Soma-Axon Coupling Configurations That Enhance Neuronal Coincidence Detection

Coincidence detector neurons transmit timing information by responding preferentially to concurrent synaptic inputs. Principal cells of the medial superior olive (MSO) in the mammalian auditory brainstem are superb coincidence detectors. They encode sound source location with high temporal precision, distinguishing submillisecond timing differences among inputs. We investigate computationally how dynamic coupling between the input region (soma and dendrite) and the spike-generating output region (axon and axon initial segment) can enhance coincidence detection in MSO neurons. To do this, we formulate a two-compartment neuron model and characterize extensively coincidence detection sensitivity throughout a parameter space of coupling configurations. We focus on the interaction between coupling configuration and two currents that provide dynamic, voltage-gated, negative feedback in subthreshold voltage range: sodium current with rapid inactivation and low-threshold potassium current, IKLT. These currents reduce synaptic summation and can prevent spike generation unless inputs arrive with near simultaneity. We show that strong soma-to-axon coupling promotes the negative feedback effects of sodium inactivation and is, therefore, advantageous for coincidence detection. Furthermore, the feedforward combination of strong soma-to-axon coupling and weak axon-to-soma coupling enables spikes to be generated efficiently (few sodium channels needed) and with rapid recovery that enhances high-frequency coincidence detection. These observations detail the functional benefit of the strongly feedforward configuration that has been observed in physiological studies of MSO neurons. We find that IKLT further enhances coincidence detection sensitivity, but with effects that depend on coupling configuration. For instance, in models with weak soma-to-axon and weak axon-to-soma coupling, IKLT in the axon enhances coincidence detection more effectively than IKLT in the soma. By using a minimal model of soma-to-axon coupling, we connect structure, dynamics, and computation. Although we consider the particular case of MSO coincidence detectors, our method for creating and exploring a parameter space of two-compartment models can be applied to other neurons

Financing structural interventions: going beyond HIV-only value for money assessments.

OBJECTIVE: Structural interventions can reduce HIV vulnerability. However, HIV-specific budgeting, based on HIV-specific outcomes alone, could lead to the undervaluation of investments in such interventions and suboptimal resource allocation. We investigate this hypothesis by examining the consequences of alternative financing approaches. METHODS: We compare three approaches for deciding whether to finance a structural intervention to keep adolescent girls in school in Malawi. In the first, HIV and non-HIV budget holders participate in a cross-sectoral cost-benefit analysis and fund the intervention if the benefits outweigh the costs. In the second silo approach, each budget holder considers the cost-effectiveness of the intervention in terms of their own objectives and funds the intervention on the basis of their sector-specific thresholds of what is cost-effective or not. In the third cofinancing approach, budget holders use cost-effectiveness analysis to determine how much they would be willing to contribute towards the intervention, provided that other sectors are willing to pay for the remaining costs. In addition, we explore approaches for determining the HIV share in the cofinancing scenario. RESULTS: We find that efficient structural interventions may be less likely to be prioritized, financed and taken to scale where sectors evaluate their options in isolation. A cofinancing approach minimizes welfare loss and could be incorporated in a sector budgeting perspective. CONCLUSION: Structural interventions may be underimplemented and their cross-sectoral benefits foregone. Cofinancing provides an opportunity for multiple HIV, health and development objectives to be achieved simultaneously, but will require effective cross-sectoral coordination mechanisms for planning, implementation and financing

Climate Research Wageningen UR : Projects, researchers and expertise

Wageningen UR focuses not only on the global climate system but also on regional and local climate phenomena, taking both scientific and social aspects into account in an integral way. Wageningen UR wants to play an effective role in the transition to a world that is both climate neutral and climate proof. Our strength is using the limited space available in our delta, in a climate-proof manner, thus providing opportunities for among others agriculture, horticulture, aquaculture, recreation and living

Cost-Effectiveness Thresholds in Global Health: Taking a Multisectoral Perspective.

Good health is a function of a range of biological, environmental, behavioral, and social factors. The consumption of quality health care services is therefore only a part of how good health is produced. Although few would argue with this, the economic framework used to allocate resources to optimize population health is applied in a way that constrains the analyst and the decision maker to health care services. This approach risks missing two critical issues: 1) multiple sectors contribute to health gain and 2) the goods and services produced by the health sector can have multiple benefits besides health. We illustrate how present cost-effectiveness thresholds could result in health losses, particularly when considering health-producing interventions in other sectors or public health interventions with multisectoral outcomes. We then propose a potentially more optimal second best approach, the so-called cofinancing approach, in which the health payer could redistribute part of its budget to other sectors, where specific nonhealth interventions achieved a health gain more efficiently than the health sector's marginal productivity (opportunity cost). Likewise, other sectors would determine how much to contribute toward such an intervention, given the current marginal productivity of their budgets. Further research is certainly required to test and validate different measurement approaches and to assess the efficiency gains from cofinancing after deducting the transaction costs that would come with such cross-sectoral coordination

Financing essential HIV services: a new economic agenda.

