A cost-effectiveness analysis of lung cancer screening with low-dose computed tomography and a polygenic risk score.

INTRODUCTION: Several studies have proved that Polygenic Risk Score (PRS) is a potential candidate for realizing precision screening. The effectiveness of low-dose computed tomography (LDCT) screening for lung cancer has been proved to reduce lung cancer specific and overall mortality, but the cost-effectiveness of diverse screening strategies remained unclear. METHODS: The comparative cost-effectiveness analysis used a Markov state-transition model to assess the potential effect and costs of the screening strategies incorporating PRS or not. A hypothetical cohort of 300,000 heavy smokers entered the study at age 50-74 years and were followed up until death or age 79 years. The model was run with a cycle length of 1 year. All the transition probabilities were validated and the performance value of PRS was extracted from published literature. A societal perspective was adopted and cost parameters were derived from databases of local medical insurance bureau. Sensitivity analyses and scenario analyses were conducted. RESULTS: The strategy incorporating PRS was estimated to obtain an ICER of CNY 156,691.93 to CNY 221,741.84 per QALY gained compared with non-screening with the initial start age range across 50-74 years. The strategy that screened using LDCT alone from 70-74 years annually could obtain an ICER of CNY 80,880.85 per QALY gained, which was the most cost-effective strategy. The introduction of PRS as an extra eligible criteria was associated with making strategies cost-saving but also lose the capability of gaining more LYs compared with LDCT screening alone. CONCLUSION: The PRS-based conjunctive screening strategy for lung cancer screening in China was not cost-effective using the willingness-to-pay threshold of 1 time Gross Domestic Product (GDP) per capita, and the optimal screening strategy for lung cancer still remains to be LDCT screening for now. Further optimization of the screening modality can be useful to consider adoption of PRS and prospective evaluation remains a research priority.

Cost-Effectiveness of a Government Policy to Incentivise Chronic Disease Management following Stroke: A Modelling Study.

INTRODUCTION: Little is known about the cost-effectiveness of government policies that support primary care physicians to provide comprehensive chronic disease management (CDM). This paper aimed to estimate the potential cost-effectiveness of CDM policies over a lifetime for long-time survivors of stroke. METHODS: A Markov model, using three health states (stable, hospitalised, dead), was developed to simulate the costs and benefits of CDM policies over 30 years (with 1-year cycles). Transition probabilities and costs from a health system perspective were obtained from the linkage of data between the Australian Stroke Clinical Registry (cohort n = 12,368, 42% female, median age 70 years, 45% had CDM claims) and government-held hospital, Medicare, and pharmaceutical claims datasets. Quality-adjusted life years (QALYs) were obtained from a comparable cohort (n = 512, 34% female, median age 69.6 years, 52% had CDM claims) linked with Medicare claims and death data. A 3% discount rate was applied to costs in Australian dollars (AUD, 2016) and QALYs beyond 12 months. Probabilistic sensitivity analyses were used to understand uncertainty. RESULTS: Per-person average total lifetime costs were AUD 142,939 and 8.97 QALYs for those with a claim, and AUD 103,889 and 8.98 QALYs for those without a claim. This indicates that these CDM policies were costlier without improving QALYs. The probability of cost-effectiveness of CDM policies was 26.1%, at a willingness-to-pay threshold of AUD 50,000/QALY. CONCLUSION: CDM policies, designed to encourage comprehensive care, are unlikely to be cost-effective for stroke compared to care without CDM. Further research to understand how to deliver such care cost-effectively is needed.

Modelling cost-effectiveness of replacement strategies for ambulance services in the Ministry of Health Malaysia.

