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Abstract The efficacy of anthracycline-based chemotherapeutics, which include doxorubicin and its structural relatives daunorubicin and idarubicin, remains almost unmatched in oncology, despite a side effect profile including cumulative dose-dependent cardiotoxicity, therapy-related malignancies and infertility. Detoxifying anthracyclines while preserving their anti-neoplastic effects is arguably a major unmet need in modern oncology, as cardiovascular complications that limit anti-cancer treatment are a leading cause of morbidity and mortality among the 17 million cancer survivors in the U.S. In this study, we examined different clinically relevant anthracycline drugs for a series of features including mode of action (chromatin and DNA damage), bio-distribution, anti-tumor efficacy and cardiotoxicity in pre-clinical models and patients. The different anthracycline drugs have surprisingly individual efficacy and toxicity profiles. In particular, aclarubicin stands out in pre-clinical models and clinical studies, as it potently kills cancer cells, lacks cardiotoxicity, and can be safely administered even after the maximum cumulative dose of either doxorubicin or idarubicin has been reached. Retrospective analysis of aclarubicin used as second-line treatment for relapsed/refractory AML patients showed survival effects similar to its use in first line, leading to a notable 23% increase in 5-year overall survival compared to other intensive chemotherapies. Considering individual anthracyclines as distinct entities unveils new treatment options, such as the identification of aclarubicin, which significantly improves the survival outcomes of AML patients while mitigating the treatment-limiting side-effects. Building upon these findings, an international multicenter Phase III prospective study is prepared, to integrate aclarubicin into the treatment of relapsed/refractory AML patients.

Abstract Background Procedural sedation and analgesia (PSA) is a technique of administering sedatives to induce a state that allows the patient to tolerate painful procedures while maintaining cardiorespiratory function, a condition that is frequently desired prehospital. Non-physician prehospital clinicians often have a limited scope of practice when it comes to providing analgesia and sedation; sometimes resulting in a crew request for back-up from physician-staffed prehospital services.“. This is also the case if sedation is desirable. Advanced practice providers (APPs), who are legally authorized and trained to carry out this procedure, may be a solution when the physician-staffed service is not available or will not be available in time. Methods The aim of this study is to gain insight in the circumstances in which an APP, working at the Dutch ambulance service “RAV Brabant MWN” from January 2019 to December 2022, uses propofol for PSA or to provide sedation. With this a retrospective observational document study we describe the characteristics of patients and ambulance runs and evaluates the interventions in terms of safety. Results During the study period, the APPs administered propofol 157 times for 135 PSA and in 22 cases for providing sedation. The most common indication was musculoskeletal trauma such as fracture care or the reduction of joint dislocation. In 91% of the situations where propofol was used, the predetermined goal e.g. alignment of fractured extremity, repositioning of luxated joint or providing sedation the goal was achieved. There were 12 cases in which one or more adverse events were documented and all were successfully resolved by the APP. There were no cases of laryngospam, airway obstruction, nor anaphylaxis. None of the adverse events led to unexpected hospitalization or death. Conclusion During the study period, the APPs performed 135 PSAs and provided 22 sedations. The success rate of predetermined goals was higher than that stated in the literature. Although there were a number of side effects, their incidences were lower than those reported in the literature, and these were resolved by the APP during the episode of care. Applying a PSA by an APP at the EMS “RAV Brabant MWN” appears to be safe with a high success rate.

Abstract Background For most acute conditions, the phase prior to emergency department (ED) arrival is largely unexplored. However, this prehospital phase has proven an important part of the acute care chain (ACC) for specific time-sensitive conditions, such as stroke and myocardial infarction. For patients with undifferentiated complaints, exploration of the prehospital phase of the ACC may also offer a window of opportunity for improvement of care. This study aims to explore the ACC of ED patients with undifferentiated complaints, with specific emphasis on time in ACC and patient experience. Methods This Dutch prospective observational study, included all adult (≥ 18 years) ED patients with undifferentiated complaints over a 4-week period. We investigated the patients’ journey through the ACC, focusing on time in ACC and patient experience. Additionally, a multivariable linear regression analysis was employed to identify factors independently associated with time in ACC. Results Among the 286 ED patients with undifferentiated complaints, the median symptom duration prior to ED visit was 6 days (IQR 2–10), during which 58.6% of patients had contact with a healthcare provider before referral. General Practitioners (GPs) referred 80.4% of the patients, with the predominant patient journey (51.7%) involving GP referral followed by self-transportation to the ED. The median time in ACC was 5.5 (IQR 4.0-8.4) hours of which 40% was spent before the ED visit. GP referral and referral to pulmonology were associated with a longer time in ACC, while referral during evenings was associated with a shorter time in ACC. Patients scored both quality and duration of the provided care an 8/10. Conclusion Dutch ED patients with undifferentiated complaints consulted a healthcare provider in over half of the cases before their ED visit. The median time in ACC is 5.5 h of which 40% is spent in the prehospital phase. Those referred by a GP and to pulmonology had a longer, and those in the evening a shorter time in ACC. The acute care journey starts hours before patients arrive at the ED and 6 days of complaints precede this journey. This timeframe could serve as a window of opportunity to optimise care.

