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.

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.

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.

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.

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.

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.

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.

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.

Unreliability of radiographic diagnosis of septic hip in children.

The radiographs of 19 pediatric patients with aspiration-proven bacterial infections of the hip were analyzed. The hip radiograph was abnormal in all neonates showing lateral subluxation. The radiograph was negative in eight of ten children more than 1 year of age. It is emphasized that children with suspected septic hip require immediate joint aspiration regardless of radiographic findings.

Inflammatory pseudotumor: a gallium-avid mobile mesenteric mass.

An 8-yr-old boy with a 1-mo history of culture-negative fever and anemia underwent gallium, ultrasound, and computed tomography studies as part of the evaluation of a fever of unknown origin. These studies revealed a mobile gallium-avid solid abdominal mass subsequently proven to be an inflammatory pseudotumor of the mesentery, a rare benign mass. This report documents the gallium-avid nature of this rare lesion and discusses associated characteristic clinical, pathologic, and radiographic features.

Ultrastructures of Reilly bodies (metachromatic granules) in the Maroteaux-Lamy syndrome (mucopolysaccharidosis VI). A histochemical study.

The leukocytes from an 8-year-old white girl having features of the Maroteaux-Lamy syndrome (mucopolysaccharidosis VI) contained large granular inclusions (Reilly granules). Light and electron microscopy showed that these granules had characteristics of those seen in several other types of mucopolysaccharidoses, including Morquio's syndrome, which are of a different structure than those of other types of mucopolysaccharidosis. Similar granules were seen in the platelets, a finding which, so far as we know, has never been reported before. The granules contained an acid mucosubstance demonstrated by cytochemical studies.

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.

Sonolucencies in fetal and infant abdomen: implications for management.

The increased use of prenatal and antenatal ultrasonography will detect predictably abnormalities of fetal and infant anatomy not assessed or suspected previously. Three cases are presented illustrating similar ultrasonographic findings with different diagnoses and prognoses, and comparisons are made with other cases reported in the literature. Caution should be used in interpreting sonolucencies in fetal and infant abdomen to be diagnostic of a particular defect since further studies are required to define properly the specific abnormality so that proper treatment can be instituted.

Diagnosis of ectopic ureterocele using ultrasound.

Three children with ectopic ureteroceles were examined with ultrasound, excretory urography, and voiding cystography. In all cases the ultrasound studies outlined the ectopic ureterocele within the bladder.

Preoperative diagnosis of unilateral multicystic kidney with hydropelvis.

We present 2 patients with congenital unialteral multicystic kidney disease with hydropelvis. In the first patient the diagnosis was made by precutaneous puncture of a renal cyst followed by injection of contrast medium; in the second the diagnosis was confirmed by percutaneous puncture of the renal pelvis and injection of contrast medium, although an earlier ultrasonic examination had been strongly suggestive. Since in this condition the cysts and the renal pelvis communicate, either can be punctured to make the diagnosis. The procedures herein described are definitive for the diagnosis and should be followed whenever the urologist desires such a diagnosis.

Pediatric upper gastrointestinal tract.

In conclusion, plain-film radiography and the UGI series are useful, easily obtained tests for screening the pediatric UGI tract and differentiating between medical and surgical disease. Ultrasound continues to develop as an initial test for evaluation of the vomiting infant because of its reliability in diagnosing HPS. Endoscopy remains the superior method for diagnosis of mucosal diseases given the limitations of single-contrast barium studies and the newcomer status of ultrasound. Although scintigraphy is the most sensitive and physiologic imaging method for evaluation of gastroesophageal reflux, the UGI series and endoscopy currently play dominant roles in the evaluation of the child with "significant" GERD. CT, MR imaging, and endoscopy are secondary procedures because of their preparation, sedation, monitoring requirements, and cost. Each modality provides the radiologist a different perspective on pediatric UGI disease and therefore improves our ability to understand and diagnose abnormalities in the pediatric UGI tract.

CT of the pediatric gastrointestinal tract.

Despite the fact that children are not small adults, some children will invariably be evaluated with adult imaging protocols. As CT gains popularity in the evaluation of the adult gastrointestinal (GI) tract, there will undoubtedly be some spillover into the pediatric age group. This pictorial essay reviews the CT appearance of some common pediatric GI disorders as common diseases may present uncommonly, both clinically and radiographically.

Hypophosphatasia and nephrocalcinosis demonstrated by ultrasound and CT.

A case of medullary type of nephrocalcinosis in hypophosphatasia is presented. Sonography revealed medullary calcification not visible on abdominal radiography. Calcification could also be demonstrated by CT scanning.

Congenital cyst of the pancreas.

The case of a 4-month-old girl with a rare multilocular congenital pancreatic cyst is presented, along with radiological/pathological correlation and a review of the literature. Congenital cyst of the pancreas is a rare lesion most often seen in infant girls, although it may be demonstrated in utero. Conventional radiographic signs and clinical symptoms primarily reflect mass effects, whereas imaging modalities show the cystic nature of the mass. Although rare, this cyst should be considered in the differential diagnosis of fetal and pediatric cystic abdominal masses.