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Background: As lockdown measures to slow the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection begin to ease in the UK, it is important to assess the impact of any changes in policy, including school reopening and broader relaxation of physical distancing measures. We aimed to use an individual-based model to predict the impact of two possible strategies for reopening schools to all students in the UK from September, 2020, in combination with different assumptions about relaxation of physical distancing measures and the scale-up of testing., Methods: In this modelling study, we used Covasim, a stochastic individual-based model for transmission of SARS-CoV-2, calibrated to the UK epidemic. The model describes individuals' contact networks stratified into household, school, workplace, and community layers, and uses demographic and epidemiological data from the UK. We simulated six different scenarios, representing the combination of two school reopening strategies (full time and a part-time rota system with 50% of students attending school on alternate weeks) and three testing scenarios (68% contact tracing with no scale-up in testing, 68% contact tracing with sufficient testing to avoid a second COVID-19 wave, and 40% contact tracing with sufficient testing to avoid a second COVID-19 wave). We estimated the number of new infections, cases, and deaths, as well as the effective reproduction number (R) under different strategies. In a sensitivity analysis to account for uncertainties within the stochastic simulation, we also simulated infectiousness of children and young adults aged younger than 20 years at 50% relative to older ages (20 years and older)., Findings: With increased levels of testing (between 59% and 87% of symptomatic people tested at some point during an active SARS-CoV-2 infection, depending on the scenario), and effective contact tracing and isolation, an epidemic rebound might be prevented. Assuming 68% of contacts could be traced, we estimate that 75% of individuals with symptomatic infection would need to be tested and positive cases isolated if schools return full-time in September, or 65% if a part-time rota system were used. If only 40% of contacts could be traced, these figures would increase to 87% and 75%, respectively. However, without these levels of testing and contact tracing, reopening of schools together with gradual relaxing of the lockdown measures are likely to induce a second wave that would peak in December, 2020, if schools open full-time in September, and in February, 2021, if a part-time rota system were adopted. In either case, the second wave would result in R rising above 1 and a resulting second wave of infections 2·0-2·3 times the size of the original COVID-19 wave. When infectiousness of children and young adults was varied from 100% to 50% of that of older ages, we still found that a comprehensive and effective test-trace-isolate strategy would be required to avoid a second COVID-19 wave., Interpretation: To prevent a second COVID-19 wave, relaxation of physical distancing, including reopening of schools, in the UK must be accompanied by large-scale, population-wide testing of symptomatic individuals and effective tracing of their contacts, followed by isolation of diagnosed individuals., Funding: None., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Sharks are an interesting group of vertebrates, as many species swim continuously to "ram" oxygen-rich seawater over their gills (ram ventilators), whereas other species "pump" seawater over their gills by manipulating buccal cavity volume while remaining motionless (buccal pumpers). This difference in respiratory physiology raises the question: What are the implications of these differences in lifestyle for circadian rhythms? We investigated the diel activity patterns of 5 species of sharks, including 3 ram ventilating species: the school shark ( Galeorhinus galeus ), the spotted estuary smooth-hound ( Mustelus lenticulatus ), and the spiny dogfish ( Squalus acanthias ); and 2 buccal pumping species: the Port Jackson ( Heterodontus portusjacksoni ) and draughtsboard ( Cephaloscyllium isabellum ) sharks. We measured the amount, duration, and distance traveled while swimming over multiple days under a 12:12 light:dark light regime for all species and used modified light regimes for species with a clear diel rhythm in activity. We identified a surprising diversity of activity rhythms. The school shark and smooth-hound swam continuously; however, whereas the school shark swam at the same speed and covered the same distance during the day and night, the smooth-hound swam slower at night and traversed a shorter distance. A similar pattern was observed in the spiny dogfish, although this shark swam less overall. Both the Port Jackson and draughtsboard sharks showed a marked nocturnal preference for swimming. This pattern was muted and disrupted during constant light and constant dark regimes, although circadian organization of this pattern was maintained under certain conditions. The consequences of these patterns for other biological processes, such as sleep, remain unclear. Nonetheless, these 5 species demonstrate remarkable diversity within the activity rhythms of sharks.

Background: Health resources are limited, which means spending should be focused on the people, places and programs that matter most. Choosing the mix of programs to maximize a health outcome is termed allocative efficiency. Here, we extend the methodology of allocative efficiency to answer the question of how resources should be distributed among different geographic regions., Methods: We describe a novel geographical optimization algorithm, which has been implemented as an extension to the Optima HIV model. This algorithm identifies an optimal funding of services and programs across regions, such as multiple countries or multiple districts within a country. The algorithm consists of three steps: (1) calibrating the model to each region, (2) determining the optimal allocation for each region across a range of different budget levels, and (3) finding the budget level in each region that minimizes the outcome (such as reducing new HIV infections and/or HIV-related deaths), subject to the constraint of fixed total budget across all regions. As a case study, we applied this method to determine an illustrative allocation of HIV program funding across three representative oblasts (regions) in Ukraine (Mykolayiv, Poltava, and Zhytomyr) to minimize the number of new HIV infections., Results: Geographical optimization was found to identify solutions with better outcomes than would be possible by considering region-specific allocations alone. In the case of Ukraine, prior to optimization (i.e. with status quo spending), a total of 244,000 HIV-related disability-adjusted life years (DALYs) were estimated to occur from 2016 to 2030 across the three oblasts. With optimization within (but not between) oblasts, this was estimated to be reduced to 181,000. With geographical optimization (i.e., allowing reallocation of funds between oblasts), this was estimated to be further reduced to 173,000., Conclusions: With the increasing availability of region- and even facility-level data, geographical optimization is likely to play an increasingly important role in health economic decision making. Although the largest gains are typically due to reallocating resources to the most effective interventions, especially treatment, further gains can be achieved by optimally reallocating resources between regions. Finally, the methods described here are not restricted to geographical optimization, and can be applied to other problems where competing resources need to be allocated with constraints, such as between diseases.

The viviparous sea snakes (Hydrophiinae) are a secondarily aquatic radiation of more than 60 species that possess many phenotypic adaptations to marine life. However, virtually nothing is known of the role and sensitivity of hearing in sea snakes. This study investigated the hearing sensitivity of the fully marine sea snake Hydrophis stokesii by measuring auditory evoked potential (AEP) audiograms for two individuals. AEPs were recorded from 40 Hz (the lowest frequency tested) up to 600 Hz, with a peak in sensitivity identified at 60 Hz (163.5 dB re. 1 µPa or 123 dB re. 1 µm s -2 ). Our data suggest that sea snakes are sensitive to low-frequency sounds but have relatively low sensitivity compared with bony fishes and marine turtles. Additional studies are required to understand the role of sound in sea snake life history and further assess these species' vulnerability to anthropogenic noise., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2019. Published by The Company of Biologists Ltd.)

Introduction: Cascades, which track the progressive stages of engagement on the path towards a successful outcome, are increasingly being employed to quantitatively assess progress towards targets associated with health and development responses. Maximizing the proportion of people with successful outcomes within a budget-constrained context requires identifying and implementing interventions that are not only effective, but also cost-effective. Methods: We developed a software application called the Cascade Analysis Tool that implements advanced analysis and optimization methods for understanding cascades, combined with the flexibility to enable application across a wide range of areas in health and development. The tool allows users to design the cascade, collate and enter data, and then use the built-in analysis methods in order to answer key policy questions, such as: understanding where the biggest drop-offs along the cascade are; visualizing how the cascade varies by population; investigating the impact of introducing a new intervention or scaling up/down existing interventions; and estimating how available funding should be optimally allocated among available interventions in order to achieve a variety of different objectives selectable by the user (such as optimizing cascade outcomes in target years). The Cascade Analysis Tool is available via a user-friendly web-based application, and comes with a user guide, a library of pre-made examples, and training materials. Discussion: Whilst the Cascade Analysis Tool is still in the early stages of existence, it has already shown promise in preliminary applications, and we believe there is potential for it to help make sense of the increasing quantities of data on cascades., Competing Interests: No competing interests were disclosed., (Copyright: © 2019 Kedziora DJ et al.)

