Jasmina Panovska-Griffiths

A gene regulatory motif that generates oscillatory or multiway switch outputs

The pattern of gene expression in a developing tissue determines the spatial organization of cell type generation. We previously defined regulatory interactions between a set of transcription factors that specify the pattern of gene expression in progenitors of different neuronal subtypes of the vertebrate neural tube. These transcription factors form a circuit that acts as a multistate switch, patterning the tissue in response to a gradient of Sonic Hedgehog. Here, by simplifying aspects of the regulatory interactions, we found that the topology of the circuit allows either switch-like or oscillatory behaviour depending on parameter values. The qualitative dynamics appear to be controlled by a simpler sub-circuit, which we term the AC–DC motif. We argue that its topology provides a natural way to implement a multistate gene expression switch and we show that the circuit is readily extendable to produce more distinct stripes of gene expression. Our analysis also suggests that AC–DC motifs could be deployed in tissues patterned by oscillatory mechanisms, thus blurring the distinction between pattern-formation mechanisms relying on temporal oscillations or graded signals. Furthermore, during evolution, mechanisms of gradient interpretation might have arisen from oscillatory circuits, or vice versa.

Effect of mass paediatric influenza vaccination on existing influenza vaccination programmes in England and Wales: a modelling and cost-effectiveness analysis

Summary Background In 2013 England and Wales began to fund a live attenuated influenza vaccine programme for individuals aged 2–16 years. Mathematical modelling predicts substantial beneficial herd effects for the entire population as a result of reduced influenza transmission. With a decreased influenza-associated disease burden, existing immunisation programmes might be less cost-effective. The aim of this study was to assess the epidemiological effect and cost-effectiveness of the existing elderly and risk group vaccination programme under the new policy of mass paediatric vaccination in England. Methods For this cost-effectiveness analysis, we used a transmission model of seasonal influenza calibrated to 14 seasons of weekly consultation and virology data in England and Wales. We combined this model with an economic evaluation to calculate the incremental cost-effectiveness ratios, measured in cost per quality-adjusted life-years (QALY) gained. Findings Our results suggest that well timed administration of paediatric vaccination would reduce the number of low-risk elderly influenza cases to a greater extent than would vaccination of the low-risk elderly themselves if the elderly uptake is achieved more slowly. Although high-risk vaccination remains cost-effective, substantial uncertainty exists as to whether low-risk elderly vaccination remains cost-effective, driven by the choice of cost-effectiveness threshold. Under base case assumptions and a cost-effectiveness threshold of £15 000 per QALY, the low-risk elderly seasonal vaccination programme will cease to be cost-effective with a mean incremental cost-effectiveness ratio of £22 000 per QALY and a probability of cost-effectiveness of 20%. However, under a £30 000 per QALY threshold, the programme will remain cost-effective with 83% probability. Interpretation With the likely move to decreased cost-effectiveness thresholds, reassessment of existing risk group-based vaccine programme cost-effectiveness in the presence of the paediatric vaccination programme is needed. Funding National Institute for Health Research, the Medical Research Council.

Monitoring cerebral autoregulation after brain injury: multimodal assessment of cerebral slow-wave oscillations using near-infrared spectroscopy

BACKGROUND:Continuous monitoring of cerebral autoregulation might provide novel treatment targets and identify therapeutic windows after acute brain injury. Slow oscillations of cerebral hemodynamics (0.05–0.003 Hz) are visible in multimodal neuromonitoring and may be analyzed to provide novel, surrogate measures of autoregulation. Near-infrared spectroscopy (NIRS) is an optical neuromonitoring technique, which shows promise for widespread clinical applicability because it is noninvasive and easily delivered across a wide range of clinical scenarios. The aim of this study is to identify the relationship between NIRS signal oscillations and multimodal neuromonitoring, examining the utility of near infrared derived indices of cerebrovascular reactivity. METHODS:Twenty-seven sedated, ventilated, brain-injured patients were included in this observational study. Intracranial pressure, transcranial Doppler–derived flow velocity in the middle cerebral artery, and ipsilateral cerebral NIRS variables were continuously monitored. Signals were compared using wavelet measures of phase and coherence to examine the spectral features involved in reactivity index calculations. Established indices of autoregulatory reserve such as the pressure reactivity index (PRx) and mean velocity index (Mx) and the NIRS indices such as total hemoglobin reactivity index (THx) and tissue oxygen reactivity index (TOx) were compared using correlation and Bland-Altman analysis. RESULTS:NIRS indices correlated significantly between PRx and THx (rs = 0.63, P < 0.001), PRx and TOx (r = 0.40, P = 0.04), and Mx and TOx (r = 0.61, P = 0.004) but not between Mx and THx (rs = 0.26, P = 0.28) and demonstrated wide limits between these variables: PRx and THx (bias, −0.06; 95% limits, −0.44 to 0.32) and Mx and TOx (bias, +0.15; 95% limits, −0.34 to 0.64). Analysis of slow-wave activity throughout the intracranial pressure, transcranial Doppler, and NIRS recordings revealed statistically significant interrelationships, which varied dynamically and were nonsignificant at frequencies <0.008 Hz. CONCLUSIONS:Although slow-wave activity in intracranial pressure, transcranial Doppler, and NIRS is significantly similar, it varies dynamically in both time and frequency, and this manifests as incomplete agreement between reactivity indices. Analysis informed by a priori knowledge of physiology underpinning NIRS variables combined with sophisticated analysis techniques has the potential to deliver noninvasive surrogate measures of autoregulation, guiding therapy.

