFBackground: An adverse maternal outcome, such as anemia, postpartum hemorrhage, and postpartum eclampsia, poses a significant risk to women. While studies on the burden of adverse maternal outcomes have been conducted in various countries, including Ethiopia, many predictors beyond obstetric factors have not been fully explored. This study aimed to determine the magnitude and factors associated with adverse maternal outcomes among women who gave birth at selected public hospitals in eastern Ethiopia.Methods: A hospital-based cross-sectional study was conducted among 2,608 randomly selected women who gave birth in six public hospitals in eastern Ethiopia from November 2023 to March 2024. Data were collected through face-to-face interviews and clinical chart reviews. Factors associated with adverse maternal outcomes were identified using bivariable and multivariable robust Poisson regression analyses. Adjusted relative risk (ARR) with a 95% confidence interval (CI) was used to report the strength of the association. The variables with a p-value of <0.05 were considered statistically significant.Results: The magnitude of adverse maternal outcomes was 15.68% (95% CI: 14.70%–16.66%). A poor wealth index (ARR = 4.41; 95% CI: 3.46–5.62), having danger signs at admission (ARR = 1.86; 95% CI: 1.18–2.91), alcohol use during pregnancy (ARR = 1.86; 95% CI: 1.32–2.62), duration of labor ≥24 h (ARR = 1.69; 95% CI: 1.00–2.85), and maternal age greater than 35 years (ARR = 1.39; 95% CI: 1.03–1.86) increased the risk of adverse maternal outcomes. In contrast, folic acid intake during pregnancy (ARR = 0.47; 95% CI: 0.38–0.57), having partner support (ARR = 0.70; 95% CI: 0.59–0.83), and spontaneous vaginal delivery (ARR = 0.58; 95% CI: 0.49–0.68) reduced the risk of adverse maternal outcomes.Conclusion: One in six women who gave birth in eastern Ethiopia experienced adverse maternal outcomes. This rate was determined to be moderate when compared to the WHO projections for lower- and middle-income countries and better than the higher averages reported by the WHO. Targeted intervention programs, such as targeted education and empowerment programs, and the strengthening of the community health worker program would help address socioeconomic disparities and improve early detection and management of danger signs during pregnancy, which would aid in averting the occurrence of adverse outcomes.</p
Point-of-care ultrasound reveals extensive pathology in Gabonese preschool-age children with urogenital schistosomiasis.
Get PDFUrogenital schistosomiasis (UGS) is a waterborne parasitic disease mainly resulting from infection with Schistosoma haematobium. It belongs to the neglected tropical diseases and affects almost 240 million people worldwide [1]. Untreated infection causes substantial morbidity of both the urinary and genital tract in endemic areas. Urinary tract pathology occurs in the early stage of infection, mainly affects the bladder wall and distal ureters and is often reversible after treatment [2]. In chronically infected patients, UGS can cause persistent bladder wall changes, irreversible hydronephrosis with a risk for kidney failure as well as squamous cell carcinoma of the bladder [3–5]. Genital schistosomiasis (GS) is a still underrated manifestation of S. haematobium infection, which can lead to sexual dysfunction and infertility in both females and males and increases the risk for ectopic pregnancies [6].In Gabon, UGS is endemic and preventive chemotherapy is generally recommended by the WHO [7]. The local epidemiology differs substantially between provinces and different areas, with S. haematobium prevalence estimates ranging from 0.8 to 45% in school-age children [8]. While data on the epidemiology of UGS has increased during the last two decades, most of it is limited to parasitological determinants. Evaluation of morbidity has been rarely undertaken, as access to diagnostic tools such as ultrasound was limited; thus, little remains known about the prevalence and extent of associated urinary tract pathology. However, morbidity data across the age ranges is needed to estimate the disease burden for the local population and to guide local control strategies.Our study aimed to detect urinary tract pathology in symptomatic UGS patients in an endemic area and to correlate the findings with demographic, clinical, and parasitological factors.</p
Endoscopic variceal ligation combined with carvedilol versus endoscopic variceal ligation combined with propranolol for the treatment of oesophageal variceal bleeding in cirrhosis: study protocol for a multicentre, randomised controlled trial
Get PDFIntroduction Liver cirrhosis and its severe complication, oesophageal variceal bleeding (EVB), pose significant health risks. Standard treatment for EVB combines non-selective beta-blockers (NSBB) with endoscopic variceal ligation (EVL). Carvedilol, an NSBB with additional benefits, is preferred for compensated cirrhosis. However, no randomised controlled trial (RCT) has compared carvedilol with propranolol, a conventional NSBB, in combination with EVL for secondary prophylaxis. This study aims to compare the effectiveness and safety of these treatments in preventing variceal rebleeding or death in patients with cirrhosis and EVB.Methods and analysis This multicentre, RCT is scheduled to begin in December 2024, with recruitment and follow-up continuing until December 2026. Eligible participants are patients with liver cirrhosis and EVB. Participants are randomly assigned in a 1:1 ratio to receive EVL combined with either carvedilol or propranolol. The primary endpoint is the incidence of variceal rebleeding or all-cause death. Secondary endpoints include all-cause death, liver-related death, each of the complications of portal hypertension (overt ascites, overt hepatic encephalopathy, spontaneous bacterial