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Importance of Lysosomal Trapping and Plasmodium Parasite Infection on the Pharmacokinetics of Pyronaridine: A Physiologically Based Pharmacokinetic Model-Based Study.
Get PDFBACKGROUND AND OBJECTIVE: Pyronaridine is a blood schizonticide with a high blood-to-plasma ratio, effective against Plasmodium parasites. As a lipophilic, moderately strong base, it accumulates in low-pH compartments such as lysosomes and parasite food vacuoles, leading to tissue accumulation and differences in drug exposure between healthy individuals and patients with malaria. This study applied physiologically based pharmacokinetic (PBPK) modeling to evaluate the effects of lysosomal sequestration, red blood cell (RBC) accumulation, and parasitemia on pyronaridine pharmacokinetics.
METHODS: Data were available from a phase I clinical trial and the PYRAPREG study. PBPK models were developed in PK-Sim® and MoBi®. A standard multicompartment structure was expanded by adding lysosome compartments to relevant organs. To account for malaria infection, Plasmodium parasite compartments were incorporated into RBCs, with volume scaled by parasitemia.
RESULTS: Data from 52 healthy individuals and 25 patients with malaria were used for model optimization. Incorporating lysosomal sequestration was essential for capturing pyronaridine distribution. In patients with malaria, incorporating low hemoglobin (Hb) and drug accumulation in the parasite compartment enabled an adequate description of whole blood pharmacokinetics. Simulations showed that free pyronaridine concentrations in the parasite compartment were over 10-fold higher than that in whole blood. Higher parasitemia was associated with increased area under the curve (AUC)0-24h and Cmax, mainly on day 1, as parasitemia decreased rapidly. However, the subsequent decrease in Hb had the opposite effect, lowering AUC0-24h and Cmax on the following days.
CONCLUSIONS: This study demonstrates the value of PBPK modeling in elucidating key pharmacokinetic mechanisms, revealing the critical roles of lysosomal sequestration, Hb level, and parasitemia in pyronaridine disposition
Optimizing the implementation of case-area targeted interventions during cholera outbreaks with context-specific delivery mechanisms.
Get PDFCholera, a severe fecal-oral disease, disproportionately affects the poorest communities who lack access to safe water and sanitation. Individuals living in the same household, or within a few hundred meters, of a patient are at increased risk of infection. Thus, during cholera outbreaks, targeted response strategies, such as case-area targeted interventions (CATIs), provide health (e.g., vaccination and antibiotic prophylaxis) and water, sanitation, and hygiene services for affected households and at-risk neighbors living in a defined ring. Previous research on CATIs has focused on impact and effectiveness, and less on implementation processes. As cholera outbreaks occur in diverse settings with differentiated challenges, we investigated how CATI and CATI-like mechanisms can be best used and adapted. Drawing on 43 peer-reviewed articles and gray literature sources retrieved through a narrative review, and 15 key informant interviews conducted using a snowball sampling approach, we identified 27 CATI or CATI-like experiences across 15 countries in Africa, Asia, the Caribbean, and Middle East between 2004 and 2024. Four delivery mechanisms were identified: CATI, pre-CATI, case-cluster, and health-facility-based interventions (HBI). Challenges to implementation included: delays in response; difficulty accessing populations; resource shortages to initiate, maintain, or scale up response; overwhelmed response capacity; limited skills and knowledge; low uptake and acceptance; weak coordination; poor reporting and monitoring; and sustainability concerns. Implementers adapted delivery to overcome challenges, particularly in outbreaks with high case-loads and in insecure and hard-to-reach contexts by ensuring readiness and early activation, strengthening local actors' capacity, optimizing resources, adjusting ring sizes, and prioritizing cases. Based on these results, we developed a practitioner-centered framework to optimize programmatic implementation through context-specific delivery mechanism and ultimately decrease cholera incidence
Portable devices for the diagnosis of glaucoma: a scoping review.