Optimal Allocation of Resources in Female Sex Worker Targeted HIV Prevention Interventions: Model Insights from Avahan in South India

Background The Avahan programme has provided HIV prevention activities, including condom promotion, to female sex workers (FSWs) in southern India since 2004. Evidence suggests Avahan averted 202,000 HIV infections over 4 years. For replicating this intervention elsewhere, it is essential to understand how the intervention’s impact could have been optimised for different budget levels. Methods Behavioural data were used to determine how condom use varied for FSWs with different levels of intervention intensity. Cost data from 64 Avahan districts quantified how district-level costs related to intervention scale and intensity. A deterministic model for HIV transmission amongst FSWs and clients projected the impact and cost of intervention strategies for different scale and intensity, and identified the optimal strategies that maximise impact for different budget levels. Results As budget levels increase, the optimal intervention strategy is to first increase intervention intensity which achieves little impact, then scale-up coverage to high levels for large increases in impact, and lastly increase intensity further for small additional gains. The cost-effectiveness of these optimal strategies generally improves with increasing resources, while straying from these strategies can triple costs for the same impact. Projections suggest Avahan was close to being optimal, and moderate budget reductions (≥20%) would have reduced impact considerably (>40%). Discussion Our analysis suggests that tailoring the design of HIV prevention programmes for FSWs can improve impact, and that a certain level of resources are required to achieve demonstrable impact. These insights are critical for optimising the use of limited resources for preventing HIV.

Modelling cerebrovascular reactivity: a novel near-infrared biomarker of cerebral autoregulation?

Understanding changes in cerebral oxygenation, haemodynamics and metabolism holds the key to individualised, optimised therapy after acute brain injury. Near-infrared spectroscopy (NIRS) offers the potential for non-invasive, continuous bedside measurement of surrogates for these processes. Interest has grown in applying this technique to interpret cerebrovascular pressure reactivity (CVPR), a surrogate of the brain’s ability to autoregulate blood flow. We describe a physiological model-based approach to NIRS interpretation which predicts autoregulatory efficiency from a model parameter k_aut. Data from three critically brain-injured patients exhibiting a change in CVPR were investigated. An optimal value for k_aut was determined to minimise the difference between measured and simulated outputs. Optimal values for k_aut appropriately tracked changes in CVPR under most circumstances. Further development of this technique could be used to track CVPR providing targets for individualised management of patients with altered vascular reactivity, minimising secondary neurological insults.

How should HIV resources be allocated? Lessons learnt from applying Optima HIV in 23 countries

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.

Mathematical Modelling of Near-Infrared Spectroscopy Signals and Intracranial Pressure in Brain-Injured Patients

Raised intracranial pressure (ICP) is a key concern following acute brain injury as it may be associated with cerebral hypoperfusion and poor outcome. In this research we describe a mathematical physiological model designed to interpret cerebral physiology from neuromonitoring: ICP, near-infrared spectroscopy and transcranial Doppler flow velocity. This aims to characterise the complex dynamics of cerebral compliance, cerebral blood volume, cerebral blood flow and their regulation in individual patients. Analysis of data from six brain-injured patients produces cohesive predictions of cerebral biomechanics suggesting reduced cerebral compliance, reduced volume compensation and impaired blood flow autoregulation. Patient-specific physiological modelling has the potential to predict the key biomechanical and haemodynamic changes following brain injury in individual patients, and might be used to inform individualised treatment strategies.

A novel approach to evaluating the UK childhood immunisation schedule: estimating the effective coverage vector across the entire vaccine programme

BackgroundThe availability of new vaccines can prompt policy makers to consider changes to the routine childhood immunisation programme in the UK. Alterations to one aspect of the schedule may have implications for other areas of the programme (e.g. adding more injections could reduce uptake of vaccines featuring later in the schedule). Colleagues at the Department of Health (DH) in the UK therefore wanted to know whether assessing the impact across the entire programme of a proposed change to the UK schedule could lead to different decisions than those made on the current case-by-case basis. This work is a first step towards addressing this question.MethodsA novel framework for estimating the effective coverage against all of the diseases within a vaccination programme was developed. The framework was applied to the current (August 2015) UK childhood immunisation programme, plausible extensions to it in the foreseeable future (introducing vaccination against Meningitis B and/or Hepatitis B) and a “what-if” scenario regarding a Hepatitis B vaccine scare that was developed in close collaboration with DH.ResultsOur applications of the framework demonstrate that a programme-view of hypothetical changes to the schedule is important. For example, we show how introducing Hepatitis B vaccination could negatively impact aspects of the current programme by reducing uptake of vaccines featuring later in the schedule, and illustrate that the potential benefits of introducing any new vaccine are susceptible to behaviour changes affecting uptake (e.g. a vaccine scare). We show how it may be useful to consider the potential benefits and scheduling needs of all vaccinations on the horizon of interest rather than those of an individual vaccine in isolation, e.g. how introducing Meningitis B vaccination could saturate the early (2-month) visit, thereby potentially restricting scheduling options for Hepatitis B immunisation should it be introduced to the programme in the future.ConclusionsOur results demonstrate the potential benefit of considering the programme-wide impact of changes to an immunisation schedule, and our framework is an important step in the development of a means for systematically doing so.

