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Syntheses of benzothiazole amidoximes and arylimidamides and evaluation of their ADME and DNA binding properties and activity against Trypanosoma brucei.
Get PDFNovel 6-amidoxime- and 6-arylimidamide-substituted benzothiazoles were synthesised to investigate their activity against Trypanosoma brucei, the causative agent of African trypanosomiasis. Benzothiazole amidoxime 12b, with diethylaminoethyl and fluorine substituents on a phenoxymethylene linker exhibited pronounced (IC50 = 0.92 μM) and selective (SI = 18) antitrypanosomal activity. ADME profiling showed that the majority of compounds synthesised are metabolically stable and that arylimidamides have low membrane permeability, while amidoximes, including 12b, have moderate to high permeability. Binding assays indicate that amidoxime 12b binds to DNA/RNA by intercalation, whereas arylimidamide 29b displays groove binding. 12b was found to be a substrate of the P-glycoprotein efflux pump, a factor that may have limited its activity in a murine model of infection, despite the other favourable properties. Structural diversification of aryl-substituted motif in amidoxime benzothiazole series will be explored to further optimize activity and ADME properties, and to overcome issues associated with low membrane permeability
Metrics for biodiversity and health policy integration.
Get PDFDespite over a decade of progressive commitments from parties to the Convention on Biological Diversity (CBD), integrated biodiversity and health indicators and monitoring mechanisms remain limited, hampering achievement of the sustainable development goals and improvements in health and well-being. Adoption of the Kunming-Montreal Global Biodiversity Framework (2022) and the Global Action Plan on Biodiversity and Health (2024) provide a renewed entry point to shape the way governments approach health and wellbeing and address the environmental burden of disease. This is a critical opportunity that scholars at the health-environment nexus should not miss. This Perspective outlines building blocks to mobilize the field, starting with essential terminology and a scope of metrics needed by governments. We then evaluate elements to be considered in the construction of integrated metrics, including concepts, overarching challenges, a review of scientific hypotheses from an ecological perspective, as well as a set of principles and characteristics for indicators. To raise awareness across parallel communities of practice working at the health-environment nexus, we then briefly examine four approaches to integrated metrics developed by: conservationists, Indigenous scholars, One Health experts, and planetary health experts. We conclude with actionable steps to enhance governance, mobilize funding, and apply integrated indicators in national and global strategies. A broad science community is needed to support national governments to meet global commitments to address biodiversity loss and the environmental burden of disease concurrently. The overall aim of this paper is to contribute to addressing biodiversity loss by effectively linking policy and transdisciplinary practice at the health-environment nexus
Characterisation of chikungunya virus neutralising monoclonal antibodies expressed in tobacco plants.
Get PDFChikungunya virus (CHIKV) causes a debilitating musculoskeletal disease, characterised by flu-like symptoms, rash, and severe joint pain, which can last for months, even after the resolution of infection. Although the first CHIKV vaccine was approved in the USA in 2023 for use in adults, there is currently no specific antiviral therapy for infection. While neutralising antibody-based prophylactic and therapeutic agents have been considered, affordability and accessibility are major barriers to global regions where Chikungunya disease is epidemic. Here, we expressed five anti-CHIKV neutralising IgG monoclonal antibodies (mAbs) in N. benthamiana plants to investigate the potential use of this manufacturing platform. Plants produced IgG mAbs that compared favourably to mammalian cell-expressed antibodies, including for binding kinetics to CHIKV antigens and neutralisation activity. The yields of mAbs from plants were variable, as three of the antibodies' yields would need further expression optimisation to warrant future development. The successful expression of these antibodies in N. benthamiana plants supports the growing pipeline of Global Health product targets that could be developed using a highly transferable, low-cost, low-tech plant production platform in resource-poor countries
Mapping Community Vulnerability to reduced Vaccine Impact in Uganda and Kenya: A spatial Data-driven Approach.
