The effect of new Mycobacterium tuberculosis infection on the sensitivity of prognostic TB signatures.

BACKGROUND: Tests that identify individuals at greatest risk of TB will allow more efficient targeting of preventive therapy. The WHO target product profile for such tests defines optimal sensitivity of 90% and minimum sensitivity of 75% for predicting incident TB. The CORTIS (Correlate of Risk Targeted Intervention Study) evaluated a blood transcriptomic signature (RISK11) for predicting incident TB in a high transmission setting. RISK11 is able to predict TB disease progression but optimal prognostic performance was limited to a 6-month horizon.METHODS: Using a mathematical model, we estimated how subsequent Mycobacterium tuberculosis (MTB) infection may have contributed to the decline in sensitivity of RISK11. We calculated the effect at different RISK11 thresholds (60% and 26%) and for different assumptions about the risk of MTB infection.RESULTS: Modelled sensitivity over 15 months, excluding new infection, was 28.7% (95% CI 12.3-74.1) compared to 25.0% (95% CI 12.7-45.9) observed in the trial. Modelled sensitivity exceeded the minimum criteria (>75%) over a 9-month horizon at the 60% threshold and over 12 months at the 26% threshold.CONCLUSIONS: The effect of new infection on prognostic signature performance is likely to be small. Signatures such as RISK11 may be most useful in individuals, such as household contacts, where probable time of infection is known.

Evidence-informed policy making at country level: lessons learned from the South African Tuberculosis Think Tank.

BACKGROUND: National Tuberculosis Programmes (NTPs) require specialist input to support the development of policy and practice informed by evidence, typically against tight deadlines. OBJECTIVE: To describe lessons learned from establishing a dedicated tuberculosis (TB) think tank to advise the South African NTP on TB policy. INTERVENTION AND EVALUATION METHODS: A national TB think tank was established to advise the NTP in support of evidence-informed policy. Support was provided for activities, including meetings, modelling and regular telephone calls, with a wider network of unpaid expert advisers under an executive committee and working groups. Intervention evaluation used desktop analysis of documentary evidence, interviews and direct observation. RESULTS: The TB Think Tank evolved over time to acquire three key roles: an 'institution', a 'policy dialogue forum' and an 'interface'. Although enthusiasm was high, motivating participation among the NTP and external experts proved challenging. Motivation of working groups was most successful when aligned to a specific need for NTP decision making. Despite challenges, the TB Think Tank contributed to South Africa's first ever TB and human immunodeficiency virus (HIV) investment case, and the decision to create South Africa's first ever ring-fenced grant for TB. The TB Think Tank also assisted the NTP in formulating strategy to accelerate progress towards reaching World Health Organization targets. DISCUSSION: With partners, the TB Think Tank achieved major successes in supporting evidence-informed decision making, and garnered increased funding for TB in South Africa. Identifying ways to increase the involvement of NTP staff and other experts, and keeping the scope of the Think Tank well defined, could facilitate greater impact. Think tank initiatives could be replicated in other settings to support evidence-informed policy making.

Global tuberculosis targets and milestones set for 2016-2035: definition and rationale.

BACKGROUND: Global tuberculosis (TB) targets were set as part of the World Health Organization's End TB Strategy (2016-2035) and the Sustainable Development Goals (2016-2030). OBJECTIVE: To define and explain the rationale for these targets. DESIGN: Scenarios for plausible reductions in TB deaths and cases were developed using empirical evidence from best-performing countries and modelling of the scale-up of under-used interventions and hypothetical TB vaccines. Results were discussed at consultations in 2012 and 2013. A final proposal was presented to the World Health Assembly in 2014 and unanimously endorsed by all Member States. RESULTS: The 2030 targets are a 90% reduction in TB deaths and 80% reduction in TB incidence compared with 2015 levels. The 2035 targets are for reductions of 95% and 90%, respectively. A third target-that no TB-affected households experience catastrophic costs due to the disease by 2020-was also agreed. CONCLUSION: The global TB targets and milestones set for the period 2016-2035 are ambitious. Achieving them requires concerted action on several fronts, but two things are fundamental: 1) progress towards universal health coverage to ensure that everyone with TB can access high-quality treatment; and 2) substantial investment in research and development for new tools to prevent TB disease among the approximately 1.7 billion people infected.

Is IPT more effective in high-burden settings? Modelling the effect of tuberculosis incidence on IPT impact.

