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Abstract Freshwaters play an essential role in providing ecosystem services worldwide, however, the water quality of different water bodies is strongly influenced by human activities such as urbanization, industry and agriculture. In this study, water and biofilm samples were collected from the main channel of the Danube River upstream and downstream of a metropolitan, from a regulated side arm within an urbanized area, and from two differently separated oxbow lakes located in nature conservation areas. The taxonomic diversity of bacterial communities was revealed by 16S rRNA gene-based amplicon sequencing using Illumina MiSeq platform. The results showed that all samples were dominated by phyla Pseudomonadota, Actinobacteriota and Bacteroidota. The bacterial community structures, however, clearly differentiated according to planktonic and epilithic or epiphytic habitats, as well as by riverine body types (main channel, side arm, oxbow lakes). The taxonomic diversity of biofilm communities was higher than that of planktonic ones in all studied habitats. Human impacts were mainly reflected in the slowly changing biofilm composition compared to the planktonic ones. Genera with pollution tolerance and/or degradation potential, such as Acinetobacter, Pseudomonas and Shewanella were mainly detected in biofilm communities of the highly urbanized section of the river side arm.

Objectives To estimate the economic burden of informal caregivers not in the labour force (NILF) due to caring for a person with arthritis in Australia, with projections of these costs from 2015 to 2030.Design Static microsimulation modelling using national survey data.Setting Australia nationwide survey.Participants Participants include respondents to the Survey of Disability, Ageing and Carers who are informal carers of a person who has arthritis as their main chronic condition and non-carers.Outcome measures Estimating the economic impact and national aggregated costs of informal carers NILF to care for a person with arthritis and projecting these costs from 2015 to 2030 in 5-year intervals.Results On a per-person basis, when adjusted for age, sex and highest education attained, the difference in average weekly total income between informal carers and non-carers employed in the labour force is $A1051 (95% CI: $A927 to $A1204) in 2015 and projected to increase by up to 22% by 2030. When aggregated, the total national annual loss of income to informal carers NILF is estimated at $A388.2 million (95% CI: $A324.3 to $A461.9 million) in 2015, increasing to $A576.9 million (95% CI: $A489.2 to $A681.8 million) by 2030. The national annual tax revenue lost to the government of the informal carers NILF is estimated at $A99 million (95% CI: $A77.9 to $A126.4 million) in 2015 and is projected to increase 49% by 2030.Conclusion Informal carers NILF are economically worse off than employed non-carers, and the aggregated national annual costs are substantial. The future economic impact of informal carers NILF to care for a person with arthritis in Australia is projected to increase, with the estimated differences in income between informal carers and employed non-carers increasing by 22% from 2015 to 2030.

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.

BackgroundRifampicin resistant tuberculosis remains a global health problem with almost half a million new cases annually. In high-income countries patients empirically start a standardized treatment regimen, followed by an individualized regimen guided by drug susceptibility test (DST) results. In most settings, DST information is not available or is limited to isoniazid and fluoroquinolones. Whole genome sequencing could more accurately guide individualized treatment as the full drug resistance profile is obtained with a single test. Whole genome sequencing has not reached its full potential for patient care, in part due to the complexity of translating a resistance profile into the most effective individualized regimen.MethodsWe developed a treatment recommender clinical decision support system (CDSS) and an accompanying web application for user-friendly recommendation of the optimal individualized treatment regimen to a clinician.ResultsFollowing expert stakeholder meetings and literature review, nine drug features and 14 treatment regimen features were identified and quantified. Using machine learning, a model was developed to predict the optimal treatment regimen based on a training set of 3895 treatment regimen-expert feedback pairs. The acceptability of the treatment recommender CDSS was assessed as part of a clinical trial and in a routine care setting. Within the clinical trial setting, all patients received the CDSS recommended treatment. In 8 of 20 cases, the initial recommendation was recomputed because of stock out, clinical contra-indication or toxicity. In routine care setting, physicians rejected the treatment recommendation in 7 out of 15 cases because it deviated from the national TB treatment guidelines. A survey indicated that the treatment recommender CDSS is easy to use and useful in clinical practice but requires digital infrastructure support and training.ConclusionsOur findings suggest that global implementation of the novel treatment recommender CDSS holds the potential to improve treatment outcomes of patients with RR-TB, especially those with 'difficult-to-treat' forms of RR-TB.

Objective When considering proposals to improve diets, it is important to understand how factors like price and income can affect saturated fat (SF) intake and demand. In this study, we examine and estimate the influence of price and income on intake across 160 countries, by age and sex, and derive sensitivity measures (price elasticities) that vary by age, sex and world region.Design We econometrically estimate intake responsiveness to income and prices across countries, accounting for differences by world region, age and sex. Intake data by age, sex and country were obtained from the 2018 Global Dietary Database. These data were then linked to global price data for select food groups from the World Bank International Comparison Programme and income data from the World Development Indicators Databank (World Bank).Results Intake differences due to price were highly significant, with a 1% increase in price associated with a lower SF intake (% energy/d) of about 4.3 percentage points. We also find significant differences across regions. In high-income countries, median (age 40) intake reductions were 1.4, 0.8 and 0.2 percentage points, given a 1% increase in the price of meat, dairy, and oils and fats, respectively. Price elasticities varied with age but not sex. Intake differences due to income were insignificant when regional binary variables were included in the analysis.Conclusion The results of this study show heterogeneous associations among prices and intake within and across countries. Policymakers should consider these heterogeneous effects as they address global nutrition and health challenges.

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.

Following a huge global effort, the first World Health Organization (WHO)-endorsed catalogue of 17,356 variants in the Mycobacterium tuberculosis complex along with their classification as associated with resistance (interim), not associated with resistance (interim) or uncertain significance was made public In June 2021. This marks a critical step towards the application of next generation sequencing (NGS) data for clinical care. Unfortunately, the variant format used makes it difficult to look up variants when NGS data is generated by other bioinformatics pipelines. Furthermore, the large number of variants of uncertain significance in the catalogue hamper its useability in clinical practice. We successfully converted 98.3% of variants from the WHO catalogue format to the standardized HGVS format. We also created TBProfiler version 4.4.0 to automate the calling of all variants located in the tier 1 and 2 candidate resistance genes along with their classification when listed in the WHO catalogue. Using a representative sample of 339 clinical isolates from South Africa containing 691 variants in a tier 1 or 2 gene, TBProfiler classified 105 (15%) variants as conferring resistance, 72 (10%) as not conferring resistance and 514 (74%) as unclassified, with an average of 29 unclassified variants per isolate. Using a second cohort of 56 clinical isolates from a TB outbreak in Spain containing 21 variants in the tier 1 and 2 genes, TBProfiler classified 13 (61.9%) as unclassified, 7 (33.3%) as not conferring resistance, and a single variant (4.8%) classified as conferring resistance. Continued global efforts using standardized methods for genotyping, phenotyping and bioinformatic analyses will be essential to ensure that knowledge on genomic variants translates into improved patient care.