Get PDFBACKGROUND: Despite global efforts to improve on vaccine impact, many African countries have failed to achieve equitable vaccine benefits. Reduced vaccine impact may result from interplay between structural, social, and biological factors, that limit communities from fully benefiting from vaccination programs. However, the combined influence of these factors to reduced vaccine impact and the spatial distribution of vulnerable communities remains poorly understood. We developed a Community Vaccine Impact Vulnerability Index (CVIVI) that integrates data on multiple risk factors associated with reduced vaccine impact, to identify communities at risk, and key drivers of vulnerability. METHODS: The index was constructed using 17 indicators selected through literature review and categorised into structural, social, and biological domains. Secondary data was obtained from national Demographic and Health surveys from Uganda (2016) and Kenya (2022), covering 123 districts and 47 counties, respectively. Percentile rank methodology was used to construct domain-specific and overall vulnerability indices.. Geo-spatial techniques were used to classify and map districts/counties from least to most vulnerable. RESULTS: We observed distinct geographical patterns in vulnerability.. In Kenya, the most vulnerable counties were clustered in the northeast and eastern counties such as Turkana, Mandera, and West Polot. In Uganda, vulnerability was more dispersed, with the most vulnerable districts in the northeast (e.g. Amudat, Lamwo) and southwest e.g. Buliisa,Kyenjojo). Key drivers of vulnerability included long distance to health facilities, low maternal education, poverty, malnutrition, limited access to postnatal care, and limited access to mass media. Some areas with high vaccine coverage also showed high vulnerability, suggesting coverage data may not reliably reflect vaccine impact. Each community showed a unique vulnerability profile, shaped by different combinations of social, structural and biological factors, highlighting the need for context specific interventions. CONCLUSIONS: The CVIVI is a useful tool for identifying vulnerable communities and underlying factors. It can guide the design of tailored strategies to improve vaccine impact in vulnerable settings
Implications of reference equations for interpretation of spirometry in three African countries: a cross-sectional study.
Get PDFBACKGROUND: The Global Lung Function Initiative (GLI) and American Thoracic Society recently endorsed a race-composite spirometry reference equation ("GLI Global"). Africa (outside North Africa) is not represented in the underlying dataset; GLI Global has not been evaluated in the region. We evaluated the fit and diagnostic implications of GLI and African (identified by scoping review) reference equations in three East/Southern African countries. METHODS: Among healthy participants from a tuberculosis household contact cohort study in Mozambique, Tanzania and Zimbabwe (age ≥10 years) with post-bronchodilator spirometry we calculated forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC z-scores using different equations, the proportion of people with obstructive airways disease or preserved-ratio-impaired spirometry by different equations. We compared these measures across reference equations. RESULTS: In total, 806 healthy people had good-quality post-bronchodilator spirometry. Across GLI equations, "African American" fitted best (mean±sd FEV1 z-score -0.12±1.20, mean FVC z-score -0.35±1.19). Compared with "African American", GLI Global resulted in twice as many people being identified as having preserved-ratio impaired spirometry (22% versus 11%) with a similar proportion having obstruction (4.2% versus 3.8%). Reference equations developed in Africa conferred similar fit compared with the GLI African American equation. CONCLUSIONS: Reference equations have clinical and public health implications that demand careful consideration, particularly in resource-constrained environments. Use of GLI Global may result more people being identified as having lung function impairment. Further work that includes clinical outcomes is needed to ensure that GLI Global is globally representative. The key limitation of this work is the potential for people with undiagnosed respiratory disease to have been included in the analysis
Effectiveness of peer support for people with severe mental health conditions in high-, middle- and low-income countries: multicentre randomised controlled trial.