Abstract Background Providing individualised healthcare in line with patient wishes is a particular challenge for emergency healthcare professionals. Documentation of patient wishes (DPW), e.g. as advance directives, can guide clinicians in making end-of-life decisions that respect the patient’s wishes and autonomy. However, patient centered decisions are hindered by limited availability of DPWs in emergency settings. Objective This systematic review aims to congregate present data on recorded rates for DPW existence and availability in the emergency department (ED) as well as contributing factors for these rates. Methods We searched MEDLINE, Google Scholar, Embase and Web of Science databases in September 2023. Publications providing primary quantitative data on DPW in the ED were assessed. Publications referring only to a subset of ED patients (other than geriatric) and investigating DPW issued after admission were excluded. Results A total of 22 studies from 1996 to 2021 were included in the analysis. Most were from the US (n = 12), followed by Australia (n = 4), Canada (n = 2), South Korea, Germany, the United Kingdom and Switzerland (n = 1 each). In the general adult population presenting to the ED, 19.9–27.8% of patients reported having some form of DPW, but only in 6.8% or less it was available on presentation. In the geriatric population, DPW rates (2.6–79%) as well as their availability (1.1–48.8%) varied widely. The following variables were identified as positive predictors of having DPW, among others: higher age, poorer overall health, as well as sociodemographic factors, such as female gender, having children, being in a relationship, higher level of education or a recent previous presentation to hospital. Conclusions Existence and availability of a recorded DPW among ED patients was low in general and even in geriatric populations mostly well below 50%. While we were able to gather data on prevalence and predictors, this was limited by heterogeneous data. We believe further research is needed to explore the quality of DPW and measures to increase both rates of existence and availability of DPW in the ED.

Abstract Background The global increase in mean body mass index has resulted in a substantial increase of non-communicable diseases (NCDs), including in many low- and middle-income countries such as Kenya. This paper assesses four interventions for the prevention and control of overweight and obesity in Kenya to determine their potential health and economic impact and cost effectiveness. Methods We reviewed the literature to identify evidence of effect, determine the intervention costs, disease costs and total healthcare costs. We used a proportional multistate life table model to quantify the potential impacts on health conditions and healthcare costs, modelling the 2019 Kenya population over their remaining lifetime. Considering a health system perspective, two interventions were assessed for cost-effectiveness. In addition, we used the Human Capital Approach to estimate productivity gains. Results Over the lifetime of the 2019 population, impacts were estimated at 203,266 health-adjusted life years (HALYs) (95% uncertainty interval [UI] 163,752 − 249,621) for a 20% tax on sugar-sweetened beverages, 151,718 HALYs (95% UI 55,257 − 250,412) for mandatory kilojoule menu labelling, 3.7 million HALYs (95% UI 2,661,365–4,789,915) for a change in consumption levels related to supermarket food purchase patterns and 13.1 million HALYs (95% UI 11,404,317 − 15,152,341) for a change in national consumption back to the 1975 average levels of energy intake. This translates to 4, 3, 73 and 261 HALYs per 1,000 persons. Lifetime healthcare cost savings were approximately United States Dollar (USD) 0.14 billion (USD 3 per capita), USD 0.08 billion (USD 2 per capita), USD 1.9 billion (USD 38 per capita) and USD 6.2 billion (USD 124 per capita), respectively. Lifetime productivity gains were approximately USD 1.8 billion, USD 1.2 billion, USD 28 billion and USD 92 billion. Both the 20% tax on sugar sweetened beverages and the mandatory kilojoule menu labelling were assessed for cost effectiveness and found dominant (health promoting and cost-saving). Conclusion All interventions evaluated yielded substantive health gains and economic benefits and should be considered for implementation in Kenya.

Abstract Background The majority of patients with recurrent or metastasized head and neck squamous cell carcinoma (HNSCC) do not benefit from immune checkpoint blockade (ICB) while several patients experience severe and persistent immune-mediated side effects. Therefore, predictive biomarkers are urgently needed to allow for a personalized treatment. In this study, we investigated DNA methylation of the immune checkpoint gene CTLA4 with regard to its predictive value. Methods We analyzed CTLA4 promoter methylation in tumors of HNSCC patients (N = 29) treated with ICB at the University Medical Center Bonn with regard to response to ICB and progression-free survival. We further analyzed a second cohort (N = 138) of patients that did not receive ICB with regard to CTLA4 promoter methylation, CTLA-4 protein expression, and immune cell infiltrates. Finally, we tested inducibility of CTLA-4 protein expression in HNSCC cells using the DNA methyltransferase inhibitor decitabine. Results Lower CTLA4 promoter methylation correlated with response to ICB and prolonged progression-free survival. We could show that not only tumor infiltrating immune cells, but also HNSCC cells harbor cytoplasmic and nuclear CTLA-4 expression. CTLA4 promoter methylation inversely correlated with infiltrates of CD3+, CD4+, CD8+, and CD45+ immune cells. CTLA4 methylation did not correlate with protein expression in tumors, however, decitabine treatment led to decreased CTLA4 methylation and an induction of CTLA4 mRNA and CTLA-4 protein expression in HNSCC cell lines. Conclusions Our results indicate that CTLA4 DNA hypomethylation is a predictive biomarker for response to ICB in HNSCC. Our study warrants further analyses of the predictive value of CTLA4 DNA methylation in clinical trials of anti-PD-1 and/or anti-CTLA-4 immunotherapy in HNSCC.