Introduction: Globally, there is increased focus on getting the greatest impact from available health funding. However, the pursuit of overall welfare maximization may mean some are left worse off than before. Pareto efficiency takes welfare shifts into account by ruling out funding reallocations that worsen outcomes for any person or group., Methods: Using the Optima HIV model, studies of HIV response efficiency were conducted in Sudan in 2014 and Togo in 2015. In this article, we estimate the welfare maximizing and Pareto efficient allocations for these two national HIV budgets, using data from the original studies., Results: We estimate that, if the 2013 HIV budget for Sudan was annually available to 2020 but with funds reallocated according to the welfare maximizing allocation, a 36% reduction in cumulative new infections could be achieved between 2014 and 2020. We also find that this is Pareto efficient. In Togo, however, we find that it is possible to reduce overall new infections but applying the Pareto efficiency criterion means that shifts in emphases cannot occur in the HIV response without additional resources., Discussion: Protecting service coverage for key population groups is not necessarily equivalent to protecting health outcomes. In some cases, requiring Pareto efficiency may reduce the potential for population-wide welfare gains, but this is not always the case., Conclusion: Pareto efficiency may be an appropriate addition to the quantitative toolset for evaluating HIV responses.

The effect of sound on the behaviour of sharks has not been investigated since the 1970s. Sound is, however, an important sensory stimulus underwater, as it can spread in all directions quickly and propagate further than any other sensory cue. We used a baited underwater camera rig to record the behavioural responses of eight species of sharks (seven reef and coastal shark species and the white shark, Carcharodon carcharias) to the playback of two distinct sound stimuli in the wild: an orca call sequence and an artificially generated sound. When sounds were playing, reef and coastal sharks were less numerous in the area, were responsible for fewer interactions with the baited test rigs, and displayed less 'inquisitive' behaviour, compared to during silent control trials. White sharks spent less time around the baited camera rig when the artificial sound was presented, but showed no significant difference in behaviour in response to orca calls. The use of the presented acoustic stimuli alone is not an effective deterrent for C. carcharias. The behavioural response of reef sharks to sound raises concern about the effects of anthropogenic noise on these taxa.

Biophysical modeling of neuronal networks helps to integrate and interpret rapidly growing and disparate experimental datasets at multiple scales. The NetPyNE tool (www.netpyne.org) provides both programmatic and graphical interfaces to develop data-driven multiscale network models in NEURON. NetPyNE clearly separates model parameters from implementation code. Users provide specifications at a high level via a standardized declarative language, for example connectivity rules, to create millions of cell-to-cell connections. NetPyNE then enables users to generate the NEURON network, run efficiently parallelized simulations, optimize and explore network parameters through automated batch runs, and use built-in functions for visualization and analysis - connectivity matrices, voltage traces, spike raster plots, local field potentials, and information theoretic measures. NetPyNE also facilitates model sharing by exporting and importing standardized formats (NeuroML and SONATA). NetPyNE is already being used to teach computational neuroscience students and by modelers to investigate brain regions and phenomena., Competing Interests: SD, BS, PG, DK, GC, CK, SN, RM, MH, GS, WL No competing interests declared, MC, FR is affiliated with MetaCell LLC. The author has no other competing interests to declare. AQ is affiliated with EyeSeeTea Ltd. The author has no other competing interests to declare., (© 2019, Dura-Bernal et al.)

Personal shark deterrents offer the potential of a non-lethal solution to protect individuals from negative interactions with sharks, but the claims of effectiveness of most deterrents are based on theory rather than robust testing of the devices themselves. Therefore, there is a clear need for thorough testing of commercially available shark deterrents to provide the public with information on their effectiveness. Using a modified stereo-camera system, we quantified behavioural interactions between Carcharodon carcharias (white sharks) and a baited target in the presence of a commercially available electric anklet shark deterrent, the Electronic Shark Defense System (ESDS). The stereo-camera system enabled accurate assessment of the behavioural responses of C. carcharias when approaching an ESDS. We found that the ESDS had limited meaningful effect on the behaviour of C. carcharias, with no significant reduction in the proportion of sharks interacting with the bait in the presence of the active device. At close proximity (< 15.5 cm), the active ESDS did show a significant reduction in the number of sharks biting the bait, but this was countered by an increase in other, less aggressive, interactions. The ESDS discharged at a frequency of 7.8 Hz every 5.1 s for 2.5 s, followed by an inactive interval of 2.6 s. As a result, many sharks may have encountered the device in its inactive state, resulting in a reduced behavioural response. Consequently, decreasing the inactive interval between pulses may improve the overall effectiveness of the device, but this would not improve the effective deterrent range of the device, which is primarily a factor of the voltage gradient rather than the stimulus frequency. In conclusion, given the very short effective range of the ESDS and its unreliable deterrent effect, combined with the fact that shark-bite incidents are very rare, it is unlikely that the current device would significantly reduce the risk of a negative interaction with C. carcharias., Competing Interests: Oceans Research is a commercial operation that provided logistical support and resources to help facilitate this research. Author EG is the director of Oceans Research and provided editorial assistance in the manuscript preparation, but played no role in the study design, data collection and analysis, or decision to publish. EG’s commercial affiliation with Oceans Research does not alter our adherence to PLOS ONE policies on sharing data and materials. Furthermore, the authors are not aware of any competing interests.

Pharmacoresistant epilepsy is a common neurological disorder in which increased neuronal intrinsic excitability and synaptic excitation lead to pathologically synchronous behavior in the brain. In the majority of experimental and theoretical epilepsy models, epilepsy is associated with reduced inhibition in the pathological neural circuits, yet effects of intrinsic excitability are usually not explicitly analyzed. Here we present a novel neural mass model that includes intrinsic excitability in the form of spike-frequency adaptation in the excitatory population. We validated our model using local field potential (LFP) data recorded from human hippocampal/subicular slices. We found that synaptic conductances and slow adaptation in the excitatory population both play essential roles for generating seizures and pre-ictal oscillations. Using bifurcation analysis, we found that transitions towards seizure and back to the resting state take place via Andronov-Hopf bifurcations. These simulations therefore suggest that single neuron adaptation as well as synaptic inhibition are responsible for orchestrating seizure dynamics and transition towards the epileptic state.

Evoked response potentials (ERPs) and other transients are modeled as impulse responses using physiology-based neural field theory (NFT) of the corticothalamic system of neural activity in the human brain that incorporates synaptic and dendritic dynamics, firing response, axonal propagation, and corticocortical and corticothalamic pathways. The properties of model-predicted ERPs are explored throughout the stability zone of the corticothalamic system, and predicted time series and wavelet spectra are also analyzed. This provides a unified treatment of predicted ERPs for both normal and abnormal states within the brain's stability zone, including likely parameters to represent abnormal states of reduced arousal.

Background: Antiretroviral therapy (ART) reduces HIV transmission, but treated patients may again become infectious. We used a mathematical model to determine whether ART as prevention is more effective if viral load (VL) is routinely monitored and patients lost to follow-up (LTFU) traced., Methods: We simulated ART cohorts to parameterize a deterministic transmission model calibrated to Malawi. We investigated the following strategies for improving treatment and retention: monitoring VL every 12 or 24 months, tracing patients LTFU, or a generic strategy leading to uninterrupted treatment. We tested 3 scenarios, where ART scale-up continues at current (Universal ART), reduced (Failed scale-up), or accelerated speed (Test&Treat)., Results: In the Universal ART scenario, between 2017 and 2020 (2050), monitoring VL every 24 months prevented 0.5% (0.9%), monitoring every 12 months prevented 0.8% (1.4%), tracing prevented 0.3% (0.5%), and uninterrupted treatment prevented 5.5% (9.9%) of HIV infections. Failed scale-up resulted in 25% more infections than the Universal ART scenarios, whereas Test&Treat resulted in 7%-8% less., Conclusions: Test&Treat reduces transmission of HIV, despite individual cases of treatment failure and ART interruption. Whereas viral load monitoring and tracing have only a minor impact on transmission, interventions that aim to minimize treatment interruptions can further increase the preventive effect of ART.

It has been highlighted that the original manuscript [1] contains a typesetting error in the name of Meera Shekar. This had been incorrectly captured as Meera Shekhar in the original article which has since been updated.