SETTING: Isoniazid preventive therapy (IPT) is effective for preventing active tuberculosis (TB), although its mechanism of action is poorly understood and the optimal disease burden for IPT use has not been defined. OBJECTIVE: To describe the relationship between TB incidence and IPT effectiveness. METHODS: We constructed a model of TB transmission dynamics to investigate IPT effectiveness under various epidemiological settings. The model structure was intended to be highly adaptable to uncertainty in both input parameters and the mechanism of action of IPT. To determine the optimal setting for IPT use, we identified the lowest number needed to treat (NNT) with IPT to prevent one case of active TB. RESULTS: We found that the NNT as a function of TB incidence shows a 'U-shape', whereby IPT impact is greatest at an intermediate incidence and attenuated at both lower and higher incidence levels. This U-shape was observed over a broad range of parameter values; the optimal TB incidence was between 500 and 900 cases per 100 000 per year. CONCLUSIONS: TB burden is a critical factor to consider when making decisions about communitywide implementation of IPT. We believe that the total disease burden should not preclude programmatic application of IPT.

TIME Impact - a new user-friendly tuberculosis (TB) model to inform TB policy decisions.

Tuberculosis (TB) is the leading cause of death from infectious disease worldwide, predominantly affecting low- and middle-income countries (LMICs), where resources are limited. As such, countries need to be able to choose the most efficient interventions for their respective setting. Mathematical models can be valuable tools to inform rational policy decisions and improve resource allocation, but are often unavailable or inaccessible for LMICs, particularly in TB. We developed TIME Impact, a user-friendly TB model that enables local capacity building and strengthens country-specific policy discussions to inform support funding applications at the (sub-)national level (e.g. Ministry of Finance) or to international donors (e.g. the Global Fund to Fight AIDS, Tuberculosis and Malaria).TIME Impact is an epidemiological transmission model nested in TIME, a set of TB modelling tools available for free download within the widely-used Spectrum software. The TIME Impact model reflects key aspects of the natural history of TB, with additional structure for HIV/ART, drug resistance, treatment history and age. TIME Impact enables national TB programmes (NTPs) and other TB policymakers to better understand their own TB epidemic, plan their response, apply for funding and evaluate the implementation of the response.The explicit aim of TIME Impact's user-friendly interface is to enable training of local and international TB experts towards independent use. During application of TIME Impact, close involvement of the NTPs and other local partners also builds critical understanding of the modelling methods, assumptions and limitations inherent to modelling. This is essential to generate broad country-level ownership of the modelling data inputs and results. In turn, it stimulates discussions and a review of the current evidence and assumptions, strengthening the decision-making process in general.TIME Impact has been effectively applied in a variety of settings. In South Africa, it informed the first South African HIV and TB Investment Cases and successfully leveraged additional resources from the National Treasury at a time of austerity. In Ghana, a long-term TIME model-centred interaction with the NTP provided new insights into the local epidemiology and guided resource allocation decisions to improve impact.

A Comparison of Dynamics in Two Models for the Spread of a Vector-Borne Disease.

In 2007, bluetongue virus (BTV) was introduced to both Denmark (DK) and the United Kingdom (UK). For this reason, simulation models were built to predict scenarios for future incursions. The DK and UK models have a common description of within-herd dynamics, but differ greatly in their descriptions of between-herd spread, one using an explicit representation of vector dispersal, the other a transmission kernel. Here, we compare model predictions for the dynamics of bluetongue in the UK, based on the 2007 incursion and vaccination rollout in 2008. We demonstrate how an agent-based model shows greater sensitivity to the level of vaccine uptake and has lower variability compared with a kernel-based model. However, a model using a transmission kernel requires less detailed data and is often faster.

Dangling conversations: reflections on the process of creating digital stories during a workshop with people with early-stage dementia.

Care and compassion are key features of the NHS Constitution. Recent reports have identified a lack of compassion in the care and treatment of older people. Nurses draw on aesthetic knowledge, developed through engagement with the experience of others, when providing compassionate care. Patient Voices reflective digital stories are used in healthcare education to facilitate student engagement with the patient experience. Digital stories were made with seven people with early-stage dementia as part of a learning package for student nurses. In this paper the authors reflect on their experience and observations from facilitating the 4-day digital story-making workshop. Social theories of dementia provide a theoretical framework for understanding these reflections. Despite considerable challenges in developing a story, and anxiety about using the technology, reading and speaking, all participants engaged in creating their own digital stories. Positive changes in the participants' interactions were observed. These improvements appeared to be the product of the person-centred facilitation and the creative process which supported self-expression and a sense of identity. Nurses working in this way could facilitate ability of the person with dementia to participate in their care, and improve their sense of well-being by supporting self-expression.