Using transient climate forcing based on simulations from the Alfred Wegener Institute Earth System Model (AWI-ESM), we simulate the evolution of the Greenland Ice Sheet (GrIS) from the last interglacial (125 ka, kiloyear before present) to 2100 AD with the Parallel Ice Sheet Model (PISM). The impact of paleoclimate, especially Holocene climate, on the present and future evolution of the GrIS is explored. Our simulations of the past show close agreement with reconstructions with respect to the recent timing of the peaks in ice volume and the climate of Greenland. The maximum and minimum ice volume at around 18–17 ka and 6–5 ka lag the respective extremes in climate by several thousand years, implying that the ice volume response of the GrIS strongly lags climatic changes. Given that Greenland’s climate was getting colder from the Holocene Thermal Maximum (i.e., 8 ka) to the Pre-Industrial era, our simulation implies that the GrIS experienced growth from the mid-Holocene to the industrial era. Due to this background trend, the GrIS still gains mass until the second half of the 20th century, even though anthropogenic warming begins around 1850 AD. This is also in agreement with observational evidence showing mass loss of the GrIS does not begin earlier than the late 20th century. Our results highlight that the present evolution of the GrIS is not only controlled by the recent climate changes, but is also affected by paleoclimate, especially the relatively warm Holocene climate. We propose that the GrIS was not in equilibrium throughout the entire Holocene and that the slow response to Holocene climate needs to be represented in ice sheet simulations in order to predict ice mass loss, and therefore sea level rise, accurately.

Using transient climate forcing based on simulations from the Alfred Wegener Institute Earth System Model (AWI-ESM), we simulate the evolution of the Greenland Ice Sheet (GrIS) from the last interglacial (125 ka, kiloyear before present) to 2100 AD with the Parallel Ice Sheet Model (PISM). The impact of paleoclimate, especially Holocene climate, on the present and future evolution of the GrIS is explored. Our simulations of the past show close agreement with reconstructions with respect to the recent timing of the peaks in ice volume and the climate of Greenland. The maximum and minimum ice volume at around 18-17 ka and 6-5 ka lag the respective extremes in climate by several thousand years, implying that the ice volume response of the GrIS strongly lags climatic changes. Given that Greenland's climate was getting colder from the Holocene Thermal Maximum (i.e., 8 ka) to the Pre-Industrial era, our simulation implies that the GrIS experienced growth from the mid-Holocene to the industrial era. Due to this background trend, the GrIS still gains mass until the second half of the 20th century, even though anthropogenic warming begins around 1850 AD. This is also in agreement with observational evidence showing mass loss of the GrIS does not begin earlier than the late 20th century. Our results highlight that the present evolution of the GrIS is not only controlled by the recent climate changes, but is also affected by paleoclimate, especially the relatively warm Holocene climate. We propose that the GrIS was not in equilibrium throughout the entire Holocene and that the slow response to Holocene climate needs to be represented in ice sheet simulations in order to predict ice mass loss, and therefore sea level rise, accurately.

Objective To explore the stakeholders’ perceptions of current practices and challenges in priority setting for non-communicable disease (NCD) control in Kenya.Design A qualitative study approach conducted within a 1-day stakeholder workshop that followed a deliberative dialogue process.Setting Study was conducted within a 1-day stakeholder workshop that was held in October 2019 in Nairobi, Kenya.Participants Stakeholders who currently participate in the national level policymaking process for health in Kenya.Outcome measure Priority setting process for NCD control in Kenya.Results Donor funding was identified as a key factor that informed the priority setting process for NCD control. Misalignment between donors’ priorities and the country’s priorities for NCD control was seen as a hindrance to the process. It was identified that there was minimal utilisation of context-specific evidence from locally conducted research. Additional factors seen to inform the priority setting process included political leadership, government policies and budget allocation for NCDs, stakeholder engagement, media, people’s cultural and religious beliefs.Conclusion There is an urgent need for development aid partners to align their priorities to the specific NCD control priority areas that exist in the countries that they extend aid to. Additionally, context-specific scientific evidence on effective local interventions for NCD control is required to inform areas of priority in Kenya and other low-income and middle-income countries. Further research is needed to develop best practice guidelines and tools for the creation of national-level priority setting frameworks that are responsive to the identified factors that inform the priority setting process for NCD control.

Background Reducing dietary sodium (salt) intake has been proposed as a population-wide strategy to reduce blood pressure and cardiovascular disease (CVD). The cost-effectiveness of such strategies has hitherto not been investigated in Cameroon.Methods A multicohort multistate life table Markov model was used to evaluate the cost-effectiveness of three population salt reduction strategies: mass media campaign, school-based salt education programme and low-sodium salt substitute. A healthcare system perspective was considered and adults alive in 2016 were simulated over the life course. Outcomes were changes in disease incidence, mortality, health-adjusted life years (HALYs), healthcare costs and incremental cost-effectiveness ratios (ICERs) over the lifetime. Probabilistic sensitivity analysis was used to quantify uncertainty.Results Over the life span of the cohort of adults alive in Cameroon in 2016, substantial numbers of new CVD events could be prevented, with over 10 000, 79 000 and 84 000 CVD deaths that could be averted from mass media, school education programme and salt substitute interventions, respectively. Population health gains over the lifetime were 46 700 HALYs, 348 800 HALYs and 368 400 HALYs for the mass media, school education programme and salt substitute interventions, respectively. ICERs showed that all interventions were dominant, with probabilities of being cost-saving of 84% for the school education programme, 89% for the mass media campaign and 99% for the low sodium salt substitute. Results were largely robust in sensitivity analysis.Conclusion All the salt reduction strategies evaluated were highly cost-effective with very high probabilities of being cost-saving. Salt reduction in Cameroon has the potential to save many lives and offers good value for money.