Background: To move towards ending AIDS by 2030, HIV resources should be allocated cost-effectively. We used the Optima HIV model to estimate how global HIV resources could be retargeted for greatest epidemiological effect and how many additional new infections could be averted by 2030., Methods: We collated standard data used in country modelling exercises (including demographic, epidemiological, behavioural, programmatic, and expenditure data) from Jan 1, 2000, to Dec 31, 2015 for 44 countries, capturing 80% of people living with HIV worldwide. These data were used to parameterise separate subnational and national models within the Optima HIV framework. To estimate optimal resource allocation at subnational, national, regional, and global levels, we used an adaptive stochastic descent optimisation algorithm in combination with the epidemic models and cost functions for each programme in each country. Optimal allocation analyses were done with international HIV funds remaining the same to each country and by redistributing these funds between countries., Findings: Without additional funding, if countries were to optimally allocate their HIV resources from 2016 to 2030, we estimate that an additional 7·4 million (uncertainty range 3·9 million-14·0 million) new infections could be averted, representing a 26% (uncertainty range 13-50%) incidence reduction. Redistribution of international funds between countries could avert a further 1·9 million infections, which represents a 33% (uncertainty range 20-58%) incidence reduction overall. To reduce HIV incidence by 90% relative to 2010, we estimate that more than a three-fold increase of current annual funds will be necessary until 2030. The most common priorities for optimal resource reallocation are to scale up treatment and prevention programmes targeting key populations at greatest risk in each setting. Prioritisation of other HIV programmes depends on the epidemiology and cost-effectiveness of service delivery in each setting as well as resource availability., Interpretation: Further reductions in global HIV incidence are possible through improved targeting of international and national HIV resources., Funding: World Bank and Australian NHMRC., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Introduction: With limited funds available, meeting global health targets requires countries to both mobilize and prioritize their health spending. Within this context, countries have recognized the importance of allocating funds for HIV as efficiently as possible to maximize impact. Over the past six years, the governments of 23 countries in Africa, Asia, Eastern Europe and Latin America have used the Optima HIV tool to estimate the optimal allocation of HIV resources., Methods: Each study commenced with a request by the national government for technical assistance in conducting an HIV allocative efficiency study using Optima HIV. Each study team validated the required data, calibrated the Optima HIV epidemic model to produce HIV epidemic projections, agreed on cost functions for interventions, and used the model to calculate the optimal allocation of available funds to best address national strategic plan targets. From a review and analysis of these 23 country studies, we extract common themes around the optimal allocation of HIV funding in different epidemiological contexts., Results and Discussion: The optimal distribution of HIV resources depends on the amount of funding available and the characteristics of each country's epidemic, response and targets. Universally, the modelling results indicated that scaling up treatment coverage is an efficient use of resources. There is scope for efficiency gains by targeting the HIV response towards the populations and geographical regions where HIV incidence is highest. Across a range of countries, the model results indicate that a more efficient allocation of HIV resources could reduce cumulative new HIV infections by an average of 18% over the years to 2020 and 25% over the years to 2030, along with an approximately 25% reduction in deaths for both timelines. However, in most countries this would still not be sufficient to meet the targets of the national strategic plan, with modelling results indicating that budget increases of up to 185% would be required., Conclusions: Greater epidemiological impact would be possible through better targeting of existing resources, but additional resources would still be required to meet targets. Allocative efficiency models have proven valuable in improving the HIV planning and budgeting process., (© 2018 The Authors. Journal of the International AIDS Society published by John Wiley & sons Ltd on behalf of the International AIDS Society.)

Background: Child stunting due to chronic malnutrition is a major problem in low- and middle-income countries due, in part, to inadequate nutrition-related practices and insufficient access to services. Limited budgets for nutritional interventions mean that available resources must be targeted in the most cost-effective manner to have the greatest impact. Quantitative tools can help guide budget allocation decisions., Methods: The Optima approach is an established framework to conduct resource allocation optimization analyses. We applied this approach to develop a new tool, 'Optima Nutrition', for conducting allocative efficiency analyses that address childhood stunting. At the core of the Optima approach is an epidemiological model for assessing the burden of disease; we use an adapted version of the Lives Saved Tool (LiST). Six nutritional interventions have been included in the first release of the tool: antenatal micronutrient supplementation, balanced energy-protein supplementation, exclusive breastfeeding promotion, promotion of improved infant and young child feeding (IYCF) practices, public provision of complementary foods, and vitamin A supplementation. To demonstrate the use of this tool, we applied it to evaluate the optimal allocation of resources in 7 districts in Bangladesh, using both publicly available data (such as through DHS) and data from a complementary costing study., Results: Optima Nutrition can be used to estimate how to target resources to improve nutrition outcomes. Specifically, for the Bangladesh example, despite only limited nutrition-related funding available (an estimated $0.75 per person in need per year), even without any extra resources, better targeting of investments in nutrition programming could increase the cumulative number of children living without stunting by 1.3 million (an extra 5%) by 2030 compared to the current resource allocation. To minimize stunting, priority interventions should include promotion of improved IYCF practices as well as vitamin A supplementation. Once these programs are adequately funded, the public provision of complementary foods should be funded as the next priority. Programmatic efforts should give greatest emphasis to the regions of Dhaka and Chittagong, which have the greatest number of stunted children., Conclusions: A resource optimization tool can provide important guidance for targeting nutrition investments to achieve greater impact.

When standard optimization methods fail to find a satisfactory solution for a parameter fitting problem, a tempting recourse is to adjust parameters manually. While tedious, this approach can be surprisingly powerful in terms of achieving optimal or near-optimal solutions. This paper outlines an optimization algorithm, Adaptive Stochastic Descent (ASD), that has been designed to replicate the essential aspects of manual parameter fitting in an automated way. Specifically, ASD uses simple principles to form probabilistic assumptions about (a) which parameters have the greatest effect on the objective function, and (b) optimal step sizes for each parameter. We show that for a certain class of optimization problems (namely, those with a moderate to large number of scalar parameter dimensions, especially if some dimensions are more important than others), ASD is capable of minimizing the objective function with far fewer function evaluations than classic optimization methods, such as the Nelder-Mead nonlinear simplex, Levenberg-Marquardt gradient descent, simulated annealing, and genetic algorithms. As a case study, we show that ASD outperforms standard algorithms when used to determine how resources should be allocated in order to minimize new HIV infections in Swaziland.

Introduction: In 2014, city leaders from around the world endorsed the Paris Declaration on Fast-Track Cities, pledging to achieve the 2020 and 2030 HIV targets championed by UNAIDS. The City of Johannesburg - one of South Africa's metropolitan municipalities and also a health district - has over 600,000 people living with HIV (PLHIV), more than any other city worldwide. We estimate what it would take in terms of programmatic targets and costs for the City of Johannesburg to meet the Fast-Track targets, and demonstrate the impact that this would have., Methods: We applied the Optima HIV epidemic and resource allocation model to demographic, epidemiological and behavioural data on 26 sub-populations in Johannesburg. We used data on programme costs and coverage to produce baseline projections. We calculated how many people must be diagnosed, put onto treatment and maintained with viral suppression to achieve the 2020 and 2030 targets. We also estimated how treatment needs - and therefore fiscal commitments - could be reduced if the treatment targets are combined with primary HIV prevention interventions (voluntary medical male circumcision (VMMC), an expanded condom programme, and comprehensive packages for female sex workers (FSW) and young females)., Results: If current programmatic coverage were maintained, Johannesburg could expect 303,000 new infections and 96,000 AIDS-related deaths between 2017 and 2030 and 769,000 PLHIV by 2030. Achieving the Fast-Track targets would require an additional 135,000 diagnoses and 232,000 people on treatment by 2020 (an increase in around 80% over 2016 treatment numbers), but would avert 176,000 infections and 56,500 deaths by 2030. Assuming stable ART unit costs, this would require ZAR 29 billion (USD 2.15 billion) in cumulative treatment investments over the 14 years to 2030. Plausible scale-ups of other proven interventions (VMMC, condom distribution and FSW strategies) could yield additional reductions in new infections (between 4 and 15%), and in overall treatment investment needs. Scaling up VMMC in line with national targets is found to be cost-effective in the medium term., Conclusions: The scale-up in testing and treatment programmes over this decade has been rapid, but these efforts must be doubled to reach 2020 targets. Strategic investments in proven interventions will help Johannesburg achieve the treatment targets and be on track to end AIDS by 2030., (© 2018 The Authors. Journal of the International AIDS Society published by John Wiley & sons Ltd on behalf of the International AIDS Society.)