BACKGROUND: Emergency Medical Service (EMS) is a very crucial aspect of the healthcare system in providing urgent management and transportation of patients during emergencies. The sustainability of the services is however greatly impacted by the quality and age of ambulances. While this has led to numerous replacement policy recommendations, the implementations are often limited due to a lack of evidence and financial constraints. This study thus aims to develop a cost-effectiveness model and testing the model by evaluating the cost-effectiveness of 10-year and 15-year compulsory ambulance replacement strategies in public healthcare for the Malaysian Ministry of Health (MOH). METHODS: A Markov model was developed to estimate the cost and outcomes ambulance replacement strategies over a period of 20 years. The model was tested using two alternative strategies of 10-year and 15-year. Model inputs were derived from published literature and local study. Model development and economic analysis were accomplished using Microsoft Excel 2016. The outcomes generated were costs per year, the number of missed trips and the number of lives saved, in addition to the Incremental Cost-Effectiveness Ratio (ICER). One-Way Deterministic Sensitivity Analysis (DSA) and Probabilistic Sensitivity Analysis (PSA) were conducted to identify the key drivers and to assess the robustness of the model. RESULTS: Findings showed that the most expensive strategy, which is the implementation of 10 years replacement strategy was more cost-effective than 15 years ambulance replacement strategy, with an ICER of MYR 11,276.61 per life saved. While an additional MYR 13.0 million would be incurred by switching from a 15- to 10-year replacement strategy, this would result in 1,157 deaths averted or additional live saved per year. Sensitivity analysis showed that the utilization of ambulances and the mortality rate of cases unattended by ambulances were the key drivers for the cost-effectiveness of the replacement strategies. CONCLUSIONS: The cost-effectiveness model developed suggests that an ambulance replacement strategy of every 10 years should be considered by the MOH in planning sustainable EMS. While this model may have its own limitation and may require some modifications to suit the local context, it can be used as a guide for future economic evaluations of ambulance replacement strategies and further exploration of alternative solutions.

Cost-effectiveness of population screening for atrial fibrillation: the STROKESTOP study.

AIMS: Previous studies on the cost-effectiveness of screening for atrial fibrillation (AF) are based on assumptions of long-term clinical effects. The STROKESTOP study, which randomised 27 975 persons aged 75/76 years into a screening invitation group and a control group, has a median follow-up time of 6.9 years. The aim of this study was to estimate the cost-effectiveness of population-based screening for AF using clinical outcomes. METHODS AND RESULTS: The analysis is based on a Markov cohort model. The prevalence of AF, the use of oral anticoagulation, clinical event data, and all-cause mortality were taken from the STROKESTOP study. The cost for clinical events, age-specific utilities, utility decrement due to stroke, and stroke death was taken from the literature. Uncertainty in the model was considered in a probabilistic sensitivity analysis. Per 1000 individuals invited to the screening, there were 77 gained life years and 65 gained quality-adjusted life years. The incremental cost was €1.77 million lower in the screening invitation group. Gained quality-adjusted life years to a lower cost means that the screening strategy was dominant. The result from 10 000 Monte Carlo simulations showed that the AF screening strategy was cost-effective in 99.2% and cost-saving in 92.7% of the simulations. In the base-case scenario, screening of 1000 individuals resulted in 10.6 [95% confidence interval (CI): -22.5 to 1.4] fewer strokes (8.4 ischaemic and 2.2 haemorrhagic strokes), 1.0 (95% CI: -1.9 to 4.1) more cases of systemic embolism, and 2.9 (95% CI: -18.2 to 13.1) fewer bleedings associated with hospitalization. CONCLUSION: Based on the STROKESTOP study, this analysis shows that a broad AF screening strategy in an elderly population is cost-effective. Efforts should be made to increase screening participation.

Accounting for behaviour in fine-scale habitat selection: A case study highlighting methodological intricacies.

Animal habitat selection-central in both theoretical and applied ecology-may depend on behavioural motivations such as foraging, predator avoidance, and thermoregulation. Step-selection functions (SSFs) enable assessment of fine-scale habitat selection as a function of an animal's movement capacities and spatiotemporal variation in extrinsic conditions. If animal location data can be associated with behaviour, SSFs are an intuitive approach to quantify behaviour-specific habitat selection. Fitting SSFs separately for distinct behavioural states helped to uncover state-specific selection patterns. However, while the definition of the availability domain has been highlighted as the most critical aspect of SSFs, the influence of accounting for behaviour in the use-availability design has not been quantified yet. Using a predator-free population of high-arctic muskoxen Ovibos moschatus as a case study, we aimed to evaluate how (1) defining behaviour-specific availability domains, and/or (2) fitting separate behaviour-specific models impacts (a) model structure, (b) estimated selection coefficients and (c) model predictive performance as opposed to behaviour-unspecific approaches. To do so, we first applied hidden Markov models to infer different behavioural modes (resting, foraging, relocating) from hourly GPS positions (19 individuals, 153-1062 observation days/animal). Using SSFs, we then compared behaviour-specific versus behaviour-unspecific habitat selection in relation to terrain features, vegetation and snow conditions. Our results show that incorporating behaviour into the definition of the availability domain primarily impacts model structure (i.e. variable selection), whereas fitting separate behaviour-specific models mainly influences selection strength. Behaviour-specific availability domains improved predictive performance for foraging and relocating models (i.e. behaviours with medium to large spatial displacement), but decreased performance for resting models. Thus, even for a predator-free population subject to only negligible interspecific competition and human disturbance we found that accounting for behaviour in SSFs impacted model structure, selection coefficients and predictive performance. Our results indicate that for robust inference, both a behaviour-specific availability domain and behaviour-specific model fitting should be explored, especially for populations where strong spatiotemporal selection trade-offs are expected. This is particularly critical if wildlife habitat preferences are estimated to inform management and conservation initiatives.