Backgroundtrans-fatty acids (TFAs) are a well-known risk factor of ischemic heart disease (IHD). In Australia, the highest TFA intake is concentrated to the most socioeconomically disadvantaged groups. Elimination of industrial TFA (iTFA) from the Australian food supply could result in reduced IHD mortality and morbidity while improving health equity. However, such legislation could lead to additional costs for both government and food industry. Thus, we assessed the potential cost-effectiveness, health gains, and effects on health equality of an iTFA ban from the Australian food supply.Methods and findingsMarkov cohort models were used to estimate the impact on IHD burden and health equity, as well as the cost-effectiveness of a national ban of iTFA in Australia. Intake of TFA was assessed using the 2011-2012 Australian National Nutrition and Physical Activity Survey. The IHD burden attributable to TFA was calculated by comparing the current level of TFA intake to a counterfactual setting where consumption was lowered to a theoretical minimum distribution with a mean of 0.5% energy per day (corresponding to TFA intake only from nonindustrial sources, e.g., dairy foods). Policy costs, avoided IHD events and deaths, health-adjusted life years (HALYs) gained, and changes in IHD-related healthcare costs saved were estimated over 10 years and lifetime of the adult Australian population. Cost-effectiveness was assessed by calculation of incremental cost-effectiveness ratios (ICERs) using net policy cost and HALYs gained. Health benefits and healthcare cost changes were also assessed in subgroups based on socioeconomic status, defined by Socio-Economic Indexes for Areas (SEIFA) quintile, and remoteness. Compared to a base case of no ban and current TFA intakes, elimination of iTFA was estimated to prevent 2,294 (95% uncertainty interval [UI]: 1,765; 2,851) IHD deaths and 9,931 (95% UI: 8,429; 11,532) IHD events over the first 10 years. The greatest health benefits were accrued to the most socioeconomically disadvantaged quintiles and among Australians living outside of major cities. The intervention was estimated to be cost saving (net cost ConclusionsOur model estimates that a ban of iTFAs could avert substantial numbers of IHD events and deaths in Australia and would likely be a highly cost-effective strategy to reduce social-economic and urban-rural inequalities in health. These findings suggest that elimination of iTFA can cost-effectively improve health and health equality even in countries with low iTFA intake.

[This corrects the article DOI: 10.1371/journal.pmed.1002326.].

The aim of the ACE-Obesity Policy study was to assess the economic credentials of a suite of obesity prevention policies across multiple sectors and areas of governance for the Australian setting. The study aimed to place the cost-effectiveness results within a broad decision-making context by providing an assessment of the key considerations for policy implementation. The Assessing Cost-Effectiveness (ACE) approach to priority-setting was used. Systematic literature reviews were undertaken to assess the evidence of intervention effectiveness on body mass index and/or physical activity for selected interventions. A standardised evaluation framework was used to assess the cost-effectiveness of each intervention compared to a 'no intervention' comparator, from a limited societal perspective. A multi-state life table Markov cohort model was used to estimate the long-term health impacts (quantified as health adjusted life years (HALYs)) and health care cost-savings resulting from each intervention. In addition to the technical cost-effectiveness results, qualitative assessments of implementation considerations were undertaken. All 16 interventions evaluated were found to be cost-effective (using a willingness-to-pay threshold of AUD50,000 per HALY gained). Eleven interventions were dominant (health promoting and cost-saving). The incremental cost-effectiveness ratio for the non-dominant interventions ranged from AUD1,728 to 28,703 per HALY gained. Regulatory interventions tended to rank higher on their cost-effectiveness results, driven by lower implementation costs. However, the program-based policy interventions were generally based on higher quality evidence of intervention effectiveness. This comparative analysis of the economic credentials of obesity prevention policies for Australia indicates that there are a broad range of policies that are likely to be cost-effective, although policy options vary in strength of evidence for effectiveness, affordability, feasibility, acceptability to stakeholders, equity impact and sustainability. Implementation of these policies will require sustained co-ordination across jurisdictions and multiple government sectors in order to generate the predicted health benefits for the Australian population.

BackgroundOf all cancer types, healthcare for lung cancer is the third most costly in Australia, but there is little detailed information about these costs. Our aim was to provide detailed population-based estimates of health system costs for lung cancer care, as a benchmark prior to wider availability of targeted therapies/immunotherapy and to inform cost-effectiveness analyses of lung cancer screening and other interventions in Australia.MethodsHealth system costs were estimated for incident lung cancers in the Australian 45 and Up Study cohort, diagnosed between recruitment (2006-2009) and 2013. Costs to June 2016 included services reimbursed via the Medicare Benefits Schedule, medicines reimbursed via the Pharmaceutical Benefits Scheme, inpatient hospitalisations, and emergency department presentations. Costs for cases and matched, cancer-free controls were compared to derive excess costs of care. Costs were disaggregated by patient and tumour characteristics. Data for more recent cases identified in hospital records provided preliminary information on targeted therapy/immunotherapy.Results994 eligible cases were diagnosed with lung cancer 2006-2013; 51% and 74% died within one and three years respectively. Excess costs from one-year pre-diagnosis to three years post-diagnosis averaged ~$51,900 per case. Observed costs were higher for cases diagnosed at age 45-59 ($67,700) or 60-69 ($63,500), and lower for cases aged ≥80 ($29,500) and those with unspecified histology ($31,700) or unknown stage ($36,500). Factors associated with lower costs generally related to shorter survival: older age (p0.50). For 465 cases diagnosed 2014-2015, 29% had subsidised molecular testing for targeted therapy/immunotherapy and 4% had subsidised targeted therapies.ConclusionsLung cancer healthcare costs are strongly associated with survival-related factors. Costs appeared stable over the period 2006-2013. This study provides a framework for evaluating the health/economic impact of introducing lung cancer screening and other interventions in Australia.

Abstract Rising temperatures in the Arctic cause accelerated mass loss from the Greenland Ice Sheet and reduced sea ice cover. Tidewater outlet glaciers represent direct connections between glaciers and the ocean where melt rates at the ice-ocean interface are influenced by ocean temperature and circulation. However, few measurements exist near outlet glaciers from the northern coast towards the Arctic Ocean that has remained nearly permanently ice covered. Here we present hydrographic measurements along the terminus of a major retreating tidewater outlet glacier from Flade Isblink Ice Cap. We show that the region is characterized by a relatively large change of the seasonal freshwater content, corresponding to ~2 m of freshwater, and that solar heating during the short open water period results in surface layer temperatures above 1 °C. Observations of temperature and salinity supported that the outlet glacier is a floating ice shelf with near-glacial subsurface temperatures at the freezing point. Melting from the surface layer significantly influenced the ice foot morphology of the glacier terminus. Hence, melting of the tidewater outlet glacier was found to be critically dependent on the retreat of sea ice adjacent to the terminus and the duration of open water.