Background: Prioritizing investments across health interventions is complicated by the nonlinear relationship between intervention coverage and epidemiological outcomes. It can be difficult for countries to know which interventions to prioritize for greatest epidemiological impact, particularly when budgets are uncertain., Methods: We examined four case studies of HIV epidemics in diverse settings, each with different characteristics. These case studies were based on public data available for Belarus, Peru, Togo, and Myanmar. The Optima HIV model and software package was used to estimate the optimal distribution of resources across interventions associated with a range of budget envelopes. We constructed "investment staircases", a useful tool for understanding investment priorities. These were used to estimate the best attainable cost-effectiveness of the response at each investment level., Findings: We find that when budgets are very limited, the optimal HIV response consists of a smaller number of 'core' interventions. As budgets increase, those core interventions should first be scaled up, and then new interventions introduced. We estimate that the cost-effectiveness of HIV programming decreases as investment levels increase, but that the overall cost-effectiveness remains below GDP per capita., Significance: It is important for HIV programming to respond effectively to the overall level of funding availability. The analytic tools presented here can help to guide program planners understand the most cost-effective HIV responses and plan for an uncertain future.

Background: The high burden of malaria and limited funding means there is a necessity to maximize the allocative efficiency of malaria control programmes. Quantitative tools are urgently needed to guide budget allocation decisions., Methods: A geospatial epidemic model was coupled with costing data and an optimization algorithm to estimate the optimal allocation of budgeted and projected funds across all malaria intervention approaches. Interventions included long-lasting insecticide-treated nets (LLINs), indoor residual spraying (IRS), intermittent presumptive treatment during pregnancy (IPTp), seasonal mass chemoprevention in children (SMC), larval source management (LSM), mass drug administration (MDA), and behavioural change communication (BCC). The model was applied to six geopolitical regions of Nigeria in isolation and also the nation as a whole to minimize incidence and malaria-attributable mortality., Results: Allocative efficiency gains could avert approximately 84,000 deaths or 15.7 million cases of malaria in Nigeria over 5 years. With an additional US$300 million available, approximately 134,000 deaths or 37.3 million cases of malaria could be prevented over 5 years. Priority funding should go to LLINs, IPTp and BCC programmes, and SMC should be expanded in seasonal areas. To minimize mortality, treatment expansion is critical and prioritized over some LLIN funding, while to minimize incidence, LLIN funding remained a priority. For areas with lower rainfall, LSM is prioritized over IRS but MDA is not recommended unless all other programmes are established., Conclusions: Substantial reductions in malaria morbidity and mortality can be made by optimal targeting of investments to the right malaria interventions in the right areas.

To interrelate K-complexes, spindles, evoked response potentials (ERPs), and spontaneous electroencephalography (EEG) using neural field theory (NFT), physiology-based NFT of the corticothalamic system is used to model cortical excitatory and inhibitory populations and thalamic relay and reticular nuclei. The impulse response function of the model is used to predict the responses to impulses, which are compared with transient waveforms in sleep studies. Fits to empirical data then allow underlying brain physiology to be inferred and compared with other waves. Spontaneous K-complexes, spindles, and other transient waveforms can be reproduced using NFT by treating them as evoked responses to impulsive stimuli with brain parameters appropriate to spontaneous EEG in sleep stage 2. Using this approach, spontaneous K-complexes and sleep spindles can be analyzed using the same single theory as previously been used to account for waking ERPs and other EEG phenomena. As a result, NFT can explain a wide variety of transient waveforms that have only been phenomenologically classified to date. This enables noninvasive fitting to be used to infer underlying physiological parameters. This physiology-based model reproduces the time series of different transient EEG waveforms; it has previously reproduced experimental EEG spectra, and waking ERPs, and many other observations, thereby unifying transient sleep waveforms with these phenomena.

Biomimetic simulation permits neuroscientists to better understand the complex neuronal dynamics of the brain. Embedding a biomimetic simulation in a closed-loop neuroprosthesis, which can read and write signals from the brain, will permit applications for amelioration of motor, psychiatric, and memory-related brain disorders. Biomimetic neuroprostheses require real-time adaptation to changes in the external environment, thus constituting an example of a dynamic data-driven application system. As model fidelity increases, so does the number of parameters and the complexity of finding appropriate parameter configurations. Instead of adapting synaptic weights via machine learning, we employed major biological learning methods: spike-timing dependent plasticity and reinforcement learning. We optimized the learning metaparameters using evolutionary algorithms, which were implemented in parallel and which used an island model approach to obtain sufficient speed. We employed these methods to train a cortical spiking model to utilize macaque brain activity, indicating a selected target, to drive a virtual musculoskeletal arm with realistic anatomical and biomechanical properties to reach to that target. The optimized system was able to reproduce macaque data from a comparable experimental motor task. These techniques can be used to efficiently tune the parameters of multiscale systems, linking realistic neuronal dynamics to behavior, and thus providing a useful tool for neuroscience and neuroprosthetics.

Background: Despite a non-decreasing HIV epidemic, international donors are soon expected to withdraw funding from Kazakhstan. Here we analyze how allocative, implementation, and technical efficiencies could strengthen the national HIV response under assumptions of future budget levels., Methodology: We used the Optima model to project future scenarios of the HIV epidemic in Kazakhstan that varied in future antiretroviral treatment unit costs and management expenditure-two areas identified for potential cost-reductions. We determined optimal allocations across HIV programs to satisfy either national targets or ambitious targets. For each scenario, we considered two cases of future HIV financing: the 2014 national budget maintained into the future and the 2014 budget without current international investment., Findings: Kazakhstan can achieve its national HIV targets with the current budget by (1) optimally re-allocating resources across programs and (2) either securing a 35% [30%-39%] reduction in antiretroviral treatment drug costs or reducing management costs by 44% [36%-58%] of 2014 levels. Alternatively, a combination of antiretroviral treatment and management cost-reductions could be sufficient. Furthermore, Kazakhstan can achieve ambitious targets of halving new infections and AIDS-related deaths by 2020 compared to 2014 levels by attaining a 67% reduction in antiretroviral treatment costs, a 19% [14%-27%] reduction in management costs, and allocating resources optimally., Significance: With Kazakhstan facing impending donor withdrawal, it is important for the HIV response to achieve more with available resources. This analysis can help to guide HIV response planners in directing available funding to achieve the greatest yield from investments. The key changes recommended were considered realistic by Kazakhstan country representatives.

Sharks play a vital role in the health of marine ecosystems, but the potential threat that sharks pose to humans is a reminder of our vulnerability when entering the ocean. Personal shark deterrents are being marketed as the solution to mitigate the threat that sharks pose. However, the effectiveness claims of many personal deterrents are based on our knowledge of shark sensory biology rather than robust testing of the devices themselves, as most have not been subjected to independent scientific studies. Therefore, there is a clear need for thorough testing of commercially available shark deterrents to provide the public with recommendations of their effectiveness. Using a modified stereo-camera system, we quantified behavioural interactions between white sharks (Carcharodon carcharias) and a baited target in the presence of a commercially available, personal electric shark deterrent (Shark Shield Freedom7™). The stereo-camera system enabled an accurate assessment of the behavioural responses of C. carcharias when encountering a non-lethal electric field many times stronger than what they would naturally experience. Upon their first observed encounter, all C. carcharias were repelled at a mean (± std. error) proximity of 131 (± 10.3) cm, which corresponded to a mean voltage gradient of 9.7 (± 0.9) V/m. With each subsequent encounter, their proximity decreased by an average of 11.6 cm, which corresponded to an increase in tolerance to the electric field by an average of 2.6 (± 0.5) V/m per encounter. Despite the increase in tolerance, sharks continued to be deterred from interacting for the duration of each trial when in the presence of an active Shark Shield™. Furthermore, the findings provide no support to the theory that electric deterrents attract sharks. The results of this study provide quantitative evidence of the effectiveness of a non-lethal electric shark deterrent, its influence on the behaviour of C. carcharias, and an accurate method for testing other shark deterrent technologies.