Balance between competing spectral states in subthalamic nucleus is linked to motor impairment in Parkinson's disease.

Exaggerated local field potential bursts of activity at frequencies in the low beta band are a well-established phenomenon in the subthalamic nucleus of patients with Parkinson's disease. However, such activity is only moderately correlated with motor impairment. Here we test the hypothesis that beta bursts are just one of several dynamic states in the subthalamic nucleus local field potential in Parkinson's disease, and that together these different states predict motor impairment with high fidelity. Local field potentials were recorded in 32 patients (64 hemispheres) undergoing deep brain stimulation surgery targeting the subthalamic nucleus. Recordings were performed following overnight withdrawal of anti-parkinsonian medication, and after administration of levodopa. Local field potentials were analysed using hidden Markov modelling to identify transient spectral states with frequencies under 40 Hz. Findings in the low beta frequency band were similar to those previously reported; levodopa reduced occurrence rate and duration of low beta states, and the greater the reductions, the greater the improvement in motor impairment. However, additional local field potential states were distinguished in the theta, alpha and high beta bands, and these behaved in an opposite manner. They were increased in occurrence rate and duration by levodopa, and the greater the increases, the greater the improvement in motor impairment. In addition, levodopa favoured the transition of low beta states to other spectral states. When all local field potential states and corresponding features were considered in a multivariate model it was possible to predict 50% of the variance in patients' hemibody impairment OFF medication, and in the change in hemibody impairment following levodopa. This only improved slightly if signal amplitude or gamma band features were also included in the multivariate model. In addition, it compares with a prediction of only 16% of the variance when using beta bursts alone. We conclude that multiple spectral states in the subthalamic nucleus local field potential have a bearing on motor impairment, and that levodopa-induced shifts in the balance between these states can predict clinical change with high fidelity. This is important in suggesting that some states might be upregulated to improve parkinsonism and in suggesting how local field potential feedback can be made more informative in closed-loop deep brain stimulation systems.

Energy-mediated responses to changing prey size and distribution in marine top predator movements and population dynamics.

Climate change is modifying the structure of marine ecosystems, including that of fish communities. Alterations in abiotic and biotic conditions can decrease fish size and change community spatial arrangement, ultimately impacting predator species which rely on these communities. To conserve predators and understand the drivers of observed changes in their population dynamics, we must advance our understanding of how shifting environmental conditions can impact populations by limiting food available to individuals. To investigate the impacts of changing fish size and spatial aggregation on a top predator population, we applied an existing agent-based model parameterized for harbour porpoises Phocoena phocoena which represents animal energetics and movements in high detail. We used this framework to quantify the impacts of shifting prey size and spatial aggregation on porpoise movement, space use, energetics and population dynamics. Simulated individuals were more likely to switch from area-restricted search to transit behaviour with increasing prey size, particularly when starving, due to elevated resource competition. In simulations with highly aggregated prey, higher prey encounter rates counteracted resource competition, resulting in no impacts of prey spatial aggregation on movement behaviour. Reduced energy intake with decreasing prey size and aggregation level caused population decline, with a 15% decrease in fish length resulting in total population collapse Increasing prey consumption rates by 42.8 ± 4.5% could offset population declines; however, this increase was 21.3 ± 12.7% higher than needed to account for changes in total energy availability alone. This suggests that animals in realistic seascapes require additional energy to locate smaller prey which should be considered when assessing the impacts of decreased energy availability. Changes in prey size and aggregation influenced movements and population dynamics of simulated harbour porpoises, revealing that climate-induced changes in prey structure, not only prey abundance, may threaten predator populations. We demonstrate how a population model with realistic animal movements and process-based energetics can be used to investigate population consequences of shifting food availability, such as those mediated by climate change, and provide a mechanistic explanation for how changes in prey structure can impact energetics, behaviour and ultimately viability of predator populations.

Single-molecule FRET dynamics of molecular motors in an ABEL trap.