ObjectiveTo estimate the productivity impacts of a policy intervention on the prevention of premature mortality due to obesity.MethodsA simulation model of the Australian population over the period from 2003 to 2030 was developed to estimate productivity gains associated with premature deaths averted due to an obesity prevention intervention that applied a 10% tax on unhealthy foods. Outcome measures were the total working years gained, and the present value of lifetime income (PVLI) gained. Impacts were modelled over the period from 2003 to 2030. Costs are reported in 2018 Australian dollars and a 3% discount rate was applied to all future benefits.ResultsPremature deaths averted due to a junk food tax accounted for over 8,000 additional working years and a $307 million increase in PVLI. Deaths averted in men between the ages of 40 to 59, and deaths averted from ischaemic heart disease, were responsible for the largest gains.ConclusionsThe productivity gains associated with a junk food tax are substantial, accounting for almost twice the value of the estimated savings to the health care system. The results we have presented provide evidence that the adoption of a societal perspective, when compared to a health sector perspective, provides a more comprehensive estimate of the cost-effectiveness of a junk food tax.

BACKGROUND:Cancer care represents a substantial and rapidly rising healthcare cost in Australia. Our aim was to provide accurate population-based estimates of the health services cost of cancer care using large-scale linked patient-level data. METHODS:We analysed data for incident cancers diagnosed 2006-2010 and followed to 2014 among 266,793 eligible participants in the 45 and Up Study. Health system costs included Medicare and pharmaceutical claims, inpatient hospital episodes and emergency department presentations. Costs for cancer cases and matched cancer-free controls were compared, to estimate monthly/annual excess costs of cancer care by cancer type, before and after diagnosis and by phase of care (initial, continuing, terminal). Total costs incurred in 2013 were also estimated for all people diagnosed in Australia 2009-2013. RESULTS:7624 participants diagnosed with cancer were matched with up to three controls. The mean excess cost of care per case was AUD$1,622 for the year before diagnosis, $33,944 for the first year post-diagnosis and $8,796 for the second year post-diagnosis, with considerable variation by cancer type. Mean annual cost after the initial treatment phase was $4,474/case and the mean cost for the last year of life was $49,733/case. In 2013 the cost for cancers among people in Australia diagnosed during 2009-2013 was ~$6.3billion (0.4% of Gross Domestic Product; $272 per capita), with the largest costs for colorectal cancer ($1.1billion), breast cancer ($0.8billion), lung cancer ($0.6billion) and prostate cancer ($0.5billion). CONCLUSIONS:The cost of cancer care is substantial and varies by cancer type and time since diagnosis. These findings emphasise the economic importance of effective primary and secondary cancer prevention strategies.

BackgroundA sugar-sweetened beverage (SSB) tax in Mexico has been effective in reducing consumption of SSBs, with larger decreases for low-income households. The health and financial effects across socioeconomic groups are important considerations for policy-makers. From a societal perspective, we assessed the potential cost-effectiveness, health gains, and financial impacts by socioeconomic position (SEP) of a 20% SSB tax for Australia.Methods and findingsAustralia-specific price elasticities were used to predict decreases in SSB consumption for each Socio-Economic Indexes for Areas (SEIFA) quintile. Changes in body mass index (BMI) were based on SSB consumption, BMI from the Australian Health Survey 2011-12, and energy balance equations. Markov cohort models were used to estimate the health impact for the Australian population, taking into account obesity-related diseases. Health-adjusted life years (HALYs) gained, healthcare costs saved, and out-of-pocket costs were estimated for each SEIFA quintile. Loss of economic welfare was calculated as the amount of deadweight loss in excess of taxation revenue. A 20% SSB tax would lead to HALY gains of 175,300 (95% CI: 68,700; 277,800) and healthcare cost savings of AU$1,733 million (m) (95% CI: $650m; $2,744m) over the lifetime of the population, with 49.5% of the total health gains accruing to the 2 lowest quintiles. We estimated the increase in annual expenditure on SSBs to be AU$35.40/capita (0.54% of expenditure on food and non-alcoholic drinks) in the lowest SEIFA quintile, a difference of AU$3.80/capita (0.32%) compared to the highest quintile. Annual tax revenue was estimated at AU$642.9m (95% CI: $348.2m; $1,117.2m). The main limitations of this study, as with all simulation models, is that the results represent only the best estimate of a potential effect in the absence of stronger direct evidence.ConclusionsThis study demonstrates that from a 20% tax on SSBs, the most HALYs gained and healthcare costs saved would accrue to the most disadvantaged quintiles in Australia. Whilst those in more disadvantaged areas would pay more SSB tax, the difference between areas is small. The equity of the tax could be further improved if the tax revenue were used to fund initiatives benefiting those with greater disadvantage.

Introduction: The healthcare systems in many Low-and Middle-Income Countries (LMICs) like Nepal have long focused on preventing and treating infectious diseases. Little is known about their preparedness to address the increasing prevalence of Non-Communicable Diseases (NCDs). Aim: This study aimed to investigate the use of healthcare services by patients with NCDs in Nepal. Materials and Methods: Nine healthcare providers (including health assistants, pharmacy assistants, nurse, specialised nurse, practicing pharmacists, chief hospital pharmacist, doctors and specialised doctor) from Pokhara, Nepal, were recruited using purposive sampling. In depth interviews about the magnitude of NCDs, first point of care, screening and diagnosis, prevention and management, follow-up, and healthcare system responses to NCD burden were conducted. Data were thematically analysed with a deductive approach. Results: Although the healthcare system in Nepal is still primarily focused on communicable infectious diseases, healthcare providers are aware of the increasing burden of NCDs and NCD risk factors. The first points of care for patients with NCDs are government primary healthcare facilities and private pharmacies. NCDs are often diagnosed late and opportunistically. NCD prevention and treatment is unaffordable for many people. There are no government sponsored NCD screening programs. Conclusion: There are problems associated with screening, diagnosis, treatment and follow-up of patients with NCDs in Nepal. Healthcare providers believe that the current healthcare system in Nepal is inadequate to address the growing problem of NCDs. The health system of Nepal will face challenges to incorporate programs to prevent and treat NCDs in addition to the pre-existing communicable diseases.

BackgroundAn increasing number of countries are implementing taxes on unhealthy foods and drinks to address the growing burden of dietary-related disease, but the cost-effectiveness of combining taxes on unhealthy foods and subsidies on healthy foods is not well understood.Methods and findingsUsing a population model of dietary-related diseases and health care costs and food price elasticities, we simulated the effect of taxes on saturated fat, salt, sugar, and sugar-sweetened beverages and a subsidy on fruits and vegetables, over the lifetime of the Australian population. The sizes of the taxes and subsidy were set such that, when combined as a package, there would be a negligible effect on average weekly expenditure on food (ConclusionsWith potentially large health benefits for the Australian population and large benefits in reducing health sector spending on the treatment of non-communicable diseases, the formulation of a tax and subsidy package should be given a more prominent role in Australia's public health nutrition strategy.