Estimates for quality of life loss due to RSV

A number of vaccines against Respiratory Syncytial Virus (RSV) infection are approaching licensure. Deciding which RSV vaccine strategy, if any, to introduce, will partly depend on cost-effectiveness analyses, which compares the relative costs and health benefits of a potential vaccination programme. Health benefits are usually measured in Quality Adjusted Life Year (QALY) loss, however, there are no QALY loss estimates for RSV that have been determined using standardised instruments. Moreover, in children under the age of five years in whom severe RSV episodes predominantly occur, there are no appropriate standardised instruments to estimate QALY loss. We estimated the QALY loss due to RSV across all ages by developing a novel regression model which predicts the QALY loss without the use of standardised instruments. To do this, we conducted a surveillance study which targeted confirmed episodes in children under the age of five years (confirmed cases) and their household members who experienced symptoms of RSV during the same time (suspected cases.) All participants were asked to complete questions regarding their health during the infection, with the suspected cases aged 5–14 and 15+ years old additionally providing Health-Related Quality of Life (HR-QoL) loss estimates through completing EQ-5D-3L-Y and EQ-5D-3L instruments respectively. The questionnaire responses from the suspected cases were used to calibrate the regression model. The calibrated regression model then used other questionnaire responses to predict the HR-QoL loss without the use of EQ-5D instruments. The age-specific QALY loss was then calculated by multiplying the HR-QoL loss on the worst day predicted from the regression model, with estimates for the duration of infection from the questionnaires and a scaling factoring for disease severity. Our regression model for predicting HR-QoL loss estimates that for the worst day of infection, suspected RSV cases in persons five years and older who do and do not seek healthcare have an HR-QoL loss of 0·616 (95% CI 0·155–1·371) and 0·405 (95% CI 0·111–1·137) respectively. This leads to a QALY loss per RSV episode of 1·950 × 10−3 (95% CI 0·185 × 10−3 –9·578 × 10−3) and 1·543 × 10−3 (95% CI 0·136 × 10−3 –6·406 × 10−3) respectively. For confirmed cases in a child under the age of five years who sought healthcare, our model predicted a HR-QoL loss on the worst day of infection of 0·820 (95% CI 0·222–1·450) resulting in a QALY loss per RSV episode of 3·823 × 10−3 (95% CI 0·492 × 10−3 –12·766 × 10−3). Combing these results with previous estimates of RSV burden in the UK, we estimate the annual QALY loss of healthcare seeking RSV episodes as 1,199 for individuals aged five years and over and 1,441 for individuals under five years old. The QALY loss due to an RSV episode is less than the QALY loss due to an Influenza episode. These results have important implications for potential RSV vaccination programmes, which has so far focused on preventing infections in infants—where the highest reported disease burden lies. Future potential RSV vaccination programmes should also evaluate their impact on older children and adults, where there is a substantial but unsurveilled QALY loss.

A method for evaluating and comparing immunisation schedules that cover multiple diseases: Illustrative application to the UK routine childhood vaccine schedule

BACKGROUND In the UK, the childhood immunisation programme is given in the first 5 years of life and protects against 12 vaccine-preventable diseases. Recently, this programme has undergone changes with addition of vaccination against Meningitis B from September 2015 and the removal of the primary dose of protection against Meningitis C from July 2016. These hanges have direct impact on the associated diseases but in addition may induce indirect effects on the vaccines that are given simultaneously or later in the programme. In this work, we developed a novel formal method to evaluate the impact of vaccination changes to one aspect of the programme across an entire vaccine programme. METHODS Firstly, we combined transmission modelling (for four diseases) and historic data synthesis (for eight diseases) to project, for each disease, the disease burden at different levels of effective coverage against the associated disease. Secondly, we used a simulation model to determine the vector of effective coverage against each disease under three variations of the current childhood schedule. Combining these, we calculated the vector of disease burden across the programme under different scenarios, and assessed the direct and indirect effects of the schedule changes. RESULTS Through illustrative application of our novel framework to three scenarios of the current childhood immunisation programme in the UK, we demonstrated the feasibility of this unifying approach. For each disease in the programme, we successfully quantified the residual disease burden due to the change. For some diseases, the change was indirectly beneficial and reduced the burden, whereas for others the effect was adverse and the change increased the disease burden. CONCLUSIONS Our results demonstrate the potential benefit of considering the programme-wide impact of changes to an immunisation schedule, and our framework is an important step in the development of a means for systematically doing so.