Introduction: HIV prevalence is declining in key populations in Armenia including in people who inject drugs (PWID), men who have sex with men, prison inmates, and female sex workers (FSWs); however, prevalence is increasing among Armenians who seasonally migrate to work in countries with higher HIV prevalence, primarily to the Russian Federation., Methods: We conducted a modelling study using the Optima model to assess the optimal resource allocation to meet targets from the 2013 to 2016 national strategic plan to minimize HIV incidence and AIDS-related deaths by 2020. Demographic, epidemiological, behavioural, and programme cost data from 2000 through 2014 were used to inform the model. The levels of coverage that could be attained among targeted populations with different investments, as well as their expected outcomes, were determined. In the absence of evidence of the efficacy of HIV programmes targeted at seasonal labour migrants, we conducted a sensitivity analysis to determine the cost-effective funding threshold for the seasonal labour migrant programme., Results: The optimization analysis revealed that shifts in funding allocations could further minimize incidence and deaths by 2020 within the available resource envelope. The largest emphasis should be on antiretroviral therapy (ART), with the optimal investment to increase treatment coverage by 40%. Optimal investments also involve increases in opiate substitution therapy and FSW programmes, as well as maintenance of other prevention programmes for PWID and prevention of mother-to-child transmission. Additional funding for these increases should come from budgets for general population programmes. This is projected to avert 17% of new infections and 29% of AIDS-related deaths by 2020 compared to a baseline scenario of maintaining 2013 spending. Our sensitivity analysis demonstrated that, at current spending, coverage of annual testing among migrants of at least 43% should be achieved to warrant continuation of funding for this programme., Conclusions: Optimization of HIV/AIDS investment in Armenia, with a main priority for scaling-up ART, and less emphasis on primary prevention in the general non-key population could significantly reduce incidence and deaths by 2020.

Introduction: International investment in the response to HIV and AIDS has plateaued and its future level is uncertain. With many countries committed to ending the epidemic, it is essential to allocate available resources efficiently over different response periods to maximize impact. The objective of this study is to propose a technique to determine the optimal allocation of funds over time across a set of HIV programmes to achieve desirable health outcomes., Methods: We developed a technique to determine the optimal time-varying allocation of funds (1) when the future annual HIV budget is pre-defined and (2) when the total budget over a period is pre-defined, but the year-on-year budget is to be optimally determined. We use this methodology with Optima, an HIV transmission model that uses non-linear relationships between programme spending and associated programmatic outcomes to quantify the expected epidemiological impact of spending. We apply these methods to data collected from Zambia to determine the optimal distribution of resources to fund the right programmes, for the right people, at the right time., Results and Discussion: Considering realistic implementation and ethical constraints, we estimate that the optimal time-varying redistribution of the 2014 Zambian HIV budget between 2015 and 2025 will lead to a 7.6% (7.3% to 7.8%) decrease in cumulative new HIV infections compared with a baseline scenario where programme allocations remain at 2014 levels. This compares to a 5.1% (4.6% to 5.6%) reduction in new infections using an optimal allocation with constant programme spending that recommends unrealistic programmatic changes. Contrasting priorities for programme funding arise when assessing outcomes for a five-year funding period over 5-, 10- and 20-year time horizons., Conclusions: Countries increasingly face the need to do more with the resources available. The methodology presented here can aid decision-makers in planning as to when to expand or contract programmes and to which coverage levels to maximize impact.

Background: In some countries, HIV surveillance is based on case-reporting of newly diagnosed infections. We present a new back-projection method for estimating HIV-incidence trends using individuals' CD4 cell counts at diagnosis., Methods: On the basis of a review of CD4 cell count distributions among HIV-uninfected people, CD4 cell count following primary infection, and rates of CD4 cell count decline over time among people with HIV, we simulate the expected distribution in time between infection and diagnosis. Applying this to all diagnosed individuals provides a distribution of likely infection times and estimates for population incidence, level of undiagnosed HIV, and the average time from infection to diagnosis each year. We applied this method to the national HIV case surveillance data of Australia for 1983-2013., Results: The estimated number of new HIV infections in Australia in 2013 was 912 (95% uncertainty bound 835-1002). We estimate that 2280 (95% uncertainty bound 1900-2830) people were living with undiagnosed HIV at the end of 2013, corresponding to approximately 9.4% (95% uncertainty bound 7.8-10.1%) of all people living with HIV. With increases in the average CD4 count at diagnosis, the inferred HIV testing rate has been increasing over time and the estimated mean and median times between infection and diagnosis have decreased substantially. However, the estimated mean time between infection and diagnosis is considerably greater than the median, indicating that some people remain undiagnosed for long periods. Differences were found between cases attributable to male homosexual exposure versus other cases., Conclusion: This methodology provides a novel way of estimating population incidence by combining diagnosis dates and CD4 cell counts at diagnosis.

Introduction: Vietnam has been largely reliant on international support in its HIV response. Over 2006-2010, a total of US$480 million was invested in its HIV programmes, more than 70% of which came from international sources. This study investigates the potential epidemiological impacts of these programmes and their cost-effectiveness., Methods: We conducted a data synthesis of HIV programming, spending, epidemiological, and clinical outcomes. Counterfactual scenarios were defined based on assumed programme coverage and behaviours had the programmes not been implemented. An epidemiological model, calibrated to reflect the actual epidemiological trends, was used to estimate plausible ranges of programme impacts. The model was then used to estimate the costs per averted infection, death, and disability adjusted life-year (DALY)., Results: Based on observed prevalence reductions amongst most population groups, and plausible counterfactuals, modelling suggested that antiretroviral therapy (ART) and prevention programmes over 2006-2010 have averted an estimated 50,600 [95% uncertainty bound: 36,300-68,900] new infections and 42,600 [36,100-54,100] deaths, resulting in 401,600 [312,200-496,300] fewer DALYs across all population groups. HIV programmes in Vietnam have cost an estimated US$1,972 [1,447-2,747], US$2,344 [1,843-2,765], and US$248 [201-319] for each averted infection, death, and DALY, respectively., Conclusions: Our evaluation suggests that HIV programmes in Vietnam have most likely had benefits that are cost-effective. ART and direct HIV prevention were the most cost-effective interventions in reducing HIV disease burden.

Optima is a software package for modeling HIV epidemics and interventions that we developed to address practical policy and program problems encountered by funders, governments, health planners, and program implementers. Optima's key feature is its ability to perform resource optimization to meet strategic HIV objectives, including HIV-related financial commitment projections and health economic assessments. Specifically, Optima allows users to choose a set of objectives (such as minimizing new infections, minimizing HIV-related deaths, and/or minimizing long-term financial commitments) and then determine the optimal resource allocation (and thus program coverage levels) for meeting those objectives. These optimizations are based on the following: calibrations to epidemiological data; assumptions about the costs of program implementation and the corresponding coverage levels; and the effects of these programs on clinical, behavioral, and other epidemiological outcomes. Optima is flexible for which population groups (specified by behavioral, epidemiological, and/or geographical factors) and which HIV programs are modeled, the amount of input data used, and the types of outputs generated. Here, we introduce this model and compare it with existing HIV models that have been used previously to inform decisions about HIV program funding and coverage targets. Optima has already been used in more than 20 countries, and there is increasing demand from stakeholders to have a tool that can perform evidence-based HIV epidemic analyses, revise and prioritize national strategies based on available resources, set program coverage targets, amend subnational program implementation plans, and inform the investment strategies of governments and their funding partners.