INTRODUCTION:An alarmingly high proportion of the Australian adult population does not meet national physical activity guidelines (57%). This is concerning because physical inactivity is a risk factor for several chronic diseases. In recent years, an increasing emphasis has been placed on the potential for transport and urban planning to contribute to increased physical activity via greater uptake of active transport (walking, cycling and public transport). In this study, we aimed to estimate the potential health gains and savings in health care costs of an Australian city achieving its stated travel targets for the use of active transport. METHODS:Additional active transport time was estimated for the hypothetical scenario of Brisbane (1.1 million population 2013) in Australia achieving specified travel targets. A multi-state life table model was used to estimate the number of health-adjusted life years, life-years, changes in the burden of diseases and injuries, and the health care costs associated with changes in physical activity, fine particle (

This paper aims to estimate the consequences of an additional 20% tax on sugar-sweetened beverages (SSBs) on health and health care expenditure. Participants were adult (aged > = 20) Australians alive in 2010, who were modelled over their remaining lifetime. We used lifetable-based epidemiological modelling to examine the potential impact of a 20% valoric tax on SSBs on total lifetime disability-adjusted life years (DALYs), incidence, prevalence, and mortality of obesity-related disease, and health care expenditure. Over the lifetime of adult Australian alive in 2010, seemingly modest estimated changes in average body mass as a result of the SSB tax translated to gains of 112,000 health-adjusted life years for men (95% uncertainty interval [UI]: 73,000-155,000) and 56,000 (95% UI: 36,000-76,000) for women, and a reduction in overall health care expenditure of AUD609 million (95% UI: 368 million- 870 million). The tax is estimated to reduce the number of new type 2 diabetes cases by approximately 800 per year. Twenty-five years after the introduction of the tax, there would be 4,400 fewer prevalent cases of heart disease and 1,100 fewer persons living with the consequences of stroke, and an estimated 1606 extra people would be alive as a result of the tax. The tax would generate an estimated AUD400 million in revenue each year. Governments should consider increasing the tax on sugared drinks. This would improve population health, reduce health care costs, as well as bring in direct revenue.

BackgroundObesity is a major risk factor for emerging non-communicable diseases (NCDS) in middle income countries including South Africa (SA). Understanding the multiple and complex determinants of obesity and their true population attributable impact is critical for informing and developing effective prevention efforts using scientific based evidence. This study identified contextualised high impact factors associated with obesity in South Africa.MethodsAnalysis of three national cross sectional (repeated panel) surveys, using a multilevel logistic regression and population attributable fraction estimation allowed for identification of contextualised high impact factors associated with obesity (BMI>30 kg/m2) among adults (15 years+).ResultsObesity prevalence increased significantly from 23.5% in 2008 to 27.2% in 2012, with a significantly (p-valueConclusionsThe rising prevalence of obesity in South Africa is significant and over the past 5 years the rising prevalence of Type-2 diabetes has mirrored this pattern, especially among females. Targeting young adolescent girls should be a priority. Addressing determinants of obesity will involve a multifaceted strategy and requires at individual and population levels. With rising costs in the private and public sector to combat obesity related NCDS, this analysis can inform culturally sensitive mass communications and wellness campaigns. Knowledge of social determinants is critical to develop "best buys".

BackgroundDiabetes is a debilitating and costly condition. The costs of reduced labour force participation due to diabetes can have severe economic impacts on individuals by reducing their living standards during working and retirement years.MethodsA purpose-built microsimulation model of Australians aged 45-64 years in 2010, Health&WealthMOD2030, was used to estimate the lost savings at age 65 due to premature exit from the labour force because of diabetes. Regression models were used to examine the differences between the projected savings and retirement incomes of people at age 65 for those currently working full or part time with no chronic health condition, full or part time with diabetes, and people not in the labour force due to diabetes.ResultsAll Australians aged 45-65 years who are employed full time in 2010 will have accumulated some savings at age 65; whereas only 90.5% of those who are out of the labour force due to diabetes will have done so. By the time they reach age 65, those who retire from the labour force early due to diabetes have a median projected savings of less than $35,000. This is far lower than the median value of total savings for those who remained in the labour force full time with no chronic condition, projected to have $638,000 at age 65.ConclusionsNot only does premature retirement due to diabetes limit the immediate income available to individuals with this condition, but it also reduces their long-term financial capacity by reducing their accumulated savings and the income these savings could generate in retirement. Policies designed to support the labour force participation of those with diabetes, or interventions to prevent the onset of the disease itself, should be a priority to preserve living standards comparable with others who do not suffer from this condition.

The artisanal fisheries of Ecuador operate within one of the most dynamic and productive marine ecosystems of the world. This study investigates the catch composition of the Ecuadorian artisanal fishery for large pelagic fishes, including aspects of its spatio-temporal dynamics. The analyses of this study are based on the most extensive dataset available to date for this fishery: a total of 106,963 trip-landing inspection records collected at its five principal ports during 2008 ‒ 2012. Ecuadorian artisanal fisheries remove a substantial amount of biomass from the upper trophic-level predatory fish community of the eastern tropical Pacific Ocean. It is estimated that at least 135 thousand metric tons (mt) (about 15.5 million fish) were landed in the five principal ports during the study period. The great novelty of Ecuadorian artisanal fisheries is the "oceanic-artisanal" fleet component, which consists of mother-ship (nodriza) boats with their towed fiber-glass skiffs (fibras) operating with pelagic longlines. This fleet has fully expanded into oceanic waters as far offshore as 100°W, west of the Galapagos Archipelago. It is estimated that nodriza operations produce as much as 80% of the total catches of the artisanal fishery. The remainder is produced by independent fibras operating in inshore waters with pelagic longlines and/or surface gillnets. A multivariate regression tree analysis was used to investigate spatio-environmental effects on the nodriza fleet (n = 6,821 trips). The catch species composition of the nodriza fleet is strongly influenced by the northwesterly circulation of the Humboldt Current along the coast of Peru and its associated cold waters masses. The target species and longline gear-type used by nodrizas change seasonally with the incursion of cool waters (< 25°C) from the south and offshore. During this season, dolphinfish (Coryphaena hippurus) dominates the catches. However, in warmer waters, the fishery changes to tuna-billfish-shark longline gear and the catch composition becomes much more diverse.