Single-molecule Förster resonance energy transfer (smFRET) of molecular motors provides transformative insights into their dynamics and conformational changes both at high temporal and spatial resolution simultaneously. However, a key challenge of such FRET investigations is to observe a molecule in action for long enough without restricting its natural function. The Anti-Brownian ELectrokinetic Trap (ABEL trap) sets out to combine smFRET with molecular confinement to enable observation times of up to several seconds while removing any requirement of tethered surface attachment of the molecule in question. In addition, the ABEL trap's inherent ability to selectively capture FRET active molecules accelerates the data acquisition process. In this work we exemplify the capabilities of the ABEL trap in performing extended timescale smFRET measurements on the molecular motor Rep, which is crucial for removing protein blocks ahead of the advancing DNA replication machinery and for restarting stalled DNA replication. We are able to monitor single Rep molecules up to 6 seconds with sub-millisecond time resolution capturing multiple conformational switching events during the observation time. Here we provide a step-by-step guide for the rational design, construction and implementation of the ABEL trap for smFRET detection of Rep in vitro. We include details of how to model the electric potential at the trap site and use Hidden Markov analysis of the smFRET trajectories.

Identification of Latent Alcohol Use Groups and Transitions over Time Using a 9-Year Follow-Up Study in the Adult General Population.

INTRODUCTION: Studies investigating latent alcohol use groups and transitions of these groups over time are scarce, while such knowledge could facilitate efficient use of screening and preventive interventions for groups with a high risk of problematic alcohol use. Therefore, the present study examines the characteristics, transitions, and long-term stability of adult alcohol use groups and explores some of the possible predictors of the transitions. METHODS: Data were used from the baseline, 3-, 6-, and 9-year follow-up waves of the Netherlands Mental Health Survey and Incidence Study-2 (NEMESIS-2), a representative study of Dutch adults aged 18-64 at baseline (N = 6,646; number of data points: 20,574). Alcohol consumption, alcohol use disorder (AUD), and mental disorders were assessed with the Composite International Diagnostic Interview 3.0. Latent Markov Modelling was used to identify latent groups based on high average alcohol consumption (HAAC) and AUD and to determine transition patterns of people between groups over time (stayers vs. movers). RESULTS: The best fitting model resulted in four latent groups: one nonproblematic group (91%): no HAAC, no AUD; and three problematic alcohol use groups (9%): HAAC, no AUD (5%); no HAAC, often AUD (3%); and HAAC and AUD (1%). HAAC, no AUD was associated with a high mean age (55 years) and low educational level (41%), and no HAAC, often AUD with high proportions of males (78%) and people with high educational level (46%). Eighty-seven percent of all respondents - mostly people with no HAAC, no AUD - stayed in their original group during the whole 9-year period. Among movers, people in a problematic alcohol use group (HAAC and/or AUD) mostly transitioned to another problematic alcohol use group and not to the nonproblematic alcohol use group (no HAAC, no AUD). Explorative analyses suggested that lack of physical activity possibly plays a role in transitions both from and to problematic alcohol use groups over time. CONCLUSION: The detection of three problematic alcohol use groups - with transitions mostly between the different problematic alcohol use groups and not to the group without alcohol problems - points to the need to explicitly address both alcohol consumption and alcohol-related problems (AUD criteria) in screening measures and interventions in order not to miss and to adequately treat all problematic alcohol users. Moreover, explorative findings suggest that prevention measures should also include physical activity.

Transient spectral events in resting state MEG predict individual task responses.

Even in response to simple tasks such as hand movement, human brain activity shows remarkable inter-subject variability. Recently, it has been shown that individual spatial variability in fMRI task responses can be predicted from measurements collected at rest; suggesting that the spatial variability is a stable feature, inherent to the individual's brain. However, it is not clear if this is also true for individual variability in the spatio-spectral content of oscillatory brain activity. Here, we show using MEG (N â€‹= â€‹89) that we can predict the spatial and spectral content of an individual's task response using features estimated from the individual's resting MEG data. This works by learning when transient spectral 'bursts' or events in the resting state tend to reoccur in the task responses. We applied our method to motor, working memory and language comprehension tasks. All task conditions were predicted significantly above chance. Finally, we found a systematic relationship between genetic similarity (e.g. unrelated subjects vs. twins) and predictability. Our approach can predict individual differences in brain activity and suggests a link between transient spectral events in task and rest that can be captured at the level of individuals.

Hypothetical treatment of patients with non-alcoholic steatohepatitis: Potential impact on important clinical outcomes.