Abstract Introduction As a high-quality TUR-BT is important to ensure adequate treatment for bladder cancer patients, the aim of the current study is to investigate the impact of patient-related, surgical and tumor-specific parameters on detrusor muscle (DM) absence (primary objective) and to assess the impact of DM on the prognosis after a TUR-BT (secondary objective). Patients and methods Transurethral resection of bladder tumors (TUR-BTs) between 2009 and 2021 were retrospectively screened (n = 3237). We included 2058 cases (1472 patients) for the primary and 472 patients for secondary objective. Clinicopathological variables including tumor size, localization, multifocality, configuration, operation time and skill-level of the urologist were assessed. We analyzed predictors for missing DM and prognostic factors for recurrence-free survival (RFS) for the complete cohort and subgroups. Results DM was present in 67.6% (n = 1371/2058). Surgery duration (continuous, minutes) was an independent predictor for absence of DM in the complete cohort (OR:0.98, r:0.012, 95%CI:0.98–0.99, p = 0.001). Other significant risk factors for missing DM were papillary tumors (OR:1.99, r:0.251, 95%CI:1.22–3.27, p = 0.006) in the complete cohort and bladder-roof and posterior-bladder-wall localization for re-resections. Absence of DM in high-grade BC correlated with reduced RFS (HR:1.96, 95%CI:1.0–3.79, p = 0.045). Conclusion Sufficient time for a TUR-BT is mandatory to assure DM in the TUR-BT specimen. Also, cases with more difficult locations of bladder tumors should be performed with utmost surgical diligence and endourological training should incorporate how to perform such operations. Of note, DM correlates with improved oncological prognosis in high-grade BC.

Abstract Background Although some jurisdictions have implemented particular adjustments to accommodate often-expensive orphan drugs in their healthcare systems, availability of these drugs remains complex. This study investigates alternative financing models and early access schemes for orphan drugs in the context of the Belgian healthcare system. Methods Three focus group discussions were held with a panel of eleven experts from the Belgian Drug Reimbursement Committee, the Colleges for Orphan Drugs, the pharmaceutical industry, physicians, ethicists and pharmacists. Retrieved data were pseudonymised, analysed and coded according to the Qualitative Analysis Guide of Leuven. Results Experts disfavoured the insulated fund as well as private insurance for financing orphan drugs, as, respectively, isolation of a separate budget and a mostly profit-driven mechanism would contradict the Belgian fundamental principle of solidarity. Moreover, an insulated fund could, albeit on a smaller scale, reproduce the same budgetary constraints as the general reimbursement system. As the Special Solidarity Fund is intended for urgent care and exclusively accommodates financial needs subject to eligibility criteria, its design would not allow general financing of orphan drugs. Overall, implementation of an alternative financing model was not endorsed, instead, improving the current reimbursement system was preferred. Suggestions mentioned were; increased collaboration and transparency, robust and quality real-world evidence but also digitalization of data. Alleviating administrative burden and simplifying the admission process of compassionate use program, medical need program and early treatment reimbursement should be prioritized to facilitate early access. Furthermore, a legal framework for off-label use could stimulate proper implementation. Efforts on collaboration of expertise centres and coordination of orphan drug databases across Europe could foster a robust data network to support orphan drug availability in individual countries. Conclusions This research reveals that reassessing current financing models and early access schemes by eliminating inadequacies, may be more conducive than establishing alternative systems to increase availability of orphan drugs in Belgium. Other jurisdictions may rely on this information to review their own models of early access and financing to cultivate a more sustainable delivery of orphan drugs.

Abstract Background Rifampicin-resistant tuberculosis (RR-TB) remains an important global health problem. Ideally, the complete drug-resistance profile guides individualized treatment for all RR-TB patients, but this is only practised in high-income countries. Implementation of whole genome sequencing (WGS) technologies into routine care in low and middle-income countries has not become a reality due to the expected implementation challenges, including translating WGS results into individualized treatment regimen composition. Methods This trial is a pragmatic, single-blinded, randomized controlled medical device trial of a WGS-guided automated treatment recommendation strategy for individualized treatment of RR-TB. Subjects are 18 years or older and diagnosed with pulmonary RR-TB in four of the five health districts of the Free State province in South Africa. Participants are randomized in a 1:1 ratio to either the intervention (a WGS-guided automated treatment recommendation strategy for individualized treatment of RR-TB) or control (RR-TB treatment according to the national South African guidelines). The primary effectiveness outcome is the bacteriological response to treatment measured as the rate of change in time to liquid culture positivity during the first 6 months of treatment. Secondary effectiveness outcomes include cure rate, relapse rate (recurrence of RR-TB disease) and TB free survival rate in the first 12 months following RR-TB treatment completion. Additional secondary outcomes of interest include safety, the feasibility of province-wide implementation of the strategy into routine care, and health economic assessment from a patient and health systems perspective. Discussion This trial will provide important real-life evidence regarding the feasibility, safety, cost, and effectiveness of a WGS-guided automated treatment recommendation strategy for individualized treatment of RR-TB. Given the pragmatic nature, the trial will assist policymakers in the decision-making regarding the integration of next-generation sequencing technologies into routine RR-TB care in high TB burden settings. Trial registration ClinicalTrials.gov NCT05017324. Registered on August 23, 2021.