Get PDFBACKGROUND: Glaucoma is a leading cause of irreversible blindness worldwide. Early detection and continuous monitoring are essential to preventing vision loss, yet traditional diagnostic tools remain largely inaccessible in low-resource settings. PURPOSE: This scoping review aimed to map the existing evidence on the use of portable devices for the detection, diagnosis and monitoring of glaucoma. METHODS: We conducted a scoping review in accordance with the Joanna Briggs Institute Manual and Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews guidelines. A comprehensive search was performed across major databases to identify studies that evaluated handheld tonometers, portable fundus cameras and visual field testing devices. Data were extracted on study design, population characteristics, devices used, comparators and reported outcomes. RESULTS: A total of 216 studies published between 1975 and 2024 were included. Most studies (90.3%) were method agreement studies, primarily focused on intraocular pressure (IOP) devices. Only two studies evaluated all three glaucoma assessment domains (IOP, visual fields and fundus imaging). Most studies were conducted in high-income countries, with a smaller number from low- and middle-income countries. Despite variability in performance, many devices demonstrated acceptable agreement with gold standard methods and were assessed in a range of clinical and community settings. CONCLUSION: This review highlights the range and characteristics of portable glaucoma devices and their potential for enhancing access to diagnosis and monitoring, particularly in underserved settings. However, the predominance of method agreement studies and the limited integration of multimodal assessments point to gaps in the literature. Future research should focus on comprehensive diagnostic pathways using multiple portable tools and on expanding evaluations in low-resource settings to inform policy and service planning
Risk of Ischaemic Stroke Varies With Antithrombotic Drugs Use in Proton Pump Inhibitor Users: A Self-Controlled Case Series Study.
Get PDFBACKGROUND: The conflicting findings on the association between proton pump inhibitors (PPIs) and ischaemic stroke could be due to residual confounding. Self-controlled case series (SCCS) can be used to avoid time-invariant confounding. Additionally, different baseline risks of stroke should be considered, as some individuals may be prescribed PPIs for gastroprotection from bleeding with antithrombotic drugs.
METHODS: We identified adult patients with incident ischaemic stroke from 2003 to 2014 in Hong Kong and applied the modified SCCS. The exposure window was pre-defined as Days 1-30, 31-60, 61-90, and 91 to the prescription end, since the PPI prescription. All other periods were referent windows. We estimated incidence rate ratios (IRR) and stratified them further using antithrombotic drugs.
RESULTS: A total of 18 170 patients were included. The IRRs for ischaemic stroke were 1.55 (95% CI: 1.00-2.42) during days 61 to 90, 1.51 (95% CI: 1.14-2.00) during days 91 to end, versus the referent window. There was no evidence of an increased risk in other risk windows versus the referent windows. In the stratified analysis, we observed an increased risk in people co-prescribed PPIs with antithrombotic drugs in all risk periods, but no increased risks among those with PPI monotherapy versus the referent window.
CONCLUSION: No evidence of a higher ischaemic stroke after monotherapy of PPI use. The increased risk of ischaemic stroke associated with PPIs could be due to their high baseline risk prescribed with antithrombotic drugs for primary prevention. Clinical monitoring of ischaemic stroke is recommended in these people
Burden of pulmonary tuberculosis among Ethiopians seeking jobs in the Middle East: a retrospective study.
Get PDFBACKGROUND: Globally, pre-and post-migration TB screening are integral to controlling TB among migrants. Annually, approximately 300,000 Ethiopians migrate to the Middle East in search of job opportunities. But prior to their trip the migrants are randomly distributed by Wafid to 12 authorized clinics in Addis Ababa, for pre-migration medical screening for communicable diseases including Tuberculosis (TB), which is one of the main concerns and screened using chest X-ray (CXR). Based on the screening results, the job seekers are classified as Fit or Unfit to travel to the Middle East. This study aimed to estimate the prevalence of presumptive TB among Ethiopian Migrant Workers upon screening and identify the possible associated risk factors. METHOD: A retrospective cross-sectional study was conducted using data between June,2023 and June, 2025 collected from three clinics utilizing Sefed Software Systems database. Ethiopian Migrant Domestic Workers (MDWs) are randomly placed for pre-migration screening to these health facilities by the Ministry of Labor and Skills. The prevalence of presumptive TB was estimated using STATA software version 14. Logistic regression model was applied to determine associations between X-ray TB diagnosis and with socio-demographic and clinical variables. RESULTS: Among 233,941 individuals screened during the study period, 10, 342 (4.42%) were deemed Unfit to travel due to abnormal CXR findings. Significant associations were observed between TB-suspects based on X-rays and several variables. Using multivariable logistic regression analysis, religion (OR = 1.24; 95% CI: 1.19-1.28); marital status (OR = 0.88; 95% CI: 0.84-0.93), age (OR = 3.35; 95% CI: 2.70-4.15), hepatitis B (OR = 1.71; 95% CI: 1.48-1.97), syphilis (VDRL) (OR = 1.97; 95% CI: 1.63-2.37) and pregnancy (OR = 1.56, 95% CI = 1.34-1.81) showed statistically significant association with potential TB status with P < 0.05. HIV status showed marginal association (OR = 1.40; 95% CI: 0.91-2.14). CONCLUSION: This study revealed a relatively high prevalence of presumptive TB among Ethiopian (MDWs) seeking jobs in the Middle East. The X-ray results may not be confirmatory diagnosis for TB. Therefore, further investigation is required using other confirmatory methods such as Gene Xpert or TB culture. Linking medically unfit individuals to TB care is crucial to mitigate transmission risks based on the WHO recommendations
Systematic Review and Development of Recommended Code Lists to Identify Smoking and Vaping Status in Electronic Health Records (EHR).