Type 2 diabetes poses an increasing public health burden in South Africa (SA) with obesity as the main driver of the epidemic. Consumption of sugar sweetened beverages (SSBs) is linked to weight gain and reducing SSB consumption may significantly impact the prevalence of obesity and related diseases. We estimated the effect of a 20% SSB tax on the burden of diabetes in SA.We constructed a life table-based model in Microsoft Excel (2010). Consumption data from the 2012 SA National Health and Nutrition Examination Survey, previously published own- and cross-price elasticities of SSBs and energy balance equations were used to estimate changes in daily energy intake and its projected impact on BMI arising from increased SSB prices. Diabetes 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 diabetes burden. Diabetes cost estimates were obtained from the South African Council for Medical Schemes. Over 20 years, a 20% SSB tax could reduce diabetes incident cases by 106 000 in women (95% uncertainty interval (UI) 70 000-142 000) and by 54 000 in men (95% UI: 33 000-80 000); and prevalence in all adults by 4.0% (95% UI: 2.7%-5.3%). Cumulatively over twenty years, approximately 21 000 (95% UI: 14 000-29 000) adult T2DM-related deaths, 374 000 DALYs attributed to T2DM (95% UI: 299 000-463 000) and over ZAR10 billion T2DM healthcare costs (95% UI: ZAR6.8-14.0 billion) equivalent to USD860 million (95% UI: USD570 million-USD1.2 billion) may be averted.Fiscal policy on SSBs has the potential to mitigate the diabetes epidemic in South Africa and contribute to the National Department of Health goals stated in the National NCD strategic plan.

ObjectiveTo quantify the poverty status and level of disadvantage experienced by Australians aged 45-64 years who have left the labour force due to diabetes in 2010.Research design and methodsA purpose-built microsimulation model, Health&WealthMOD2030, was used to estimate the poverty status and level of disadvantage of those aged 45-64 years who prematurely retire from the workforce due to diabetes. A multiple regression model was used to identify significant differences in rates of income poverty and the degree of disadvantage between those out of the labour force due to diabetes and those employed full- or part-time with no diabetes.Results63.9% of people aged 45-64 years who were out of the labour force due to diabetes were in poverty in 2010. The odds of being in poverty for those with no diabetes and employed full-time (OR of being in poverty 0.02 95%CI: 0.01-0.04) or part-time (OR of being in poverty 0.10 95%CI: 0.05-0.23) are significantly lower than those for persons not in the labour force due to diabetes. Amongst those with diabetes, those who were able to stay in either full- or part-time employment were as much as 97% less likely to be in poverty than those who had to retire early because of the condition. Sensitivity analysis was used to assess impacts of different poverty line thresholds and key socioeconomic predictors of poverty.ConclusionsThis study has shown that having diabetes and not being in the labour force because of this condition significantly increases the chances of living in poverty. Intervening to prevent or delay the onset of diabetes is likely to improve their living standards.

Background/objectivesThe prevalence of obesity in South Africa has risen sharply, as has the consumption of sugar-sweetened beverages (SSBs). Research shows that consumption of SSBs leads to weight gain in both adults and children, and reducing SSBs will significantly impact the prevalence of obesity and its related diseases. We estimated the effect of a 20% tax on SSBs on the prevalence of and obesity among adults in South Africa.MethodsA mathematical simulation model was constructed to estimate the effect of a 20% SSB tax on the prevalence of obesity. We used consumption data from the 2012 SA National Health and Nutrition Examination Survey and a previous meta-analysis of studies on own- and cross-price elasticities of SSBs to estimate the shift in daily energy consumption expected of increased prices of SSBs, and energy balance equations to estimate shifts in body mass index. The population distribution of BMI by age and sex was modelled by fitting measured data from the SA National Income Dynamics Survey 2012 to the lognormal distribution and shifting the mean values. Uncertainty was assessed with Monte Carlo simulations.ResultsA 20% tax is predicted to reduce energy intake by about 36 kJ per day (95% CI: 9-68 kJ). Obesity is projected to reduce by 3.8% (95% CI: 0.6%-7.1%) in men and 2.4% (95% CI: 0.4%-4.4%) in women. The number of obese adults would decrease by over 220 000 (95% CI: 24 197-411 759).ConclusionsTaxing SSBs could impact the burden of obesity in South Africa particularly in young adults, as one component of a multi-faceted effort to prevent obesity.

Swine influenza virus (SIV) has a strong tropism for pig respiratory mucosa, which consists of a mucus layer, epithelium, basement membrane and lamina propria. Sialic acids present on the epithelial surface have long been considered to be determinants of influenza virus tropism. However, mucus which is also rich in sialic acids may serve as the first barrier of selection. It was investigated how influenza virus interacts with the mucus to infect epithelial cells. Two techniques were applied to track SIV H1N1 in porcine mucus. The microscopic diffusion of SIV particles in the mucus was analyzed by single particle tracking (SPT), and the macroscopic penetration of SIV through mucus was studied by a virus in-capsule-mucus penetration system, followed by visualizing the translocation of the virions with time by immunofluorescence staining. Furthermore, the effects of neuraminidase on SIV getting through or binding to the mucus were studied by using zanamivir, a neuraminidase inhibitor (NAI), and Arthrobacter ureafaciens neuraminidase. The distribution of the diffusion coefficient shows that 70% of SIV particles were entrapped, while the rest diffused freely in the mucus. Additionally, SIV penetrated the porcine mucus with time, reaching a depth of 65 µm at 30 min post virus addition, 2 fold of that at 2 min. Both the microscopic diffusion and macroscopic penetration were largely diminished by NAI, while were clearly increased by the effect of exogenous neuraminidase. Moreover, the exogenous neuraminidase sufficiently prevented the binding of SIV to mucus which was reversely enhanced by effect of NAI. These findings clearly show that the neuraminidase helps SIV move through the mucus, which is important for the virus to reach and infect epithelial cells and eventually become shed into the lumen of the respiratory tract.