Comparison of pre-emptive and reactive strategies to control an incursion of bluetongue virus serotype 1 to Great Britain by vaccination.

Bluetongue (BT) is a disease of ruminants caused by bluetongue virus (BTV), which is spread between its hosts by Culicoides midges. Vaccination is the most effective way to protect susceptible animals against BTV and was used reactively to control the recent northern European outbreak. To assess the consequences of using vaccination pre-emptively we used a stochastic, spatially explicit model to compare reactive and pre-emptive vaccination strategies against an incursion of BTV serotype 1 (BTV-1) into Great Britain. Both pre-emptive and reactive vaccination significantly reduced the number of affected farms and limited host morbidity and mortality. In addition, vaccinating prior to the introduction of disease reduced the probability of an outbreak occurring. Of the strategies simulated, widespread reactive vaccination resulted in the lowest levels of morbidity. The predicted effects of vaccination were found to be sensitive to vaccine efficacy but not to the choice of transmission kernel.

A methodology for global-sensitivity analysis of time-dependent outputs in systems biology modelling.

One of the main challenges in the development of mathematical and computational models of biological systems is the precise estimation of parameter values. Understanding the effects of uncertainties in parameter values on model behaviour is crucial to the successful use of these models. Global sensitivity analysis (SA) can be used to quantify the variability in model predictions resulting from the uncertainty in multiple parameters and to shed light on the biological mechanisms driving system behaviour. We present a new methodology for global SA in systems biology which is computationally efficient and can be used to identify the key parameters and their interactions which drive the dynamic behaviour of a complex biological model. The approach combines functional principal component analysis with established global SA techniques. The methodology is applied to a model of the insulin signalling pathway, defects of which are a major cause of type 2 diabetes and a number of key features of the system are identified.

Scaling from challenge experiments to the field: Quantifying the impact of vaccination on the transmission of bluetongue virus serotype 8.

Bluetongue (BT) is an economically important disease of ruminants caused by bluetongue virus (BTV) and transmitted by Culicoides biting midges. The most practical and effective way to protect susceptible animals against BTV is by vaccination. Data from challenge studies in calves and sheep conducted by Intervet International b.v., in particular, presence of viral RNA in the blood of challenged animals, were used to estimate vaccine efficacy. The results of the challenge studies for calves indicated that vaccination is likely to reduce the basic reproduction number (R(0)) for BTV in cattle to below one (i.e. prevent major outbreaks within a holding) and that this reduction is robust to uncertainty in the model parameters. Sensitivity analysis showed that the whether or not vaccination is predicted to reduce R(0) to below one depended on the following assumptions: (i) whether "doubtful" results from the challenge studies are treated as negative or positive; (ii) whether or not the probability of transmission from host to vector is reduced by vaccination; and (iii) whether the extrinsic incubation period follows a realistic gamma distribution or the more commonly used exponential distribution. For sheep, all but one of the vaccinated animals were protected and, consequently, vaccination will consistently reduce R(0) in sheep to below one. Using a stochastic spatial model for the spread of BTV in Great Britain (GB), vaccination was predicted to reduce both the incidence of disease and spatial spread in simulated BTV outbreaks in GB, in both reactive vaccination strategies and when an incursion occurred into a previously vaccinated population.

A composite computational model of liver glucose homeostasis. II. Exploring system behaviour.

Using a composite model of the glucose homeostasis system, consisting of seven interconnected submodels, we enumerate the possible behaviours of the model in response to variation of liver insulin sensitivity and dietary glucose variability. The model can reproduce published experimental manipulations of the glucose homeostasis system and clearly illustrates several important properties of glucose homeostasis-boundedness in model parameters of the region of efficient homeostasis, existence of an insulin sensitivity that allows effective homeostatic control and the importance of transient and oscillatory behaviour in characterizing homeostatic failure. Bifurcation analysis shows that the appearance of a stable limit cycle can be identified.

A composite computational model of liver glucose homeostasis. I. Building the composite model.

A computational model of the glucagon/insulin-driven liver glucohomeostasis function, focusing on the buffering of glucose into glycogen, has been developed. The model exemplifies an 'engineering' approach to modelling in systems biology, and was produced by linking together seven component models of separate aspects of the physiology. The component models use a variety of modelling paradigms and degrees of simplification. Model parameters were determined by an iterative hybrid of fitting to high-scale physiological data, and determination from small-scale in vitro experiments or molecular biological techniques. The component models were not originally designed for inclusion within such a composite model, but were integrated, with modification, using our published modelling software and computational frameworks. This approach facilitates the development of large and complex composite models, although, inevitably, some compromises must be made when composing the individual models. Composite models of this form have not previously been demonstrated.