Background: Despite the high prevalence of HIV in men who have sex with men (MSM) in Bangkok, little investment in HIV prevention for MSM has been made. HIV testing and treatment coverage remains low. Through a pragmatic programme-planning approach, we assess possible service linkage and provision of HIV testing and antiretroviral treatment (ART) to MSM in Bangkok, and the most cost-effective scale-up strategy., Methods: We obtained epidemiological and service capacity data from the Thai National Health Security Office database for 2011. We surveyed 13 representative medical facilities for detailed operational costs of HIV-related services for sexually active MSM (defined as having sex with men in the past 12 months) in metropolitan Bangkok. We estimated the costs of various ART scale-up scenarios, accounting for geographical accessibility across Bangkok. We used an HIV transmission population-based model to assess the cost-effectiveness of the scenarios., Findings: For present HIV testing (23% [95% CI 17-36] of MSM at high risk in 2011) and ART provision (20% of treatment-eligible MSM at high risk on ART in 2011) to be sustained, a US$73·8 million ($51·0 million to $97·0 million) investment during the next decade would be needed, which would link an extra 43,000 (27,900-58,000) MSM at high risk to HIV testing and 5100 (3500-6700) to ART, achieving an ART coverage of 44% for MSM at high risk in 2022. An additional $55·3 million investment would link an extra 46,700 (30,300-63,200) MSM to HIV testing and 12,600 (8800-16,600) to ART, achieving universal ART coverage of this population by 2022. This increased investment is achievable within present infrastructure capacity. Consequently, an estimated 5100 (3600-6700) HIV-related deaths and 3700 (2600-4900) new infections could be averted in MSM by 2022, corresponding to a 53% reduction in deaths and a 35% reduction in infections from 2012 levels. The expansion would cost an estimated $10,809 (9071-13,274) for each HIV-related death, $14,783 (12,389-17,960) per new infection averted, and $351 (290-424) per disability-adjusted life-year averted., Interpretation: Spare capacity in Bangkok's medical facilities can be used to expand ART access for MSM with large epidemiological benefits. The expansion needs increased funding directed to MSM services, but given the epidemiological trends, is probably cost effective. Our modelling approach and outcomes are likely to be applicable to other settings., Funding: World Bank Group and Australian National Health and Medical Research Council., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Niger's low-burden, sex-work-driven HIV epidemic is situated in a context of high economic and demographic growth. Resource availability of HIV/AIDS has been decreasing recently. In 2007-2012, only 1% of HIV expenditure was for sex work interventions, but an estimated 37% of HIV incidence was directly linked to sex work in 2012. The Government of Niger requested assistance to determine an efficient allocation of its HIV resources and to strengthen HIV programming for sex workers., Methods: Optima, an integrated epidemiologic and optimization tool, was applied using local HIV epidemic, demographic, programmatic, expenditure, and cost data. A mathematical optimization algorithm was used to determine the best resource allocation for minimizing HIV incidence and disability-adjusted life years (DALYs) over 10 years., Results: Efficient allocation of the available HIV resources, to minimize incidence and DALYs, would increase expenditure for sex work interventions from 1% to 4%-5%, almost double expenditure for antiretroviral treatment and for the prevention of mother-to-child transmission, and reduce expenditure for HIV programs focusing on the general population. Such an investment could prevent an additional 12% of new infections despite a budget of less than half of the 2012 reference year. Most averted infections would arise from increased funding for sex work interventions., Conclusions: This allocative efficiency analysis makes the case for increased investment in sex work interventions to minimize future HIV incidence and DALYs. Optimal HIV resource allocation combined with improved program implementation could have even greater HIV impact. Technical assistance is being provided to make the money invested in sex work programs work better and help Niger to achieve a cost-effective and sustainable HIV response.

Unlabelled: Introduction The treatment as prevention strategy has gained popularity as a way to reduce the incidence of HIV by suppressing viral load such that transmission risk is decreased. The effectiveness of the strategy also requires early diagnosis., Methods: Informed by data on the influence of diagnosis and treatment on reducing transmission risk, a model simulated the impact of increasing testing and treatment rates on the expected incidence of HIV in Australia under varying assumptions of treatment efficacy and risk compensation. The model utilises Australia's National HIV Registry data, and simulates disease progression, testing, treatment, transmission and mortality., Results: Decreasing the average time between infection and diagnosis by 30% is expected to reduce population incidence by 12% (~126 cases per year, 95% confidence interval (CI): 82-198). Treatment of all people living with HIV with CD4 counts <500cellsμL(-1) is expected to reduce new infections by 30.9% (95% CI: 15.9-37.6%) at 96% efficacy if no risk compensation occurs. The number of infections could increase up to 12.9% (95% CI: 20.1-7.4%) at 26% efficacy if a return to prediagnosis risk levels occur., Conclusion: Treatment as prevention has the potential to prevent HIV infections but its effectiveness depends on the efficacy outside trial settings among men who have sex with men and the level of risk compensation. If antiretroviral therapy has high efficacy, risk compensation will not greatly change the number of infections. If the efficacy of antiretroviral therapy is low, risk compensation could lead to increased infections.

The deceptively simple laminar structure of neocortex belies the complexity of intra- and interlaminar connectivity. We developed a computational model based primarily on a unified set of brain activity mapping studies of mouse M1. The simulation consisted of 775 spiking neurons of 10 cell types with detailed population-to-population connectivity. Static analysis of connectivity with graph-theoretic tools revealed that the corticostriatal population showed strong centrality, suggesting that would provide a network hub. Subsequent dynamical analysis confirmed this observation, in addition to revealing network dynamics that cannot be readily predicted through analysis of the wiring diagram alone. Activation thresholds depended on the stimulated layer. Low stimulation produced transient activation, while stronger activation produced sustained oscillations where the threshold for sustained responses varied by layer: 13% in layer 2/3, 54% in layer 5A, 25% in layer 5B, and 17% in layer 6. The frequency and phase of the resulting oscillation also depended on stimulation layer. By demonstrating the effectiveness of combined static and dynamic analysis, our results show how static brain maps can be related to the results of brain activity mapping.

Multiscale modeling of neuropsychiatric illness bridges scales of clinical importance: from the highest scales (presentation of behavioral signs and symptoms), through intermediate scales (clinical testing and surgical intervention), down to the molecular scale of pharmacotherapy. Modeling of brain disease is difficult compared to modeling of other organs, because dysfunction manifests at scales where measurements are rudimentary due both to inadequate access (memory and cognition) and to complexity (behavior). Nonetheless, we can begin to explore these aspects through the use of information-theoretic measures as stand-ins for meaning at the top scales. We here describe efforts across five disorders: Parkinson's, Alzheimer's, stroke, schizophrenia, and epilepsy. We look at the use of therapeutic brain stimulation to replace lost neural signals, a loss that produces diaschisis , defined as activity changes in other brain areas due to missing inputs. These changes may in some cases be compensatory, hence beneficial, but in many cases a primary pathology, whether itself static or dynamic, sets in motion a series of dynamic consequences that produce further pathology. The simulations presented here suggest how diaschisis can be reversed by using a neuroprosthetic signal. Despite having none of the information content of the lost physiological signal, the simplified neuroprosthetic signal can restore a diaschitic area to near-normal patterns of activity. Computer simulation thus begins to explain the remarkable success of stimulation technologies - deep brain stimulation, transcranial magnetic stimulation, ultrasound stimulation, transcranial direct current stimulation - across an extremely broad range of pathologies. Multiscale modeling can help us to optimize and integrate these neuroprosthetic therapies by taking into consideration effects of different stimulation protocols, combinations of stimulation with neuropharmacological therapy, and interplay of these therapeutic modalities with particular patterns of disease focality, dynamics, and prior therapies.

Background: New WHO guidelines recommend initiation of antiretroviral therapy for HIV-positive adults with CD4 counts of 500 cells per μL or less, a higher threshold than was previously recommended. Country decision makers have to decide whether to further expand eligibility for antiretroviral therapy accordingly. We aimed to assess the potential health benefits, costs, and cost-effectiveness of various eligibility criteria for adult antiretroviral therapy and expanded treatment coverage., Methods: We used several independent mathematical models in four settings-South Africa (generalised epidemic, moderate antiretroviral therapy coverage), Zambia (generalised epidemic, high antiretroviral therapy coverage), India (concentrated epidemic, moderate antiretroviral therapy coverage), and Vietnam (concentrated epidemic, low antiretroviral therapy coverage)-to assess the potential health benefits, costs, and cost-effectiveness of various eligibility criteria for adult antiretroviral therapy under scenarios of existing and expanded treatment coverage, with results projected over 20 years. Analyses assessed the extension of eligibility to include individuals with CD4 counts of 500 cells per μL or less, or all HIV-positive adults, compared with the previous (2010) recommendation of initiation with CD4 counts of 350 cells per μL or less. We assessed costs from a health-system perspective, and calculated the incremental cost (in US$) per disability-adjusted life-year (DALY) averted to compare competing strategies. Strategies were regarded very cost effective if the cost per DALY averted was less than the country's 2012 per-head gross domestic product (GDP; South Africa: $8040; Zambia: $1425; India: $1489; Vietnam: $1407) and cost effective if the cost per DALY averted was less than three times the per-head GDP., Findings: In South Africa, the cost per DALY averted of extending eligibility for antiretroviral therapy to adult patients with CD4 counts of 500 cells per μL or less ranged from $237 to $1691 per DALY averted compared with 2010 guidelines. In Zambia, expansion of eligibility to adults with a CD4 count threshold of 500 cells per μL ranged from improving health outcomes while reducing costs (ie, dominating the previous guidelines) to $749 per DALY averted. In both countries results were similar for expansion of eligibility to all HIV-positive adults, and when substantially expanded treatment coverage was assumed. Expansion of treatment coverage in the general population was also cost effective. In India, the cost for extending eligibility to all HIV-positive adults ranged from $131 to $241 per DALY averted, and in Vietnam extending eligibility to patients with CD4 counts of 500 cells per μL or less cost $290 per DALY averted. In concentrated epidemics, expanded access for key populations was also cost effective., Interpretation: Our estimates suggest that earlier eligibility for antiretroviral therapy is very cost effective in low-income and middle-income settings, although these estimates should be revisited when more data become available. Scaling up antiretroviral therapy through earlier eligibility and expanded coverage should be considered alongside other high-priority health interventions competing for health budgets., Funding: Bill & Melinda Gates Foundation, WHO., (Copyright © 2014 Eaton et al. Open Access article distributed under the terms of CC BY-NC-ND. Published by .. All rights reserved.)