INTRODUCTION: Excessive alcohol consumption increases the risk of many diseases and injuries, and the Global Burden of Disease 2010 study estimated that 6% of the burden of disease in Denmark is due to alcohol consumption. Alcohol consumption thus places a considerable economic burden on society. METHODS: We analysed the cost-effectiveness of six interventions aimed at preventing alcohol abuse in the adult Danish population: 30% increased taxation, increased minimum legal drinking age, advertisement bans, limited hours of retail sales, and brief and longer individual interventions. Potential health effects were evaluated as changes in incidence, prevalence and mortality of alcohol-related diseases and injuries. Net costs were calculated as the sum of intervention costs and cost offsets related to treatment of alcohol-related outcomes, based on health care costs from Danish national registers. Cost-effectiveness was evaluated by calculating incremental cost-effectiveness ratios (ICERs) for each intervention. We also created an intervention pathway to determine the optimal sequence of interventions and their combined effects. RESULTS: Three of the analysed interventions (advertising bans, limited hours of retail sales and taxation) were cost-saving, and the remaining three interventions were all cost-effective. Net costs varied from € -17 million per year for advertisement ban to € 8 million for longer individual intervention. Effectiveness varied from 115 disability-adjusted life years (DALY) per year for minimum legal drinking age to 2,900 DALY for advertisement ban. The total annual effect if all interventions were implemented would be 7,300 DALY, with a net cost of € -30 million. CONCLUSION: Our results show that interventions targeting the whole population were more effective than individual-focused interventions. A ban on alcohol advertising, limited hours of retail sale and increased taxation had the highest probability of being cost-saving and should thus be first priority for implementation.

BackgroundTo examine the cost-effectiveness of providing laparoscopic adjustable gastric banding (LAGB) surgery to all morbidly obese adults in the 2003 Australian population.Methods and findingsAnalyzed costs and benefits associated with two intervention scenarios, one providing LAGB surgery to individuals with BMI >40 and another to individuals with BMI >35, with each compared relative to a 'do nothing' scenario. A multi-state, multiple cohort Markov model was used to determine the cost-effectiveness of LAGB surgery over the lifetime of each cohort. All costs and health outcomes were assessed from an Australian health sector perspective and were discounted using a 3% annual rate. Uncertainty and sensitivity analyzes were conducted to test the robustness of model outcomes. Incremental cost-effectiveness ratios (ICERs) were measured in 2003 Australian dollars per disability adjusted life year (DALY) averted. The ICER for the scenario providing LAGB surgery to all individuals with a BMI >40 was dominant [95% CI: dominant -$588] meaning that the intervention led to both improved health and cost savings. The ICER when providing surgery to those with a BMI >35 was $2,154/DALY averted [95% CI: dominant -$6,033]. Results were highly sensitive to changes in the likelihood of long-term complications.ConclusionLAGB surgery is highly cost-effective when compared to the $50,000/DALY threshold for cost-effectiveness used in Australia. LAGB surgery also ranks highly in terms of cost-effectiveness when compared to other population-level interventions for weight loss in Australia. The results of this study are in line with other economic evaluations on LAGB surgery. This study recommends that the Australian federal government provide a full subsidy for LAGB surgery to morbidly obese Australians with a BMI >40.

The utility of species distribution models for applications in invasion and global change biology is critically dependent on their transferability between regions or points in time, respectively. We introduce two methods that aim to improve the transferability of presence-only models: density-based occurrence thinning and performance-based predictor selection. We evaluate the effect of these methods along with the impact of the choice of model complexity and geographic background on the transferability of a species distribution model between geographic regions. Our multifactorial experiment focuses on the notorious invasive seaweed Caulerpa cylindracea (previously Caulerpa racemosa var. cylindracea) and uses Maxent, a commonly used presence-only modeling technique. We show that model transferability is markedly improved by appropriate predictor selection, with occurrence thinning, model complexity and background choice having relatively minor effects. The data shows that, if available, occurrence records from the native and invaded regions should be combined as this leads to models with high predictive power while reducing the sensitivity to choices made in the modeling process. The inferred distribution model of Caulerpa cylindracea shows the potential for this species to further spread along the coasts of Western Europe, western Africa and the south coast of Australia.

Pseudorabies virus (PRV) initially replicates in the porcine upper respiratory tract. It easily invades the mucosae and submucosae for subsequent spread throughout the body via blood vessels and nervous system. In this context, PRV developed ingenious processes to overcome different barriers such as epithelial cells and the basement membrane. Another important but often overlooked barrier is the substantial mucus layer which coats the mucosae. However, little is known about how PRV particles interact with porcine respiratory mucus. We therefore measured the barrier properties of porcine tracheal respiratory mucus, and investigated the mobility of nanoparticles including PRV in this mucus. We developed an in vitro model utilizing single particle tracking microscopy. Firstly, the mucus pore size was evaluated with polyethylene glycol coupled (PEGylated) nanoparticles and atomic force microscope. Secondly, the mobility of PRV in porcine tracheal respiratory mucus was examined and compared with that of negative, positive and PEGylated nanoparticles. The pore size of porcine tracheal respiratory mucus ranged from 80 to 1500 nm, with an average diameter of 455±240 nm. PRV (zeta potential: -31.8±1.5 mV) experienced a severe obstruction in porcine tracheal respiratory mucus, diffusing 59-fold more slowly than in water. Similarly, the highly negatively (-49.8±0.6 mV) and positively (36.7±1.1 mV) charged nanoparticles were significantly trapped. In contrast, the nearly neutral, hydrophilic PEGylated nanoparticles (-9.6±0.8 mV) diffused rapidly, with the majority of particles moving 50-fold faster than PRV. The mobility of the particles measured was found to be related but not correlated to their surface charge. Furthermore, PEGylated PRV (-13.8±0.9 mV) was observed to diffuse 13-fold faster than native PRV. These findings clearly show that the mobility of PRV was significantly hindered in porcine tracheal respiratory mucus, and that the obstruction of PRV was due to complex mucoadhesive interactions including charge interactions rather than size exclusion.

BACKGROUND: Many tropical marine macroalgae are reported from all three ocean basins, though these very wide distributions may simply be an artifact resulting from inadequate taxonomy that fails to take into account cryptic diversity. Alternatively, pantropical distributions challenge the belief of limited intrinsic dispersal capacity of marine seaweeds and the effectiveness of the north-south oriented continents as dispersal barriers. We aimed to re-assess the distribution of two allegedly circumtropical brown algae, Dictyota ciliolata and D. crenulata, and interpret the realized geographical range of the respective species in relation to their thermal tolerance and major tectonic and climatic events during the Cenozoic. METHODOLOGY/PRINCIPAL FINDINGS: Species delimitation was based on 184 chloroplast encoded psbA sequences, using a Generalized Mixed Yule Coalescent method. Phylogenetic relationships were inferred by analyzing a six-gene dataset. Divergence times were estimated using relaxed molecular clock methods and published calibration data. Distribution ranges of the species were inferred from DNA-confirmed records, complemented with credible literature data and herbarium vouchers. Temperature tolerances of the species were determined by correlating distribution records with local SST values. We found considerable conflict between traditional and DNA-based species definitions. Dictyota crenulata consists of several pseudocryptic species, which have restricted distributions in the Atlantic Ocean and Pacific Central America. In contrast, the pantropical distribution of D. ciliolata is confirmed and linked to its significantly wider temperature tolerance. CONCLUSIONS/SIGNIFICANCE: Tectonically driven rearrangements of physical barriers left an unequivocal imprint on the current diversity patterns of marine macroalgae, as witnessed by the D. crenulata-complex. The nearly circumglobal tropical distribution of D. ciliolata, however, demonstrates that the north-south oriented continents do not present absolute dispersal barriers for species characterized by wide temperature tolerances.