Get PDFINTRODUCTION: Vaping and smoking are important health behaviours associated with many diseases. Evaluating the association of smoking and vaping with diseases using electronic health record (EHR) data requires accurate codelists to determine smoking and vaping status. However, codelists used in studies are not always published or consistent between studies. It is important to develop standard codelists for use in future studies, and transparency is required to ensure consistency and standardization. PURPOSE: To provide an overview of the codes used in both peer-reviewed scientific literature and codelist repositories to identify smoking and vaping status in EHRs and derive a recommended codelist for use in EHRs to identify smoking and vaping status. METHODS: Publications (MEDLINE, Embase, and Scopus) and codelist repositories (LSHTM Data Compass, OpenCodelists, and the HDR UK Phenotype Library) were searched from January 2010 to April 2024. All publications or codelist repositories with codes referring to smoking/vaping status were included in this review (search terms are further addressed in Supplementary Table 1). All codes were extracted to review the frequency and consistency between studies. RESULTS: There were 100 codelists across different coding systems: 55 codelists from publications and 45 codelists from codelist repository entries. For vaping status, there were 23 codelists identified, 7 from publications, and 16 from codelist repositories. Only 10% of publications included codelists. A limited number of ICD codes were used, and more were reported using the Read or SNOMED CT codes. The codelists we subsequently developed were based on those found in the review. CONCLUSION: Very few studies have reported the use of codelists despite smoking status being a widely used variable in many publications, and vaping status is increasing. Using the information from the review, we derived codelists for smoking and vaping using a transparent methodology that can be used in future studies
Rising dengue risk with increasing El Niño-Southern Oscillation amplitude and teleconnections.
Get PDFGlobal climate variability has been linked with some of the largest dengue outbreaks, including the record-breaking 2023-2024 epidemic, but the understanding of their mechanism and evidence for their association is lacking. By incorporating reported dengue cases and climate data from 57 countries across the Americas and Asia from 1980 to 2024, we unpacked the global climate teleconnection and quantifying its impact on dengue cases. We revealed that the heterogeneity in the association between global climate variability and dengue cases across regions is affected by the strength and types of global climate teleconnections with temperature and precipitation. By controlling for the heterogeneity, 63% of the variation in dengue cases can be attributed to El Niño-Southern Oscillation fluctuations, with higher values in endemic regions. The 1982-83, 1997-98, 2015-16, and 2023-24 El Niño events were estimated to have induced an additional 0.2, 1.4, 4.1, and 9.6 million dengue cases, respectively, over regular seasonal patterns. Due to human-induced warming, El Niño events and teleconnections may cause a 39.0-81.7% increase in cumulative cases in 2020-2099. Our findings quantify the association between global climate variability and dengue epidemics and caution about the potential future risk
Youth involvement in policy processes in public health, education, and social work-A scoping review.
Get PDFINTRODUCTION: Youth involvement in policy formulation may enhance its relevance, strengthen democratic practices, and contribute to youth development. This scoping review explored the nature, extent, and impact of adolescent involvement in policy processes aimed at improving adolescent health and well-being in the public health, education, and social work sectors. METHODS: Studies of adolescent involvement in policy processes focusing on health, and well-being, including obesity prevention were eligible. We searched seven databases, reference lists of included studies, and contacted key organizations. Standard scoping review methods were applied. The results were synthesized narratively, using descriptive statistics and visuals. RESULTS: We included 33 mostly qualitative studies, mainly from the public health sector in the USA and Europe, focusing on diet, physical activity, health & well-being, or sexual and reproductive health. Adolescents were consulted or collaborated with, mostly in identifying problems or policy solutions and less often in agenda-setting, decision-making, and evaluation. Various facilitators were used to improve participation (e.g. training, adult facilitators, monetary compensation). Data on adolescents' experiences of involvement and the impact on policies were limited. CONCLUSION: Due to a paucity of impact studies, we could not determine whether adolescent involvement increased the relevance of policies or improved adolescent development. The extent to which adolescents were meaningfully involved, and had a material effect on decision-making, was largely unclear. Improved documentation, monitoring, and evaluation of youth involvement in policy using quantitative methods and standardized frameworks, can improve the evidence-based, involvement practices, and decrease inequities
Vaccination strategies to achieve outbreak control for MPXV Clade I with a one-time mass campaign in sub-Saharan Africa: A scenario-based modelling study.