Limits on the spin-dependent WIMP-nucleon cross sections from the first science run of the ZEPLIN-III experiment.

We present new experimental constraints on the WIMP-nucleon spin-dependent elastic cross sections using data from the first science run of ZEPLIN-III, a two-phase xenon experiment searching for galactic dark matter weakly interacting massive particles based at the Boulby mine. Analysis of approximately 450 kg x days fiducial exposure allow us to place a 90%-confidence upper limit on the pure WIMP-neutron cross section of sigma(n)=1.9x10(-2) pb at 55 GeV/c(2) WIMP mass. Recent calculations of the nuclear spin structure based on the Bonn charge-dependent nucleon-nucleon potential were used for the odd-neutron isotopes 129Xe and 131Xe. These indicate that the sensitivity of xenon targets to the spin-dependent WIMP-proton interaction could be much lower than implied by previous calculations, whereas the WIMP-neutron sensitivity is impaired only by a factor of approximately 2.

Fibrocartilaginous mesenchymoma of bone: case report and review of the literature.

Fibrocartilaginous mesenchymoma of bone is a rare primary neoplasm. Our literature search produced only 12 previously reported cases. Radiographic and computed tomography (CT) findings have been described, but the magnetic resonance imaging (MRI) appearance has not been reported previously. We report a patient with fibrocartilaginous mesenchymoma of the ilium and describe the imaging findings on conventional radiography, bone scan, CT, and MRI.

Diffuse neonatal hemangiomatosis with extensive involvement of the brain and cervical spinal cord.

BACKGROUND: Diffuse neonatal hemangiomatosis (DNH) is a rare disorder first recognized at birth or during the neonatal period. DNH is characterized by numerous cutaneous and visceral hemangiomas involving three or more organ systems. MATERIALS AND METHODS: Although the skin and liver are most frequently affected, we present a case of DNH demonstrating an unusual predilection for the central nervous system (CNS). RESULTS AND CONCLUSION: We report the imaging findings in a patient with this disorder, paying particular attention to the features seen on cranial sonography and spinal MR imaging.

Home-based therapies for the common cold among European American and ethnic minority families: the interface between alternative/complementary and folk medicine.

BACKGROUND: Most studies of alternative/complementary medicine use in children have focused on children with chronic illness and have not addressed the more common form of complementary medicine: popular home-based interventions and therapies for common low-morbidity sickness episodes. Also, there has often been a distinction between alternative/ complementary medical practices used by the general population and those used by members of ethnic minority groups and commonly referred to as folk medicine or ethnomedicine. OBJECTIVE: To describe the home-based therapies and practices that parents from diverse ethnocultural backgrounds use to treat the common cold in their children. METHOD: Interviews with mothers of children coming for care at a number of clinics and physicians' offices. Included were mothers from European American, African American, Puerto Rican, and West Indian-Caribbean heritages. RESULTS: Mean number of home-based remedies for the common cold did not differ among ethnic groups (controlling for maternal age, maternal education, number of children, and health insurance status). There were differences among groups regarding the frequency of use of specific remedies. CONCLUSIONS: Home-based remedies for colds in childhood are commonly used. Many of the treatments are complementary to biomedical treatment (ie, antipyretics, over-the-counter cold remedies, fluids). Very few are potentially hazardous if taken in moderation. Mothers from ethnic minorities use similar amounts of homebased interventions when compared with mothers from the majority culture.

A complex communicating bronchopulmonary foregut malformation: diagnostic imaging and pathogenesis.

We report a newborn with an esophageal lung, a rare type of communicating bronchopulmonary foregut malformation (CBPFM). Associated findings included esophageal atresia, tracheoesophageal fistula (TEF) to the distal esophagus, duodenal stenosis with annular pancreas, imperforate anus, vertebral anomalies and ambiguous genitalia. Radiologic evaluation included chest radiographs, esophagrams, chest ultrasound and chest CT. After colostomy and surgical repair of duodenal stenosis and TEF, a right thoracotomy was performed to treat an esophageal lung. Radiologic features of this unusual variant of CBPFM are presented. Accurate preoperative imaging diagnosis is essential for planning surgical treatment of an esophageal lung.