Abstract Background Quests for the global elimination of cervical cancer and its related SDG goals by 2030 are achievable if realistic approaches for improving outcomes in LMICs are entrenched. Targeting teenage high schoolers in these countries, which largely lack universally-affordable anti-cervical cancer measures, can be a game-changer. This paper evaluates a 2019 Harvard-endorsed measure that integrated relevant teachings into the curricula of some Nigerian high schools, in what was a global-first. Method A 12-month, quasi-experimental (pre-and-post-tests) research that evaluated the impact of the above initiative on three public schools randomly selected from a pool of 261 in South-east Nigeria. The intervention was “exposure” to anti-cervical teachings, which included “repetitions” and “examination/assessments” designed to enhance “engagement”. Both genders were among the 2,498 recruited participants. Data collections with questionnaires were at three different intervals over 12 months. Results At Phase-1 (baseline), there were 1,699 (68.0%) responses, while Phases 2 (one-month post-intervention) and 4 (12-month post-intervention) had 1,797 (71.9%) and 500 (20.0%) responses, respectively. COVID-19 lockdowns washed out Phase-3 (six-month post-intervention). The majority in all groups were aged 15–19 years. Males dominated in phases 1 (55.9%) and 2 (67.3%), and females (65.6%) in Phase 4. Overall, there were increased knowledge on “General Awareness”, “HPV Vaccinations”, “Risk Factors” and “Symptoms”, particularly between Phases 2 and 1. Levels at Phase-4 were higher than at Phase-2, with the exception of “Pap Smears”, as knowledge gained in half of its assessing items became negative (reversed) at Phase-4. These observed changes were non-different between gender, age groups, and classes of high schools. Relative to Phase 2, knowledge changes at Phase-4 for questions associated with established myths (“spiritual attacks”; OR 0.39; CI 0.29–0.52 and “enemy poisons”; OR 0.49; CI 0.37–0.65) were reversed, even though they were originally increased significantly between Phases 2 and 1. Conclusion Anti-cervical cancer enlightenment interventions to teenage high school students were largely effective, but appears guaranteed if engagement-enhancing measures are maintained over time. Extra efforts should be put into debunking prevailing myths.

Abstract Background Personalized medicine tailors care based on the patient’s or pathogen’s genotypic and phenotypic characteristics. An automated Clinical Decision Support System (CDSS) could help translate the genotypic and phenotypic characteristics into optimal treatment and thus facilitate implementation of individualized treatment by less experienced physicians. Methods We developed a hybrid knowledge- and data-driven treatment recommender CDSS. Stakeholders and experts first define the knowledge base by identifying and quantifying drug and regimen features for the prototype model input. In an iterative manner, feedback from experts is harvested to generate model training datasets, machine learning methods are applied to identify complex relations and patterns in the data, and model performance is assessed by estimating the precision at one, mean reciprocal rank and mean average precision. Once the model performance no longer iteratively increases, a validation dataset is used to assess model overfitting. Results We applied the novel methodology to develop a treatment recommender CDSS for individualized treatment of drug resistant tuberculosis as a proof of concept. Using input from stakeholders and three rounds of expert feedback on a dataset of 355 patients with 129 unique drug resistance profiles, the model had a 95% precision at 1 indicating that the highest ranked treatment regimen was considered appropriate by the experts in 95% of cases. Use of a validation data set however suggested substantial model overfitting, with a reduction in precision at 1 to 78%. Conclusion Our novel and flexible hybrid knowledge- and data-driven treatment recommender CDSS is a first step towards the automation of individualized treatment for personalized medicine. Further research should assess its value in fields other than drug resistant tuberculosis, develop solid statistical approaches to assess model performance, and evaluate their accuracy in real-life clinical settings.