Background: New WHO guidelines recommend ART initiation for HIV-positive persons with CD4 cell counts ≤500 cells/µL, a higher threshold than was previously recommended. Country decision makers must consider whether to further expand ART eligibility accordingly., Methods: We used multiple independent mathematical models in four settings-South Africa, Zambia, India, and Vietnam-to evaluate the potential health impact, costs, and cost-effectiveness of different adult ART eligibility criteria under scenarios of current and expanded treatment coverage, with results projected over 20 years. Analyses considered extending eligibility to include individuals with CD4 ≤500 cells/µL or all HIV-positive adults, compared to the previous recommendation of initiation with CD4 ≤350 cells/µL. We assessed costs from a health system perspective, and calculated the incremental cost per DALY averted ($/DALY) to compare competing strategies. Strategies were considered 'very cost-effective' if the $/DALY was less than the country's per capita gross domestic product (GDP; South Africa: $8040, Zambia: $1425, India: $1489, Vietnam: $1407) and 'cost-effective' if $/DALY was less than three times per capita GDP., Findings: In South Africa, the cost per DALY averted of extending ART eligibility to CD4 ≤500 cells/µL ranged from $237 to $1691/DALY compared to 2010 guidelines; in Zambia, expanded eligibility ranged from improving health outcomes while reducing costs (i.e. dominating current guidelines) to $749/DALY. Results were similar in scenarios with substantially expanded treatment access and for expanding eligibility to all HIV-positive adults. Expanding treatment coverage in the general population was therefore found to be cost-effective. In India, eligibility for all HIV-positive persons ranged from $131 to $241/DALY and in Vietnam eligibility for CD4 ≤500 cells/µL cost $290/DALY. In concentrated epidemics, expanded access among key populations was also cost-effective., Interpretation: Earlier ART eligibility is estimated to be very cost-effective in low- and middle-income settings, although these questions should be revisited as further information becomes available. Scaling-up ART should be considered among other high-priority health interventions competing for health budgets., Funding: The Bill and Melinda Gates Foundation and World Health Organization.

Neocortical mechanisms of learning sensorimotor control involve a complex series of interactions at multiple levels, from synaptic mechanisms to cellular dynamics to network connectomics. We developed a model of sensory and motor neocortex consisting of 704 spiking model neurons. Sensory and motor populations included excitatory cells and two types of interneurons. Neurons were interconnected with AMPA/NMDA and GABAA synapses. We trained our model using spike-timing-dependent reinforcement learning to control a two-joint virtual arm to reach to a fixed target. For each of 125 trained networks, we used 200 training sessions, each involving 15 s reaches to the target from 16 starting positions. Learning altered network dynamics, with enhancements to neuronal synchrony and behaviorally relevant information flow between neurons. After learning, networks demonstrated retention of behaviorally relevant memories by using proprioceptive information to perform reach-to-target from multiple starting positions. Networks dynamically controlled which joint rotations to use to reach a target, depending on current arm position. Learning-dependent network reorganization was evident in both sensory and motor populations: learned synaptic weights showed target-specific patterning optimized for particular reach movements. Our model embodies an integrative hypothesis of sensorimotor cortical learning that could be used to interpret future electrophysiological data recorded in vivo from sensorimotor learning experiments. We used our model to make the following predictions: learning enhances synchrony in neuronal populations and behaviorally relevant information flow across neuronal populations, enhanced sensory processing aids task-relevant motor performance and the relative ease of a particular movement in vivo depends on the amount of sensory information required to complete the movement.

The basal ganglia play a crucial role in the execution of movements, as demonstrated by the severe motor deficits that accompany Parkinson's disease (PD). Since motor commands originate in the cortex, an important question is how the basal ganglia influence cortical information flow, and how this influence becomes pathological in PD. To explore this, we developed a composite neuronal network/neural field model. The network model consisted of 4950 spiking neurons, divided into 15 excitatory and inhibitory cell populations in the thalamus and cortex. The field model consisted of the cortex, thalamus, striatum, subthalamic nucleus, and globus pallidus. Both models have been separately validated in previous work. Three field models were used: one with basal ganglia parameters based on data from healthy individuals, one based on data from individuals with PD, and one purely thalamocortical model. Spikes generated by these field models were then used to drive the network model. Compared to the network driven by the healthy model, the PD-driven network had lower firing rates, a shift in spectral power toward lower frequencies, and higher probability of bursting; each of these findings is consistent with empirical data on PD. In the healthy model, we found strong Granger causality between cortical layers in the beta and low gamma frequency bands, but this causality was largely absent in the PD model. In particular, the reduction in Granger causality from the main "input" layer of the cortex (layer 4) to the main "output" layer (layer 5) was pronounced. This may account for symptoms of PD that seem to reflect deficits in information flow, such as bradykinesia. In general, these results demonstrate that the brain's large-scale oscillatory environment, represented here by the field model, strongly influences the information processing that occurs within its subnetworks. Hence, it may be preferable to drive spiking network models with physiologically realistic inputs rather than pure white noise.

Electrical stimulation of the nervous system for therapeutic purposes, such as deep brain stimulation in the treatment of Parkinson's disease, has been used for decades. Recently, increased attention has focused on using microstimulation to restore functions as diverse as somatosensation and memory. However, how microstimulation changes the neural substrate is still not fully understood. Microstimulation may cause cortical changes that could either compete with or complement natural neural processes, and could result in neuroplastic changes rendering the region dysfunctional or even epileptic. As part of our efforts to produce neuroprosthetic devices and to further study the effects of microstimulation on the cortex, we stimulated and recorded from microelectrode arrays in the hand area of the primary somatosensory cortex (area 1) in two awake macaque monkeys. We applied a simple neuroprosthetic microstimulation protocol to a pair of electrodes in the area 1 array, using either random pulses or pulses time-locked to the recorded spiking activity of a reference neuron. This setup was replicated using a computer model of the thalamocortical system, which consisted of 1980 spiking neurons distributed among six cortical layers and two thalamic nuclei. Experimentally, we found that spike-triggered microstimulation induced cortical plasticity, as shown by increased unit-pair mutual information, while random microstimulation did not. In addition, there was an increased response to touch following spike-triggered microstimulation, along with decreased neural variability. The computer model successfully reproduced both qualitative and quantitative aspects of the experimental findings. The physiological findings of this study suggest that even simple microstimulation protocols can be used to increase somatosensory information flow.