Get PDFBACKGROUND: Some trials have evaluated peer support for people with mental ill health in high-income, mainly English-speaking countries, but the quality of the evidence is weak. AIMS: To investigate the effectiveness of UPSIDES peer support in high-, middle- and low-income countries. METHOD: This pragmatic multicentre parallel-group wait-list randomised controlled trial (registration: ISRCTN26008944) with three measurement points (baseline and 4 and 8 months) took place at six study sites: two in Germany, and one each in Uganda, Tanzania, Israel and India. Participants were adults with long-standing severe mental health conditions. Outcomes were improvements in social inclusion (primary) and empowerment, hope, recovery, health and social functioning (secondary). Participants allocated to the intervention group were offered UPSIDES peer support. RESULTS: Of the 615 participants (305 intervention group), 337 (54.8%) identified as women. The average age was 38.3 (s.d. = 11.2) years, and the mean illness duration was 14.9 (s.d. = 38.4) years. Those allocated to the intervention group received 6.9 (s.d. = 4.2) peer support sessions on average. Intention-to-treat analysis showed effects on two of the three subscales of the Social Inclusion Scale, Empowerment Scale and HOPE Scale. Per-protocol analysis with participants who had received three or more intervention sessions also showed an effect on the Social Inclusion Scale total score (β = 0.18, P = 0.031, 95% CI: 0.02-0.34). CONCLUSIONS: Peer support has beneficial impacts on social inclusion, empowerment and hope among people with severe mental health conditions across diverse settings. As social isolation is a key driver of mental ill health, and empowerment and hope are both crucial for recovery, peer support can be recommended as an effective component of mental healthcare. Peer support has the potential to move global mental health closer towards a recovery- and rights-based orientation
The ethics of data mining in healthcare: challenges, frameworks, and future directions.
Get PDFData mining in healthcare offers transformative insights yet surfaces multilayered ethical and governance challenges that extend beyond privacy alone. Privacy and consent concerns remain paramount when handling sensitive medical data, particularly as healthcare organizations increasingly share patient information with large digital platforms. The risks of data breaches and unauthorized access are stark: 725 reportable incidents in 2023 alone exposed more than 133 million patient records, and hacking-related breaches surged by 239% since 2018. Algorithmic bias further threatens equity; models trained on historically prejudiced data can reinforce health disparities across protected groups. Therefore, transparency must span three levels-dataset documentation, model interpretability, and post-deployment audit logging-to make algorithmic reasoning and failures traceable. Security vulnerabilities in the Internet of Medical Things (IoMT) and cloud-based health platforms amplify these risks, while corporate data-sharing deals complicate questions of data ownership and patient autonomy. A comprehensive response requires (i) dataset-level artifacts such as "datasheets," (ii) model-cards that disclose fairness metrics, and (iii) continuous logging of predictions and LIME/SHAP explanations for independent audits. Technical safeguards must blend differential privacy (with empirically validated noise budgets), homomorphic encryption for high-value queries, and federated learning to maintain the locality of raw data. Governance frameworks must also mandate routine bias and robust audits and harmonized penalties for non-compliance. Regular reassessments, thorough documentation, and active engagement with clinicians, patients, and regulators are critical to accountability. This paper synthesizes current evidence, from a 2019 European re-identification study demonstrating 99.98% uniqueness with 15 quasi-identifiers to recent clinical audits that trimmed false-negative rates via threshold recalibration, and proposes an integrated set of fairness, privacy, and security controls aligned with SPIRIT-AI, CONSORT-AI, and emerging PROBAST-AI guidelines. Implementing these solutions will help healthcare systems harness the benefits of data mining while safeguarding patient rights and sustaining public trust
A clinical rule-based indicator to identify recurrence of colorectal cancer after curative resection using linked routinely collected national data.