BACKGROUND & AIMS: Currently, standard of care (SOC) treatment for NASH is limited to lifestyle modifications. Drug regimens are being evaluated currently. We assessed the impact of a short-term hypothetical treatment on clinical outcomes of NASH. METHODS: Markov models estimated differences in outcomes between SOC and 2 hypothetical NASH treatments (A and B). We modelled 10 000 50-year-old biopsy-proven NASH patients over lifetime horizon. Health states included NASH with fibrosis (F1-F3), cirrhosis, hepatocellular carcinoma, liver transplant and mortality. Fibrosis Regression Factor (FRF) variable modelled the probability of 1-3 stage fibrosis improvement with treatment. Annual probability of treatment (ATP) ranged from 10%-70%. Treatment success was defined as regression to fibrosis, whereas failure was defined as progression to stages beyond cirrhosis. In treatment-A, successful treatment was followed by a maintenance regimen which stopped disease progression. After a successful treatment-B, patients remained at risk of disease progression. Differences in outcomes were calculated between both treatments and SOC models. We conducted a probabilistic sensitivity analysis. RESULTS: At 10% to 70% ATP, treatment-A averts 353 to 782 liver transplants and 1277 to 2381 liver-related deaths relative to SOC. Treatment-B averts 129 to 437 liver transplants and 386 to 1043 liver-related deaths. Sensitivity analysis shows our model is robust in estimating liver-related mortality and LTs averted, but is sensitive when estimating QALYs gained. CONCLUSIONS: With a small annual probability of treatment and FRF = 1, a 2-year treatment followed by maintenance of histologic improvement for patients would be highly beneficial relative to short-term treatment alone.

Ontogenetic shifts in the nesting behaviour of female crocodiles.

Body size and age are crucial factors influencing reproductive capacity and success. As females grow, their reproductive investment and success often increase due to improved overall physiological condition and experience gained through successive reproductive events. While much of this work has been conducted on birds and mammals, surprisingly little is known on how body size affects nesting decisions in other long-lived vertebrates. We monitored the movements and nesting behaviour of 57 wild female estuarine crocodiles Crocodylus porosus over a 10-year period (and across consecutive nesting seasons) using externally mounted satellite tags, implanted acoustic transmitters and a network of submerged acoustic receivers. Applying Hidden Markov models to the telemetry-derived location data revealed that female nesting behaviours could be split into three distinct states: (i) ranging movements within home ranges and at nesting sites; (ii) migrations to and from nesting sites; (iii) and nesting/nest guarding. We found that during migration events, larger females migrated further and remained away from dry season territories for longer periods than smaller individuals. Furthermore, not only were migratory movements stimulated by increases in rainfall, larger females migrated to nest sites at lower rainfall thresholds than smaller females. We provide some of the first evidence of body size influencing nesting decisions in an ectothermic vertebrate, with shifts likely resulting from an increased willingness to invest in nest protection among larger and more experienced females.

Future complications of chronic hepatitis C in a low-risk area: projections from the hepatitis c study in Northern Norway.

BACKGROUND: Hepatitis C (HCV) infection causes an asymptomatic chronic hepatitis in most affected individuals, which often remains undetected until cirrhosis and cirrhosis-related complications occur. Screening of high-risk subjects in Northern Norway has revealed a relatively low prevalence in the general population (0.24%). Despite this, late complications of HCV infection are increasing. Our object was to estimate the future prevalence and complications of chronic HCV infection in the period 2013-2050 in a low-risk area. METHODS: We have entered available data into a prognostic Markov model to project future complications to HCV infection. RESULTS: The model extrapolates the prevalence in the present cohort of HCV-infected individuals, and assumes a stable low incidence in the projection period. We predict an almost three-fold increase in the incidence of cirrhosis (68 per 100,000), of decompensated cirrhosis (21 per 100,000) and of hepatocellular carcinoma (4 per 100,000) by 2050, as well as a six-fold increase in the cumulated number of deaths from HCV-related liver disease (170 per 100,000 inhabitants). All estimates are made assuming an unchanged treatment coverage of approximately 15%. The estimated numbers can be reduced by approximately 50% for cirrhosis, and by approximately one third for the other endpoints if treatment coverage is raised to 50%. CONCLUSION: These projections from a low-prevalence area indicate a substantial rise in HCV-related morbidity and mortality in the coming years. The global HCV epidemic is of great concern and increased treatment coverage is necessary to reduce the burden of the disease.

Is bronchial thermoplasty cost-effective as treatment for problematic asthma patients? Singapore's perspective on a global model.