Abstract Background Australian governments are increasingly mandating the use of cost–benefit analysis (CBA) to inform the efficient allocation of government resources. CBA is likely to be useful when evaluating preventive health interventions that are often cross-sectoral in nature and require Cabinet approval prior to implementation. This study outlines a CBA framework for the evaluation of preventive health interventions that balances the need for consistency with other agency guidelines whilst adhering to guidelines and conventions for health economic evaluations. Methods We analysed CBA and other evaluation guidance documents published by Australian federal and New South Wales (NSW) government departments. Data extraction compared the recommendations made by different agencies and the impact on the analysis of preventive health interventions. The framework specifies a reference case and sensitivity analyses based on the following considerations: (1) applied economic evaluation theory; (2) consistency between CBA across different government departments; (3) the ease of moving from a CBA to a more conventional cost-effectiveness/cost-utility analysis framework often used for health interventions; (4) the practicalities of application; and (5) the needs of end users being both Cabinet decision-makers and health policy-makers. Results Nine documents provided CBA or relevant economic evaluation guidance. There were differences in terminology and areas of agreement and disagreement between the guidelines. Disagreement between guidelines involved (1) the community included in the societal perspective; (2) the number of options that should be appraised in ex ante analyses; (3) the appropriate time horizon for interventions with longer economic lives; (4) the theoretical basis and value of the discount rate; (5) parameter values for variables such as the value of a statistical life; and (6) the summary measure for decision-making. Conclusions This paper addresses some of the methodological challenges that have hindered the use of CBA in prevention by outlining a framework that is consistent with treasury department guidelines whilst considering the unique features of prevention policies. The effective use and implementation of a preventive health CBA framework is likely to require considerable investment of time and resources from state and federal government departments of health and treasury but has the potential to improve decision-making related to preventive health policies and programmes.

Abstract Background This study was done as part of a larger study that aims to identify the most impactful and cost-effective strategies for the prevention and control of overweight and obesity in Kenya. Our objective was to involve stakeholders in the identification of the strategies that would be included in our larger study. The results from the stakeholder engagement are analyzed and reported in this paper. Design This was a qualitative study. A one-day stakeholder workshop that followed a deliberative dialogue process was conducted. Participants A sample of stakeholders who participate in the national level policymaking process for health in Kenya. Outcome measure Strategies for the prevention and control of overweight and obesity in Kenya. Results Out of the twenty-three stakeholders who confirmed attendance, fifteen participants attended the one-day workshop. The stakeholders identified a total of 24 strategies for the prevention and control of overweight and obesity in Kenya. From the ranking process carried out the top six strategies identified were: a research-based strategy for the identification of the nutritional value of indigenous foods, implementation of health promotion strategies that focus on the creation of healthy environments, physical activity behavior such as gym attendance, jogging, walking, and running at the individual level, implementation of school curricula on nutrition and health promotion, integration of physical education into the new Competency-Based Education policy, and policies that increase use of public transport. Conclusion The stakeholders identified and ranked strategies for the prevention and control of overweight and obesity in Kenya. This informs future overweight and obesity prevention research and policy in Kenya and similar settings.

Abstract Background Cardiovascular disease (CVD) is the largest contributor to the non-communicable diseases (NCD) burden in Cameroon, but data on its economic burden is lacking. Methods A prevalence-based cost-of-illness study was conducted from a healthcare provider perspective and enrolled patients with ischaemic heart disease (IHD), ischaemic stroke, haemorrhagic stroke and hypertensive heart disease (HHD) from two major hospitals between 2013 and 2017. Determinants of cost were explored using multivariate generalized linear models. Results Overall, data from 850 patients: IHD (n = 92, 10.8%), ischaemic stroke (n = 317, 37.3%), haemorrhagic stroke (n = 193, 22.7%) and HHD (n = 248, 29.2%) were analysed. The total cost for these CVDs was XAF 676,694,000 (~US$ 1,224,918). The average annual direct medical costs of care per patient were XAF 1,395,200 (US$ 2400) for IHD, XAF 932,700 (US$ 1600) for ischaemic stroke, XAF 815,400 (US$ 1400) for haemorrhagic stroke, and XAF 384,300 (US$ 700) for HHD. In the fully adjusted models, apart from history of CVD event (β = − 0.429; 95% confidence interval − 0.705, − 0.153) that predicted lower costs in patients with IHD, having of diabetes mellitus predicted higher costs in patients with IHD (β = 0.435; 0.098, 0.772), ischaemic stroke (β = 0.188; 0.052, 0.324) and HHD (β = 0.229; 0.080, 0.378). Conclusions This study reveals substantial economic burden due to CVD in Cameroon. Diabetes mellitus was a consistent driver of elevated costs across the CVDs. There is urgent need to invest in cost-effective primary prevention strategies in order to reduce the incidence of CVD and consequent economic burden on a health system already laden with the impact of communicable diseases.