BackgroundHerpes simplex virus infections are highly prevalent in humans. However, the current therapeutics suffer important drawbacks such as limited results in neonates, increasing occurrence of resistance and impeded treatment of stromal infections. Remarkably, interactions of herpesviruses with human mucosa, the locus of infection, remain poorly understood and the underlying mechanisms in stromal infection remain controversial.Methodology/principal findingsA human model consisting of nasal respiratory mucosa explants was characterised. Viability and integrity were examined during 96 h of cultivation. HSV1-mucosa interactions were analysed. In particular, we investigated whether HSV1 is able to reach the stroma. Explant viability and integrity remained preserved. HSV1 induced rounding up and loosening of epithelial cells with very few apoptotic and necrotic cells observed. Following 16-24 h of infection, HSV1 penetrated the basement membrane and replicated in the underlying lamina propria.Conclusions/significanceThis human explant model can be used to study virus-mucosa interactions and viral mucosal invasion mechanisms. Using this model, our results provide a novel insight into the HSV1 stromal invasion mechanism and for the first time directly demonstrate that HSV1 can penetrate the basement membrane.

AIMS: Obesity causes a high disease burden in Australia and across the world. We aimed to analyse the cost-effectiveness of weight reduction with pharmacotherapy in Australia, and to assess its potential to reduce the disease burden due to excess body weight. METHODS: We constructed a multi-state life-table based Markov model in Excel in which body weight influences the incidence of stroke, ischemic heart disease, hypertensive heart disease, diabetes mellitus, osteoarthritis, post-menopausal breast cancer, colon cancer, endometrial cancer and kidney cancer. We use data on effectiveness identified from PubMed searches, on mortality from Australian Bureau of Statistics, on disease costs from the Australian Institute of Health and Welfare, and on drug costs from the Department of Health and Ageing. We evaluate 1-year pharmacological interventions with sibutramine and orlistat targeting obese Australian adults free of obesity-related disease. We use a lifetime horizon for costs and health outcomes and a health sector perspective for costs. Incremental Cost-Effectiveness Ratios (ICERs) below A$50 000 per Disability Adjusted Life Year (DALY) averted are considered good value for money. RESULTS: The ICERs are A$130 000/DALY (95% uncertainty interval [UI] 93 000-180 000) for sibutramine and A$230 000/DALY (170 000-340 000) for orlistat. The interventions reduce the body weight-related disease burden at the population level by 0.2% and 0.1%, respectively. Modest weight loss during the interventions, rapid post-intervention weight regain and low adherence limit the health benefits. CONCLUSIONS: Treatment with sibutramine or orlistat is not cost-effective from an Australian health sector perspective and has a negligible impact on the total body weight-related disease burden.

Fruits and vegetables are an essential part of the human diet, but many people do not consume the recommended serves to prevent cardiovascular disease and cancer. In this research, we evaluate the cost-effectiveness of interventions to promote fruit and vegetable consumption to determine which interventions are good value for money, and by how much current strategies can reduce the population disease burden.In a review of published literature, we identified 23 interventions for promoting fruit and vegetable intake in the healthy adult population that have sufficient evidence for cost-effectiveness analysis. For each intervention, we model the health impacts in disability-adjusted life years (DALYs), the costs of intervention and the potential cost-savings from averting disease treatment, to determine cost-effectiveness of each intervention over the lifetime of the population, from an Australian health sector perspective. Interventions that rely on dietary counselling, telephone contact, worksite promotion or other methods to encourage change in dietary behaviour are not highly effective or cost-effective. Only five out of 23 interventions are less than an A$50,000 per disability-adjusted life year cost-effectiveness threshold, and even the most effective intervention can avert only 5% of the disease burden attributed to insufficient fruit and vegetable intake.We recommend more investment in evaluating interventions that address the whole population, such as changing policies influencing price or availability of fruits and vegetables, to see if these approaches can provide more effective and cost-effective incentives for improving fruit and vegetable intake.

Catheter-related bloodstream infection (CRBSI) results in significant attributable morbidity and mortality. In this randomized, double-blind, placebo-controlled trial, we studied the efficacy and safety of a daily ethanol lock for the prevention of CRBSI in patients with a tunnelled central venous catheter (CVC).From 2005 through 2008, each lumen of the CVC of adult hematology patients was locked for 15 minutes per day with either 70%-ethanol or placebo, where after the lock solution was flushed through. As a primary endpoint, the incidence rates of endoluminal CRBSI were compared.The intent-to-treat analysis was based on 376 patients, accounting for 448 CVCs and 27,745 catheter days. For ethanol locks, the incidence of endoluminal CRBSI per 1000 CVC-days was 0.70 (95%-CI, 0.4-1.3), compared to 1.19 (95% confidence interval, 0.7-1.9) for placebo (incidence rate-ratio, 0.59; 95% confidence interval, 0.27-1.30; P = .19). For endoluminal CRBSI according to the strictest definition (positive hub culture and identical bacterial strain in blood), a 3.6-fold, non-significant, reduction was observed for patients receiving ethanol (2 of 226 versus 7 of 222; P = .103). No life-threatening adverse events were observed. More patients receiving ethanol discontinued lock-therapy (11 of 226 versus 1 of 222; P = .006) or continued with decreased lock-frequency (10 of 226 versus 0 of 222; P = .002), due to non-severe adverse events.In this study, the reduction in the incidence of endoluminal CRBSI using preventive ethanol locks was non-significant, although the low incidence of endoluminal CRBSI precludes definite conclusions. Therefore, the lack of statistical significance may partially reflect a lack of power. Significantly more patients treated with ethanol locks discontinued their prophylactic treatment due to adverse effects, which were non-severe but reasonably ethanol related. Additional studies should be performed in populations with higher incidence of (endoluminal) CRBSI. Alternative sources of bacteremia, like exoluminal CRBSI or microbial translocation during chemotherapy-induced mucositis may have been more important in our patients.ClinicalTrials.gov NCT00122642.