Objective: To evaluate the impact and cost-effectiveness of needle-syringe programs (NSPs) with respect to HIV and hepatitis C virus (HCV) infections among Australian injecting drug users (IDUs)., Design/methods: A health economic analysis was conducted incorporating a mathematical model of HIV and HCV transmission among IDUs. An empirical relationship between syringe availability and receptive syringe sharing (RSS) was assessed. We compared the epidemiological outcomes and costs of NSP coverage (status quo RSS of 15-17%) with scenarios that had no NSPs (RSS of 25-50%). Outcomes included numbers of HIV and HCV infections averted, lifetime health sector costs, and cost per quality-adjusted life year (QALY) gained. Discounting was applied at 3% (sensitivity: 0%, 5%) per annum., Results: We estimated that NSPs reduced incidence of HIV by 34-70% (192-873 cases) and HCV by 15-43% (19 000-77 000 cases) during 2000-2010, leading to 20 000-66 000 QALYs gained. Economic analysis showed that NSP coverage saved A$70-220 million in healthcare costs during 2000-2010 and will save an additional A$340-950 million in future healthcare costs. With NSPs costing A$245 million, the programs are very cost-effective at A$416-8750 per QALY gained. Financial investment in NSPs over 2000-2010 is estimated to be entirely recovered in healthcare cost savings by 2032 with a total future return on investment of $1.3-5.5 for every $1 invested., Conclusion: Australia's early introduction and high coverage of NSPs has significantly reduced the prevalence of HIV and HCV among IDUs. NSPs are a cost-effective public health strategy and will result in substantial net cost savings in the future.

Damage to a cortical area reduces not only information transmitted to other cortical areas, but also activation of these areas. This phenomenon, whereby the dynamics of a follower area are dramatically altered, is typically manifested as a marked reduction in activity. Ideally, neuroprosthetic stimulation would replace both information and activation. However, replacement of activation alone may be valuable as a means of restoring dynamics and information processing of other signals in this multiplexing system. We used neuroprosthetic stimulation in a computer model of the cortex to repair activation dynamics, using a simple repetitive stimulation to replace the more complex, naturalistic stimulation that had been removed. We found that we were able to restore activity in terms of neuronal firing rates. Additionally, we were able to restore information processing, measured as a restoration of causality between an experimentally recorded signal fed into the in silico brain and a cortical output. These results indicate that even simple neuroprosthetics that do not restore lost information may nonetheless be effective in improving the functionality of surrounding areas of cortex.

Sensorimotor control has traditionally been considered from a control theory perspective, without relation to neurobiology. In contrast, here we utilized a spiking-neuron model of motor cortex and trained it to perform a simple movement task, which consisted of rotating a single-joint "forearm" to a target. Learning was based on a reinforcement mechanism analogous to that of the dopamine system. This provided a global reward or punishment signal in response to decreasing or increasing distance from hand to target, respectively. Output was partially driven by Poisson motor babbling, creating stochastic movements that could then be shaped by learning. The virtual forearm consisted of a single segment rotated around an elbow joint, controlled by flexor and extensor muscles. The model consisted of 144 excitatory and 64 inhibitory event-based neurons, each with AMPA, NMDA, and GABA synapses. Proprioceptive cell input to this model encoded the 2 muscle lengths. Plasticity was only enabled in feedforward connections between input and output excitatory units, using spike-timing-dependent eligibility traces for synaptic credit or blame assignment. Learning resulted from a global 3-valued signal: reward (+1), no learning (0), or punishment (-1), corresponding to phasic increases, lack of change, or phasic decreases of dopaminergic cell firing, respectively. Successful learning only occurred when both reward and punishment were enabled. In this case, 5 target angles were learned successfully within 180 s of simulation time, with a median error of 8 degrees. Motor babbling allowed exploratory learning, but decreased the stability of the learned behavior, since the hand continued moving after reaching the target. Our model demonstrated that a global reinforcement signal, coupled with eligibility traces for synaptic plasticity, can train a spiking sensorimotor network to perform goal-directed motor behavior.

Background: The RV144 trial conducted in Thailand was the first to demonstrate modest protective efficacy of an HIV vaccine. Its estimated initial efficacy was ∼74%, but this waned considerably over time., Methods: We developed a mathematical model to reflect historical and current HIV trends across different at-risk populations in Thailand. The model was used to estimate the expected number of infections that would be averted if a vaccine with outcome characteristics similar to the RV144 vaccine was implemented in Thailand at varying levels of coverage., Results: In the absence of a vaccine, we projected roughly 65,000 new HIV infections among adults during the period between 2011 and 2021. Due to the waning efficacy of the vaccine, vaccination campaigns were found to have modest long-term public health benefit unless re-vaccination occurred. We forecast that an RV144-like vaccine with coverage of 30% of the population would lead to a 3% reduction in HIV incidence during the next 10 years. In comparison, 30% coverage of annual or biennial re-vaccination with the vaccine was found to result in 23% and 14% reductions in incidence, respectively. Coverage of 60% without re-vaccination resulted in a 7% reduction. Epidemiological outcomes were found to depend primarily on three factors: vaccination coverage, vaccine efficacy, and the duration of protection the vaccine provided., Discussion: Due to the short duration of protection the vaccine provides without re-vaccination, our model predicts modest benefit from a vaccination campaign with an RV144-like HIV vaccine in Thailand. Annual or biannual re-vaccination is predicted to greatly increase the long-term public health benefits of a vaccination campaign. The feasibility of vaccine implementation, as well as its economic viability, remains to be determined., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Objective: To investigate age trends, sex differences, and splitting of alpha peaks of the EEG spectrum in the healthy population., Methods: An automated multi-site algorithm was used to parametrize the alpha rhythm in 1498 healthy subjects aged 6-86 years. Alpha peaks identified from multiple electrode sites were organized into clusters of similar frequencies whose sex differences and age trends were investigated., Results: Significant age-related trends were observed for frequency, position, and amplitude of dominant alpha peaks. Occipital sites had alpha clusters of higher average frequency, higher power, and greater presence across the scalp. Frequency and power differences were found between the sexes., Conclusion: Observed increases in alpha frequency in children and decreases in the elderly were consistent with those from earlier studies. A large fraction of participants (≈ 44%) showed multiple distinct alpha rhythm thus investigations which only examine the alpha frequency with the highest peak power can produce misleading results. The strong dependence of alpha frequency on age and anterior-posterior position indicates use of a fixed alpha frequency band is insufficient to capture the full characteristics of the alpha rhythm., Significance: This study establishes alpha rhythm parameter ranges (including power and frequency) in the healthy population, and quantifies the variation in alpha frequency across the scalp. The automated characterization enables objective evaluations of alpha band activities over large samples. These findings are potentially useful in testing theories of alpha generation, where splitting of the alpha rhythm has been theoretically predicted to occur in individuals with large differences in axon length between anterior and posterior corticothalamic loops., (Crown Copyright © 2011. Published by Elsevier Ireland Ltd. All rights reserved.)

Auditory event-related potentials (ERPs) have been extensively studied in patients with depression, but most studies have focused on purely phenomenological analysis methods, such as component scoring. In contrast, this study applies two recently developed physiology-based methods-fitting using a thalamocortical model of neuronal activity and waveform deconvolution - to data from a selective-attention task in four subject groups (49 patients with melancholic depression, 34 patients with non-melancholic depression, 111 participants with subclinical depressed mood, and 98 healthy controls), to yield insight into physiological differences in attentional processing between participants with major depression and controls. This approach found evidence that: participants with depressed mood, regardless of clinical status, shift from excitation in the thalamocortical system towards inhibition; that clinically depressed participants have decreased relative response amplitude between target and standard waveforms; and that patients with melancholic depression also have increased thalamocortical delays. These findings suggest possible physiological mechanisms underlying different depression subtypes, and may eventually prove useful in motivating new physiology-based diagnostic methods., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Objective: The physiological basis for the changes in auditory evoked potentials (AEPs) during development and aging is currently unknown. This study investigates age- and task-related changes via a mathematical model of neuronal activity, which allows a number of physiological changes to be inferred., Methods: A quantitative, physiology-based model of activity in cortical and thalamic neurons was used to analyze oddball AEPs recorded from 1498 healthy subjects aged 6-86 years., Results: Differences between standard and target responses can be largely explained by differences in connection strengths between thalamic and cortical neurons. The time it takes signals to travel between the thalamus and cortex decreases during development and increases during aging. Strong age trends are also seen in intracortical and thalamocortical neuronal connection strengths., Conclusions: Changes in AEP latency can be attributed to changes in the thalamocortical signal propagation time. Large changes in the connection strengths between neuronal populations occur during development, resulting in increased thalamocortical inhibition and decreased thalamocortical excitation. Standard and target parameters are similar in children but diverge during adolescence, due to changes in thalamocortical loop activity., Significance: Model-based AEP analysis links age-related changes in brain electrophysiology to underlying changes in brain anatomy and physiology, and yields quantitative predictions of several currently unknown physiological and anatomical properties of the brain., (Copyright © 2010 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)