Abstract Background The rapid and often uncontrolled rural–urban migration in Sub-Saharan Africa is transforming urban landscapes expected to provide shelter for more than 50% of Africa’s population by 2030. Consequently, the burden of malaria is increasingly affecting the urban population, while socio-economic inequalities within the urban settings are intensified. Few studies, relying mostly on moderate to high resolution datasets and standard predictive variables such as building and vegetation density, have tackled the topic of modeling intra-urban malaria at the city extent. In this research, we investigate the contribution of very-high-resolution satellite-derived land-use, land-cover and population information for modeling the spatial distribution of urban malaria prevalence across large spatial extents. As case studies, we apply our methods to two Sub-Saharan African cities, Kampala and Dar es Salaam. Methods Openly accessible land-cover, land-use, population and OpenStreetMap data were employed to spatially model Plasmodium falciparum parasite rate standardized to the age group 2–10 years (PfPR2–10) in the two cities through the use of a Random Forest (RF) regressor. The RF models integrated physical and socio-economic information to predict PfPR2–10 across the urban landscape. Intra-urban population distribution maps were used to adjust the estimates according to the underlying population. Results The results suggest that the spatial distribution of PfPR2–10 in both cities is diverse and highly variable across the urban fabric. Dense informal settlements exhibit a positive relationship with PfPR2–10 and hotspots of malaria prevalence were found near suitable vector breeding sites such as wetlands, marshes and riparian vegetation. In both cities, there is a clear separation of higher risk in informal settlements and lower risk in the more affluent neighborhoods. Additionally, areas associated with urban agriculture exhibit higher malaria prevalence values. Conclusions The outcome of this research highlights that populations living in informal settlements show higher malaria prevalence compared to those in planned residential neighborhoods. This is due to (i) increased human exposure to vectors, (ii) increased vector density and (iii) a reduced capacity to cope with malaria burden. Since informal settlements are rapidly expanding every year and often house large parts of the urban population, this emphasizes the need for systematic and consistent malaria surveys in such areas. Finally, this study demonstrates the importance of remote sensing as an epidemiological tool for mapping urban malaria variations at large spatial extents, and for promoting evidence-based policy making and control efforts.

Abstract Background Most studies measure the impact of ischemic heart disease (IHD) on individuals using quality of life metrics such as disability-adjusted life-years (DALYs); however, IHD also has an enormous impact on productive life years (PLYs). The objective of this study was to project the indirect costs of IHD resulting from lost PLYs to older Australian workers (45–64 years), government, and society 2015–2030. Methods Nationally representative data from the Surveys of Disability, Ageing and Carers (2003, 2009) were used to develop the base population in the microsimulation model (Health&WealthMOD2030), which integrated data from established microsimulation models (STINMOD, APPSIM), Treasury’s population and workforce projections, and chronic conditions trends. Results We projected that 6700 people aged 45–64 were out of the labour force due to IHD in 2015, increasing to 8100 in 2030 (21 increase). National costs consisted of a loss of AU$273 (US$263) million in income for people with IHD in 2015, increasing to AU$443 ($US426) million (62% increase). For the government, extra welfare payments increased from AU$106 (US$102) million in 2015 to AU$143 (US$138) million in 2030 (35% increase); and lost income tax revenue increased from AU$74 (US$71) million in 2015 to AU$117 (US$113) million in 2030 (58% increase). A loss of AU$785 (US$755) million in GDP was projected for 2015, increasing to AU$1125 (US$1082) million in 2030. Conclusions Significant costs of IHD through lost productivity are incurred by individuals, the government, and society. The benefits of IHD interventions include not only improved health but also potentially economic benefits as workforce capacity.

Abstract Background A consensus is emerging in the literature that urban form can impact health by either facilitating or deterring physical activity (PA). However, there is a lack of evidence measuring population health and the economic benefits relating to alternative urban forms. We examined the issue of housing people within two distinct types of urban development forms: a medium-density brownfield development in an established area with existing amenities (e.g. daily living destinations, transit), and a low-density suburban greenfield development. We predicted the health and economic benefits of a brownfield development compared with a greenfield development through their influence on PA. Methods We combined a new Walkability Planning Support System (Walkability PSS) with a quantitative health impact assessment model. We used the Walkability PSS to estimate the probability of residents’ transport walking, based on their exposure to urban form in the brownfield and greenfield developments. We developed the underlying algorithms of the Walkability PSS using multi-level multivariate logistic regression analysis based on self-reported data for transport walking from the Victorian Integrated Survey of Transport and Activity 2009–10 and objectively measured urban form in the developments. We derived the difference in transport walking minutes per week based on the probability of transport walking in each of the developments and the average transport walking time per week among those who reported any transport walking. We then used the well-established method of the proportional multi-cohort multi-state life table model to translate the difference in transport walking minutes per week into health and economic benefits. Results If adult residents living in the greenfield neighbourhood were instead exposed to the urban development form observed in a brownfield neighbourhood, the incidence and mortality of physical inactivity-related chronic diseases would decrease. Over the life course of the exposed population (21,000), we estimated 1600 health-adjusted life years gained and economic benefits of A$94 million. Discussion Our findings indicate that planning policies that create walkable neighbourhoods with access to shops, services and public transport will lead to substantial health and economic benefits associated with reduced incidence of physical inactivity related diseases and premature death.