BACKGROUND AND OBJECTIVE: Bronchial thermoplasty (BT) has been shown to be effective at reducing asthma exacerbations and improving asthma control for patients with severe persistent asthma but it is also expensive. Evidence on its cost-effectiveness is limited and inconclusive. In this study, we aim to evaluate the incremental cost-effectiveness of BT combined with optimized asthma therapy (BT-OAT) relative to OAT for difficult-to-treat and severe asthma patients in Singapore, and to provide a general framework for determining BT's cost-effectiveness in other healthcare settings. METHODS: We developed a Markov model to estimate the costs and quality-adjusted life years (QALYs) gained with BT-OAT versus OAT from the societal and health system perspectives. The model was populated using Singapore-specific costs and transition probabilities and utilities from the literature. Sensitivity analyses were conducted to identify the main factors determining cost-effectiveness of BT-OAT. RESULTS: BT-OAT is not cost-effective relative to OAT over a 5-year time horizon with an incremental cost-effectiveness ratio (ICER) of $US138 889 per QALY from the societal perspective and $US139 041 per QALY from the health system perspective. The cost-effectiveness of BT-OAT largely depends on a combination of the cost of the BT procedure and the cost of asthma-related hospitalizations and emergency department (ED) visits. CONCLUSION: Based on established thresholds for cost-effectiveness, BT-OAT is not cost-effective compared with OAT in Singapore. Given its current clinical efficacy, BT-OAT is most likely to be cost-effective in a setting where the cost of BT procedure is low and costs of hospitalization and ED visits are high.

Cost-effectiveness of medical primary prevention strategies to reduce absolute risk of cardiovascular disease in Tanzania: a Markov modelling study.

BACKGROUND: Cardiovascular disease (CVD) is a growing cause of mortality and morbidity in Tanzania, but contextualized evidence on cost-effective medical strategies to prevent it is scarce. We aim to perform a cost-effectiveness analysis of medical interventions for primary prevention of CVD using the World Health Organization's (WHO) absolute risk approach for four risk levels. METHODS: The cost-effectiveness analysis was performed from a societal perspective using two Markov decision models: CVD risk without diabetes and CVD risk with diabetes. Primary provider and patient costs were estimated using the ingredients approach and step-down methodologies. Epidemiological data and efficacy inputs were derived from systematic reviews and meta-analyses. We used disability- adjusted life years (DALYs) averted as the outcome measure. Sensitivity analyses were conducted to evaluate the robustness of the model results. RESULTS: For CVD low-risk patients without diabetes, medical management is not cost-effective unless willingness to pay (WTP) is higher than US$1327 per DALY averted. For moderate-risk patients, WTP must exceed US$164 per DALY before a combination of angiotensin converting enzyme inhibitor (ACEI) and diuretic (Diu) becomes cost-effective, while for high-risk and very high-risk patients the thresholds are US$349 (ACEI, calcium channel blocker (CCB) and Diu) and US$498 per DALY (ACEI, CCB, Diu and Aspirin (ASA)) respectively. For patients with CVD risk with diabetes, a combination of sulfonylureas (Sulf), ACEI and CCB for low and moderate risk (incremental cost-effectiveness ratio (ICER) US$608 and US$115 per DALY respectively), is the most cost-effective, while adding biguanide (Big) to this combination yielded the most favourable ICERs of US$309 and US$350 per DALY for high and very high risk respectively. For the latter, ASA is also part of the combination. CONCLUSIONS: Medical preventive cardiology is very cost-effective for all risk levels except low CVD risk. Budget impact analyses and distributional concerns should be considered further to assess governments' ability and to whom these benefits will accrue.

Modelling the cost-effectiveness of a new infant vaccine to prevent tuberculosis disease in children in South Africa.