Get PDFBACKGROUND: Cancer recurrence is under-recorded in most national cancer registries. We developed and validated a clinical rule-based indicator to identify recurrence after curative major resection in patients with non-metastatic colorectal cancer (CRC), based on national routinely collected administrative hospital records and chemotherapy and radiotherapy datasets. METHODS: Recurrence was defined as the cancer becoming clinically detectable again after a period of "remission" (nine months to five years after curative major resection). 34,984 CRC patients aged 18-75 years undergoing curative major resection for non-metastatic disease diagnosed between August 2014 and September 2019 in the English Cancer Registry were identified and linked to records of outpatient visits and admissions in English administrative hospital data and to chemotherapy and radiotherapy datasets. The indicator was developed with a panel of surgical and oncological experts, based on relevant diagnosis (ICD-10), procedure (OPCS-4), and administrative codes. RESULTS: Of the 34,984 patients, the indicator identified 6556 (18.7 %) as having recurrence. 6173 (94.2 %) of which could be identified using administrative hospital data of admitted patients alone. Recurrence was found in a greater proportion of rectal cancer patients, and in those with more advanced T stage and N stage, and higher cancer grade. Overall and recurrence-free five-year survival from surgery was 88.7 % and 77.4 %, respectively. Two-year overall survival after recurrence was 63.9 %. 135 (82.8 %) of the 163 patients who self-reported recurrence in a national patient experience survey, and 1412 (95.2 %) of the 1483 patients with reported recurrence/progression in Cancer Registry data had recurrence defined by the developed indicator. CONCLUSIONS: The validity of the CRC recurrence indicator was supported by observed associations with tumour characteristics, self-reported recurrence, and poor overall survival in patients with recurrence. This indicator can be used in research and service evaluation, to overcome the problem of incomplete cancer recurrence recording in most national cancer registries
Concurrent Alcohol Use and the Relative Risk of Community-Acquired Pneumonia Associated With Anticholinergic and Non-Anticholinergic Neurocognitively Active Medication Receipt: A National Nested Case-Control Study Among US Veterans.
Get PDFPURPOSE: Anticholinergic medications and alcohol each independently increase the risk of community-acquired pneumonia (CAP). Whether non-anticholinergic neurocognitively active medications also increase risk, and if alcohol modifies these associations, remains unclear. METHODS: We conducted a nested case-control study using Veterans Aging Cohort Study (VACS)-National data. We identified 157 185 incident CAP cases requiring hospitalization between 2010 and 2022. Cases were matched 1:5 to controls without CAP on demographics, cohort entry date, and dwell time in the underlying cohort study using incidence density (risk-set) sampling. CAP index date was hospital admission for cases and the equivalent follow-up date for controls. Primary exposures were receipt of anticholinergic and non-anticholinergic neurocognitively active medications within 90 days prior to the index date. Concurrent alcohol use was based on self-reported measures in the year prior to the index date. We estimated odds ratios (ORs) for associations between medication use, alcohol consumption, and CAP using logistic regression, adjusting for confounders. RESULTS: Median age was 69 years (interquartile range 62-78); 97% were male. Both medication types were independently associated with increased odds of CAP (anticholinergic: OR 1.62, 95% CI 1.57-1.67; non-anticholinergic: OR 1.61, 95% CI 1.57-1.66). Concurrent alcohol use modified these associations. For anticholinergics, ORs were 1.74 (95% CI 1.66-1.83) for at-risk consumption and 2.13 (95% CI 1.96-2.31) for hazardous/binge consumption. For non-anticholinergics, ORs were 1.74 (95% CI 1.67-1.81) and 2.20 (95% CI 2.06-2.34), respectively. CONCLUSIONS: Non-anticholinergic neurocognitively active medications showed similar CAP association patterns as anticholinergics, with the highest odds among those consuming alcohol. These findings highlight the need for caution when prescribing these medications and incorporating alcohol use into risk-benefit assessments
Priority climate and health modelling needs.
No full textClimate and health modelling is necessary for improving understanding of the current and future distribution and timing of climate-related health risks. However, underinvestment in this area has limited the understanding required to inform policies that enable multisectoral interventions to safeguard health. We synthesised insights from a survey of 65 global climate and health modelling experts and 36 participants in a hybrid meeting to identify priority strategies for enhancing the validity, utility, and policy relevance of climate and health models. Foundational investments to support modelling included strengthening research capacity, establishing a network of multinational centres of excellence for transdisciplinary research and capacity building, improving data collection and sharing infrastructure, investing in scenario development and quantitative elaboration, assessing adaptation effectiveness, and committing to intermodel comparisons and interdisciplinary modelling activities. Specific recommendations included updating the 2014 WHO Quantitative Risk Assessment to cover a wider range of causal pathways and health endpoints, using interdisciplinary methods that facilitate model intercomparisons. Additional recommendations included supporting modelling of a broader set of climate-health outcomes, developing models to support early warning systems and investments in their implementation, evaluation, and maintenance, and improving health system capacity for modelling in low-resource settings