Abstract Background Cardiovascular disease (CVD) is the leading cause of deaths globally, with greatest premature mortality in the low- and middle-income countries (LMIC). Many of these countries, especially in sub-Saharan Africa, have significant budget constraints. The need for current evidence on which interventions offer good value for money to stem this CVD epidemic motivates this study. Methods In this systematic review, we included studies reporting full economic evaluations of individual and population-based interventions (pharmacologic and non-pharmacologic), for primary and secondary prevention of CVD among adults in LMIC. Several medical (PubMed, EMBASE, SCOPUS, Web of Science) and economic (EconLit, NHS EED) databases and grey literature were searched. Screening of studies and data extraction was done independently by two reviewers. Drummond’s checklist and the National Institute for Health and Care Excellence quality rating scale were used in the quality appraisal for all studies used to inform this evidence synthesis. Results From a pool of 4059 records, 94 full texts were read and 50 studies, which met our inclusion criteria, were retained for our narrative synthesis. Most of the studies were from middle-income countries and predominantly of high quality. The majority were modelled evaluations, and there was significant heterogeneity in methods. Primary prevention studies dominated secondary prevention. Most of the economic evaluations were performed for pharmacological interventions focusing on blood pressure, cholesterol lowering and antiplatelet aggregants. The greatest majority were cost-effective. Compared to individual-based interventions, population-based interventions were few and mostly targeted reduction in sodium intake and tobacco control strategies. These were very cost-effective with many being cost-saving. Conclusions This evidence synthesis provides a contemporary update on interventions that offer good value for money in LMICs. Population-based interventions especially those targeting reduction in salt intake and tobacco control are very cost-effective in LMICs with potential to generate economic gains that can be reinvested to improve health and/or other sectors. While this evidence is relevant for policy across these regions, decision makers should additionally take into account other multi-sectoral perspectives, including considerations in budget impact, fairness, affordability and implementation while setting priorities for resource allocation.

Abstract Background While the direct (medical) costs of arthritis are regularly reported in cost of illness studies, the 'true' cost to indivdiuals and goverment requires the calculation of the indirect costs as well including lost productivity due to ill-health. Methods Respondents aged 45-64 in the ABS Survey of Disability, Ageing and Carers 2003, 2009 formed the base population. We projected the indirect costs of arthritis using Health&WealthMOD2030 – Australia’s first microsimulation model on the long-term impacts of ill-health in older workers – which incorporated outputs from established microsimulation models (STINMOD and APPSIM), population and labour force projections from Treasury, and chronic conditions trends for Australia. All costs of arthritis were expressed in real 2013 Australian dollars, adjusted for inflation over time. Results We estimated there are 54,000 people aged 45-64 with lost PLYs due to arthritis in 2015, increasing to 61,000 in 2030 (13% increase). In 2015, people with lost PLYs are estimated to receive AU$706.12 less in total income and AU$311.67 more in welfare payments per week than full-time workers without arthritis, and pay no income tax on average. National costs include an estimated loss of AU$1.5 billion in annual income in 2015, increasing to AU$2.4 billion in 2030 (59% increase). Lost annual taxation revenue was projected to increase from AU$0.4 billion in 2015 to $0.5 billion in 2030 (56% increase). We projected a loss in GDP of AU$6.2 billion in 2015, increasing to AU$8.2 billion in 2030. Conclusions Significant costs of arthritis through lost PLYs are incurred by individuals and government. The effectiveness of arthritis interventions should be judged not only on healthcare use but quality of life and economic wellbeing.

Abstract Background Adequate awareness of cardiovascular diseases (CVD) and their risk factors may help reduce the population’s exposure to modifiable risk factors and thereby contribute to prevention and control strategies. There is limited data on knowledge among the general population in sub-Saharan Africa regarding CVD and risk factors. We aimed to assess the population awareness (and associated factors) of CVD types and risk factors in Buea, Cameroon. Methods This was a community-based cross-sectional study conducted in 2016 among randomly selected adults (>18 years). Data on socio-demographic characteristics, knowledge about CVD types, their risk factors and warning signs for CVD events (stroke and heart attack) were acquired using a self-administered questionnaire. Logistic regression analysis was used to investigate factors associated with moderate-to-good knowledge. Results Of the 1162 participants (61.7% women, mean age 32 years), 52.5% had overall poor knowledge (mean score 12.1 on total of 25) on CVD with only about a quarter correctly identifying types of CVD. Overall, 36, 63 and 45% were unaware of CVD risk factors, warning signs of heart attack and stroke respectively. In multivariable analysis; high level of education (aOR = 2.26 (1.69–3.02), p

Abstract Background There is growing evidence indicating that the built environment is a determinant of physical activity. However, despite the well-established health benefits of physical activity this is rarely considered in urban planning. We summarised recent Australian evidence for the association built environment-physical activity among adults. This summary aims to inform policy makers who advocate for the consideration of health in urban planning. Methods A combination of built environment and physical activity terms were used to systematically identify relevant peer reviewed and grey literature. Results A total of 23 studies were included, providing 139 tests of associations between specific built environment features and physical activity. Of the total, 84 relationships using objective measures of built environment attributes were evaluated, whereas 55 relationships using self-reported measures were evaluated. Our results indicate that walkable neighbourhoods with a wide range of local destinations to go to, as well as a diverse use of land, encourage physical activity among their residents. Conclusions This research provides a summary of recent Australian evidence on built environments that are most favourable for physical activity. Features of walkability and availability of destinations within walking distance should be accounted for in the development or redevelopment of urban areas. Our findings emphasise the importance of urban planning for health via its impact on population levels of physical activity.