BACKGROUND: Tuberculosis remains the leading cause of death in South Africa. A number of potential new TB vaccine candidates have been identified and are currently in clinical trials. One such candidate is MVA85A. This study aimed to estimate the cost-effectiveness of adding the MVA85A vaccine as a booster to the BCG vaccine in children from the perspective of the South African government. METHODS: The cost-effectiveness was assessed by employing Decision Analytic Modelling, through the use of a Markov model. The model compared the existing strategy of BCG vaccination to a new strategy in which infants receive BCG and a booster vaccine, MVA85A, at 4 months of age. The costs and outcomes of the two strategies are estimated through modelling the vaccination of a hypothetical cohort of newborns and following them from birth through to 10 years of age, employing 6-monthly cycles. RESULTS: The results of the cost-effectiveness analysis indicate that the MVA85A strategy is both more costly and more effective - there are fewer TB cases and deaths from TB than BCG alone. The South African government would need to spend an additional USD 1,105 for every additional TB case averted and USD 284,017 for every additional TB death averted. The threshold analysis shows that, if the efficacy of the MVA85A vaccine was 41.3% (instead of the current efficacy of 17.3%), the two strategies would have the same cost but more cases of TB and more deaths from TB would be prevented by adding the MVA85A vaccine to the BCG vaccine. In this case, the government chould consider the MVA85A strategy. CONCLUSIONS: At the current level of efficacy, the MVA85A vaccine is neither effective nor cost-effective and, therefore, not a good use of limited resources. Nevertheless, this study contributes to developing a standardized Markov model, which could be used, in the future, to estimate the potential cost-effectiveness of new TB vaccines compared to the BCG vaccine, in children between the ages of 0-10 years. It also provides an indicative threshold of vaccine efficacy, which could guide future development.

Transitions to polysubstance use: Prospective cohort study of adolescents in Australia.

BACKGROUND AND AIMS: Adolescent polysubstance use has been associated with adverse social and health outcomes. Our aim was to measure rates and transitions to polysubstance use during adolescence and identify factors associated with initiation and discontinuation of polysubstance use. DESIGN: Prospective cohort study. Multistate Markov modelling was used to estimate rates and identify correlates of transitions between substance use states. SETTING AND PARTICIPANTS: Adolescent-parent dyads (n = 1927; adolescents in grade 7, age ≈13 years) were recruited from Australian schools during 2010/11 (Wave 1). Adolescents were surveyed annually until 2016/17 (n = 1503; age ≈19 years; Wave 7) and parents were surveyed annually until 2014/15 (Wave 5). MEASUREMENTS: Alcohol, tobacco, cannabis and 3,4-methylenedioxymethamphetamine (MDMA) use outcomes were collected at Waves 3-7. Potential confounders were collected at Waves 1-6 and consisted of sex, anxiety and depression symptoms and externalizing problems, parental monitoring, family conflict and cohesion, parental substance use and peer substance use. Covariates were age and family socioeconomic status. FINDINGS: Few adolescents engaged in polysubstance use at earlier waves (Wave 3: 5%; Wave 4: 8%), but proportions increased sharply across adolescence (Waves 5-7: 17%, 24%, 36%). Rates of transitioning to polysubstance use increased with age, with few (<9%) adolescents transitioning out. More externalizing problems (odds ratio [OR] = 1.10; 99.6% confidence interval [CI] = 1.07-1.14), parental heavy episodic drinking (OR = 1.22; 99.6% CI = 1.07-1.40), parental illicit substance use (OR = 3.56; 99.6% CI = 1.43-8.86), peer alcohol use (OR = 5.68; 99.6% CI = 1.59-20.50) and peer smoking (OR = 4.18; 99.6% CI = 1.95-8.81) were associated with transitioning to polysubstance use. CONCLUSIONS: Polysubstance use in Australia appears to be rare during early adolescence but more common in later adolescence with low rates of transitioning out. Externalizing problems and greater parental and peer substance use are risk factors for adolescent polysubstance use that may be suitable intervention targets.

Population-level detection of early loss of kidney function: 7-year follow-up of a young adult cohort at risk of Mesoamerican nephropathy.

BACKGROUND: Mesoamerican nephropathy is a leading contributor to premature mortality in Central America. Efforts to identify the cause are hampered by difficulties in distinguishing associations with potential initiating factors from common exposures thought to exacerbate the progression of all forms of established chronic kidney disease (CKD). We explored evidence of disease onset or departure from the healthy estimated glomerular filtration rate distribution [departure from ∼eGFR(healthy)] in an at-risk population. METHODS: Two community-based cohorts (adults aged 18-30 years, n = 351 and 420) from 11 rural communities in Northwest Nicaragua were followed up over 7 and 3 years respectively. We examined associations with both (i) incident CKD and (ii) the time point of departure from ∼eGFR(healthy), using a hidden Markov model. RESULTS: CKD occurred in men only (male incidence rate: 0.7%/year). Fifty-three (out of 1878 visits, 2.7%) and 8 (out of 1067 visits, 0.8%) episodes of probable departure from ∼eGFR(healthy) occurred in men and women, respectively. Cumulative time in sugarcane work and symptoms of excess occupational sun exposure were associated with incident CKD. The same exposures were associated with probability of departure from ∼eGFR(healthy) in time-updated analyses along with measured and self-reported weight loss, nausea, vomiting and cramps, as well as non-steroidal anti-inflammatory drug use. CONCLUSIONS: CKD burden in this population is high and risk factors for established disease are occupational. Additionally, a syndrome suggesting an alternative exposure is associated with evidence of disease onset supporting a possible separate unknown initiating factor for which further investigation is needed. Interventions to reduce the impact of occupational risks should be pursued meanwhile.