Anna Vassall and colleagues discuss the need for, and challenges facing, innovative and sustainable financing of the HIV response. Please see later in the article for the Editors' Summary

An assessment of equity in the distribution of non-financial health care inputs across public primary health care facilities in Tanzania.

BACKGROUND: There is limited evidence on how health care inputs are distributed from the sub-national level down to health facilities and their potential influence on promoting health equity. To address this gap, this paper assesses equity in the distribution of health care inputs across public primary health facilities at the district level in Tanzania. METHODS: This is a quantitative assessment of equity in the distribution of health care inputs (staff, drugs, medical supplies and equipment) from district to facility level. The study was carried out in three districts (Kinondoni, Singida Rural and Manyoni district) in Tanzania. These districts were selected because they were implementing primary care reforms. We administered 729 exit surveys with patients seeking out-patient care; and health facility surveys at 69 facilities in early 2014. A total of seventeen indices of input availability were constructed with the collected data. The distribution of inputs was considered in relation to (i) the wealth of patients accessing the facilities, which was taken as a proxy for the wealth of the population in the catchment area; and (ii) facility distance from the district headquarters. We assessed equity in the distribution of inputs through the use of equity ratios, concentration indices and curves. RESULTS: We found a significant pro-rich distribution of clinical staff and nurses per 1000 population. Facilities with the poorest patients (most remote facilities) have fewer staff per 1000 population than those with the least poor patients (least remote facilities): 0.6 staff per 1000 among the poorest, compared to 0.9 among the least poor; 0.7 staff per 1000 among the most remote facilities compared to 0.9 among the least remote. The negative concentration index for support staff suggests a pro-poor distribution of this cadre but the 45 degree dominated the concentration curve. The distribution of vaccines, antibiotics, anti-diarrhoeal, anti-malarials and medical supplies was approximately proportional (non dominance), whereas the distribution of oxytocics, anti-retroviral therapy (ART) and anti-hypertensive drugs was pro-rich, with the 45 degree line dominating the concentration curve for ART. CONCLUSION: This study has shown there are inequities in the distribution of health care inputs across public primary care facilities. This highlights the need to ensure a better coordinated and equitable distribution of inputs through regular monitoring of the availability of health care inputs and strengthening of reporting systems

Individualized Angiotensin‐Converting Enzyme (ACE)‐Inhibitor Therapy in Stable Coronary Artery Disease Based on Clinical and Pharmacogenetic Determinants: The PERindopril GENEtic (PERGENE) Risk Model

Patients with stable coronary artery disease (CAD) constitute a heterogeneous group in which the treatment benefits by angiotensin-converting enzyme (ACE)-inhibitor therapy vary between individuals. Our objective was to integrate clinical and pharmacogenetic determinants in an ultimate combined risk prediction model.Clinical, genetic, and outcomes data were used from 8726 stable CAD patients participating in the EUROPA/PERGENE trial of perindopril versus placebo. Multivariable analysis of phenotype data resulted in a clinical risk score (range, 0-21 points). Three single-nucleotide polymorphisms (rs275651 and rs5182 in the angiotensin-II type I-receptor gene and rs12050217 in the bradykinin type I-receptor gene) were used to construct a pharmacogenetic risk score (PGXscore; range, 0-6 points). Seven hundred eighty-five patients (9.0%) experienced the primary endpoint of cardiovascular mortality, nonfatal myocardial infarction or resuscitated cardiac arrest, during 4.2 years of follow-up. Absolute risk reductions ranged from 1.2% to 7.5% in the 73.5% of patients with PGXscore of 0 to 2. As a consequence, estimated annual numbers needed to treat ranged from as low as 29 (clinical risk score ≥10 and PGXscore of 0) to 521 (clinical risk score ≤6 and PGXscore of 2). Furthermore, our data suggest that long-term perindopril prescription in patients with a PGXscore of 0 to 2 is cost-effective.Both baseline clinical phenotype, as well as genotype determine the efficacy of widely prescribed ACE inhibition in stable CAD. Integration of clinical and pharmacogenetic determinants in a combined risk prediction model demonstrated a very wide range of gradients of absolute treatment benefit