Abstract Background Stroke poses a growing human and economic burden in South Africa. Excess sugar consumption, especially from sugar-sweetened beverages (SSBs), has been associated with increased obesity and stroke risk. Research shows that price increases for SSBs can influence consumption and modelling evidence suggests that taxing SSBs has the potential to reduce obesity and related diseases. This study estimates the potential impact of an SSB tax on stroke-related mortality, costs and health-adjusted life years in South Africa. Methods A proportional multi-state life table-based model was constructed in Microsoft Excel (2010). We used consumption data from the 2012 South African National Health and Nutrition Examination Survey, previously published own and cross price elasticities of SSBs and energy balance equations to estimate changes in daily energy intake and BMI arising from increased SSB prices. Stroke relative risk, and prevalent years lived with disability estimates from the Global Burden of Disease Study and modelled disease epidemiology estimates from a previous study, were used to estimate the effect of the BMI changes on the burden of stroke. Results Our model predicts that an SSB tax may avert approximately 72 000 deaths, 550 000 stroke-related health-adjusted life years and over ZAR5 billion, (USD400 million) in health care costs over 20 years (USD296-576 million). Over 20 years, the number of incident stroke cases may be reduced by approximately 85 000 and prevalent cases by about 13 000. Conclusions Fiscal policy has the potential, as part of a multi-faceted approach, to mitigate the growing burden of stroke in South Africa and contribute to the achievement of the target set by the Department of Health to reduce relative premature mortality (less than 60 years) from non-communicable diseases by the year 2020.

Abstract Several alphaherpesviruses breach the basement membrane during mucosal invasion. In the present study, the role of proteases in this process was examined. The serine protease-specific inhibitor AEBSF inhibited penetration of the basement membrane by the porcine alphaherpesvirus pseudorabies virus (PRV) by 88.1% without affecting lateral spread. Inhibitors of aspartic-, cysteine-, and metalloproteases did not inhibit viral penetration of the basement membrane. Further analysis using the Soybean Type I-S trypsin inhibitor for the serine protease subcategory of trypsin-like serine proteases resulted in a 96.9% reduction in plaque depth underneath the basement membrane. These data reveal a role of a trypsin-like serine protease in PRV penetration of the basement membrane.

Abstract In general, members of the Alphaherpesvirinae use the epithelium of the upper respiratory and/or genital tract as a preferential site for primary replication. Bovine herpesvirus type 1 (BoHV-1) may replicate at both sites and cause two major clinical entities designated as infectious bovine rhinotracheitis (IBR) and infectious pustular vulvovaginitis/balanoposthitis (IPV/IPB) in cattle. It has been hypothesized that subtype 1.1 invades preferentially the upper respiratory mucosa whereas subtype 1.2 favors replication at the peripheral genital tract. However, some studies are in contrast with this hypothesis. A thorough study of primary replication at both mucosae could elucidate whether or not different BoHV-1 subtypes show differences in mucosa tropism. We established bovine respiratory and genital organ cultures with emphasis on maintenance of tissue morphology and viability during in vitro culture. In a next step, bovine respiratory and genital mucosa explants of the same animals were inoculated with several BoHV-1 subtypes. A quantitative analysis of viral invasion in the mucosa was performed at 0 h, 24 h, 48 h and 72 h post inoculation (pi) by measuring plaque latitude and penetration depth underneath the basement membrane. All BoHV-1 subtypes exhibited a more profound invasion capacity in respiratory tissue compared to that in genital tissue at 24 h pi. However, at 24 h pi plaque latitude was found to be larger in genital tissue compared to respiratory tissue and this for all subtypes. These similar findings among the different subtypes take the edge off the belief of the existence of specific mucosa tropisms of different BoHV-1 subtypes.

Abstract Background This study quantifies the burden of road traffic injuries (RTIs) in Thailand in 2004, incorporating new Thai data on mortality and the frequency and severity of long-term disability. Methods We quantified the uncertainty around national RTI mortality estimates based on a verbal autopsy study that was conducted to correct for the large proportion of ill-defined deaths in the vital registration system. The number of nonfatal RTI victims was estimated using hospital and survey data. We used the proportion and severity of long-term disabilities from a recent Thai study, instead of the standard Global Burden of Disease assumptions, to calculate the burden due to long-term disability. To evaluate changes over time, we also calculated the burden of RTIs in 2004 using the method and assumptions used in 1999, when standard Global Burden of Disease assumptions were used. Results The total loss of disability-adjusted life years due to RTIs was 673,000 (95% uncertainty interval [UI]: 546,000-881,000). Mortality contributed 88% of this burden. The use of local data led to a significantly higher estimate of the burden of long-term disability due to RTIs (74,000 DALYs [95% UI: 55,400-88,500] vs. 43,000 [UI: 42,700-43,600]) using standard Global Burden of Disease methods. However, this difference constituted only a small proportion of the total burden. Conclusions The burden of RTIs in 2004 remained at the same high level as in 1999. The use of local data on the long-term health consequences of RTIs enabled an estimate of this burden and its uncertainty that is likely to be more valid.