Linking fine-scale behaviour to the hydraulic environment shows behavioural responses in riverine fish.

BACKGROUND: Fish migration has severely been impacted by dam construction. Through the disruption of fish migration routes, freshwater fish communities have seen an incredible decline. Fishways, which have been constructed to mitigate the problem, have been shown to underperform. This is in part due to fish navigation still being largely misunderstood. Recent developments in tracking technology and modelling make it possible today to track (aquatic) animals at very fine spatial (down to one meter) and temporal (down to every second) scales. Hidden Markov models are appropriate models to analyse behavioural states at these fine scales. In this study we link fine-scale tracking data of barbel (Barbus barbus) and grayling (Thymallus thymallus) to a fine-scale hydrodynamic model. With a HMM we analyse the fish's behavioural switches to understand their movement and navigation behaviour near a barrier and fishway outflow in the Iller river in Southern Germany. METHODS: Fish were tracked with acoustic telemetry as they approached a hydropower facility and were presented with a fishway. Tracking resulted in fish tracks with variable intervals between subsequent fish positions. This variability stems from both a variable interval between tag emissions and missing detections within a track. After track regularisation hidden Markov models were fitted using different parameters. The tested parameters are step length, straightness index calculated over a 3-min moving window, and straightness index calculated over a 10-min window. The best performing model (based on a selection by AIC) was then expanded by allowing flow velocity and spatial velocity gradient to affect the transition matrix between behavioural states. RESULTS: In this study it was found that using step length to identify behavioural states with hidden Markov models underperformed when compared to models constructed using straightness index. Of the two different straightness indices assessed, the index calculated over a 10-min moving window performed better. Linking behavioural states to the ecohydraulic environment showed an effect of the spatial velocity gradient on behavioural switches. On the contrary, flow velocity did not show an effect on the behavioural transition matrix. CONCLUSIONS: We found that behavioural switches were affected by the spatial velocity gradient caused by the attraction flow coming from the fishway. Insight into fish navigation and fish reactions to the ecohydraulic environment can aid in the construction of fishways and improve overall fishway efficiencies, thereby helping to mitigate the effects migration barriers have on the aquatic ecosystem.

Long-Term Outcomes of Eladocagene Exuparvovec Compared with Standard of Care in Aromatic L-Amino Acid Decarboxylase (AADC) Deficiency: A Modelling Study.

INTRODUCTION: Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare disease with symptoms including movement disorders, developmental delays, and autonomic symptoms starting from birth; further, patients with AADC deficiency are at a high risk of death in the first decade of life. Limited information on the impact of treatment with gene therapy on patients' disease trajectories and survival, quality-of-life, and resource usage benefits are available. METHOD: A cohort-based model with a lifetime horizon has been developed, based on motor milestones, to estimate the long-term benefits for patients after treatment with eladocagene exuparvovec compared to best supportive care (BSC). The model takes a National Health Service (NHS) perspective using a UK setting. The model comprises two parts: the developmental phase, in which patients with initially no motor function can progress to other motor milestone states, and a long-term projection phase. Efficacy for eladocagene exuparvovec is derived from clinical trial data with a duration up to 120 months. As the incidence of AADC deficiency is low, data for key model inputs is lacking; therefore estimates of survival by motor milestone were based on proxy diseases. A disease-specific utility study provided quality of life inputs and a burden of illness study informed inputs for disease management. RESULTS: The model indicates survival (25.25 undiscounted life years gained) and quality-of-life benefits (20.21 undiscounted quality-adjusted life years [QALYs] gained) for patients treated with eladocagene exuparvovec compared to BSC. Resource usage costs are greater for patients treated with eladocagene exuparvovec, mainly due to the increased life expectancy during which patients accrue additional healthcare resource usage. Scenario analyses indicate robust results. CONCLUSION: This study assessed long-term outcomes for patients with AADC deficiency. Patients treated with eladocagene exuparvovec were found to have improved survival and quality of life benefits compared to patients treated with BSC.