Get PDFBACKGROUND: Limited mpox vaccination coverage, declining cross-protection from historical smallpox vaccination campaigns, and persistent zoonotic reservoirs leave many sub-Saharan countries susceptible to mpox outbreaks. With millions of vaccine doses made available to the region since late 2024 and the absence of country-specific guidelines for allocation, estimating the country-specific impact of one-time mass vaccination strategies is necessary for ongoing outbreaks and other countries at future risk.
METHODS AND FINDINGS: We adapted a next generation matrix model to project disease transmission potential for 47 sub-Saharan countries from 2025 to 2050 under four transmission scenarios with different contributions of community versus sexual contacts. The model was informed by mpox datasets from Clade Ia and Ib outbreaks in the Democratic Republic of Congo (DRC), and incorporated country-specific demographics, contact patterns, and historical smallpox vaccination coverage. We then assessed strategies to reduce disease transmissibility by calculating country-specific minimum vaccine coverages and evaluating one-time, age-specific mass vaccination campaigns. At least 20 of the 47 countries are estimated to require vaccination in 2025, and 36 in 2050, to guard against potentially forthcoming national outbreaks. For 11 Clade I-affected countries, the minimum required coverage is estimated to range from 0%-4.8% to 14.5%-19.5% in 2025 with increasing sexual transmission, rising to 0%-10.8% and 22.6%-26.0% in 2050, respectively. The prioritised age group for vaccination shifts from 0-4 years to 20-29 years with additional sexual transmission. Note that all the projections were based on the best available evidence of Clade I transmission in the DRC as of December 2024.
INTERPRETATION: With diminishing smallpox-vaccination-induced immunity, increasing disease transmissibility and potential for persistent outbreaks are expected for mpox, necessitating growing vaccine demand for outbreak containment. Given probable supply constraints, our findings could guide the ongoing and future mass vaccination efforts in sub-Saharan Africa by emphasising the prioritisation of high-risk groups, where allocation strategies are tailored to the evolving epidemiological landscape of each country
Outcomes and level of evidence in radiation therapy research and different categories of radiotherapy innovations: an ESTRO-VBRO bibliometrics analysis of the literature.
Get PDFAIM: The ESTRO-Value-Based Radiation Oncology project aims to enhance patient access to high-value radiotherapy innovations, by identifying interventions delivering meaningful benefit. To understand the role of the quality of evidence in implementation decisions, this paper analyses the study designs and endpoints used to appraise selected types of radiotherapy innovations in the literature.
METHODS: This review used a quantitative bibliometric approach to analyse a representative set of 23 radiotherapy innovations, identified within the radiation therapy research published between 2012 and 2022 in the Web of Science database. Abstracts were searched manually to extract information about study designs and endpoints. Interventions were allocated into one of four defined radiotherapy categories, based on a decision algorithm developed in a parallel project.
RESULTS: 3,721 abstracts were identified and categorised using the decision algorithm into four categories: Drug-centred, Radiation-centred, Radiation-enabling or Operational radiotherapy interventions. The study designs were highly variable across these categories: in Drug-centred innovations, 20.3% were clinical trials compared to 6.8% for Radiation-centred. The predominant design across all categories was Prospective observational studies, ranging from 53.9% in Radiation-enabling to 23.0% in Drug-centred innovations. Regarding endpoints, the main focus for Drug-centred innovations was on Clinical endpoints and Overall survival. For Radiation-centred and Radiation-enabling innovations, Toxicity endpoints were more frequently reported.
CONCLUSION: This analysis demonstrates the differences in radiotherapy research output for various categories of radiotherapy interventions. This supports the development of a tailored appraisal strategy for each category, based on the required level of evidence and meaningful endpoints to support reimbursement and clinical implementation