peritonitis, hepatorenal syndrome, portal vein thrombosis), hepatocellular carcinoma, changes in liver function (assessed by Child-Pugh and Model for End-Stage Liver Disease scores), changes in liver stiffness, changes in spleen stiffness, and adverse events. Subgroup and sensitivity analyses will be conducted to evaluate the consistency and robustness of the treatment effects. A total sample size of 524 patients (262 per group) is required to detect a significant difference between the treatment arms.Ethics and dissemination The study protocol has been approved by the ethics committee of the First Hospital of China Medical University (No. 2024-656-2). The study will follow the Declaration of Helsinki and Good Clinical Practice guidelines. The findings of this trial will be disseminated through peer-reviewed publications, conference presentations and healthcare professionals to guide future clinical practice.</p
Field evaluation of the Bioline Malaria Ag P.f/Pan rapid diagnostic test: causes of microscopy discordance and performance in Uganda
Get PDFBackgroundHistidine Rich Protein 2 (HRP2)/pan-Lactate Dehydrogenase (pLDH) combination rapid diagnostic tests (RDTs) may address the shortcomings of RDTs that detect HRP2 alone. However, the relative contribution of the possible causes of discordant results (RDT-negative and microscopy-positive) and performance in field settings across Uganda are poorly quantified.MethodsThis study utilized samples from two cross-sectional surveys conducted in 32 districts at 64 sites across Uganda between November 2021 and March 2023 that enrolled 6354 febrile participants ≥ two years of age. Discordant samples (negative by HRP2/pLDH RDT and positive by microscopy) underwent quantitative PCR (qPCR) to detect and quantify parasitaemia. Those confirmed to be positive for Plasmodium falciparum at > 1 parasites/microlitre (p/µL) were tested for pfhrp2 and pfhrp3 deletions using digital PCR. Those that were negative or had P. falciparum detected at ≤ 1 p/µL underwent Plasmodium species testing using nested PCR. The performance of the Bioline Malaria Ag P.f/Pan combination RDT was evaluated by comparison with microscopy and qPCR.ResultsThere were 166 (8.4%) discordant samples out of 1988 microscopy positive samples. Of these, 90/166 (54.2%) were confirmed to contain P. falciparum at levels > 1 p/µL, whereas 76/166 (45.8%) were negative or had P. falciparum levels ≤ 1 p/µL. Only one P. falciparum positive sample was confirmed to have a deletion in pfhrp3. The primary reasons for RDT-negative, microscopy-positive discordance in samples testing negative for P. falciparum by PCR were non-falciparum species (37/76, 48.7%) or false positives by microscopy (31/76, 40.8%). The sensitivity of the Bioline Malaria Ag P.f/Pan combination RDT was high (> 91%) using either microscopy or qPCR as the gold standard. However, specificity was low (56.7%) when microscopy was used as the gold standard; it improved to 64.0% when qPCR was used as the gold standard.ConclusionThe Bioline Malaria Ag P.f/Pan combination RDT was found to be highly sensitive in Uganda and reliable for ruling out malaria. False negative RDT results were primarily due to low density P. falciparum infections, non-falciparum infections, or incorrect microscopy results. In contrast, false positive RDT results were common, most likely due to persistent HRP2 antigenaemia in this high transmission setting though causes of false positive RDTs were not investigated. The low specificity of HRP2-based RDTs may result in overuse of anti-malarial drugs and missed diagnoses of non-malarial febrile illnesses.</p
A noninferiority cluster randomised evaluation of a broflanilide indoor residual spraying insecticide, VECTRON T500, for malaria vector control in Tanzania
Get PDFEffective malaria vector control is being undermined by the rapid spread of insecticide resistance. VECTRON T500, a new indoor residual spraying (IRS) product containing the active ingredient broflanilide as a 50% wettable powder (WP), was previously shown to be efficacious in experimental hut trials. A two-arm non-inferiority cluster randomized controlled community trial was conducted in Muheza District, Tanga Region, Tanzania. VECTRON T500 was compared to the IRS product Fludora Fusion (clothianidin 50% + deltamethrin 6.25% WP-SB). Sixteen village clusters were pair-matched on baseline vector densities and allocated to reference and intervention arms. Monthly CDC light trapping sampled mosquitoes to estimate vector density, indoor biting, sporozoite and entomological inoculation rate (EIR). The non-inferiority margin of mosquito density was defined as a density ratio of 1.5. Susceptibility to IRS active ingredients was assessed in one of the local vectors, Anopheles gambiae sensu lato (s.l.), using WHO/CDC bottle bioassays. The residual efficacy of both IRS products was monitored for 12 months using susceptible and pyrethroid resistant An. gambiae sensu stricto (s.s.) mosquitoes. This study is registered with ClinicalTrials.gov (NCT05150808). A total of 916 and 844 houses were sprayed with Fludora Fusion and VECTRON T500, respectively, with equitable spray coverage. An. gambiae s.l. was resistant to deltamethrin but susceptible to clothianidin and broflanilide. The density ratio adjusted for baseline Anopheline mosquito density was 0.77 (95% CI: 0.45–1.29). The baseline adjusted sporozoite rate and EIR differences between the two trial arms were 0.84% and 15.61%, respectively. The residual efficacy was > 80% mortality for VECTRON T500 and Fludora Fusion, on both mud and concrete walls, 12 months post spraying. VECTRON T500 was non-inferior to Fludora Fusion in terms of its ability to reduce vector density, sporozoite rate and EIR, providing an additional vector control tool with a new mode of action for malaria prevention and insecticide resistance management